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Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study

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• Peer review
• Akbar K Waljee , assistant professor 1 2 3 4 ,
• Mary A M Rogers , research associate professor 2 4 5 ,
• Paul Lin , statistican 2 ,
• Amit G Singal , associate professor 6 ,
• Joshua D Stein , associate professor 2 7 8 ,
• Rory M Marks , associate professor 9 ,
• John Z Ayanian , professor 2 5 8 ,
• Brahmajee K Nallamothu , professor 1 2 4 10
• 1 VA Center for Clinical Management Research, Ann Arbor, MI, USA
• 2 University of Michigan Medical School, Institute for Healthcare Policy and Innovation, Ann Arbor, MI, USA
• 3 University of Michigan Medical School, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Ann Arbor, MI, USA
• 4 Michigan Integrated Center for Health Analytics and Medical Prediction (MiCHAMP), Ann Arbor, MI, USA
• 5 University of Michigan Medical School, Department of Internal Medicine, Division of General Medicine, Ann Arbor, MI, USA
• 6 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
• 7 University of Michigan Medical School, Department of Ophthalmology and Visual Science, Ann Arbor, MI, USA
• 8 University of Michigan School of Public Health, Department of Health Management and Policy, University of Michigan, Ann Arbor, MI, USA
• 9 University of Michigan Medical School, Department of Internal Medicine, Division of Rheumatology, Ann Arbor, MI, USA
• 10 University of Michigan Medical School, Department of Internal Medicine, Division of Cardiovascular Medicine, Ann Arbor, MI, USA
• Correspondence to: A K Waljee awaljee{at}med.umich.edu
• Accepted 14 March 2017

Objective  To determine the frequency of prescriptions for short term use of oral corticosteroids, and adverse events (sepsis, venous thromboembolism, fractures) associated with their use.

Design  Retrospective cohort study and self controlled case series.

Setting  Nationwide dataset of private insurance claims.

Participants  Adults aged 18 to 64 years who were continuously enrolled from 2012 to 2014.

Main outcome measures  Rates of short term use of oral corticosteroids defined as less than 30 days duration. Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation.

Results  Of 1 548 945 adults, 327 452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P<0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001).

Conclusion  One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.

Introduction

Corticosteroids are powerful anti-inflammatory drugs that have been used to treat a variety of diseases for over seven decades, dating back to their introduction for rheumatoid arthritis in 1949. 1 2 3 4 5 A strong driver of corticosteroid use is the potent symptomatic relief they give many patients. Yet long term use of corticosteroids is generally avoided, given the risks of serious acute complications such as infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other features of iatrogenic Cushing’s syndrome. 6 7 8 9 10 11 12 13 14 15 16 17 18 Indeed, corticosteroids are one of the most common reasons for admission to hospital for drug related adverse events, 19 and optimizing their long term use has been a major focus for clinical guidelines across diverse specialties for many years. 20 21 22 23 24 25 26

In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient to guide clinicians. In the outpatient setting, brief courses of oral corticosteroids are often used to treat conditions with clearly defined inflammatory pathophysiology for which there is clinical consensus for efficacy, such as asthma, chronic obstructive lung disease, rheumatoid arthritis, and inflammatory bowel disease. 27 28 29 30 31 Yet anecdotally corticosteroids are also used often in the short term to treat many other prevalent conditions where evidence is lacking, such as non-specific musculoskeletal pain and rashes. Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.

In this study we characterized short term use of oral corticosteroids in a contemporary outpatient population, and the risk of acute adverse events. We describe those who use oral corticosteroids in the short term in an outpatient setting and then report (absolute) incidence rates of adverse events in users and non-users. We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids (sepsis, venous thromboembolism, fracture). Given the inherent challenges related to confounding, we employed a self controlled case series (SCCS) design. This design has been used to examine drug and vaccine safety. 32 33 Using this method, each individual serves as his or her own control allowing for comparisons of adverse event rates during periods after exposure to corticosteroids versus rates during periods when not exposed.

Study design and population

The Clinformatics DataMart database (OptumInsight, Eden Prairie, MN) contains comprehensive, deidentified records of enrollees covered through a large nationwide healthcare insurer and its pharmacy services for outpatient drugs. All enrollees are included in a denominator file, regardless of whether they received services (eg, clinic visits, drug prescriptions, hospital admissions).

We identified all adults aged 18 to 64 years who were continuously enrolled between 1 January 2012 and 31 December 2014 (n=2 234 931). Those who were 65 years or older at any point during the study were excluded, owing to their eligibility for the federal Medicare program.

Patients were also required to have at least one year of continuous enrollment before the study period (1 January 2011 to 31 December 2011) to capture past use of corticosteroids and baseline comorbid conditions. To focus on new users, we excluded those who received any oral corticosteroids during 2011 (n=293 456). In addition, we excluded from the study cohort enrollees exclusively receiving non-oral forms of corticosteroids (eg, inhaler, intravenous route, or intra-articular injections only) or prescriptions for oral budesonide (n=102 243), and those with solid organ or bone marrow transplants, or malignancy (n=224 658) (see web appendix table 1). We also excluded patients who were prescribed oral corticosteroids for 30 days or more cumulatively over the study period (n=28 540). Finally, we excluded those with a history of adverse events in 2011 (n=37 089) (fig 1 ⇓ ). Non-users in the study cohort were defined as those without any corticosteroid prescriptions who remained in the cohort after the exclusions. No additional patients were excluded from the study.

Fig 1  Flow diagram of study inclusion and exclusion criteria

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For each enrollee, we obtained demographic information on age, sex, race or ethnicity, highest level of education, and region of the country based on a residential zip code. Race and ethnicity were identified using information obtained by OptumInsight from public records (eg, driver’s license data), the surname and first names of the beneficiary, and the census block of residence (E-Tech, Ethnic Technologies, South Hackensack, NJ). Studies comparing a similar approach with information collected from self report showed a positive predictive value of 71%. 34 Missing demographic variables were uncommon (<1%) and are listed as “unknown” for the descriptive analyses only. Comorbid conditions were ascertained from outpatient and inpatient claims available for each enrollee during the study period using ICD-9-CM (international classification of diseases, ninth revision) diagnosis codes that were subsequently grouped into Elixhauser categories. 35

Our primary exposure of interest was an outpatient prescription for an oral formulation of corticosteroids for less than 30 days, as obtained from detailed information in each pharmacy claim. Oral corticosteroid was defined by the dosage form, as categorized by the National Drug Data File from First Data Bank. The duration of corticosteroid use was based on the “days supply” variable provided within the pharmacy claim, which was defined as the “estimated day count the medication supply should last.” Importantly, this information captures actual prescriptions filled (not just prescriptions written). To calculate standardized doses for each patient, all corticosteroid formulations were converted into a daily dose based on prednisone equivalent doses (see web appendix table 2). 36 37 38 We also identified multiple outpatient prescriptions for patients and tabulated the number of repeated doses.

Among all patients in the study cohort, we identified the specialty type of the prescribing physician and clinical conditions for which corticosteroids were administered by linking a patient’s first prescription with the principal ICD-9-CM diagnosis code in the outpatient claim closest to the date of the prescription. If the closest claim was beyond three days from the prescription, we labeled this information for that patient as unknown. Overall, we were able to link 215 639 of 327 452 (65.9%) prescribing physicians and 278 425 of 327 452 (85.0%) patients who received a prescription to an ICD-9-CM diagnosis code. Diagnosis codes were grouped using clinical classification software obtained from the Agency for Healthcare Research and Quality. 35 39

We assessed three acute adverse events associated with short term corticosteroid use: sepsis, venous thromboembolism, and fractures. These events were identified using ICD-9-CM diagnosis codes that reflected acute presentations, with chronic or personal history codes not included (see web appendix table 3). We specifically selected these events as they represent a broad range of corticosteroid related acute complications. Each also has been listed on the FDA mandated drug label as possible adverse reactions, can be reliably identified in claims data, and has supporting evidence of pathogenesis early after drug initiation was available. 17 40 41 42 43 44 45 46 For sepsis, the outcome was admission to hospital for reason of sepsis (inpatient claims with a primary diagnosis of sepsis). For venous thromboembolism and fractures, we used both outpatient and inpatient claims to identify events.

Statistical analyses

Description of corticosteroid users.

We tabulated short term use of oral corticosteroids by age group (in 2014), sex, race, education, region, and number of Elixhauser comorbidities (grouped as 0, 1 to 2, and ≥3). Student t tests and χ 2 tests were used to assess differences by group. Regional variation in corticosteroid use was graphed by census division. We ranked the most common reasons for visits associated with the prescription, as well as specialty types of the prescribing providers.

Incidence rates of adverse events

For the entire cohort we calculated incidence rates of adverse events per 1000 person years at risk for corticosteroid users and non-users. Rates were also stratified by age, sex, and race. In addition, we calculated the cumulative risk of adverse events during the five to 90 day period after a clinic visit for corticosteroid users and non-users.

Self controlled case series

To control for patient specific characteristics while investigating the risk of adverse events, we used a self controlled case series (SCCS) design. 32 33 47 This method uses a within person approach to compare the rates of events after corticosteroid use (5-30 days and 31-90 days after the prescription was filled) with the rates before use (see web appendix figure 1). To be conservative, we modified the SCCS design so that adverse events within a four day window of when the prescription was filled were excluded to remove those who might have potentially received the oral corticosteroid concomitantly with the adverse event.

To preclude capturing multiple follow-up visits after the initial diagnosis of an adverse event, we only recorded the first event. Those who experienced an adverse event in the prestudy period of 2011 were excluded to avoid detecting legacy effects from past episodes. Patients were excluded if they were admitted to hospital within a 14 day period before the corticosteroid prescription date so that potential effects related to a recent hospital admission would be removed. Adjustment was made for time varying covariates related to concomitant drug use. In these analyses, the most commonly used classes of drugs (42 classes) were coded for each period and included in the full model; only those drug classes associated with each outcome (sepsis, venous theomboembolism, fracture) were retained in the final models.

Fixed (conditional) Poisson regression was used to calculate incidence rate ratios, offset by the natural logarithm of the days at risk to correct for differences in the lengths of observation. Effect modification by demographic factors (age, sex, race) were assessed by an interaction term.

Sensitivity analyses

We performed an analysis to deal with concerns that we were simply detecting more adverse events as a result of exposure to medical care rather than exposure to corticosteroids. For this analysis, we compared 30 day rates of hospital admissions for sepsis, venous thromboembolism, and fractures after a clinic visit in patients with matched diagnoses who did not receive corticosteroids and those who did receive corticosteroids after adjusting for age, sex, and race. Secondly, we used the cohort from the SCCS design and recalculated the incidence rate ratios after stratification by respiratory conditions or musculoskeletal conditions. These analyses assessed whether adverse events were being driven potentially by misdiagnosis (eg, sepsis may be more common because pneumonia is misdiagnosed as asthma, or fracture may be more common because vertebral fracture is misdiagnosed as back strain). Thirdly, in another sensitivity analysis we excluded patients who were using concomitant non-oral forms of corticosteroids. Lastly, we extended the four day period around the date of the prescription being filled to a seven day period.

Analyses were conducted with SAS software, v9.4 (SAS Institute), and Stata/MP14.1 (StataCorp, College Station, TX). Two tailed P values are reported for all analyses, with α=0.05. The institutional review board of the University of Michigan determined the study to be exempt from further review and waived the requirement for informed consent.

Patient involvement

No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.

Among 1 548 945 adults in the study cohort, 327 452 (21.1%) received at least one outpatient prescription for short term oral corticosteroids during the three year study period. The mean age for users was 45.5 (SD 11.6) years compared with 44.1 (SD 12.2) years for non-users (P<0.001). Among the 327 452 corticosteroid users, the median number of days of use was 6 (interquartile range 6-12 days) with 47.4% (n=155 171 of 327 452) receiving treatment for seven or more days. Overall, the median prednisone equivalent daily dose was 20 mg/day (interquartile range 17.5-36.8 mg/day) with 23.4% (n=76 701 of 327 452) receiving ≥40 mg/day. The most common prescription written for oral corticosteroids was a six day methylprednisolone “dosepak,” which accounted for 46.9% (n=216 437 of 461 208) of prescriptions during the study period. Among corticosteroid users, 70.5% (n=230 980 of 327 452) received one course of treatment, 20.7% (n=67 732 of 327 452) received two courses, and 8.8% (n=28 740 of 327 452) received three or more courses. For those patients with two or more prescriptions, the average prescription count was 2.4 (SD 0.7).

Compared with non-users, short term oral corticosteroid users were more often older, women, white, and had a greater number of comorbid conditions (table 1 ⇓ , all P<0.001). People residing in the Pacific region had the lowest use of short term oral corticosteroids (12.4%, n=15 762 of 127 112), whereas people in the east south central region (29.4%, n=14 892 of 50 669) and west south central region (27.6%, n=66 353 of 240 678) had the highest usage (see web appendix figure 2).

Demographic characteristics of participants according to short term use or non-use of oral corticosteroids

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The most common indications for short term oral corticosteroid use were upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and (non-bronchitic) lower respiratory tract disorders (see web appendix table 4). These five conditions were associated with about half of all prescriptions. The two most common specialty types of physicians prescribing short term oral corticosteroids were family medicine and general internal medicine, accounting for most prescriptions (see web appendix table 4). These drugs were also frequently prescribed by specialists in emergency medicine, otolaryngology, and orthopedics.

Incidence rates of sepsis, venous thromboembolism, and fracture were statistically significantly higher in short term users of oral corticosteroid than in non-users (table 2 ⇓ ). The differences were evident across age, sex, and race stratums. Fractures were the most common complication in users (21 events for every 1000 users annually), followed by venous thromboembolism (5 events for every 1000 users annually) and hospital admissions for sepsis (2 events for every 1000 users annually).

Incidence rates of adverse events by short term use of oral corticosteroids

The absolute risk of an adverse event during the five to 90 day period after a clinic visit was calculated. For those patients with a visit, the risk of hospital admission for sepsis was 0.05% (n=170 of 327 452) in steroid users compared with 0.02% (n=293 of 1 221 493) in non-users during this period. The risk of venous thromboembolism was 0.14% (n=472 of 327 452) in users compared with 0.09% (n=1054 of 1 221 493) in non-users, and the risk of fracture was 0.51% (n=1657 of 327 452) in users compared with 0.39% (n=4735 of 1 221 493) in non-users in the 90 days after a clinic visit.

Table 3 ⇓ displays the results of the SCCS. Overall, risks for sepsis, venous thromboembolism, and fracture increased within the first 30 days after initiation of corticosteroids. For example, the risk of hospital admission for sepsis increased fivefold (above baseline risk) after oral corticosteroids were used. This relation was consistent across doses. The long term risk for adverse events (31-90 days) diminished as the time from initial exposure increased.

Incidence rate ratios for adverse events associated with short term use of oral corticosteroids

To examine risks for particular types of patients, we explored effect modification by age, sex, and race. No significant effect modification was found after adjustment for time varying covariates, except for race; white patients had a higher short term risk of fractures than non-white patients (incidence rate ratio 2.02, 95% confidence interval 1.81 to 2.26 for white patients; 1.42, 1.14 to 1.77 for non-white patients; P=0.006 interaction term).

Web appendix table 5 displays the results of our analysis of 30 day rates of hospital admission for sepsis, venous thromboembolism, and fractures after a clinic visit in patients with matched diagnoses who did not receive corticosteroids and those who did receive corticosteroids after adjusting for age, sex, and race. It shows consistently higher incidence rates of adverse events in the patients who received corticosteroids. In the SCCS stratified by respiratory conditions or musculoskeletal conditions, the incidence rate ratios were recalculated (table 4 ⇓ ). The 30 day risk of venous thromboembolism, fracture, and hospital admission for sepsis was statistically significantly increased for patients presenting with both respiratory conditions and musculoskeletal conditions. When we excluded patients using concomitant non-oral forms of corticosteroids from the analyses, the results were similar (see web appendix table 6). In the 5-30 day window the incidence rate ratio for sepsis was 4.84, for venous thromboembolism was 3.29, and for fracture was 1.92 (all P<0.001). Extending the four day period around the date of prescription to a seven day period also did not appreciably change the results (see web appendix table 7). The incidence rate ratio for sepsis was 4.33 (95% confidence interval 3.04 to 6.17), for venous thromboembolism was 2.94 (2.42 to 3.56), and for fracture was 1.65 (1.49 to 1.84).

Incidence rate ratios for adverse events associated with short term use of oral corticosteroids, by reason for medical visit

In this large, population based study of privately insured non-elderly (<64 years) adults in the US, one in five received a new outpatient prescription for short term use of oral corticosteroids over a three year period. These drugs were used for a wide range of conditions, such as upper respiratory tract infections, spinal conditions, and allergies and were commonly prescribed by both generalist and specialist physicians. Importantly, these prescriptions were associated with statistically significantly higher rates of sepsis, venous thromboembolism, and fracture despite being used for a relatively brief duration.

