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Extended report
Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis
  1. Rohit Aggarwal1,
  2. Galina Marder2,
  3. Diane Carol Koontz1,
  4. Preeya Nandkumar2,
  5. Zengbiao Qi1,
  6. Chester V Oddis1
  1. 1 Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  2. 2 Northwell Health, Formerly North Shore–Long Island Jewish Medical Center, Great Neck, New York, USA
  1. Correspondence to Dr Rohit Aggarwal, Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15217, USA; aggarwalr{at}upmc.edu

Abstract

Aim To evaluate the efficacy, safety, tolerability and steroid-sparing effect of repository corticotropin injection (RCI), in an open-label clinical trial, in refractory adult polymyositis (PM) and dermatomyositis (DM).

Methods Adults with refractory PM and DM were enrolled by two centres. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or ≥1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and >2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm Visual Analogue Scale score of ≥3 cm and at least three other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice weekly for 24 weeks. The primary end point for the trial was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR)

Results Ten of the 11 enrolled subjects (6 DM, 4 PM) completed the study. Seven of 10 met the primary end point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) vs 2.3 (3.2); P<0.01). Most individual CSMs improved at week 24 compared with the baseline, with the muscle strength improving by >10% and the physician global by >40%. RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of haemoglobin A1c or cushingoid features.

Conclusion Treatment with RCI was effective in 70% of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs.

Trial registration number NCT01906372; Results.

  • dermatomyositis
  • polymyositis
  • autoimmune diseases
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Introduction

Idiopathic inflammatory myopathies (commonly referred to as myositis) are a group of systemic autoimmune muscle diseases characterised by inflammation of skeletal muscle, the most common of which include dermatomyositis (DM) and polymyositis (PM). The treatment of PM and DM is unsatisfactory as many patients either require high doses of glucocorticoids with significant side effects or are refractory to conventional immunosuppressive drugs.1 2 Neither glucocorticoids or immunosuppressive agents are Food and Drug Administration (FDA)-approved for myositis, but H.P. Acthar Gel (repository corticotropin injection (RCI)) has been an FDA-approved treatment for myositis since 1952, and in 2010 the FDA retained this indication. RCI is a long-acting full-sequence adrenocorticotropic hormone (ACTH1–39) and includes other pro-opiomelanocortin peptides thought to have anti-inflammatory and immunomodulatory effects mediated through melanocortin (MC) receptors. It is indicated for other immune-mediated disorders including multiple sclerosis, nephrotic syndrome and infantile spasm syndromes. Despite its FDA approval for PM and DM, as well as possible glucocorticoid-independent immune-mediated effects, there are limited data on its clinical utility in myositis. A recent retrospective review of five patients with refractory myositis demonstrated improved muscle strength after RCI,3 but was limited due to its retrospective design, lack of long-term follow-up and evaluation of validated outcome measures. These reports led to a prospective pilot clinical trial of RCI in patients with refractory myositis using the six validated core set measures (CSMs) and outcome measures proposed by the International Myositis Assessment and Clinical Studies (IMACS) group. Herein we assess the efficacy, safety, tolerability and steroid-sparing effect of RCI in adult patients with refractory PM and DM.

Patients and methods

Study population

This study was conducted at two sites (University of Pittsburgh Medical Center and Northwell Health, formerly North Shore Long Island Jewish Medical Center) with an expected enrolment of 10 patients with PM/DM. Written informed consent was obtained from each study subject.