Comparison with other studies

Estimates of corticosteroid use from cross sectional studies range from 0.5% to 1.2% over various study periods. 7 9 10 An analysis of the National Health and Nutrition Examination Survey described self reported use of drugs taken within the previous 30 days. 7 Its findings indicated a mean duration of corticosteroid use exceeding four years among users—thus capturing a larger proportion of chronic treatment but potentially underreporting short term use. Furthermore, although the analyses were weighted, the actual sample of corticosteroid users included only 356 people. In our longitudinal analysis of 1.5 million insured Americans, the incidence was approximately 7% for short term oral corticosteroid use on a yearly basis.

Though the long term complications of chronic corticosteroid use are well known, there is a paucity of clinical data on the potential short term adverse effects of corticosteroid use, despite the existence of pathophysiological evidence suggesting possible early changes after drug initiation. For example, the impact of corticosteroids on the immune system has been widely studied, and in randomized controlled trials of prednisone (versus placebo) in healthy adults there were effects on peripheral cell lines (eg, peripheral white blood cells) within the first day after drug ingestion that were noticeable with 10 mg, 25 mg, and 60 mg doses. 48 49 Rapid alteration in markers of bone metabolism has also been documented with the initiation of corticosteroid use; mean serum concentrations of osteocalcin and both serum propeptide of type I N-terminal and C-terminal procollagen were statistically significantly decreased in the early weeks after starting prednisone. 43 The mechanisms underlying the increase in venous thromboembolism are not fully known. However, infection is a common trigger of thrombosis, 50 suggesting that both venous thromboembolism and sepsis may be potentially mediated through changes in the immune system. Further work is needed to clarify whether and how our observations in this large population may be linked to potential causal pathways.

Strengths and limitations of this study

Our findings are particularly of concern given the large number of patients exposed to short term oral corticosteroids in the general adult population. Clinical guidelines typically recommend using the lowest dose of steroids for the shortest period to prevent adverse events. 24 25 However, we found that even short durations of use, regardless of dose, were associated with increased risks of adverse events and that few patients were using very low doses. Only 6.3% of the prescriptions were for a prednisone equivalent dose of less than 17.5 mg/day, and 1.0% of prescriptions were for less than 7.5 mg/day; therefore, we were unable to examine events in patients given very low doses for short periods. A major reason for the higher than expected doses was the widespread use of “fixed dose” methylprednisolone dosepaks that are tapered over a short period. These dosepaks offer ease of use but do not permit the individualization of drug dosing to minimize exposure.

A substantial challenge to improving use of oral corticosteroids will be the diverse set of conditions and types of providers who administer these drugs in brief courses. This raises the need for early general medical education of clinicians about the potential risks of oral corticosteroids and the evidence basis for their use, given that use may not be specific to a particular disease or specialty. Suprisingly, the most common prescribers were not subspecialists, such as rheumatologists, who are most experienced with treating inflammatory conditions and the long term use of these drugs. We also found that the most common indications for corticosteroid use included conditions such as upper respiratory tract infections, spinal conditions, and allergies, which often have marginal benefit and for which alternate treatments may be similarly effective and safer. For example, a multimodal pain treatment regimen can be used to treat spinal pain, and non-sedating antihistamines can be used for allergies. An examination of potential determinants of corticosteroid use will be needed to inform future intervention strategies. If corticosteroid use is driven by patient preferences, education on the potential harms should be expanded. If prescriptions are primarily driven by provider decisions, decision support tools to identify alternatives to corticosteroids (eg, non-steroidal anti-inflammatory drugs for acute gout 30 or tricyclic antidepressants for neuropathic pain 51 ) may be a more effective approach, but additional studies will be required to substantiate these possible alternatives as some of these drugs are available over the counter.

Our study has several limitations. Firstly, our cohort only includes commercially insured adults and excludes patients aged more than 64 years, which potentially limits the generalisability of our findings. We focused on younger adults as these individuals tend to have fewer comorbid conditions, and therefore our findings may be less likely to be biased by the high prevalence of age related comorbid conditions. Although our reference population is commercially insured adults, we have no reason to suspect this characteristic should bias a possible association between corticosteroid use and adverse events. Secondly, we determined the indication for corticosteroid use and the specific provider prescribing the drug by linking outpatient claims recorded most closely to the prescription date; thus we might have misclassified some treatment indications and specialties. Thirdly, we were unable to adequately assess the risks of adverse events at very low doses of corticosteroids, given the infrequency of use at these doses.

Fourthly, we did not evaluate all of the possible adverse events linked to oral corticosteroids but focused on three acute adverse reactions. This makes our findings even more striking as they are likely a conservative estimate of the associated risks of adverse events. For example, we only focused on hospital admissions for sepsis, ignoring less serious but likely important infections, and we did not assess some adverse events such as behavioral or psychiatric conditions. In addition, a dose- response trend was not seen and may reflect our selection criteria of using prescriptions of less than 30 days. Fifthly, although we used a within person approach to control for genetic predisposition, health related behaviors, and comorbid conditions and adjusted for time varying use of different drugs, other time varying factors could be differentially distributed between the risk and baseline periods. However, the incidence rate ratios were strong (many >3.0) so that any residual confounding would have to be appreciable to fully explain our findings. Assumptions of the SCCS design were mitigated by using only the first event for each of the three outcomes, and therefore independence of recurrent events and the potential influence of past events on subsequent drug use (if this occurred) yielded incidence rate ratios that might be somewhat conservative. Survival bias was not an issue since by design all patients were alive during the periods when the outcomes were measured (ie, the comparator period was before the first use of corticosteroids).

Oral corticosteroids are frequently prescribed for short term use in the US for a variety of common conditions and by numerous provider specialties. Over a three year period, approximately one in five American adults in a commercially insured plan used oral corticosteroids for less than 30 days. The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses. Additional studies are needed to identify optimal use of corticosteroids and to explore whether treatment alternatives may improve patient safety.

What is already known on this topic

Complications with chronic use of corticosteroids include a wide spectrum of effects on the cardiovascular, musculoskeletal, digestive, endocrine, ophthalmic, skin, and nervous systems

However, the potential risks associated with the use of short term oral corticosteroids and their overall use in a general population has not been fully characterized

What this study adds

This study of 1.5 million privately insured adults (18-64 years) in the US found that one in five patients in an outpatient setting used short term oral corticosteroid over a three year period (2012-14)

Within 30 days of corticosteroid initiation, the incidence of acute adverse events that result in major morbidity and mortality (sepsis, venous thromboembolism, fracture) increased by twofold, to fivefold above background rates

Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety

Contributors: AKW and BKN had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. They are the guarantors. AKW and MAMR conceived and designed the study. All authors acquired, analysed, and interpreted the data; critically revised the manuscript; and gave final approval of the manuscript. AKW and BKN drafted the manuscript. AKW, MAMR, and PL were responsible for the figures. The authors are solely responsible for the design, conduct, data analyses, and drafting and editing of the manuscript and its final content. The contents do not represent the views of the US Department of Veterans Affairs or the United States government.

Funding: AKW is supported by a career development grant award (CDA 11-217) from the United States Department of Veterans Affairs Health Services Research and Development Service. AKW and BKN are supported by funding from the Michigan Institute for Data Science (MIDAS). JDS is supported by grants from Research to Prevent Blindness and WK Kellogg Foundation. Data acquisition and statistical and administrative support was supported by the Institute for Healthcare Policy and Innovation at the University of Michigan. These funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: This study was approved by the University of Michigan institutional research board.

Data sharing: No additional data are available.

Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Prednisolone

Generic name: prednisolone [  pred-NIS-oh-lone  ] Brand names: Flo-Pred , Millipred , Orapred , Pediapred , Veripred 20 , ... show all 15 brands Prelone, Hydeltra-T.B.A., Hydeltrasol, Key-Pred, Cotolone, Predicort, Medicort, Predcor, Bubbli-Pred, and others Dosage forms: oral liquid, oral suspension, oral syrup, oral tablet, oral disintegrating tablet Drug class: Glucocorticoids

Medically reviewed by Carmen Pope, BPharm . Last updated on Aug 7, 2023.

What is prednisolone?

Prednisolone is a corticosteroid that may be used to reduce inflammation and calm down an overactive immune system. It works by mimicking the effects of cortisol, a hormone released by the adrenal glands (located on top of the kidneys) that regulates metabolism and stress. Prednisolone prevents the release of substances in the body that cause inflammation.

Prednisolone is used to treat many different inflammatory conditions such as arthritis, lupus , psoriasis , ulcerative colitis , allergic disorders, gland (endocrine) disorders, and conditions that affect the skin, eyes, lungs, stomach, nervous system, or blood cells.

Prednisolone has predominantly glucocorticoid activity, which means it mainly affects our immune response and reduces inflammation, rather than affecting the body's balance of electrolytes and water (this is called mineralocorticoid activity).

Prednisolone was FDA approved in 1955.

You should not use prednisolone if you have a fungal infection anywhere in your body.

Before taking this medicine

You should not use prednisolone if you are allergic to it, or if you have:

a fungal infection anywhere in your body.

Prednisolone can weaken your immune system, making it easier for you to get an infection. Steroids can also worsen an infection you already have, or reactivate an infection you recently had. Tell your doctor about any illness or infection you have had within the past several weeks.

To make sure prednisolone is safe for you, tell your doctor if you have ever had:

active tuberculosis ;

a thyroid disorder;

herpes infection of the eyes;

stomach ulcers, ulcerative colitis , or diverticulitis ;

depression , mental illness, or psychosis;

liver disease (especially cirrhosis );

high blood pressure ;

osteoporosis ;

a muscle disorder such as myasthenia gravis ; or

multiple sclerosis .

Also tell your doctor if you have diabetes. Steroid medicines may increase the glucose (sugar) levels in your blood or urine. You may also need to adjust the dose of your diabetes medications.

It is not known whether prednisolone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether prednisolone passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding.

How should I take prednisolone?

Take prednisolone exactly as prescribed by your doctor. Your doctor may occasionally change your dose. Do not use prednisolone in larger or smaller amounts or for longer than recommended.

Prednisolone is sometimes taken every other day. Follow your doctor's dosing instructions very carefully.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

You may need to shake the oral suspension (liquid) well just before you measure a dose. Follow the directions on your medicine label.

Keep prednisolone disintegrating tablets in their blister pack until you are ready to take the medicine. Open the package using dry hands, and peel back the foil from the tablet blister (do not push the tablet through the foil). Remove the tablet and place it in your mouth. Allow the disintegrating tablet to dissolve in your mouth without chewing. Swallow several times as the tablet dissolves. If desired, you may drink liquid to help swallow the dissolved tablet.

Your dose needs may change if you have unusual stress such as a serious illness, fever or infection, or if you have surgery or a medical emergency. Tell your doctor about any such situation that affects you.

Prednisolone can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using prednisolone.

You should not stop using prednisolone suddenly. Follow your doctor's instructions about tapering your dose.

Wear a medical alert tag or carry an ID card stating that you take prednisolone. Any medical care provider who treats you should know that you take steroid medication.

If you need surgery, tell the surgeon ahead of time that you are using prednisolone. You may need to stop using the medicine for a short time.

Store prednisolone at room temperature away from moisture and heat.

What happens if I miss a dose?

Call your doctor for instructions if you miss a dose of prednisolone.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of prednisolone is not expected to produce life threatening symptoms. However, long term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence , or loss of interest in sex.

What should I avoid while taking prednisolone?

Do not receive a "live" vaccine while using prednisolone. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster ( shingles ), and nasal flu ( influenza ) vaccine.

Do not receive a smallpox vaccine or you could develop serious complications.

Avoid being near people who are sick or have infections. Call your doctor for preventive treatment if you are exposed to chickenpox or measles. These conditions can be serious or even fatal in people who are using steroid medication.

Prednisolone side effects

Get emergency medical help if you have signs of an allergic reaction to prednisolone. : hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Prednisolone may cause serious side effects. Call your doctor at once if you have:

shortness of breath (even with mild exertion), swelling, rapid weight gain;

bruising, thinning skin, or any wound that will not heal;

severe depression, changes in personality, unusual thoughts or behavior;

new or unusual pain in an arm or leg or in your back;

bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

severe pain in your upper stomach spreading to your back, nausea and vomiting;

a seizure (convulsions); or

low potassium --leg cramps, constipation , irregular heartbeats, fluttering in your chest, increased thirst or urination, numbness or tingling.

Steroids can affect growth in children. Tell your doctor if your child is not growing at a normal rate while using prednisolone.

Common side effects of prednisolone may include:

fluid retention (swelling in your hands or ankles);

dizziness, spinning sensation;

changes in your menstrual periods;

muscle pain or weakness; or

stomach discomfort, bloating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect prednisolone?

Other drugs may interact with prednisolone, including prescription and over-the-counter medicines, vitamins , and herbal products . Tell your doctor about all your current medicines and any medicine you start or stop using.

Popular FAQ

If you are taking Prednisone just once a day, take it in the morning with breakfast. The morning is best as it mimics the timing of your body's own production of cortisone. Taking your dose of prednisone too late in the evening may cause difficulty sleeping. Continue reading

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Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use prednisolone only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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Prednisone and other corticosteroids.

Weigh the benefits and risks of corticosteroids, such as prednisone, when choosing a medicine.

Corticosteroid medicines include cortisone, hydrocortisone and prednisone. They are useful in treating rashes, inflammatory bowel disease, asthma and other conditions. But corticosteroids also carry a risk of side effects.

How do corticosteroids work?

When prescribed in certain doses, corticosteroids help reduce inflammation. This can ease symptoms of inflammatory conditions, such as arthritis, asthma and skin rashes.

Corticosteroids also suppress the immune system. This can help control conditions in which the immune system mistakenly attacks its own tissues.

How are corticosteroids used?

Corticosteroid medicines are used to treat rheumatoid arthritis, inflammatory bowel disease (IBD), asthma, allergies and many other conditions. They also are used to prevent organ rejection in transplant recipients. They do that by helping to suppress the immune system. Corticosteroids also treat Addison's disease. This is a rare disease that occurs when the adrenal glands don't produce enough of the corticosteroid that the body needs.

Corticosteroids are given in many different ways, depending on the condition being treated:

• By mouth. Tablets, capsules or syrups help treat the inflammation and pain associated with certain chronic conditions, such as rheumatoid arthritis and lupus.
• By inhaler and intranasal spray. These forms help control inflammation associated with asthma and nasal allergies.
• In the form of eye drops. This form helps treat swelling after eye surgery.
• Topically. Creams and ointments can help heal many skin conditions.
• By injection. This form is often used to treat muscle and joint symptoms, such as the pain and inflammation of tendinitis.

What side effects can corticosteroids cause?

Corticosteroids carry a risk of side effects. Some side effects can cause serious health problems. When you know what side effects are possible, you can take steps to control their impact.

Side effects of corticosteroids taken by mouth

Corticosteroids that you take by mouth affect your entire body. For this reason, they are the most likely type of corticosteroid to cause side effects. Side effects depend on the dose of medication you receive and may include:

• A buildup of fluid, causing swelling in your lower legs.
• High blood pressure.
• Problems with mood swings, memory, behavior, and other psychological effects, such as confusion or delirium.
• Upset stomach.
• Weight gain in the belly, face and back of the neck.

When taking corticosteroids by mouth for a longer term, you may experience:

• Problems with the eyes, such as glaucoma or cataracts.
• A round face, which is sometimes called moon face.
• High blood sugar, which can trigger or worsen diabetes.
• Increased risk of infections, especially with common bacterial, viral and fungal microorganisms.
• Bone fractures and thinning bones, called osteoporosis.
• Fatigue, loss of appetite, nausea and muscle weakness.
• Thin skin, bruising and slower wound healing.

Side effects of inhaled corticosteroids

When using a corticosteroid that you breathe in, some of the drug may deposit in your mouth and throat instead of making it to your lungs. This can cause:

• Fungal infection in the mouth, known as oral thrush.
• Hoarseness.

You may be able to avoid mouth and throat irritation if you gargle and rinse your mouth with water after each puff on your corticosteroid inhaler. Be sure not to swallow the rinse water. Some researchers think that inhaled corticosteroid drugs may slow growth rates in children who use them for asthma.

Side effects of topical corticosteroids

Topical corticosteroids can lead to thin skin, skin lesions and acne.

Side effects of injected corticosteroids

Injected corticosteroids can cause temporary side effects near the site of the shot. These side effects include skin thinning, loss of color in the skin and intense pain. This pain is known as post-injection flare. Other symptoms may include facial flushing, insomnia and high blood sugar. Health care providers usually limit corticosteroid injections to three or four a year, depending on each person's situation.

Reduce your risk of corticosteroid side effects

To get the most benefit from corticosteroid medicines with the least amount of risk:

• Ask your health care provider about trying lower doses or intermittent dosing. Newer forms of corticosteroids come in various strengths and lengths of action. Ask your provider about using low-dose, short-term medications or taking oral corticosteroids every other day instead of daily.
• Talk to your provider about switching to nonoral forms of corticosteroids. Inhaled corticosteroids for asthma, for example, reach lung surfaces directly. This reduces the rest of your body's exposure to them and may lead to fewer side effects.
• Ask your provider if you should take calcium and vitamin D supplements. Long-term corticosteroid therapy may cause thinning bones, called osteoporosis. Talk with your provider about taking calcium and vitamin D supplements to help protect your bones.
• Take care when discontinuing therapy. If you take oral corticosteroids for a long time, your adrenal glands may produce less of their natural steroid hormones. To give your adrenal glands time to recover this function, your provider may reduce your dose gradually. If the dosage is reduced too quickly, your adrenal glands may not have time to recover and you may experience fatigue, body aches and lightheadedness.
• Wear a medical alert bracelet. This or similar identification is recommended if you've been using corticosteroids for a long time.
• See your health care provider regularly. If you're taking long-term corticosteroid therapy, see your provider regularly to check for side effects.

Weigh the risks and benefits of corticosteroids

Corticosteroids may cause a range of side effects. But they also may relieve the inflammation, pain and discomfort of many different diseases and conditions. Talk with your health care provider to help you better understand the risks and benefits of corticosteroids and make informed choices about your health.

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• Wilkinson JM (expert opinion). Mayo Clinic. Nov. 20, 2020.
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Side effects of prednisolone tablets and liquid

The higher the dose of prednisolone that you take and the longer you take it for, the greater the chance of side effects. You're less likely to get side effects if you take a relatively low dose of prednisolone daily.

If you have been taking prednisolone for more than a few weeks, check with your doctor before stopping it suddenly to reduce your chances of withdrawal side effects.

Some side effects, such as stomach upset or mood changes, can happen straight away. Others, such as getting a rounder face, happen after weeks or months.

Common side effects

These common side effects of prednisolone happen in more than 1 in 100 people. There are things you can do to help cope with them:

If you have to take prednisolone for more than a few weeks, it's likely that you'll put on weight. Prednisolone can make you hungrier and also can make you retain more water in your body.

Try to eat well without increasing your portion sizes. Regular exercise will also help to keep your weight stable.

Once you stop taking prednisolone, your appetite and the way your body retains water should return to normal.

Take prednisolone with food to reduce the chances of stomach problems. It may also help if you avoid rich or spicy food while you're taking this medicine.

If symptoms carry on, ask your doctor if you may benefit from taking an additional medicine to protect your stomach.

Take prednisolone in the morning so the levels are the lowest at bedtime.

If you're feeling restless when you're trying to sleep, take prednisolone in the morning so the levels are the lowest at bedtime.

Try wearing loose clothing and use a strong anti-perspirant. If this does not help, talk to your doctor as you may be able to try a different medicine.

Prednisolone can affect your mood in different ways. Talk to your doctor if you are finding it hard to cope.

Speak to a doctor or pharmacist if the advice on how to cope does not help and any of these side effects bother you or last more than a few days.

Serious side effects

You are more likely to have a serious side effect if you take a higher dose of prednisolone or if you have been taking it for more than a few weeks.

Call a doctor or call 111 straight away if you get:

• a high temperature, chills, a very sore throat, ear or sinus pain, a cough, more saliva or a change in colour of saliva (yellowish and possibly with streaks of blood), pain when you pee, mouth sores or a wound that will not heal – these can be signs of an infection
• sleepy or confused, feeling very thirsty or hungry, peeing more often, flushing, breathing quickly or breath that smells like fruit – these can be signs of high blood sugar
• weight gain in your upper back or belly, "moon face" (a puffy, rounded face), very bad headaches and slow wound healing – these can be signs of Cushing's syndrome
• a very upset stomach or you're being sick (vomiting), very bad dizziness or passing out, muscle weakness, feeling very tired, mood changes, loss of appetite and weight loss – these can be signs of adrenal gland problems
• muscle pain or weakness, muscle cramps, or changes in your heart rate – these can be signs of low potassium levels
• severe stomach pain, severe back pain, severe upset stomach or you're being sick – these can be signs of pancreas problems
• breathlessness
• swelling in your arms or legs
• changes in your eyesight
• any bruising or bleeding that is not normal
• red or black poo

Immediate action required: Call 999 or go to A&E if:

• you have black or dark brown vomit or you're vomiting blood

Find your nearest A&E

Mood changes

You may notice mood changes and mental health problems while taking prednisolone.

Talk to your doctor or contact 111 if you have any mood changes including:

• feeling depressed
• feeling high, or moods that go up and down
• feeling anxious, having problems sleeping, difficulty in thinking, or being confused and losing your memory
• feeling, seeing or hearing things that do not exist ( hallucinations )
• having strange and frightening thoughts, changing how you act, or having feelings of being alone

The higher the dose, the more intense the mood changes can be.

Go to 111.nhs.uk or call 111 .

• you have thoughts about harming yourself or ending your life

Serious allergic reaction

In rare cases, it's possible to have a serious allergic reaction ( anaphylaxis ) to prednisolone.

Immediate action required: Call 999 now if:

• your lips, mouth, throat or tongue suddenly become swollen
• you're breathing very fast or struggling to breathe (you may become very wheezy or feel like you're choking or gasping for air)
• your throat feels tight or you're struggling to swallow
• your skin, tongue or lips turn blue, grey or pale (if you have black or brown skin, this may be easier to see on the palms of your hands or soles of your feet)
• you suddenly become very confused, drowsy or dizzy
• someone faints and cannot be woken up
• a child is limp, floppy or not responding like they normally do (their head may fall to the side, backwards or forwards, or they may find it difficult to lift their head or focus on your face)

You or the person who's unwell may also have a rash that's swollen, raised, itchy, blistered or peeling.

These can be signs of a serious allergic reaction and may need immediate treatment in hospital.

Long-term side effects

Taking prednisolone for a long time can lead to side effects such as:

• thinner bones ( osteoporosis )
• poorly controlled diabetes
• eyesight problems
• high blood pressure (hypertension)

Children and teenagers

Taking prednisolone at higher doses for a long time can slow down the normal growth of children and teenagers.

Your child's doctor will monitor their height and weight carefully for as long as they're taking this medicine. This will help them spot any slowing down of your child's growth and change their treatment if needed.

Even if your child's growth slows down, it does not seem to have much effect on their eventual adult height.

Talk to your doctor if you're worried. They'll be able to explain the benefits and risks of giving your child prednisolone.

Other side effects

These are not all the side effects of prednisolone. For a full list, see the leaflet inside your medicine packet.

You can report any suspected side effect using the Yellow Card safety scheme.

Visit Yellow Card for further information .

Page last reviewed: 24 February 2022 Next review due: 24 February 2025

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• Drugs & Medications
• Prednisolone

Prednisolone - Uses, Side Effects, and More

Generic name: prednisolone, side effects, precautions, interactions.

• Reviews (71)

How to use Prednisolone

Take this medication by mouth , with food or milk to prevent stomach upset, exactly as directed by your doctor. Carefully measure the dose using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.

There are many brands, strengths, and forms of liquid prednisolone available. Read the dosing instructions carefully for each product because the amount of prednisolone may be different between products. See also Precautions and Storage sections.

Follow the dosing schedule carefully. The dosage and length of treatment are based on your medical condition and response to treatment. Your doctor may direct you to take prednisolone 1 to 4 times a day or take a single dose every other day. It may help to mark your calendar with reminders.

Do not stop taking this medication without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Your dose may need to be gradually decreased.

If you suddenly stop using this medication, you may have withdrawal symptoms (such as weakness , weight loss , nausea , muscle pain , headache , tiredness, dizziness ). To help prevent withdrawal, your doctor may lower your dose slowly. Withdrawal is more likely if you have used prednisolone for a long time or in high doses. Tell your doctor or pharmacist right away if you have withdrawal. See also Precautions section.

Nausea , heartburn , headache , dizziness , menstrual period changes, trouble sleeping , increased sweating , or acne may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Because this drug works by weakening the immune system , it may lower your ability to fight infections. This may make you more likely to get a serious (rarely fatal) infection or make any infection you have worse. Tell your doctor right away if you have any signs of infection (such as cough , sore throat , fever, chills). Use of this medication for prolonged or repeated periods may result in oral thrush or a yeast infection . Contact your doctor if you notice white patches in your mouth or a change in vaginal discharge .

This medication may rarely make your blood sugar rise, which can cause or worsen diabetes . Tell your doctor right away if you have symptoms of high blood sugar such as increased thirst/urination. If you already have diabetes, check your blood sugar regularly as directed and share the results with your doctor. Your doctor may need to adjust your diabetes medication, exercise program , or diet.

Tell your doctor right away if you have any serious side effects, including: unusual tiredness, swelling ankles /feet, unusual weight gain , vision problems, easy bruising/bleeding, puffy face, unusual hair growth, mental/mood changes (such as depression , mood swings, agitation), muscle weakness /pain, thinning skin , slow wound healing, bone pain, symptoms of stomach /intestinal bleeding (such as stomach / abdominal pain , black/tarry stools, vomit that looks like coffee grounds).

Get medical help right away if you have any very serious side effects, including: chest pain , seizures .

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction , including: rash , itching /swelling (especially of the face/ tongue /throat), severe dizziness, trouble breathing .

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

Before taking prednisolone , tell your doctor or pharmacist if you are allergic to it; or to prednisone ; or if you have any other allergies . This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication , tell your doctor or pharmacist your medical history, especially of: eye disease (such as cataracts , glaucoma ), heart problems (such as heart failure , recent heart attack ), high blood pressure , liver disease , kidney disease , thyroid problems , diabetes , stomach /intestinal problems (such as diverticulitis , ulcer), brittle bones ( osteoporosis ), current/past infections (such as tuberculosis , positive tuberculosis test, herpes, fungal), bleeding problems, blood clots , certain mental/mood conditions (such as psychosis , anxiety, depression ), low salts in the blood (such as low potassium or calcium ), seizures .

This drug may make you dizzy. Alcohol or marijuana ( cannabis ) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

This medicine may cause stomach bleeding. Daily use of alcohol while using this medicine may increase your risk for stomach bleeding. Limit alcoholic beverages. Consult your doctor or pharmacist for more information.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs , nonprescription drugs, and herbal products).

This product may contain alcohol, sugar, and/or aspartame. Caution is advised if you have diabetes, alcohol dependence , liver disease, phenylketonuria (PKU), or any other condition that requires you to limit/avoid these substances in your diet. Ask your doctor or pharmacist about using this product safely.

Using corticosteroid medications for a long time can make it more difficult for your body to respond to physical stress. Before having surgery or emergency treatment, or if you get a serious illness/injury, tell your doctor or dentist that you are using this medication or have used this medication within the past 12 months. Tell your doctor right away if you develop unusual/extreme tiredness or weight loss . If you will be using this medication for a long time, carry a warning card or medical ID bracelet that identifies your use of this medication.

This medication may mask signs of infection. It can make you more likely to get infections or may make current infections worse. Stay away from anyone who has an infection that may easily spread (such as chickenpox , COVID-19, measles , flu ). Talk to your doctor if you have been exposed to an infection or for more details.

Tell your health care professional that you are using prednisolone before having any immunizations / vaccinations . Avoid contact with people who have recently received live vaccines (such as flu vaccine inhaled through the nose).

This medication may slow down a child's growth if used for a long time. Consult the doctor or pharmacist for more details. See the doctor regularly so your child's height and growth can be checked.

Older adults may be more sensitive to the effects of this drug, especially bone loss /pain, stomach/intestinal bleeding, and mental/mood changes (such as confusion).

During pregnancy, prednisolone should be used only when clearly needed. It may rarely harm an unborn baby. Discuss the risks and benefits with your doctor. Infants born to mothers who have been using this medication for an extended period of time may have hormone problems. Tell your doctor right away if you notice symptoms such as nausea / vomiting that doesn't stop, severe diarrhea , or weakness in your newborn .

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist . Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: aldesleukin , desmopressin , other drugs that weaken the immune system (such as azathioprine , cyclosporine , cancer chemotherapy ), mifepristone , drugs that can cause bleeding/bruising (including antiplatelet drugs such as clopidogrel , " blood thinners " such as dabigatran / warfarin , NSAIDs such as aspirin / celecoxib / ibuprofen ).

Other medications can affect the removal of prednisolone from your body, which may affect how prednisolone works. Examples include estrogens , azole antifungals (such as itraconazole ), St. John's wort, drugs used to treat seizures (such as phenytoin), among others.

If your doctor has told you to take low-dose aspirin to prevent heart attack or stroke (usually 81-162 milligrams a day), you should keep taking the aspirin unless your doctor tells you not to. Ask your doctor or pharmacist for more details.

Do not share this medication with others.

If this medication is used for a long time, lab and/or medical tests (such as blood sugar /mineral levels, blood counts, blood pressure , bone density tests, eye exams , height/ weight measurements, X-rays) should be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details.

Store this medication according to the directions on the product package away from light and moisture. Some brands must be refrigerated, and others must be stored at room temperature. Consult your pharmacist for more details. Do not store in the bathroom. Keep all medications away from children and pets.

prednisolone 15 mg/5 mL oral solution

This medicine is a pinkish-red, clear, wild cherry, solution

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Beyond Ozempic: New GLP-1 drugs promise weight loss and health benefits

The next wave of obesity drugs is coming soon.

Drug companies are racing to develop GLP-1 drugs following the blockbuster success of Novo Nordisk’s Ozempic and Wegovy and Eli Lilly’s Mounjaro and Zepbound.

Some of the experimental drugs may go beyond diabetes and weight loss, improving liver and heart function while reducing side effects such as muscle loss common to the existing medications. At the 2024 American Diabetes Association conference in Orlando, Florida, researchers are expected to present data on 27 GLP-1 drugs in development.

“We’ve heard about Ozempic and Mounjaro and so on, but now we’re seeing lots and lots of different drug candidates in the pipeline, from very early-stage preclinical all the way through late-stage clinical,” said Dr. Marlon Pragnell, ADA’s vice president of research and science. “It’s very exciting to see so much right now.”

A large portion of the data presented comes from animal studies or early-stage human trials. However, some presentations include mid-to late-stage trials, according to a list shared by the organization.

Approval by the Food and Drug Administration is likely years away for most. Some of the drugs showcased could be available for prescription in the U.S. within the next few years.

“We’ve witnessed an unprecedented acceleration in the development of GLP drugs,” said Dr. Christopher McGowan, a gastroenterologist who runs a weight loss clinic in Cary, North Carolina. “We are now firmly entrenched in the era of the GLP.”

While the existing drugs are highly effective, new drugs that are more affordable and have fewer side effects are needed, McGowan added.

There aren’t just GLP-1 drugs in the pipeline. On Thursday, ahead of the diabetes conference, Denmark-based biotech firm Zealand Pharma released data that showed a high dose of its experimental weight loss drug petrelintide helped reduce body weight by an average of 8.6% at 16 weeks.

The weekly injectable medication is unique because it mimics the hormone amylin, which helps control blood sugar. The hope is patients will experience fewer side effects like nausea commonly associated with GLP-1 drugs such as Wegovy and Zepbound.

Can glucagon hormone help with weight loss?

GLP-1 medications work, in part, by slowing down how quickly food passes through the stomach, leading people to feel fuller longer. In several of the upcoming weight loss drugs, a different hormone called glucagon is in the spotlight. Glucagon is a key blood-sugar-regulating hormone that can mimic the effects of exercise.

One of the drugs featured at the conference on Sunday is called pemvidutide, from Maryland-based biotech firm Altimmune .

The drug contains the GLP-1 hormone, a key ingredient in Ozempic and Wegovy, in addition to glucagon.

Altimmune released data from a phase 2 trial of 391 adults with obesity or who are overweight with at least one weight-related comorbidity such as high blood pressure. Patients were randomized to either get one of three doses of pemvidutide or a placebo for 48 weeks.

Researchers found that patients who got the highest dose of the drug lost on average 15.6% of their body weight after 48 weeks, compared to the 2.2% body weight loss seen in patients who got a placebo. In similar trials, semaglutide was shown to reduce body weight by around 15% after 68 weeks.

These are not direct comparisons because the drugs weren’t compared in a head-to-head clinical trial.

Dr. Scott Harris, Altimmune’s chief medical officer, said the drug has been shown to help people lose weight, as well as provide health benefits to the liver and heart. What’s more, the drug has shown benefits in preserving lean body mass. Some studies have suggested that semaglutide, the active ingredient in Ozempic and Wegovy, can cause muscle loss.