Eligible patients included adults at least 18 years of age or older with a diagnosis of definite or probable DM or PM according to the criteria of Bohan et al.4 Patients with PM either possessed a myositis-associated autoantibody or underwent adjudication for confirmation of the PM diagnosis by another myositis expert (RA or CVO) to eliminate the enrolment of mimics of PM.5 Patients had refractory and active disease defined as failing an adequate glucocorticoid trial (≥2 months of high doses (0.75–1 mg/kg) or intolerance to such therapy) and/or ≥1 conventional immunosuppressive agent (eg, methotrexate (MTX), azathioprine (AZA), tacrolimus (TAC), ciclosporin, mycophenolate mofetil (MMF), intravenous immunoglobulin (IVIG), antitumour necrosis factor agent or rituximab) at near maximal doses for ≥3 months. It was recommended to enrol refractory patients failing (or intolerant to) both glucocorticoids and at least one conventional immunosuppressive agent. Concomitant immunosuppressive agents or glucocorticoids were allowed, but subjects should have been on these therapies at least 8 weeks (and at least 4 weeks for glucocorticoids) and on a stable dose for ≥4 weeks and ≥2 weeks, respectively, prior to the start of the trial. No dose changes other than glucocorticoid tapering were permitted during the trial except for rescue medication or changes related to patient safety or adverse events. IVIG or biological agents were not allowed during the course of the trial.

Active myositis was defined by baseline Manual Muscle Testing (MMT-8) no greater than 125/150 and at least two additional abnormal CSMs (ie, ≥2 cm on 10 cm Visual Analogue Scale (VAS) of patient global,6 physician global and extramuscular disease activity, Health Assessment Questionnaire Disability Index, minimum score of 0.25, and elevated muscle enzymes >1.3 × the upper limit of normal). To allow the enrolment of patients with active DM with a moderate to severe rash who may not meet the MMT-8 criterion noted above, patients with DM could be enrolled if their cutaneous VAS score on the Myositis Disease Activity Assessment Tool (MDAAT) was ≥3 cm on the 10 cm VAS scale and at least three of the above five CSMs were abnormal (excluding the MMT-8).

If patients discontinued immunosuppressive therapy before enrolment, a 4-week washout was required for MTX, AZA, TAC, MMF, ciclosporin and leflunomide, and an 8-week washout for infliximab or adalimumab, 2 weeks for etanercept, 6 months for rituximab, and 2 months for IVIG and cyclophosphamide. To minimise confounding, patients with the following conditions were excluded: juvenile DM or PM, myositis in overlap with another systemic autoimmune rheumatic disorder, cancer-associated myositis, inclusion body myositis or any other non-immune-mediated myopathy. Also patients with hypersensitivity to study drug, pregnant or lactating women, and any concomitant illness including severe cardiac, pulmonary disease and active infections that precluded an accurate treatment response during the trial or posed an added risk for participants were excluded. Patients with malignancy within 3 years of screening (except basal cell cancer or squamous cell cancer of skin) were excluded. We excluded patients with severe muscle damage defined as a baseline global muscle damage score on the Myositis Damage Index of ≥5 cm on a 10 cm VAS. Patients were allowed to continue an exercise programme that had been initiated before the 4-week screening period. However, no new exercise programme for muscle strengthening during the trial was permitted. The definition of worsening was the same employed in previous myositis trials.7

Methods

RCI is a highly purified sterile preparation of full-length ACTH (39 amino acid peptide) and other pro-opiomelanocortin peptides in 16% gelatin to provide a prolonged release after intramuscular or subcutaneous injection. RCI was supplied as a 5 mL multidose phial containing 80 units/mL.

Study design

This was a proof-of-concept study to evaluate efficacy, safety, tolerability and the steroid-sparing effect of RCI in patients with refractory PM and DM using a prospective, open-label design for 24 weeks. We enrolled 10 patients with active and refractory PM/DM with evaluations every 4 weeks for 24 weeks (seven total visits including baseline). Study subjects subcutaneously self-administered RCI 80 units (1 mL) twice weekly for 24 weeks. The glucocorticoid dose could be increased ≤10 mg (prednisone equivalent) daily as a rescue medication without constituting the subject as a treatment failure. However, any subject requiring rescue medication exceeding 10 mg equivalent of prednisone or an immunosuppressive agent above their baseline dose or the addition of any new immunosuppressive drug or new glucocorticoid after the 8-week time point was considered a treatment failure even though they remained in the trial to receive study drug and scheduled assessments.