“If people take the drugs long term, what’s going to be their long-term health? What’s going to be the long-term effects on their body composition, their muscle, their ability to function?” he said.

Harris said that people who got pemvidutide lost on average 21% of their lean body mass, which is lower than the around 25% of lean body mass people typically lose with diet and exercise.

“We’re the next wave of obesity drugs,” Altimmune President and CEO Vipin Garg said. “The first wave of mechanisms was all driven by appetite suppression. We are adding another component.”

Altimmune expects to begin a phase 3 trial soon. The company hopes the drug will be available in the U.S. sometime in 2028.

Competition could drive down costs

Expanding the number of weight loss drugs available is important for several reasons, experts say.

More options could also help alleviate the shortages seen in the U.S. with Novo Nordisk’s and Lilly’s weight loss drugs.

Latest news on weight loss medications

• Amid shortages, WHO warns about safety risks from fake versions of Wegovy and Zepbound.
• How one state is trying to make weight loss drugs cheaper.
• Weight loss drugs like Wegovy are meant for long-term use. What happens if you stop taking them?

Increased competition could drive down the high cost of the drugs over time. A month’s supply of Wegovy or Zepbound can cost more than $1,000, often financially untenable for many patients, experts say.

Patients can also respond differently to treatments, said Dr. Fatima Cody Stanford, an associate professor of medicine and pediatrics at Harvard Medical School. In fact, some have found the existing GLP-1 options ineffective.

“Different GLP-1 drugs may have varying levels of efficacy and potency,” she said. “Some patients may respond better to one drug over another, depending on how their body metabolizes and responds to the medication.”

Since starting Ozempic in June 2022, Danielle Griffin has not seen the results her doctor predicted. “She really expected to see a huge difference in my weight, and I just never saw it,” said the 38-year-old from Elida, New Mexico. Griffin weighed about 300 pounds and has lost only about 10 pound in two years. She said her “expectations were pretty much shattered from that.”

Amid insurance battles and shortages, she has also tried Wegovy and Mounjaro, but didn’t see a difference in her weight.

“I don’t feel like there are options, especially for myself, for someone who the medications not working for.”

The prospect of new medications on the horizon excites Griffin. “I would be willing to try it,” she said, adding that “it could be life changing, honestly, and you know that alone gives me something to look forward to.”

More drugs in the pipeline

Eli Lilly, which makes Zepbound and the diabetes version Mounjaro, has two more GLP-1 drugs in development.

On Sunday, Lilly released new data about retatrutide, an injectable drug that combines GLP-1 and glucagon , plus another hormone called GIP. GIP is thought to improve how the body breaks down sugar.

In an earlier trial, retatrutide helped people lose, on average, about 24% of their body weight, the equivalent of about 58 pounds — greater weight loss than any other drug on the market.

New findings showed the weekly medication also significantly reduced blood sugar levels in people with Type 2 diabetes.

On Saturday, there were also new findings on the experimental mazdutide, which Lilly has given permission to biotech firm Innovent Biologics to develop in China. The drug combines GLP-1 and glucagon.

In a phase 3 study of adults in China who were overweight or had obesity, researchers found that after 48 weeks, a 6-milligram dose of the drug led to an average body weight reduction of 14.4%.

The drug also led to a reduction in serum uric acid — a chemical that can build up in the bloodstream, causing health problems, and has been associated with obesity, according to Dr. Linong Ji, director of the Peking University Diabetes Center, who presented the findings.

That was “quite unique and never reported for other GLP-1-based therapies,” he said in an interview.

The drug could be approved in China in 2025, Ji said.

Improving metabolic conditions

An estimated 75% of people with obesity have nonalcoholic fatty liver disease and 34% have MASH, or metabolic dysfunction-associated steatohepatitis, according to researchers with the German drugmaker Boehringer Ingelheim. Fatty liver disease occurs when the body begins to store fat in the liver . It can progress to MASH, when fat buildup causes inflammation and scarring.

In a phase 2 trial of people who were overweight or had obesity, Boehringer Ingelheim’s survodutide, which uses both GLP-1 and glucagon, led to weight loss of 19% at 46 weeks. Another phase 2 study in people with MASH and fibrosis found that 83% of participants also showed improvement in MASH.

Survodutide “has significant potential to make a meaningful difference to people living with cardiovascular, renal and metabolic conditions,” said Dr. Waheed Jamal, Boehringer Ingelheim’s corporate vice president and head of cardiometabolic medicine.

On Friday, the company released two studies on the drug. One, in hamsters, found that weight loss was associated with improvements in insulin and cholesterol. The second, in people with Type 2 diabetes or people with obesity, found the drug helped improve blood sugar levels.  

The company is looking to begin a phase 3 trial.

CLARIFICATION (June 24, 2024, 2:31 p.m. ET): Innovent Biologics has entered into an exclusive licensed agreement with Eli Lilly for the development of mazdutide in China, not a partnership.

Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

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Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

• Educational Review
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• Published: 16 March 2018
• Volume 34 , pages 389–403, ( 2019 )

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• Anne M. Schijvens 1 ,
• Rob ter Heine 2 ,
• Saskia N. de Wildt 3 , 4 &
• Michiel F. Schreuder 1  

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Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice.

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Introduction

Nephrotic syndrome is one of the most common glomerular disorders in children and affects 1–7 per 100,000 children per year (Dutch data 1.52/100,000) with a male predominance (2:1) [ 1 ]. The disease is characterized by the triad of severe proteinuria, hypoalbuminemia, and edema. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for over 60 years, as over 80–90% of the patients achieve complete remission with prednisone or prednisolone treatment [ 2 ]. Unfortunately, 80% of these patients will have one or several relapses and will need additional courses of glucocorticoid therapy. Furthermore, approximately 10% of children with nephrotic syndrome are steroid resistant and do not respond to the standard steroid treatment regimen. Treatment guidelines for the first manifestation and a relapse of steroid-sensitive nephrotic syndrome are mostly standardized and based on practice guidelines rather than clinical trials [ 3 ]. As the optimal glucocorticoid dosing regimens for childhood nephrotic syndrome are still under debate and large-scale clinical trials are lacking, current clinical practice among physicians is variable [ 4 ], especially in the treatment of subsequent relapses and the choice of second-line immunosuppressive drugs. Unfortunately, the variability in the treatment of nephrotic syndrome is mostly based on the protocol preference of the physician, rather than the individual characteristics of the patient. Therefore, clinical trials are needed to develop international treatment guidelines with recommendations for several aspects of the treatment of nephrotic syndrome. Recently, a nationwide study in the Netherlands showed that duration of corticosteroids for the initial presentation had no impact on subsequent relapses [ 5 ]. Furthermore, a recently published abstract of the PREDNOS study indicated no clinical benefit associated with an extended steroid course for the initial presentation in UK children [ 6 ]. Currently, a few clinical trials are underway to further investigate the optimal dosing regimens for both the first manifestation ( https://clinicaltrials.gov/ct2/show/NCT02649413?recrs=abdf&cond=Nephrotic+Syndrome&age=0&draw=2&rank=13 ) as well as relapses of nephrotic syndrome [ 7 ].

Large inter-individual variation is present in children with nephrotic syndrome regarding both the clinical course of disease and the intensity and spectrum of side effects of its treatment. Nephrotic syndrome is characterized by podocyte foot process effacement; however, the exact mechanism of disease is still largely unknown and often debated. Several etiologies have been investigated over the years, and different subgroups of the disease are likely to have a different pathogenesis [ 8 , 9 ]. Damage to the filtration barrier can be caused by genetic defects primarily affecting podocytes. Patients with an underlying genetic defect are often primary steroid resistant, and to date, 53 genes associated with steroid-resistant nephrotic syndrome have been identified [ 10 ]. Furthermore, a substantial proportion of the patients is likely to have an immune-mediated circulating factor disease. These patients are also often steroid resistant, but screen negative for the known steroid-resistant nephrotic syndrome genes. The existence of a circulating permeability factor would explain the rapid recurrence of proteinuria after kidney transplantation in some patients with nephrotic syndrome [ 11 , 12 ]. Many candidates have been identified over the years; however, the definitive factor remains to be discovered [ 13 ]. Lastly, involvement of the immune system in the pathogenesis of nephrotic syndrome is highly suspected as relapses often occur after the immune system is triggered by an infection, allergy, or vaccination, and glucocorticoid treatment is effective in most patients. Nephrotic syndrome has been considered to be a T cell disorder based on several observations, including remission following measles infection, the association with Hodgkin disease, and the response to immunosuppressive drugs [ 9 ]. Furthermore, in the last few years, a potential role for B cells has been proposed as well due to the effectiveness of B cell depletion with rituximab in patients with nephrotic syndrome [ 9 , 14 ].

All in all, most children with nephrotic syndrome have a minimal change disease [ 15 ] and, therefore, the large inter-patient variability cannot fully be attributed to the disease histology. Previous research has indicated that pharmacogenetics can have an influence on both pharmacokinetics (PK) and pharmacodynamics (PD) of the individual patient [ 16 ]. Genetic factors influencing the individual pharmacokinetic and pharmacodynamic profile may account for 20–95% of the variability in the efficacy and side effects of medication [ 17 ]. Each of the processes involved in PK and PD can potentially be influenced by a clinical significant genetic variation [ 18 ]. Therefore, pharmacogenetics may have a promising role in personalized medicine. By implementing pharmacogenetics in the clinical work-up of the patients, this may ultimately lead to individualized drug therapy to maximize drug efficacy and minimize drug toxicity. In the era of precision medicine, however, current knowledge on the influence of pharmacogenetics on the steroid response in nephrotic syndrome is limited [ 19 ].

This review describes the mechanisms of glucocorticoid action and clinical PK and PD of prednisone and prednisolone in nephrotic syndrome patients. Furthermore, the current data available on pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome is summarized and areas for future research to improve individualization of glucocorticoid therapy in children with nephrotic syndrome are identified.

Mechanisms of glucocorticoid action

Glucocorticoids are potent anti-inflammatory and immunosuppressant drugs. The effects of glucocorticoids are mediated by both genomic and non-genomic mechanisms. Genomic mechanisms implicate the activation or repression of specific genes encoding anti- and pro-inflammatory proteins. As a consequence of the time-consuming mRNA transcription and translation, the genomic glucocorticoid action is characterized by a slow onset of the response. In contrast, non-genomic mechanisms do not influence gene expression and have a rapid onset and a short duration of the effect [ 20 ].

Genomic mechanisms (Fig.  1 )

Glucocorticoids are, like other steroid hormones, lipophilic molecules that can easily diffuse across the cell membrane and bind to the glucocorticoid receptors (GRs) in the cytoplasm [ 21 ]. The inactive GR is bound to a chaperone protein complex to keep the inactive GR in the correct folding for hormone binding and prevent nuclear localization of unoccupied GRs [ 19 , 22 , 23 ]. When glucocorticoids enter the cell after passive diffusion and bind to the GR in the cytoplasm, a glucocorticoid receptor/glucocorticoid (GR/GC) complex is formed. Subsequently, the chaperone protein complex dissociates, allowing the transfer of the GR/GC complex into the nucleus. The mechanism of nuclear translocation involves the nuclear import proteins importin-α and importin-13 (IPO13) [ 24 ]. After entering the nucleus, the activated GR/GC complex binds to the DNA or interacts with co-activator complexes. The activated GR/GC complex exerts its anti-inflammatory and immunosuppressive effects by increased expression of anti-inflammatory genes (transactivation) and decreased expression of pro-inflammatory genes (transrepression) [ 23 , 25 ]. Furthermore, the GR/GC complex can, either directly or indirectly, interact with pro-inflammatory transcription factors nuclear factor κB (NF-κB) and activator protein 1 (AP-1) and thus reduce their activity [ 20 , 26 ].

Molecular mechanisms of glucocorticoid action. AP-1, activator protein 1; IκB, inhibitor of kappa B; IPO-13, importin-13; NF-κB, nuclear factor κB; GRE, glucocorticoid response elements

Non-genomic effects

The non-genomic mechanisms of glucocorticoid action remain largely undefined. Glucocorticoids affect the physicochemical property of cell membranes, directly or through binding to intracellular or membrane-bound GRs [ 27 ]. The effects result in the inhibition of inflammatory cell function [ 28 ]. Another hypothesis is that non-genomic effects are mediated after GR/GC binding. When glucocorticoids bind to the GR, the aforementioned chaperone proteins are released. The release of signaling molecules from the multiprotein complex is also considered to be responsible for rapid glucocorticoid effects [ 29 ].

Pharmacokinetics

Pharmacokinetics describes the study of what the body does to a drug. PK involves the processes of absorption, distribution, metabolism, and excretion, often abbreviated as ADME.

Prednisone and prednisolone

For the treatment of nephrotic syndrome, both prednisone and prednisolone are frequently used glucocorticoids. Prednisone is a prodrug of prednisolone and is bioactivated by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD)-1. The conversion of prednisone into prednisolone occurs rapidly, and plasma concentrations of both substances reach their peaks at approximately 0.5–3 h after prednisone administration, in both patients with and without nephrotic syndrome [ 20 , 30 , 31 , 32 , 33 ]. In addition, inter-conversion is present between both substances and this varies with time and dose. However, prednisolone concentrations are four- to tenfold higher than prednisone concentrations. In children with nephrotic syndrome, both in the active phase and in remission, similar ratios were found, which indicates that nephrotic syndrome does not influence the conversion from prednisone into prednisolone [ 30 , 31 , 32 , 34 ].

Both prednisone and prednisolone are well absorbed after oral administration. A variable systemic bioavailability for prednisone and prednisolone has been reported in the literature: 84 ± 13 and 99 ± 8%, respectively [ 20 ]. The high variability in bioavailability is most likely mainly based on inter-individual differences rather than the choice of prednisone or prednisolone [ 35 ]. In the Kidney Disease: Improving Global Outcomes (KDIGO) guideline for glomerulonephritis, prednisone and prednisolone are considered equivalent and identical dosages are used for the standardized treatment regimens for patients with nephrotic syndrome [ 3 ]. Peak plasma concentrations are reached at approximately 0.5–3 h after administration. Food intake is generally considered to prolong the time to maximum drug concentration ( T max ), but not the extent of drug absorption [ 36 ].

• Nephrotic syndrome

In patients with nephrotic syndrome, a similar bioavailability profile has been described, indicating that the nephrotic state does not influence the absorption of prednisolone and prednisone [ 34 , 37 ] (Fig.  2 ).

ADME prednisone/prednisolone in patients with nephrotic syndrome

Distribution

The volume of distribution of prednisolone and prednisone in adults is 0.64 l/kg [ 38 ] and 0.4–1.0 l/kg [ 39 ], respectively. The total plasma PK of prednisolone and prednisone appears non-linear, due to non-linear protein binding. The protein-free PK, however, is linear. Non-linear protein binding is most evident in the dose range between 5 and 50 mg [ 32 ]. Prednisolone binds to the glycoprotein transcortin (i.e., corticosteroid-binding globulin) and to albumin. Transcortin is a small (50–60 kDa), high-affinity, low-capacity protein with normal blood concentrations of 32.0–50.0 mg/l. In contrast, albumin (60 kDa) has a low affinity but high capacity [ 32 , 40 ]. Protein binding of prednisolone decreases non-linearly from approximately 95% at plasma concentrations of 200 μg/l down to 60–70% at plasma concentrations of 800 μg/l. Subsequently, a dose-dependent increase in the volume of distribution and drug clearance is observed [ 20 ].

Patients with nephrotic syndrome have decreased serum albumin and transcortin levels in the active phase of disease, leading to a decreased protein binding of prednisone and prednisolone [ 37 , 38 ]. When the unbound fraction increases due to less protein binding, the drug is eliminated more rapidly and the volume of distribution of total prednisolone increases as the displaced drug spreads out. The end result is an initial increase in unbound concentration, a decrease in total drug concentration, and no change in the steady-state unbound concentration (Fig.  3 ). These findings underline the necessity of evaluating unbound concentrations in pharmacological research. Recently, Teeninga et al. showed a good correlation between salivary prednisolone levels and free serum prednisolone levels in healthy volunteers and pediatric nephrotic syndrome patients, indicating the potential use of saliva as a non-invasive and feasible method for drug monitoring of prednisolone [ 41 ].

Unchanged unbound (free) concentration in patients with nephrotic syndrome

Several pharmacokinetic studies performed in both pediatric [ 30 , 31 , 34 , 40 ] and adult [ 37 , 38 , 42 ] nephrotic syndrome patients have confirmed the increase in unbound fraction, but unchanged steady-state unbound concentration of prednisolone. Moreover, pharmacokinetic studies performed in children with nephrotic syndrome both in the active phase of disease and in remission showed that free prednisolone concentrations during the active phase did not significantly differ from those observed during remission [ 31 ]. Furthermore, pharmacokinetic studies for other highly protein-bound drugs showed similar results with an increase of total volume of distribution, total clearance, and free fraction of the drugs, but unchanged free drug concentrations in steady state [ 43 ].