Adverse events

Adverse events (AEs) and serious adverse events (SAEs) along with infusion reactions were monitored and reported in a standardised manner using the Common Terminology Criteria of the National Cancer Institute V.4.03, with clinical site investigators determining their relatedness to the study drug. An AE or SAE was regarded as possibly related to the study drug if the investigator believed (1) there was a clinically plausible time sequence between onset of the AE and the administration of RCI, and/or (2) there was a biologically plausible mechanism by which RCI could cause or contribute to the AE, and (3) the AE could not be attributed solely to the concurrent/underlying illness, other drugs or procedures. Study investigators reported each AE and SAE as one of the following: definitely related, probably related, possibly related, unlikely to be related or unrelated. For purposes of analysis, only AEs and SAEs deemed to have a definite, probable or possible relationship to the study drug were considered to be related.

Primary and secondary end points

The primary end point for the trial was the IMACS definition of improvement (DOI): three of any of the six CSMs improved by ≥20%, with no more than 2 CSMs worsening by ≥25% (worsening measure cannot include the MMT). Patients meeting DOI at any visit should continue to meet DOI on subsequent visits until study completion. Primary end points were also separately evaluated on a subset of patients with severe muscle weakness (≤125/150 of MMT at baseline) as well as moderate to severe cutaneous DM rashes (≥2.5/10 of cutaneous VAS score at baseline). Secondary safety and tolerability end points were measured by frequency and type of AEs and SAEs. AEs and SAEs were measured by detailed questionnaires, patient report and study withdrawal due to study drug side effects or tolerability problems. Additional secondary end points included (1) median change in individual CSM from baseline to end of study, (2) median time to DOI from baseline, (3) 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) myositis response criteria and (d) mean change in glucocorticoid dose (equivalent prednisone dose) at 24 weeks compared with baseline.8–11

Statistical analysis

Descriptive statistics were evaluated for baseline demographic, clinical and laboratory variables. The frequency of patients meeting primary and secondary outcome criteria at 24 weeks was evaluated based on a modified intention-to-treat analysis if the subject received at least 8 weeks of study drug. The median score of each CSM at last study visit was compared with baseline values using the Wilcoxon rank-sum test. The median time to DOI was determined by Wilcoxon rank-sum test. The frequency and severity of AEs and SAEs related/unrelated to study drug were reported. The mean change in the glucocorticoid dose (prednisone equivalent) and changes in safety labs (HbA1C, weight, hemoglobin, etc) from baseline to final evaluation was compared using paired t-test.

Results

Ten patients completed the study, each receiving RCI 80 units (1 mL) twice weekly for 24 weeks without dose modification. One patient dropped out due to heart block unrelated to the study drug and was not included in the analysis as he did not complete the minimum 8 weeks of study drug required for outcome assessment as per study protocol (patient 11 in table 1). Table 1 summarises the baseline clinical features of all 11 enrolled patients. Briefly, there were five patients with PM and six patients with DM with a mean (SD) age of 49.2 (14.6); 91% were female and 46% Caucasian, with a mean (SD) disease duration of 1.8 (1.9) years. Seven of the 10 subjects had significant muscle weakness (MMT ≤125/150), and 5 of the 10 had active and moderate to severe DM rashes (≥2.5/10 cutaneous VAS score). Overall, disease was considered active in all patients, as evidenced by the mean (SD) physician global assessment of disease activity VAS of 5.17 cm (2.1) at the study entry. All patients were refractory having failed glucocorticoids and a mean of 2.6 additional immunosuppressive agents before trial entry. Concomitant therapy remained stable from the 8-week pretrial period throughout the 24-week trial period except for decreases in prednisone dosing and the discontinuation of MMF in one patient due to safety concerns (herpes zoster). Concomitant therapy included all subjects on prednisone (19.5 (15.3) mg), as well as MTX (46%), AZA (27%), MMF (46%), TAC (9%) and hydroxychloroquine (18%). No patient received IVIG or rituximab or any other biological agent during the study, but patients 3 and 1 had failed IVIG and rituximab before the clinical trial, respectively. Autoantibody subsets were well represented, with 82% of the cohort possessing at least one myositis-associated autoantibody as determined by immunoprecipitation. This included anti-Mi-2 (n=4), anti-SRP (n=2), anti-Jo-1 (n=1), anti-EJ (n=1) and anti-SSA (n=1). Other than muscle weakness and rash, additional clinical features included four patients with dysphagia, two with arthralgia, one with calcinosis, six with myalgias, and none with ILD, Raynaud phenomenon or fever.

Table 1

Baseline characteristics of study cohort

Primary and secondary outcomes

Seven of the 10 patients completing the study met the DOI by a median (IQR) of 8 (4–20) weeks (figure 1A). Two additional subjects met the DOI initially, but their improvement was not sustained through the end of the trial; therefore, a total of three patients (table 1, patients 2, 9 and 10) did not meet the primary end point. Ninety per cent of subjects met the secondary outcome measure of minimal improvement using the new 2016 ACR-EULAR myositis response criteria, but similar to the primary outcome two patients had significant worsening before the 24-week period (figure 1B). The median (IQR) total improvement score (a metric derived from the 2016 ACR-EULAR myositis response criteria which corresponds to magnitude of improvement) was 52.5 (30–65) at 24 weeks,8 with 40%, 30% and 20% of patients achieving minimal, moderate and major improvement, respectively (figure 1B). PM and DM subjects did not differ in their response to study drug. Among the seven patients with significant muscle disease, five (71%) met primary outcome and showed a median (IQR) MMT improvement of 19.3% (11.5%–25.4%), with a 12% (−19% to 76%) improvement in the serum muscle enzyme. Similarly, among the five patients with significant DM-related cutaneous disease, four (80%) met the primary outcome and showed an 88% (83.3%–100%) improvement in the cutaneous VAS score on the MDAAT. Figure 2 depicts the improvement in rash observed in patient 6, a subject who had failed TAC, MMF, MTX and AZA before initiation of RCI. No subjects met the criteria of worsening or required glucocorticoid rescue therapy during the trial.

Figure 1

Primary outcome criteria as DOI (A) and secondary outcome criteria as 2016 American College of Rheumatology-European League Against Rheumatism myositis response criteria (B). DOI, definition of improvement.

Figure 2

Cutaneous rash improvement in a patient with dermatomyositis before and after repository corticotropin injection (RCI).

Changes in six CSMs and steroid dose reduction

Details of changes in all CSMs are summarised in online supplementary tables 1 and 2. In addition, trends of changes in the MMT and extramuscular global score in each patient are shown in figure 3. Note that the changes in extramuscular global score are predominantly due to changes in cutaneous disease activity. Overall, there were significant reductions in physician global, patient global and extramuscular global, and a significant increase in MMT scores. The key CSM of MMT improved by a median of >10% in all patients and >15% in patients (n=7) with baseline severe muscle weakness. The physician global improved by a median of >40% in all patients. The extramuscular global, primarily driven by skin rash in our study, showed a median of 10% improvement in all patients and 20% in patients with baseline moderate to severe rash. There was a significant reduction in mean (SD) prednisone dose from baseline (18.5 (15.7)) to last follow-up (2.3 (3.2), P<0.01) (figure 4), with 50% off prednisone.

Supplementary file 1

Figure 3

Longitudinal changes in Manual Muscle Testing and extramuscular disease activity in all patients over 24 weeks. VAS, Visual Analogue Scale.

Figure 4

Changes in prednisone dose at baseline and 6 months last follow-up.