Intracellular metabolism by 11β-HSD controls the availability of prednisolone for binding to the glucocorticoid and mineralocorticoid receptors. Two types of 11β-HSD are present in the body. 11β-HSD-1 acts primarily as a reductase and converts the inactive prednisone into the active prednisolone. 11β-HSD-2 acts primarily as an oxidase and converts prednisolone to prednisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol and prednisolone [ 44 ]. The undesired mineralocorticoid effects of glucocorticoid treatment will most likely be pronounced when the capacity of 11β-HSD-2 is exceeded. Therefore, the mineralocorticoid effects of glucocorticoids might depend on the administration scheme. A low glucocorticoid dose leading to concentrations just above the protective capacity of 11β-HSD-2 is expected to have reduced mineralocorticoid effects when administered as two dose fractions, because both concentration peaks would not exceed 11β-HSD-2 capacity. In contrast, higher glucocorticoid doses, exceeding the 11β-HSD-2 capacity and even leading to saturation of the mineralocorticoid receptor, are expected to have enhanced mineralocorticoid effects when administered as two dose fractions, because the total time during which mineralocorticoid receptors are occupied would be prolonged.

Prednisolone and prednisone are primarily cleared from the body by hepatic metabolism involving phase I and phase II reactions. The most important enzyme system of phase I metabolism is cytochrome P450. However, for the prednisone/prednisolone metabolism, the degree of involvement of specific cytochrome P450 (CYP)3A isoenzymes has not been fully elucidated yet. Nevertheless, co-administration of the strong CYP3A4 inhibitor ketoconazole is shown to increase total and unbound prednisolone concentrations in plasma by about 50% due to a decreased clearance [ 45 ]. In line with this, previous research has shown co-administration of enzyme inducers to cause an increased clearance and decreased half-life of prednisolone [ 46 , 47 , 48 ].

Furthermore, in vitro data suggest that prednisolone is also a substrate of P-glycoprotein. P-glycoprotein is an ATP-dependent efflux membrane transporter, which is widely distributed throughout the body and highly expressed in the small intestine and kidneys. Expression of P-glycoprotein in the intestinal epithelium limits the absorption of drug substrates from the gastrointestinal tract. Therefore, theoretically, co-administration of P-glycoprotein inhibitors could increase glucocorticoid absorption and oral bioavailability and might affect glucocorticoid distribution [ 20 ]. A previous study conducted in adult renal patients, however, showed a normal metabolism of prednisolone in patients treated with cyclosporine, which is a P-glycoprotein inhibitor [ 49 ].

For patients with nephrotic syndrome, different dosing regimens have been investigated. Single daily dosing appears to be as effective as multiple daily dosing in maintaining remission in children [ 50 ]. Serious side effects, including hypertension, Cushingoid appearance, and obesity, were less common in patients receiving the single daily dose compared to patients receiving divided doses [ 50 ]. We hypothesize that this might be due to continuously exceeding the 11β-HSD-2 capacity in case of multiple daily dosing as a consequence of the high doses of steroids given in patients with nephrotic syndrome.

Whether P-glycoprotein inhibitors are able to increase glucocorticoid availability in patients with nephrotic syndrome is unknown. In addition, glucocorticoids are known to affect the PK of other drugs by enzyme induction as well by inducing CYP3A4 [ 51 ] and P-glycoprotein [ 52 ]; however, the clinical importance of enzyme induction by prednisone/prednisolone is largely unknown [ 20 ].

P-glycoprotein is also located in the liver and kidney, resulting in enhanced excretion of drug substrates into bile and urine, respectively. In this case, co-administration of P-glycoprotein inhibitors could potentially result in decreased excretion of prednisone/prednisolone and an increased retention time [ 53 ]. The previously mentioned pharmacokinetic study in renal transplant patients, however, also showed a normal metabolic and renal clearance of prednisolone in the presence of cyclosporine [ 49 ]. Elimination half-lives ( T 1/2 ) in adults are 3.3 ± 1.3 h for prednisone and 3.2 ± 1.0 h for prednisolone [ 20 ]. In a pharmacokinetic study performed in children, lower mean elimination half-lives of 2.2 ± 0.5 h were found [ 33 ].

In the aforementioned study, children with a variety of diseases (e.g., nephrotic syndrome, asthma, systemic lupus erythematosus, congenital virilizing adrenal hyperplasia) were included. Children with congenital virilizing adrenal hyperplasia were considered to be comparable to normal subjects. No difference regarding elimination half-lives was found between this group and the children with nephrotic syndrome [ 33 ]. Similarly, Rocci et al. found no significant difference in half-life between pediatric nephrotic syndrome patients in remission and asthmatic controls. However, in the active phase of disease, the nephrotic syndrome patients did show increased T 1/2 values, which may be explained by the larger volume of distribution in active disease [ 34 ]. In patients with nephrotic syndrome, total prednisolone clearance increases proportionally to the increased unbound fraction of prednisolone [ 34 , 38 , 42 ] (Fig.  3 ). Renal excretion of unchanged drugs is approximately 2–5% for prednisone and 11–24% for prednisolone after administration of either one of the drugs [ 32 ].

In patients with nephrotic syndrome, the unbound fraction of prednisolone increases due to saturable protein binding. Subsequently, this leads to more rapid elimination and an increase in apparent volume of distribution, in the end, leading to a decrease in total drug concentrations and no change in the steady-state unbound (pharmacologically active) concentration (Fig.  3 ). Therefore, dose adjustment of prednisone/prednisolone is not necessary in nephrotic syndrome patients with normal renal clearance.

Pharmacodynamics

Pharmacodynamics refers to what the drug does to the body, including the time course and intensity of therapeutic and adverse effects.

Therapeutic effects

Clinical efficacy depends on both pharmacokinetic (e.g., what the body does to a drug) and pharmacodynamic (e.g., what the drug does to the body) characteristics of a drug. In case of glucocorticoids, PD may vary greatly among different glucocorticoids, diseases, and individuals. These differences may be explained by a variety of factors: different numbers of GRs per cell, a different glucocorticoid binding affinity, GR diversity, regulatory factors that control gene translation and protein production, and possibly also, differences in non-genomic mechanisms between cell types [ 54 ]. One way of comparing drug potency is by the concentration at which 50% of the maximum effect (EC 50 ) is achieved. Furthermore, potency is also dependent on the effect monitored. Potential biomarkers for glucocorticoids are endogenous cortisol, T helper and T suppressor lymphocytes, and neutrophil count [ 55 ].

Adverse effects

Prednisolone and prednisone therapy have been associated with a broad range of toxicities. Adverse effects are more common in patients receiving glucocorticoids in high doses or over a long period of time. Potential adverse effects include skin fragility, bodyweight gain, increased risk of infections, and fractures. Important cardiovascular and metabolic effects are hypertension, hyperglycemia, and dyslipidemia [ 48 ]. Whereas most anti-inflammatory effects of glucocorticoids are consequences of transrepression of pro-inflammatory and immune genes, adverse events appear to largely result from transactivation that leads to increased expression of regulatory and anti-inflammatory proteins [ 25 , 27 , 56 ].

As it stands, it is not completely understood how prednisolone achieves remission of nephrotic syndrome. High variability exists between individuals with nephrotic syndrome regarding both the efficacy and side effects of prednisone/prednisolone [ 57 ]. Furthermore, the molecular basis for the development of clinical resistance to glucocorticoid therapy is unclear in patients with nephrotic syndrome. Inter-individual differences in glucocorticoid handling and metabolism may partly explain the variability in the response to prednisone/prednisolone treatment. However, as previously described in the introduction, differences in disease histology, podocytes, and immunological characteristics of the individual patient may also play a significant role. Different hypotheses exist to explain the mechanism of action of prednisone/prednisolone in patients with nephrotic syndrome. These hypotheses go beyond the conventional anti-inflammatory or immunosuppressive actions, as it is unlikely that the effect is completely due to conventional anti-inflammatory effects of these drugs, since glomerular inflammation is mostly absent in steroid-sensitive nephrotic syndrome.

Previous research has indicated that glomerular podocytes may be a direct target of glucocorticoids in patients with nephrotic syndrome as human podocytes express GRs [ 58 ]. The beneficial effect of glucocorticoids might be due to direct protection of podocytes from injury and/or promotion of podocyte repair. Xing et al. showed that dexamethasone upregulated the expression of nephrin [ 59 ]. Nephrin is a key component of the slit diaphragm, the main site of control of glomerular permeability. This has resulted in the hypothesis that glucocorticoids act directly on podocytes via promotion of repair with enhanced process formation and upregulation of nephrin. Furthermore, podocyte foot processes consist of cortical actin filaments and actin-associated proteins, which ensure the dynamic maintenance and reorganization of the cytoskeleton. In vitro studies have shown the direct effects of glucocorticoids on podocytes by protection of cultured podocytes via actin filament stabilization and prevention of apoptosis [ 60 , 61 ]. The effect on apoptosis [ 61 ] and upregulation of nephrin [ 59 ] appeared to be dose-dependent, which might be an explanation for the observed differences in clinical response to glucocorticoids. Another in vitro study, performed by Guess et al., demonstrated functional glucocorticoid signaling by multiple glucocorticoid-induced responses, including downregulation of the GR [ 62 ].

Gamal et al. reported that glomerular GR expression was significantly higher in minimal change early responders in comparison to late responders. Furthermore, a significantly lower glomerular GR expression was found in patients with a steroid-resistant nephrotic syndrome compared to early responders and late responders. Therefore, evaluation of glomerular GR expression at the time of diagnosis can aid in prediction of the response to steroid therapy. This way, exposure to ineffective treatment courses may be prevented in children with nephrotic syndrome [ 63 ]. Unfortunately, this technique requires a kidney biopsy and, in daily clinical practice, a kidney biopsy is generally not performed at the time of diagnosis in children with nephrotic syndrome. Therefore, additional approaches are needed to predict the response to steroid therapy, of which pharmacogenetics may be a promising option.

• Pharmacogenetics

It is well known that different patients respond in different ways to the same medication. Many non-genetic factors influence the individual differences in drug response, including age, sex, disease, organ function, concomitant therapy, drug adherence, and drug interactions (for a review on such factors, see [ 20 , 48 ]). In addition, genetic factors may also have a major influence on the efficacy of a drug and risk of side effects [ 18 , 64 ]. Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. Genetic factors influencing the patient pharmacokinetic or pharmacodynamic profiles may account for 20–95% of variability in the efficacy and side effects of therapeutic agents [ 17 ]. For example, polymorphisms in the CYP3A5 gene account for 40–50% of the variability in tacrolimus dose requirement in Caucasians [ 65 ]. After administration, the drug is absorbed and distributed to the site of action. It interacts with targets (such as receptors and enzymes), undergoes metabolism, and is then excreted. Each of these processes could potentially involve a clinical significant genetic variation [ 18 ]. Understanding the basis of such variations, i.e., pharmacogenetics, is vital to come to personalized medicine, which ultimately may lead to individualized drug therapy to maximize drug efficacy and minimize drug toxicity.

Clinical practice

In children with nephrotic syndrome, large inter-individual variability is present in the course of disease, and efficacy and side effects of glucocorticoids. As the variable response to glucocorticoids in patients with nephrotic syndrome cannot completely be attributed to the disease histology, it is difficult to predict the response based on clinical observations alone. For nephrotic syndrome, research on the impact of genetic polymorphisms on steroid response and susceptibility to steroid-related toxicities is limited [ 19 ]. For a few other diseases, however, pharmacogenetics has already been implemented in clinical practice [ 66 , 67 ]. Furthermore, in the field of pediatric nephrology, new guidelines on tacrolimus dosing recommend involvement of CYP3A5 genotyping to optimize the immunosuppressive treatment of the individual transplant patients [ 68 ].

In line with the aforementioned examples, we believe that the involvement of pharmacogenetics in the work-up of nephrotic syndrome patients as well might be beneficial, preventing exposure to ineffective drug courses and minimizing drug toxicity. As the mechanism of action of glucocorticoids involves numerous receptors, enzymes, and proteins, a variety of potential targets of genetic polymorphisms may be present. Although limited evidence is available, an overview of previously conducted studies on pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome is provided below. Table 1 (glucocorticoid targets) and Table 2 (glucocorticoid PK) provide an overview and brief description of the most important studies conducted in pediatric patients with nephrotic syndrome in which a positive association between the polymorphism and steroid response was described. A summary of the mechanisms and most important results is provided for the targets involved.

Glucocorticoid receptor

Polymorphisms in the GR gene (NR3C1) are known to be associated with variations in the GR function, because they may alter the formation of the GR/GC complex. Therefore, the hypothesis is that genetic alterations in the gene encoding for the GR receptor may account for some degree of inter-individual variability in the glucocorticoid response and steroid-related toxicity in individuals [ 88 ]. Three polymorphisms are known to be associated with reduced sensitivity in both endogenous and exogenous glucocorticoids: TthIIII (rs10052957), ER22/23K (rs6189/rs6190), and GR-9β (rs6198). In contrast, the polymorphisms N363S (rs6195) and BC1I (rs41423247) are associated with an increased sensitivity to glucocorticoids [ 88 , 89 ]. Increased glucocorticoid sensitivity due to a genetic polymorphism might also be associated with increased susceptibility to steroid-related toxicities. Previously, Eipel et al. showed that pediatric patients with acute lymphoblastic leukemia (ALL) carrying the N363S polymorphism were more prone to steroid-related toxicities [ 90 , 91 ]. In contrast, children with the ER22/23EK polymorphism were less susceptible [ 90 ]. To our knowledge, the role of genetic polymorphisms in the GR gene in susceptibility of steroid-related toxicities has only been investigated in patients with nephrotic syndrome in one study. Teeninga et al. found no association between the GR-9β polymorphism and side effects [ 69 ]. To date, a few studies investigated the role of NR3C1 polymorphisms on the glucocorticoid response in pediatric patients with nephrotic syndrome [ 69 , 70 , 71 , 72 , 92 , 93 ]. Four studies found a potential influence of genetic polymorphisms in the GR gene on the steroid response in patients with nephrotic syndrome (Table 1 ).

Glucocorticoid receptor heterocomplex

Components of the glucocorticoid heterocomplex are essential to keep the GR in the correct folding for hormone binding and prevent nuclear localization of unoccupied GRs. Abnormalities in the chaperones and co-chaperones that make up the heterocomplex may contribute to decreased glucocorticoid responsiveness, as the integrity of the GR heterocomplex is required for optimal ligand binding and subsequent activation of the transcriptional response. For several diseases, which are treated with glucocorticoids, including nephrotic syndrome, altered levels of chaperone protein hsp90 were found in peripheral blood mononuclear cells from individuals with a steroid-resistant course of disease [ 94 , 95 , 96 ]. Although limited, some evidence exists about the association of polymorphisms in the gene encoding for one of the co-chaperones, FKBP5, with steroid resistance in Crohn’s disease [ 97 ]. Interestingly, this could also hold true for nephrotic syndrome patients as well. Recently, one study was published on the potential role of FKBP5 polymorphism (rs4713916) in a small group of pediatric nephrotic syndrome patients showing a higher frequency in patients with a steroid-dependent nephrotic syndrome [ 73 ].

Nuclear translocation receptors

Nuclear translocation receptors, known as importins, play a significant role in the mechanism of glucocorticoid action. These receptors are responsible for the effective transport of the GR/GC complex to the cell nucleus. IPO13 is a primary regulator to facilitate the transfer of the GR/GC complex across the nuclear membrane. In children with asthma, polymorphisms encoding the IPO13 gene resulted in increased sensitivity for glucocorticoids, which was most likely due to the increased availability of glucocorticoids in the nucleus [ 98 ]. The role of genetic polymorphisms in the gene encoding for IPO13 in patients with nephrotic syndrome is unknown [ 19 ].

Pro- and anti-inflammatory factors

To date, the exact underlying pathophysiological mechanisms of nephrotic syndrome are still unknown. One of the hypotheses is that nephrotic syndrome is associated with an immunoregulatory imbalance between T helper subtype 1 (Th1) and T helper subtype 2 (Th2) cells. Cytokines produced by the T helper cells play a role as mediators of inflammation. Several studies have been conducted in patients with various diseases to evaluate the association with genetic polymorphisms in the IL-1, IL-4, IL-6, IL-13, and TNF-α genes. The evidence for genetic polymorphisms in the cytokine genes in patients with nephrotic syndrome is, however, limited.