Safety and tolerability

RCI at 80 units twice weekly was generally safe and well-tolerated over the 24-week study period. There were a total of 5 SAEs in three patients and 22 AEs in eight patients during the study period, of which 3 SAEs and 22 AEs were related to study drug. Among five SAEs, two were herpes zoster infections, which were considered related to the study drug and required hospitalisation, including one with disseminated herpes zoster causing herpes pneumonitis. Both patients were treated with antiviral medications and were continued on the study drug after temporary discontinuation for antiviral treatment. The subject with disseminated zoster was admitted to hospital with chest pain, which was felt to be related to herpes pneumonitis. Both patients were on MMF, glucocorticoid as well as another immunosuppressive agent (AZA or MTX) at the time of zoster infection. One patient developed avascular necrosis (AVN) leading to total hip arthroplasty (post study) and was continued on study drug without discontinuation for AVN. This patient was being tapered down from high-dose glucocorticoid therapy (50 mg at baseline). Another subject developed third-degree atrio-ventricular (AV) heart block 6 weeks after initiating study drug and received a transvenous pacemaker and withdrew from the study. The investigator reported this event as not related to study drug, but possibly related to pre-existing history of similar conduction abnormalities. Among non-serious AEs, the most notable were worsening calcinosis, transient hyperglycaemia, transient hypertension, anxiety, insomnia and injection site bruising (table 2). However, none of the AEs required long-term dose interruption or dose reduction and were generally considered mild. There was no significant increase in mean (SD) weight from baseline (66.0 (8.7) kg) to 24 weeks (68.6 (9.7) kg; P=0.53). Only three patients gained over 5 kg (<10 kg) and all were on a high prednisone dose at baseline (42.5, 50, 15 mg, respectively). Also, the mean (SD) glycosylated haemoglobin A1c (HbA1c) did not change over 24 weeks (5.8 (0.27) to 5.6 (0.17); P=0.2), and no patient developed microalbuminuria or cushingoid features. One patient on metformin due to steroid-induced diabetes prior to enrolment was able to discontinue it due to improvement in diabetes during the trial. Further, there were no significant changes in white blood cell count, haemoglobin, platelet count, sedimentation rates, serum creatinine or blood glucose over the 24-week trial period (online supplementary table 3).

Table 2

Summary of adverse events

Discussion

This prospective, open-label clinical trial with validated end points demonstrated a clinically significant response to RCI in 70% of patients with refractory myositis. RCI was generally well-tolerated with a reasonable safety profile. This is the first clinical trial of RCI in adult DM and PM using rigorous methodology, where all six validated myositis CSMs were prospectively measured and predetermined validated outcome measures were used to determine efficacy and safety. Responders met both the IMACS DOI as well as the new ACR/EULAR myositis response criteria, which supports a more robust response. Enrolled subjects represented a generally refractory cohort who had failed glucocorticoids and, on average, 2.6 additional immunosuppressive agents. The addition of RCI led to a reduction in prednisone dose from an average of 18.5 mg at baseline to 2.3 mg at 24 weeks, with half of the patients discontinuing prednisone completely. This suggests that RCI may provide novel anti-inflammatory or immunomodulatory effects distinct from glucocorticoids that include non-steroid-dependent immune mechanisms.12 Given that all enrolled subjects had failed high doses of glucocorticoids, it is likely that a non-steroid-dependent mechanism contributed to clinical improvement in some patients. Although many of the observed AEs in this trial were similar to those seen with glucocorticoids, we did not observe significant weight gain, diabetes or cushingoid features, which are typically associated with high steroid doses given for an extended period.

There were no differences noted in PM versus DM or muscle weakness versus skin rash response rates, but the numbers studied were too small to make meaningful conclusions. Both muscle and skin disease seemed to respond to RCI as noted by the 70% and 80% response rates among patients with severe muscle disease and skin disease, respectively. Two of three patients with refractory cutaneous disease but minimal muscle involvement also improved. The median time to response was 2 months, suggesting a rather rapid onset of action, and two subjects were wheelchair users at study entry, and both were ambulating independently without assistive devices by the end of the trial.

Although RCI has an FDA-approved designation for PM and DM, there were no prospective studies demonstrating its efficacy and/or safety profile. A previous retrospective case series using the same dosing regimen employed in our trial noted similar response rates, and a follow-up retrospective study of 24 patients with myositis treated with RCI at different clinical centres showed 58.3% response rates.3 13 Another small retrospective case series demonstrated a steroid dose reduction and similar efficacy in three of four adult patients with refractory DM/PM including one patient with the anti-SRP autoantibody who failed IVIG and rituximab.14 Again no differences were noted in the response rates of DM versus PM or rates of response to muscle weakness versus cutaneous rashes in previous retrospective studies.

RCI is an injectable formulation containing porcine ACTH purified from pituitary extracts. The full-sequence ACTH1-39 hormone is one of a number of peptides produced from pro-opiomelanocortin, a family of peptides that bind to  MC receptors found in a wide variety of cells.15 Despite FDA approval for various rheumatic diseases, it was primarily being used for the treatment of infantile spasm, nephrotic syndrome and acute exacerbations of multiple sclerosis.16 17 FDA first approved ACTH for human use in 1952 after it was tested in rheumatoid arthritis (RA) in 1949.18 In the 1950s it was used for several rheumatic conditions, including RA, gout, lupus, rheumatic fever, psoriasis and others, as well as non-rheumatic autoimmune conditions such as ulcerative colitis and multiple sclerosis.17 19 20 However, after the discovery that cortisone suppressed inflammation, ACTH use became negligible. Half a century after the discovery and approval of ACTH, it again emerged with the seminal observation that the anti-inflammatory actions of ACTH were retained in an adrenalectomised mouse model of gout.21

ACTH and α-melanocyte-stimulating hormones (MSH), β-MSH and γ-MSH are the four endogenous MC peptides derived from the precursor pro-opiomelanocortin protein. MCs are produced during inflammation acting to mitigate the inflammatory process by engagement of the MC receptors (MC1–MC5). MC2 is only found in the adrenal cortex, while the remaining four MC receptors (MC1, MC3, MC4 and MC5) are expressed on a variety of immune cells.12 Thus, ACTH exerts its anti-inflammatory action via two independent mechanisms: a steroid-dependent effect and a broader, steroid-independent, anti-inflammatory effect.22 The former effect is through activation of MC2 receptor on adrenal glands leading to cortisol synthesis—this accounts for both the known anti-inflammatory effects as well as the adverse sequelae similar to steroids. The novel, steroid-independent effects of ACTH mediated through activation of MC receptors 1, 3, 4 and 5 induce a broad range of immunomodulatory effects,22–25 likely responsible for the unique effects of RCI not explained by cortisol synthesis,15 for example its efficacy in steroid-refractory infantile spasms, nephrotic syndrome and acute exacerbations of multiple sclerosis. It is the latter proposed mechanism that has led to renewed interest in ACTH and other MC for treating various diseases.26–30 The use of RCI is currently being explored in various other rheumatic diseases including sarcoidosis, lupus, RA and gout.31–36 A recent study of 181 patients with gout reported a 78% response rates within 1 day of ACTH injection with similar efficacy in pseudogout.37 38 It is not surprising that specific MC peptides are being developed for various indications to target the MC system through non-steroidogenic mechanisms.39

The MC receptors are expressed on immune cells including macrophages, mast cells, neutrophils and lymphocytes, as well as osteoclasts, osteoblasts, chondrocytes and fibroblasts.40–44 Activation of the MC receptors results in the inhibition of proinflammatory transcription factors at the molecular level, ultimately decreasing the production of cytokines, chemokines, growth factors and adhesion molecules.12 22 45 Interestingly, MC can be locally synthesised by immune cells at sites of inflammation (eg, RA synovium),46 47 suggesting a ‘local’ anti-inflammatory circuit independent of the hypothalamic–pituitary–adrenal axis. α-MSH may also play a role in energy homeostasis in skeletal muscle through the MC5 receptor, as suggested by its increased expression in regenerating and dystrophic skeletal muscle.48 49 More specifically, ACTH has a known trophic effect on skeletal muscle development in mouse model.6 50–52