Minimal change nephrotic syndrome is associated with atopy and IgE production [ 99 ]. T helper subtype 2 cytokines, such as IL-4 and IL-13, are known to be involved in the development of atopy. Previously genetic variations of IL-4 and IL-13 and their receptors have been shown to be associated with predisposition to atopy and/or elevated serum IgE levels [ 100 ]. Several studies have been conducted to investigate the role of polymorphisms in the genes coding for IL-4, IL-6, and IL-13 in pediatric patients with nephrotic syndrome [ 74 , 75 , 76 , 101 , 102 , 103 ]. The IL-4 polymorphism rs2243250 was associated with nephrotic syndrome and an increased risk of steroid resistance [ 74 , 75 , 76 ]. Furthermore, previous research conducted by Jafar et al. and Tripathi et al. indicate that a genetic polymorphism in the IL-6 gene is associated with decreased responsiveness to steroids [ 75 , 76 ]. No significant association was found between the IL-13 gene polymorphisms and disease susceptibility or steroid responsiveness [ 71 , 101 , 103 ].

An important pro-inflammatory cytokine is macrophage migration inhibitory factor (MIF). MIF has the unique ability to override the inhibitory effects of glucocorticoids on the immune system. Due to its regulatory properties, MIF is considered a critical mediator in various immune and inflammatory diseases. The allele MIF-173*C (rs755622) is associated with higher serum MIF levels. Several studies have been conducted to investigate the potential role of this genetic polymorphism in the gene encoding for MIF in patients with nephrotic syndrome [ 71 , 79 , 80 , 81 , 104 , 105 ]. A meta-analysis conducted by Tong et al. showed that the gene polymorphism rs755622 plays an important role in the risk of glucocorticoid resistance in patients with nephrotic syndrome [ 106 ]. The hypothesis is that the G/C substitution at 173 bp of the MIF gene increases the MIF level in serum and could therefore cause a pro-inflammatory response, induce injury to podocytes, and accelerate the progression of glomerulosclerosis [ 107 ]. TNF-α is also an important pro-inflammatory cytokine involved in the inflammatory process. Elevation of TNF-α has been found in the plasma and urine of patients with nephrotic syndrome [ 108 , 109 ]. Conflicting results have been published for the role polymorphisms in the gene encoding for TNF-α in patients with nephrotic syndrome [ 75 , 76 , 110 , 111 ]. Lastly, Müller-Berghaus et al. investigated the role of polymorphisms in gene encoding for pro-inflammatory mediator IL-12B and found an association of the IL12Bpro-1.1 genotype with a steroid-dependent course of disease [ 78 ].

GLCCI1 (glucocorticoid-induced transcript 1 gene)

Little is known about the exact function of GLCCI1. GLCCI1 was initially described as a thymocyte-specific transcript that is rapidly upregulated in response to dexamethasone treatment [ 112 ]. In addition, GLCCI1 is expressed in the kidney and, in particular, in the glomeruli. Knockdown of the GLCCI1 gene resulted in disruption of the glomerular permeability filter and podocyte foot process effacement. A genome-wide association study in patients with asthma showed a significant association between the genetic polymorphism rs37972 of the GLCCI1 gene and a decreased response to glucocorticoid inhalation therapy [ 113 ]. In contrast, two studies in pediatric nephrotic syndrome patients could not confirm the association between this specific polymorphism and steroid responsiveness in patients with nephrotic syndrome [ 71 , 114 ].

P-glycoprotein

P-glycoprotein is an efflux pump encoded by the multidrug resistance protein 1 gene (MDR1). Glucocorticoids are known substrates for P-glycoprotein and may also induce P-glycoprotein expression [ 52 , 115 ]. In the kidney, P-glycoprotein is expressed in the brush border membrane of proximal tubular epithelial cells. Increased expression of P-glycoprotein results in decreased intracellular drug concentrations and may consequently decrease treatment response. Previous research has shown higher expression of MDR1 and increased P-glycoprotein activity in children with steroid-resistant nephrotic syndrome [ 116 , 117 ]. To date, approximately 50 genetic polymorphisms have been reported in the MDR1 gene. Among the genetic polymorphisms, C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) are the most common variants in the coding region of MDR1. The interpretation of the influence of the genetic polymorphisms on P-glycoprotein expression, however, is unresolved and may vary depending on tissue type, pathological status, and ethnicity [ 118 ]. A recent systematic review on pharmacogenetics and adverse drug reactions in pediatric oncology patients indicated protective effects from two genetic polymorphisms of the MDR1 gene in methotrexate- and vincristine-related neurotoxicity in pediatric ALL patients [ 119 ]. In nephrotic syndrome patients, however, no studies have been conducted to investigate the potential role of genetic polymorphisms in the MDR1 gene in steroid-related toxicities. Several studies have been conducted to evaluate the association of P-glycoprotein polymorphisms with the responsiveness to glucocorticoids in patients with nephrotic syndrome. The results of these studies on the significance of the genetic polymorphisms are contradictory [ 71 , 82 , 83 , 84 , 86 , 104 , 120 , 121 ]. A recent meta-analysis concluded that there is evidence of an association between rs1128503 and increased risk of steroid resistance in children with nephrotic syndrome [ 122 ].

Pregnane X receptor

Pregnane X receptor (PXR) gene (NR1I2) encodes an intracellular receptor that, upon binding with glucocorticoids or xenobiotic substances, activates a set of genes involved in the metabolism of drugs. Turolo et al. described an association of the presence of a PXR deletion polymorphism (rs3842689) with steroid resistance. The hypothesis is that a reduced expression of PXR leads to an underexpression of GRs, which may be the explanation for the development of steroid resistance [ 87 ].

The results of the aforementioned reported papers are generally inconclusive and contradictory. However, some genetic polymorphisms appear to be promising in the prediction of steroid response or steroid-related toxicities in children with nephrotic syndrome. Especially, polymorphisms in the genes encoding for the GR and GR heterocomplex seem to have an association with steroid responsiveness. Nevertheless, most studies are hampered by small patient cohorts. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw conclusions about the influence of genetic polymorphisms on the glucocorticoid response. Furthermore, as mentioned above, pharmacogenetics may also play a role in the intensity and spectrum of side effects. Currently, little is known about the influence of pharmacogenetics on steroid-related toxicities in patients with nephrotic syndrome. However, as previous research in mostly cancer patients has shown a potential role of genetic polymorphisms in the susceptibility on steroid-related toxicities, this area is an important opportunity for future research as well.

Glucocorticoids are essential in the treatment of childhood nephrotic syndrome. Currently, standardized treatment guidelines with high doses of prednisone or prednisolone are proposed worldwide. As current treatment guidelines are largely based on empiric recommendations rather than clinical trials, large variability in the treatment of nephrotic syndrome is present among physicians [ 4 ], especially regarding the treatment of subsequent relapses and the choice of second-line immunosuppressive drugs. As large-scale clinical trials are lacking, treatment decisions are frequently based on either the preference or common practice of the treating physician or guidelines of the country, rather than the individual characteristics of the patient. Therefore, effort should be made to first provide international guidelines based on clinical trials to uniformly treat patients with nephrotic syndrome. Subsequently, effort should be made to identify specific markers to individualize treatment, as large inter-individual differences are present in both the clinical course of disease and adverse effects of glucocorticoids in children with nephrotic syndrome. Pharmacogenetics has a promising role in working towards personalized medicine. Despite the fact that the evidence about the role of pharmacogenetics in children with nephrotic syndrome is limited, we feel that available data do show a potential role for pharmacogenetics in clinical practice to maximize drug efficacy, minimize drug toxicity, and avoid exposure to ineffective drug courses. Nowadays, the evidence to implement these genetic markers in clinical practice is too little and, therefore, clinical implementation of pharmacogenetics in nephrotic syndrome patients is not possible yet. Therefore, we feel that further research is highly important to identify specific and sensitive markers for steroid resistance in patients without genetic podocyte mutations as well as for patients more at risk for steroid-related toxicities. As nephrotic syndrome is a rare kidney disease in childhood and large patient cohorts are needed to ultimately implement pharmacogenetics in the clinical work-up, we believe that this research preferably should be conducted in international collaborative studies.

Multiple choice questions (answers are provided following the reference list)

Current glucocorticoid dosing guidelines for the treatment of nephrotic syndrome are

Standardized

Individualized

Based on randomized controlled trials

The genomic glucocorticoid action is characterized by

A rapid onset of the effect

Short duration of the effect

A slow onset of the effect

Adverse events of prednisone/prednisolone largely result from

Transrepression of pro-inflammatory and immune genes

Transactivation of anti-inflammatory genes

Due to decreased protein binding of prednisone and prednisolone in patients with nephrotic syndrome and to more rapid elimination and an increase in volume of distribution, the steady-state unbound concentration

is increased

is unchanged

is decreased

Pharmacogenetics may have an influence on the profile of the individual patient

Pharmacokinetic

Pharmacodynamic

Pharmacokinetic and pharmacodynamic

None of the above

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This study was funded by the Dutch Kidney Foundation (grant number 15OKG16).

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Schijvens, A.M., ter Heine, R., de Wildt, S.N. et al. Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome. Pediatr Nephrol 34 , 389–403 (2019). https://doi.org/10.1007/s00467-018-3929-z

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• Brief Communication
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• Published: 28 June 2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient

• James J. Dowling   ORCID: orcid.org/0000-0002-3984-4169 1 , 2 , 3 ,
• Terry Pirovolakis 4 ,
• Keshini Devakandan 1 ,
• Ana Stosic 1 , 2 ,
• Mia Pidsadny 1 ,
• Elisa Nigro 2 ,
• Mustafa Sahin   ORCID: orcid.org/0000-0001-7044-2953 5 ,
• Darius Ebrahimi-Fakhari 5 ,
• Souad Messahel 6 ,
• Ganapathy Varadarajan 6 ,
• Benjamin M. Greenberg   ORCID: orcid.org/0000-0002-2091-8201 6 ,
• Xin Chen 6 ,
• Berge A. Minassian 6 ,
• Ronald Cohn   ORCID: orcid.org/0000-0002-6775-1496 1 , 3 ,
• Carsten G. Bonnemann   ORCID: orcid.org/0000-0002-5930-2324 7 &
• Steven J. Gray   ORCID: orcid.org/0000-0002-6240-8621 6  

Nature Medicine ( 2024 ) Cite this article

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• Drug development
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• Paediatric neurological disorders

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Rare diseases affect more than 400 million persons. They are associated with considerable disabilities, early mortality and disproportionate impacts on the healthcare system. Less than 5% have treatments, highlighting a critical need for new therapies. There is now the conceptual ability to develop gene- and/or mutation-specific treatments for many rare diseases 1 , 2 . However, important barriers exist, particularly related to patient numbers, development costs and lack of financial incentives.

Hereditary spastic paraplegia type 50 (SPG50) is a prototypical ultra-rare (affecting <1 in 50,000) disease, with fewer than 100 affected individuals identified 3 , 4 . It is caused by biallelic pathogenic variants in the AP4M1 gene, encoding a subunit of the adaptor protein complex 4 (AP-4) 5 , 6 , 7 , 8 , 9 . Symptom onset is typically in infancy and includes global developmental delay, progressive microcephaly and abnormalities on brain magnetic resonance imaging (MRI) 3 , 4 , 10 . The disease is progressive, with loss of motor skills due to worsening spasticity, and is associated with serious morbidities 3 , 11 . By the second decade of life, most affected individuals are wheelchair dependent and manifest severe cognitive dysfunction. Lifespan is not fully established, but the disorder is considered life-limiting.

SPG50 is an ideal candidate disease for gene therapy. The coding sequence is small (1,359 base pairs) and fits within a self-complementary adeno-associated virus (scAAV) vector. Causative mutations result in loss of expression/function, so gene re-expression is anticipated to be effective, and the nature of the AP-4 complex as an obligate heterotetramer may protect against overexpression-related toxicity 12 . There is a relatively large therapeutic window, as disease progression occurs over years, with potential for functional benefit likely before irreversible disability. However, the disorder’s rarity precludes typical drug development pathways.

We present a case wherein gene therapy was developed for a single male patient with SPG50 (Fig. 1a ). The disease was diagnosed at age 18 months by whole-exome sequencing ( AP4M1 c.916 C>T, p.R306X; c.696dupG, p.E232GfsX21) based on a presentation of developmental delay (unable to stand or walk independently, no word production) and microcephaly. At diagnosis, based on our international registry ( NCT04712812 ), the proband was the only Canadian individual with SPG50. Shortly after diagnosis, the family created the CureSPG50 Foundation with the goal of developing SPG50 gene therapy. At the predosing baseline, the patient could crawl 5 feet, pull himself up to stand momentarily at a table and walk a few steps with assistance. He had a pincer grasp and could feed himself with his hands, stack two blocks and scribble. He was nonverbal and had limited communication with gestures and nonword sounds. Physical examination was most notable for diffuse spasticity (lower extremity more affected than upper extremity) and hyperreflexia.

a , Timeline of the development of SPG50 gene therapy, from patient diagnosis through patient dosing, with key milestones highlighted. Note that the entire process, from diagnosis to dosing, took approximately 2.5 years. UTSW, University of Texas Southwestern; FDA, Food and Drug Administration; IND, investigational new drug; GLP, Good Laboratory Practice; NHP, nonhuman primate; Tox, toxicology; CTA, clinical trial application; COA, certificate of analysis. b , Outline of the single-patient clinical trial. The schematic depicts the postdosing safety and efficacy monitoring time points, along with the immunosuppression protocol. The comprehensive immunosuppression program was implemented to attempt to minimize the innate and adaptive immune responses and to promote tolerance to the gene therapy product. ‘GT’ indicates the gene therapy dosing. MRI of the brain and spine (with and without contrast) was done at baseline and at 3, 6 and 12 months after dosing. CSF analysis included cell count, protein concentration, oligoclonal bands and cytokine analysis. Exploratory tests included measurement of the AAV9 neutralizing antibody titer, serum cytokine analysis and ELISpot assay. Safety laboratory tests (‘safety labs’) included complete blood count with differential, erythrocyte sedimentation rate, C-reactive protein, liver function tests (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, alkaline phosphatase), blood urea nitrogen/creatinine, urinalysis, electrocardiography and cardiac safety panel (troponin, pro-B-type natriuretic peptide, creatine kinase isotype MB). IV MethylPred, intravenous methylprednisolone.

The investigational product was designed based on similar vectors made for CLN7 disease and giant axonal neuropathy 13 and includes codon-optimized human AP4M1 driven from the JeT promoter and encapsulated into scAAV9 (AAV9- AP4M1 ; Extended Data Fig. 1 ) 14 . Based on preclinical data 14 , a safety, toxicity and efficacy package for AAV9- AP4M1 was filed to Health Canada, along with a clinical protocol and information on chemistry, manufacturing and control. A ‘no objection letter’ was received in December 2021, 2 years and 8 months after diagnosis. The study protocol enumerated the eligibility criteria and safety assessments based on the gene therapy trial for giant axonal neuropathy ( NCT02362438 ) 15 , and efficacy measures were derived from the ongoing SPG50 natural history study ( NCT04712812 ). Institutional ethics board approval was obtained in February 2022. Although the trial was not registered with ClinicalTrials.gov until October 2023, all inclusion and exclusion criteria, safety studies and outcome measures were established before study initiation and patient enrollment.

A single-patient trial ( NCT06069687 ) was initiated (Fig. 1b ), with dosing in March 2022, 2 years and 11 months after diagnosis. The primary outcome was safety, and secondary efficacy measures were related to spasticity. AAV9- AP4M1 was administered at 1 × 10 15 vector genomes (vg) through intrathecal delivery. This is among the largest doses of AAV9-based gene therapy ever administered into the cerebrospinal fluid (CSF).

We used an extensive immunosuppression protocol (prednisolone, sirolimus and tacrolimus) designed to reduce adverse immune responses and promote tolerance to the AP4M1 protein, given the patient’s predicted lack of endogenous expression. Based on enzyme-linked immunospot (ELISpot) data, the patient has not developed any appreciable anti-AP4M1 response (Extended Data Fig. 2 ).

No serious adverse events were detected through 12 months after dosing. Notable safety-related events are presented in Fig. 2a , with all safety data listed in Extended Data Figs. 3 – 5 . Neutropenia was noted 6 days after dosing, which resolved without intervention within 1 week. At 5 months after dosing, the patient experienced severe abdominal discomfort, which has since resolved and was ultimately attributed to both Clostridioides difficile gastroenteritis and side effects of tacrolimus. We detected no clinical or electrophysiological evidence of dorsal root ganglion (DRG) toxicity; there were no neuropathic pain complaints, and the results of sensory examination and nerve conduction studies were normal (Extended Data Fig. 6 ). Contrast-enhanced brain and spine MRI at 3, 6 and 12 months after dosing showed no inflammatory changes and no progression in brain atrophy.

a , Enumeration of the adverse events reported in the clinical trial over the 1 year after dosing (IP, investigational product). No serious adverse events were observed. The patient experienced transient, asymptomatic neutropenia noted at 6 days after dosing. This resolved without intervention by day 13 after dosing. There was a prolonged episode of abdominal symptoms that included emesis, diarrhea, vomiting and abdominal pain. This episode prompted extensive evaluation, with the ultimate conclusion that the symptoms were due to side effects of tacrolimus plus C. difficile (C-diff) infection. b , Graphical representation of the longitudinal results of the Bayley Scale of Infant and Toddler Development, fourth edition. From 6 months after dosing, there were consistent increases in scores for all domains except expressive communication. This mirrors what was qualitatively observed by both the family and the examination team. c , Presentation of the longitudinal raw data from the Bayley scale (visualized graphically in b ). Of note, the baseline and 3-month studies were complicated by challenges with the patient’s tolerance of the test. d , Scores from the motor skills submodule of the Vineland Adaptive Behavior Scale. Improvements were noted in both fine and gross motor performance.

Progressive limb spasticity is a major SPG50 disease component 11 . We measured spasticity using two scales previously developed for cerebral palsy: the Tardieu 16 and modified Ashworth 17 scales. These were not well tolerated (due to the patient’s discomfort with passive joint manipulation), and data points across several assessments are missing (Extended Data Figs. 7 and 8 ). However, compared to predosing assessments, there was no negative change in successfully scored joints.

Developmental delay is also an important feature of SPG50. We examined this using two exploratory measures: the Bayley Scale of Infant and Toddler Development 18 and the Vineland Adaptive Behavior Scale 19 . Bayley scores increased across multiple domains (Fig. 2b ). Vineland scores were more variable, with a modest decline in adaptive behavior and improvements in motor domains (Fig. 2c and Extended Data Fig. 9 ).

At the time of the last examination, the patient was able to stand with his heels on the ground (Clinical Global Impression (CGI) of Improvement (CGI-I) level 3 = minimally improved; Methods )—something that had not been achieved before dosing—and to subjectively tolerate longer periods of standing in a stander and walking with an assist device. No subjective disease worsening or loss of skills was observed. The parent log data showed that, since receiving the therapy, the patient has not experienced falls or seizures. Before dosing, the patient had infrequent seizures (one seizure in the previous 24 months).

Overall, we describe the full development cycle of a single-patient gene therapy for SPG50. Typically, the implementation of new treatments comes too slowly to help the patient(s) that initially inspired them. This study represents an example of AAV-based gene therapy that was rapidly developed and administered in a timely fashion to benefit the original ‘inspirational’ patient. Therefore, it provides a potential road map for individualized genetic therapy for other ultra-rare disorders.

The primary outcome was safety, and no serious adverse events were identified despite the large dose of AAV administered intrathecally. Our immunosuppression protocol was more extensive than that used in many previous gene therapy trials, reflecting our concern about immune-mediated toxicities and our desire to promote lasting immune tolerance to the gene therapy product. While some observed side effects were attributable to immunosuppression, our patient also did not develop an anti-AP4M1 immune response. Determining whether this represents an optimal immunomodulation strategy for AAV9 gene therapy will require its use in additional patients and gene therapy programs. Of note, our patient experienced transient neutropenia and a T cell reaction to AAV9 (Extended Data Fig. 2 ), suggesting that some AAV9 had entered the systemic circulation.

Regarding efficacy, our assessments indicated possible disease stabilization after AAV9- AP4M1 treatment. Based on existing natural history data, progression is anticipated over a 1-year period 3 . Thus, our data may represent a modification of the expected disease course.

A notable aspect of this study was its rapid development. The time from diagnosis to dosing was <3 years. The speed of development was aided by several factors, including the use of an existing AAV9-based gene therapy ‘template’ and collaboration between multiple researchers. This latter aspect was facilitated by the CureSPG50 Foundation, which nucleated the work and established connections between researchers, clinicians, contract research organizations and industry partners.

There may be opportunities to accelerate future projects further. Preclinical SPG50 models had to be established. For other diseases, these could be developed in advance of therapy conception. Toxicity experiments in nonhuman primates were strongly encouraged by regulatory agencies. As more gene therapy trials are successfully completed, the requirement for such studies may be reduced. None of the preclinically identified adverse findings presented in our patient, including DRG toxicity. This highlights a broader question of the predictiveness of animal studies for safety and toxicity, something that has come to light with other gene therapy programs, in which there has been safety signal discordance between animal toxicology studies and human clinical trials 20 , 21 .

The trial design was innovative although not unique, as other single-patient genetic therapy trials have been completed 22 . We used emerging data on the disease’s natural history combined with the patient’s pretreatment data to monitor and assess efficacy—a strategy potentially applicable to future studies. Spasticity was a challenging outcome to measure, particularly in this young, nonverbal patient who did not tolerate extensive direct examination. Therefore, existing scales may not be suitable for some patients with spastic paraplegia. One future outcome could be timed heel versus toe standing, as this reflects ankle spasticity and range of motion and has functional links with pathologic toe walking.

More generally, for single-patient trials, it is crucial to establish objective and easily measurable outcomes. In individuals with epilepsy or abnormal involuntary movements, quantification of seizures or movements can provide a robust measure of treatment response. Activity-monitoring wearables may also have a role, particularly in ambulant individuals. Early-phase studies can thus serve important value in identifying and testing outcome measures that inform subsequent pivotal trials. In our case, we enumerated a potential challenge with existing spasticity scales and identified a new possible outcome measure (maximally tolerated stand time). Through outcome assessments, small- n trials can additionally provide insights into which disease elements are modifiable, as it is likely that some aspects of a genetic disorder will not be amenable to intervention even when the treatment addresses the root cause of the disease.

It is important to emphasize the limitations of single-patient studies like this one. For instance, safety data from one individual may not generalize to a broader cohort and could potentially either provide false reassurance of safety or, conversely, overestimate the expectation of harm. This could lead in subsequent patients to unanticipated risk or, instead, premature discontinuation of a promising drug program. In terms of treatment effectiveness, in the absence of a pronounced deviation from the pretreatment baseline (such as a nonambulant individual obtaining the ability to walk), single-patient data are challenging to interpret. This is particularly true for a disorder like SPG50, the natural history of which is still being established. Small improvements may be missed or else overstated as treatment associated. Furthermore, in a slowly and variably progressive condition, it may take years in a single patient to understand whether progression has truly been modified.

There were several ethical considerations, particularly as the parent-created foundation provided substantial support to product development 23 , 24 . To evaluate these considerations, we established a special review committee. The committee ( Methods ) reviewed the protocol and study design and provided input on the handling of several topics, including informed consent and mitigation of bias. Subsequent to the trial, and based on the experiences gained during the process, we formalized this committee into our Advanced Therapeutics Review Board at the Hospital for Sick Children (SickKids), which now serves to address the ethical challenges of individualized therapy development for ultra-rare diseases.

A key aspect of this study is cost. The CureSPG50 Foundation estimated that the total cost of the project for preclinical development was Canadian $3,500,000, and the cost of the clinical trial was approximately $250,000, plus expenses related to concomitant medicines (tacrolimus and sirolimus) and in-kind contributions that were difficult to estimate. While our overall workflow provides a road map applicable to other genetic diseases, it is challenging (given the cost) to consider this as a widely iterative strategy for ultra-rare disease gene therapy. Cost-reducing innovations are clearly needed. Manufacturing expenses are extremely high, particularly related to batch production for small patient numbers. A paradigm leap in production is likely required to make gene therapy viable for the largest number of patients. More immediately, consideration of the required investigational new drug-enabling preclinical studies could aid in cost reduction. Large animal studies, in particular, are key drivers of cost and development time that may be unnecessary in settings like this (ultra-rare disease, high unmet need, use of an existing vector backbone).

In conclusion, we present an individualized gene therapy trial and outline a path for future similar studies for ultra-rare diseases. Subsequently, this study has motivated a larger United States-based trial to treat additional patients with SPG50 ( NCT05518188 ).

Regulatory information and trial oversight

Approval to proceed (that is, a no objection letter) was obtained from Health Canada on 30 December 2021. The protocol (version 5) and supporting documentation were submitted to the SickKids Research Ethics Board (REB) on 7 January 2022. REB approval (REB no. 1000079110) was obtained on 15 February 2022. Protocol version 5 established the inclusion/exclusion criteria and prespecified all safety and efficacy outcome measures. Recruitment for the trial was opened at the time of the approval of protocol version 5. Subsequent amendments (versions 5.1 and 6) to this protocol addressed minor changes to the immunosuppression regimen, minor clarifications to the Bayley scale (removal of the Growth Scale Value score) and reporting change for the Vineland scale (switch from examiner to caregiver reporting).

Before submission to Health Canada, a review of the proposed study was completed by an internal ethics committee. This committee included the chair of the REB, an expert bioethicist, in-house legal counsel and members of the hospital executive leadership. The committee discussed the challenges posed by this single-patient study, including issues related to conflicts of interest and informed consent. Study submission proceeded after committee evaluation and incorporation of guidance related to trial elements, including consent and monitoring.

Informed consent was obtained following the standard operating procedure set by SickKids. Capacity assessment of the participant was completed by the study doctor. Appropriately delegated research study team members discussed the informed consent statement with both parents. The study doctor was not present during the signing of the consent form (to avoid undue influence) but was available for discussion and clarification. Ample time was provided for the family to ask questions and consider the trial. Upon discussion, the consent form was signed by the delegated study coordinator and a parent on 11 March 2022. The capacity to consent is assessed by the study doctor on an ongoing basis. If and when applicable, appropriate assent or consent will be obtained from the study participant.

Throughout the study, study conduct and data were monitored by the Clinical Research Quality and Education Board at SickKids.

Per Health Canada specifications, registration of trials in a public database is encouraged. Owing to our uncertainty at the time of obtaining the no objection letter regarding single-patient studies, the study was initially not registered. It was retrospectively registered at ClinicalTrials.gov in October 2023 ( NCT06069687 ).

Vector design, manufacturing and dosing

The design of AAV9- AP4M1 has been described previously 14 . The vector structure and sequence are presented in Extended Data Fig. 10 . The clinical AAV9- AP4M1 vector (MELPIDA) was manufactured by Viralgen in accordance with current Good Manufacturing Practice standards. Briefly, it was manufactured using Viralgen’s proprietary process involving triple-plasmid transfection into suspension HEK293 cells, followed by downstream processing to remove impurities and enrich for genome-containing AAV particles. The final solution of AAV9- AP4M1 was formulated in PBS containing 5% d -sorbitol and 0.001% pluronic F68. The final certificate of analysis is provided as Supplementary Data . A total dose of 1 × 10 15 vg was delivered to the patient over 10 min at a volume of 10 ml by lumbar intrathecal administration with the patient in 15° Trendelenburg positioning (head down). The patient was maintained in the Trendelenburg position for 1 h after infusion. The dose was derived from preclinical studies and extrapolated from calculations of normative CSF volumes.

Study objectives

The primary objective of this study was to evaluate the safety and tolerability of a single dose of AAV-AP4M1 (that is, MELPIDA) administered intrathecally to a single child with SPG50. Safety was evaluated as described below; the evaluation included serum studies related to hematologic, immune and liver function and/or injury, as well as assessment of DRG toxicity by nerve conduction studies. The secondary objective was to assess efficacy, which was determined by examining the patient for stability or improvement in spasticity (as assessed using the modified Ashworth and Tardieu scales).

Exploratory assessments included measurement of AAV9 antibody titers, evaluation of T cell responses to AAV9 and A4PM1 by whole-blood ELISpot assay, evaluations based on rating scales (Vineland Adaptive Behavior Scale (Comprehensive Parent/Caregiver Form), CGI of Overall Change by Physician, Bayley Scale of Infant and Toddler Development (fourth edition)), and use of logbooks to record the number and duration of seizures and falls daily.

The CGI assesses changes from the pretreatment baseline (CGI-I) and the severity of the current illness (CGI-S). CGI-I is a seven-point scale (1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse and 7 = very much worst). CGI-S is also a seven-point scale (1 = normal (shows no signs of illness), 2 = borderline ill, 3 = slightly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill and 7 = among the most extremely ill of patients).

Inclusion and exclusion criteria

Inclusion criteria.

Age <5 years

Confirmed diagnosis of SPG50 disease by

Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or likely pathogenic variants in the AP4M1 gene

Clinical history or physical examination consistent with SPG50

Parent/legal guardian willing to provide written informed consent for their child before study participation

Patient able to comply with all protocol requirements and procedures

Exclusion criteria

Inability of the patient to participate in study procedures, as determined by the site investigator

Presence of a concomitant medical condition that precludes lumbar puncture (LP) or use of anesthetics

History of a bleeding disorder or any other medical condition or circumstance in which LP is contraindicated according to local institutional policy

Inability of the patient to be safely sedated, in the opinion of the clinical anesthesiologist

Active infection at the time of dosing, based on clinical observations

Concomitant illness or requirement for chronic drug treatment that, in the opinion of the principal investigator, creates unnecessary risks for gene transfer

Inability of the patient to undergo MRI according to local institutional policy

Inability of the patient to undergo any other procedure required in this study

Presence of non-SPG50-related CNS impairment or behavioral disturbances that would confound the scientific rigor or the interpretation of the study results

Received an investigational drug within 30 days before screening or plan to receive an investigational drug (other than gene therapy) during the study

Enrollment and participation in another interventional clinical trial

Contraindication to AAV-AP4M1 or any of its ingredients

Contraindication to any of the immunosuppressive medications used in this study

Clinically significant abnormal laboratory values (γ-glutamyl transferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) or total bilirubin more than three times the upper limit of normal, creatinine ≥1.5 mg dl −1 , hemoglobin <6 or >20 g dl −1 , white blood cell count >20,000 per mm 3 ) before therapy

Study procedure

Study initiation. A potential participant was identified. The study team presented the study to the participant’s parents, and forms were given to the family for review. Time was provided for questions and study review. After discussion and consideration, the delegated study coordinator obtained verbal and written informed consent from the participant’s parents on 11 March 2022.

Screening visit. A ‘screening visit’ was conducted. The screening visit (−28 to −8 days before vector infusion) included confirmation of the genetic diagnosis, review of medical history and concomitant medications, a complete physical examination, vital sign assessment, height and weight measurements, 15-lead electrocardiography, liver ultrasonography, blood and urine collections for safety laboratory tests, and spasticity assessments (modified Ashworth and Tardieu scales) performed by a trained examiner.

Safety laboratory tests. These tests included complete blood count with differential, coagulation tests (international normalized ratio, prothrombin time, partial thromboplastin time), erythrocyte sedimentation rate, C-reactive protein, Na, K, Cl, Ca, CO 2 , blood urea nitrogen, creatinine, glucose, ALT, AST, total/direct/indirect bilirubin, alkaline phosphatase, GGT, serum total protein, cardiac safety panel (troponin, pro-B-type natriuretic peptide, creatine kinase isotype MB) and urinalysis (for protein, cells, glucose and bacteria). Laboratory samples were drawn at −28, −7 and −1 days before dosing and 2 days, 7 days, 14 days, 21 days, 28 days, 3 months, 6 months, 9 months and 12 months after dosing.

Dosing. Dosing was accomplished through infusion into the intrathecal space. LP was performed through interventional radiology with an anesthesiologist present to administer sedation before infusion. The participant was placed in the Trendelenburg position (head down). An atraumatic Sprotte needle (Pajunk, item no. 321151-31A) was inserted percutaneously at the lumbar level L4/L5 interspace. Needle placement was confirmed with fluoroscopic intraoperative imaging before and after administration. Before infusion, 10 ml of CSF was withdrawn from the lumbar space. MELPIDA solution was loaded into a 20-ml BD syringe connected to the needle with 60-inch mini-volume intravenous extension tubing and a Braun four-way stopcock. The infusion was administered at a rate of 1 ml min −1 , for a total of 10 ml, using a CareFusion Alaris 8110 syringe pump. Following administration, the participant remained in the Trendelenburg position (head down) for 1 h with turning (left to right, right to left) every 15 min. In addition, vital signs, including heart rate, respiratory rate, blood pressure and pulse oximetry, were monitored continuously for 1 h and then every 15 min until 2 h after infusion, every 30 min for the following 2 h (third and fourth hour following infusion), hourly for an additional 4 h and subsequently every 4 h until discharge. The patient was discharged without complications on the day following MELPIDA administration.

Immunosuppression. Three immunosuppressive agents were used (sirolimus, tacrolimus and prednisone). Sirolimus was initiated 1 week before infusion, with an initial load of 1 mg m −2 every 4 h for three doses, followed by daily enteral dosing at 1 mg m −2 per day divided two times a day. Levels were checked after 5 days of treatment and deemed to be within the acceptable range; thus, the therapy was continued at this dose. Prednisone (1 mg kg −1 per day) and tacrolimus (0.2 mg kg −1 per day divided two times a day) were started 1 day after infusion. The levels of both tacrolimus and sirolimus were monitored monthly. At 3 months, prednisone taper was started, with completion in 4 weeks. At 6 months, tacrolimus taper was initiated, with completion in 4 weeks. Both tapers were initiated after a review of brain MRI and CSF analysis results confirmed no concern for active infection or inflammation. Sirolimus wean is planned to start at 18 months.

Postdosing assessments. At 7, 14, 21 and 28 days after infusion, the participant was brought on-site for a review of vital signs, safety laboratory tests, brief physical examination, collection of viral shedding samples, documentation of concomitant medications and enumeration of any adverse events. On days 7 and 21, exploratory laboratory tests were performed. In addition, on day 21, nerve conduction studies were performed, and on day 28 a comprehensive neurological physical examination was completed. At 3, 6, 9 and 12 months, the participant was assessed for all outcome measures. In addition, as a safety measure to monitor for CNS inflammation or infection, brain and spine MRI (with and without gadolinium) and an LP for CSF analysis were performed at baseline, 3, 6 and 12 months. For all LPs, a 21-gauge standard LP needle was used. EMLA (a eutectic mixture of local anesthetics) was applied for local anesthesia, and then the LP needle was inserted into the intrathecal space between L4/L5. An appropriate quantity of CSF was removed for relevant safety laboratory studies (complete blood cell count with differential, protein, glucose, bacterial culture). Liver ultrasonography was conducted at 6 and 12 months. Nerve conduction studies were performed at 3, 6 and 12 months. Nerve conduction studies and brain MRI are planned at 18 months and 2 years after dosing and then yearly thereafter. An additional LP will be performed at 18 months, before the planned sirolimus wean.

Documentation. Adverse events and concomitant medications were monitored on a continuous basis over the course of enrollment and reviewed at each study visit. Any adverse events were reported and documented in a timely manner and in accordance with the regulatory requirements of SickKids and Health Canada. Data collection began at the time of informed consent signing. Source data included all information, original records of clinical findings, observations and all clinical trial activities, as necessary for the reconstruction and evaluation of the trial. Electronic case report forms were used to collect and store all study data in addition to maintenance of the original source documentation. The electronic data capture platform used was REDCap. Interim analyses were performed at 6 and 12 months after dosing and are planned for yearly thereafter up to 5 years. As presented in section 9.1 of the protocol (‘Database locks’ in Supplementary Information ), interim analyses were prespecified to be performed at periodic intervals per the judgment of the study team (to review ‘key deliverables requiring analysis’).

Sex and gender as biologic variables

Given that this was a single-patient study (one male participant), we are not able to adequately study or make conclusions regarding the potential impact of sex and/or gender on SPG50 and AAV9- AP4M1 gene therapy.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data availability

All data relevant to supporting the findings reported in this study are available within the paper and in the Supplementary Information . Restrictions apply to some information related to the study, which are protected per institutional review board requirements. The sequence and structure of MELPIDA are included as Extended Data Fig. 10 . For all data inquiries, please contact Ana Stosic ([email protected]) and/or James Dowling ([email protected]). Data or material transfer agreements may be required and will be assessed at the time of request (approximate timeline for review = 8 weeks).

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Acknowledgements

We acknowledge the work of the SickKids clinical research unit and supporting clinical services. In particular, thanks go to M. Shroff, S. Miller, H. Gonorazky, F. Paiz and M. Bedford. This study was funded by the sponsor (SickKids) through philanthropic donations to the SickKids Foundation and supported by the Precision Child Health initiative at SickKids. All funds went to support the trial, and the individual authors received no specific funding for this work. We further acknowledge L. Black and D. Balderson for regulatory advice and support, as well as the Columbus Children’s Foundation for its role in providing the Good Manufacturing Practice (GMP) drug product. The GMP/clinical-grade viral vector lot G-Geminis-029 was produced by Viralgen (San Sebastian, Spain). Funding from the CureSPG50 Foundation supported the GMP drug product manufacture and clinical trial application preparation.

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Authors and affiliations.

Precision Child Health, Hospital for Sick Children, Toronto, Ontario, Canada

James J. Dowling, Keshini Devakandan, Ana Stosic, Mia Pidsadny & Ronald Cohn

Division of Neurology and Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada

James J. Dowling, Ana Stosic & Elisa Nigro

Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

James J. Dowling & Ronald Cohn

CureSPG50 Foundation, Toronto, Ontario, Canada

Terry Pirovolakis

Department of Neurology, Boston Children’s Hospital, Boston, MA, USA

Mustafa Sahin & Darius Ebrahimi-Fakhari

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA

Souad Messahel, Ganapathy Varadarajan, Benjamin M. Greenberg, Xin Chen, Berge A. Minassian & Steven J. Gray

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Contributions

T.P., X.C., B.A.M. and S.J.G. conceived and developed the investigational product. M.S. and D.E.-F. defined the natural history of the disease. J.J.D., T.P., D.E.-F., S.M., G.V., B.M.G., B.A.M., R.C., C.B. and S.J.G. conceived the clinical implementation plan, developed the clinical trial protocol and helped generate the regulatory submission for Health Canada. J.J.D., K.D., A.S., M.P. and E.N. executed the clinical trial. J.J.D., K.D., A.S., D.E.-F. and S.J.G. analyzed the clinical data. J.J.D. wrote the initial draft of the manuscript. J.J.D., T.P., K.D., A.S., M.P., E.N., D.E.-F. and S.J.G. provided manuscript edits.

Corresponding author

Correspondence to James J. Dowling .

Ethics declarations

Competing interests.

S.J.G. and X.C. are inventors on a patent application for the AP4M1 vector design. Of note, T.P. is a parent of the study patient. Also, subsequent to the completion of this study, T.P. formed Elpida Therapeutics, and MELPIDA (AAV-AP4M1) represents one of the clinical programs in its developmental pipeline. S.J.G. is a nonpaid member of the Elpida board of directors, and S.M. is head of clinical operations. The other authors declare no competing interests.

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Peer review information.

Nature Medicine thanks Han-Xiang Deng, Jonathan Kimmelman, Olivia Kim McManus and Terence Flotte for their contribution to the peer review of this work. Primary Handling Editor: Anna Maria Ranzoni, in collaboration with the Nature Medicine team.

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Extended data

Extended data fig. 1 schematic of the investigational product..

Human, codon optimized AP4M1 (hAP4M1opt) with a bGH poly A tail was encapsulated into self-complementary (sc) AAV9. AP4M1 expression was governed by a ubiquitous promoter (UsP = JeT promoter with intron). See Chen et al., 2023, Journal of Clinical Investigation.

Extended Data Fig. 2 ELISpot assay reveals lack of immune response to AP4M1.

( a ) ELISpot to show IFN-y T-cell Responses toward AAV9. As expected, there is clear evidence of an immune response against AAV9. ( b ) ELISpot to show IFN-y T-cell Responses toward AP4M1. No significant response against AP4M1 was identified. ( c ) Positive control ELISpot used to confirm that the success of the assay. Multiple two-tailed t-tests were conducted to assess for significant differences between treatment responses and negative controls. *P-values were adjusted for multiple comparisons using the two-stage linear step-up method of Benjamini, Krieger, and Yekutieli (FDR = 5%).

Extended Data Fig. 3 Safety lab trends during the 12 months post dosing.

( a - d ) Presented are the main safety laboratory studies, AST ( a ), ALT ( b ), GGT ( c ), and neutrophils ( d ), from baseline to 12 months post- dosing. Normative values for age are highlighted in gray. There was a single instance of neutropenia at day 7 post- dosing (0.8×109/L). ALT and GGT values were consistently outside of the normal range, but never reached a clinically meaningful increased level, and remained < 2-fold above normal limits.

Extended Data Fig. 4 Listing of laboratory studies performed during the study.

Laboratory values obtained are listed from baseline through the first 12 months of the study. Abnormal values (i.e. values outside the normal range) are highlighted in bold. Normative values, when available, are listed in the left most column.

Extended Data Fig. 5 Listing of laboratory studies performed during the study (continued).

Extended data fig. 6 sensory nerve analyses performed during the study..

Standard nerve conduction studies were performed at baseline and then at 3 weeks, 3 months, 6 months, and 12 months. Presented are the data for the 5 sensory nerves that were studied. Values were within the normal range at all time points. Intriguingly, amplitudes increased post-dosing, suggesting, if anything, improvements in sensory nerve function. Of note, NCS was also performed on the Tibial motor nerve, and all values were within normal limits (data not shown).

Extended Data Fig. 7 Scores of the Tardieu and modified Ashworth scales for the upper limbs.

Scores from two measures of joint spasticity, the Tardieu and modified Ashworth scales. Existing natural history suggests worsening of spasticity in SPG50 over a 12-month period. We observed stabilization of scores on both scales, with no clear worsening. However, the patient poorly tolerated both outcome measures, resulting in missing data points at essentially all time points. Tardieu scale values are 0 = no resistance to passive movement, 1 = slight resistance, 2 = clear ‘catch’, interrupting passive movement, 3 = clonus ( < 10 seconds), 4 = sustained clonus. Ashworth scale values are 0 = no increase in tone, 1 = slight increase in tone, 1 + = slight increase in tone, catch/release through range of motion, 2 = marked increase in tone, 3 = marked increase in tone AND passive movement difficult, 4 = fixed contracture.

Extended Data Fig. 8 Scores of the Tardieu and modified Ashworth scales for the lower limbs.

Scores for the lower limbs for the Tardieu and Ashworth scales. Score values are presented in Extended Data Figure 7 .

Extended Data Fig. 9 Vineland Adaptive Behavior Scale (version 2).

Results from the Vineland adaptive behavior scale, parent reported. Substantial gains were noted in both gross and fine motor skills (from baseline of 48 composite to 57 at 12 months post dosing). Small declines in scores were noted in adaptive behavior. This may be related in part to non-Melpida related side effects, including prolonged gastroenteritis and abdominal pain secondary to tacrolimus, as well as social impacts of immune suppression (such as prolonged absence from school).

Extended Data Fig. 10 AP4M1 vector structure and sequence.

Melpida consists of a vector containing codon optimized AP4M1 and surrounding sequences (UsP promoter and bGH polyA tail) inserted between truncated AAV2 ITR sequences and encapsulated in AAV9. ( a ) Schematic of the vector structure. ( b ) Sequence of the vector.

Supplementary information

Supplementary information.

Clinical trial protocol v.5.0 and v.6.0.

Reporting Summary

Supplementary data.

MELPIDA certificate of analysis.

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Dowling, J.J., Pirovolakis, T., Devakandan, K. et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med (2024). https://doi.org/10.1038/s41591-024-03078-4

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Received : 02 August 2023

Accepted : 20 May 2024

Published : 28 June 2024

DOI : https://doi.org/10.1038/s41591-024-03078-4

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Prednisolone for COPD exacerbations: time for a rethink

Sanjay ramakrishnan.

1 Oxford NIHR Biomedical Research Centre and Nuffield Department of Medicine, University of Oxford, Oxford, UK

2 School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia

Treatments for COPD exacerbations have not changed in the last 30 years. Despite fewer than 800 patients ever having been enrolled in placebo-controlled trials [1], systemic corticosteroids have become the main treatment of COPD exacerbations. Most of the trials were performed prior to the widespread use of inhaled corticosteroids. We know our treatment is ineffective. 28% of patients who are treated for a COPD exacerbation require re-treatment within a month [1]. We also accept a lot of harm for this marginal benefit. A meta-analysis of placebo-controlled trials concluded that prescribing prednisolone for COPD exacerbations caused more harm than benefit [1].

Tweetable abstract

Prednisolone given universally for COPD exacerbations causes harm without any benefit. Patients deserve blood eosinophil-guided prednisolone treatment for COPD exacerbations. https://bit.ly/3pR2BSY

Treatments for COPD exacerbations have not changed in the last 30 years. Despite fewer than 800 patients ever having been enrolled in placebo-controlled trials [ 1 ], systemic corticosteroids have become the main treatment of COPD exacerbations. Most of the trials were performed prior to the widespread use of inhaled corticosteroids. We know our treatment is ineffective. 28% of patients who are treated for a COPD exacerbation require re-treatment within a month [ 1 ]. We also accept a lot of harm for this marginal benefit. A meta-analysis of placebo-controlled trials concluded that prescribing prednisolone for COPD exacerbations caused more harm than benefit [ 1 ]. For systemic corticosteroids to prevent one treatment failure, 10 patients had to be treated. Meanwhile, only five patients needed to be treated to cause harm. Disappointingly, pulmonary-indicated prescriptions of prednisolone now account for most of the prescriptions of prednisolone [ 2 ]. Unlike our colleagues in gastroenterology and rheumatology, we have not managed any meaningful reductions in prednisolone prescriptions in the last decade. The big question remains: how effective are systemic corticosteroids in the treatment of COPD exacerbations, particularly in primary care?

The BECOMEG study, now published in ERJ Open Research , tried to answer this important question. T hebault et al. [ 3 ] set out to recruit patients presenting to general practitioners in France with symptoms consistent with a COPD exacerbation. The authors had an ambitious target to randomise 1014 participants when the study commenced. They later revised the target down to 404 patients. Unfortunately, only 175 patients were randomised between February 2015 and May 2017. Remarkably, this is still the second largest placebo-controlled trial of prednisolone ever conducted in primary care. The difficulty the authors had recruiting participants, despite the frequency of primary care-treated COPD exacerbations, underlies the difficulty of re-evaluating entrenched interventions. Recent trials have used repeat randomisations of recruited participants to improve recruitment rates [ 4 , 5 ].

Despite not reaching the prespecified sample size, the findings from the BECOMEG trial are stark. At best, prednisolone treatment failed in 42% of patients within 8 weeks after a course of treatment. Most disappointingly, placebo treatment was just as good as prednisolone therapy. Importantly, these treatment failures are not benign. A third of patients treated for a COPD exacerbation needed unplanned urgent assessment in primary care or at an emergency department. Our best treatment, prednisolone, is unhelpful and does not reduce expensive healthcare utilisation.

To make matters worse, systemic corticosteroids are one of the most harmful treatments physicians prescribe [ 6 ]. The BECOMEG investigators use an innovative analysis, Quality-Adjusted Time Without Symptoms and Toxicity (Q-TWIST), to quantify the significant harms we cause our patients by prescribing prednisolone for COPD exacerbations. This analysis is often used in oncology to assess the value of chemotherapy despite the side-effects [ 7 ]. This is exactly how we should think about prednisolone in COPD exacerbations. To do this, the authors assumed that an exacerbation lasts 8 days and weighted different adverse events that occurred in the study. This is an arbitrary simplification, not in keeping with expert consensus [ 8 ], but an important first step. The Q-TWIST analysis showed that patients treated with placebo had more exacerbation-free days than patients treated with prednisolone. There was, however, no difference in days spent with toxicity, or in time without symptoms or toxicity. Thus, unselected prednisolone for all COPD exacerbations causes the same amount of harm as placebo and fewer days without symptoms.

Where next? Three separate randomised trials [ 4 , 5 , 9 ] have now shown that there is a clear biomarker, the blood eosinophil count, to predict the patients who need to be treated with prednisolone. A point-of-care blood eosinophil count-guided model has been shown to be feasible and safe in primary care, while reducing prednisolone prescriptions by 30%. Prednisolone does have a role in COPD exacerbations, but only in eosinophil-high exacerbations. Placebo was better than prednisolone when treating patients with low blood eosinophils at the time of COPD exacerbation [ 4 , 5 ]. Eosinophil count-guided prednisolone therapy is being tested again in a large hospital-based placebo-controlled trial in France (eo-Drive study, www.clinicaltrials.gov identifier number {"type":"clinical-trial","attrs":{"text":"NCT04234360","term_id":"NCT04234360"}} NCT04234360 ), which will hopefully put this question beyond doubt.

Patients with COPD want and deserve detailed assessment of their biology at the time of exacerbation to guide therapy. In a large multinational survey, patients with COPD insisted that they are willing to undergo detailed standardised physiological, imaging and biochemical testing at exacerbation and at follow-up [ 10 ]. Instead of assuming that less is more in COPD exacerbations, respiratory and family physicians need to lean into the challenge. International guidelines should be guided by these latest randomised controlled trial data [ 3 – 5 , 9 ] and our patients' views [ 10 ], and argue for more intensive assessment and care for this morbid and deadly condition.

Provenance: Commissioned article, peer reviewed.

Conflict of interest: S. Ramakrishnan reports a research grant to his institution from AstraZeneca, speaker fees from AstraZeneca and conference travel support from AstraZeneca, all outside the submitted work.