In our trial, RCI was well-tolerated, with no patient requiring prolonged discontinuation from RCI adverse effects. Injection site reactions were very mild. Infections should be considered as a potential risk of RCI similar to glucocorticoids. Calcinosis occurred in one responder without previous clinically known calcinosis and worsened in one non-responder. AVN was seen in one patient also taking concomitant glucocorticoids, perhaps implicating the known steroidogenesis effect discussed above. In contrast ACTH through its steroid independent effect is thought to have protective actions on bone and joints due to a reduction in osteoclastogenesis and metalloproteases produced by chondrocytes.53 54 Although two patients had hypertension and three had hyperglycaemia during the trial, these were transient and resolved spontaneously. Contrary to common side effects seen with high doses of glucocorticoids, no patient developed significant weight gain (≥10 kg), cushingoid features, diabetes, persistent hypertension or hyperglycaemia, or an increase of HbA1c (≥1). This is plausible given that many of the metabolic side effects of glucocorticoids are mediated through transcription of glucocorticoid responsive elements which is coupled to the anti-inflammatory effects primarily through nuclear factor kappa B (NF-kB)mediated transcription.30 In contrast, α-MSH directly inhibits NF-kB activation, perhaps leading to the beneficial anti-inflammatory effect of RCI without a similar degree of metabolic side effects associated with glucocorticoids.45 We did not measure bone density before and after administration of study drug. The safety and tolerability results seen in this trial are similar to what has been observed in myositis and non-myositis studies.3 14

Despite reasonable biological plausibility, the lack of a control group and randomisation in this trial does dampen the enthusiasm regarding efficacy of RCI for PM and DM. Also, the dose and interval of administration of RCI therapy in myositis are unclear and also were not addressed in this pilot trial. However, we employed the standard dosing regimen used in previously reported retrospective studies. It may be possible to use RCI at higher doses to induce disease remission of disease with subsequent tapering similar to the clinical strategy currently used for glucocorticoids. Given the small sample size, it is difficult to evaluate clinical predictors of response to Acthar in PM and DM. Moreover, long-term outcome studies of efficacy and safety with comparison to high doses of glucocorticoids are required to better delineate the role of RCI in myositis beyond its use in refractory cases.

To summarise, the results from this prospective, open-label pilot trial are encouraging and, perhaps, support the concept of RCI as a novel immunomodulatory therapy for myositis beyond the steroidogenesis effect.22 Treatment with RCI may provide an alternative to glucocorticoids and other immunosuppressive agents, especially in patients who are refractory or intolerant to conventional agents.1 2 However, given the cost of RCI, it is unlikely to be used as first-line therapy in myositis. Perhaps, a future cost benefit analysis will be helpful in defining the proper place of RCI in the treatment algorithm of myositis. While this is the largest prospective trial of RCI in myositis providing excellent data on efficacy and safety profile, a larger, randomised control trial is necessary to conclusively establish the efficacy of RCI in myositis. Nevertheless, this study has demonstrated that treatment with RCI was effective in 70% of refractory cases, safe and led to a reduction in concomitant glucocorticoid dosing in myositis.

References

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors RA and CVO planned the study and wrote the protocol. RA, CVO and GM enrolled patients and evaluated outcome measures. DCK and PN executed the study from patient enrolment to data collection, to data management. ZQ planned the biospecimen and laboratory data collection, and executed the biospecimen sample collection and laboratory results. All authors participated in data analysis and manuscript write-up.

  • Funding This was an investigator-initiated clinical trial funded by Mallinckrodt.

  • Competing interests RA, CVO and GM received an honorarium from Mallinckrodt for an advisory board unrelated to this trial.

  • Ethics approval University of Pittsburgh IRB. The protocol was approved by the Institutional Review Board at each location.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data used for the publication and additional unpublished data from the study can be shared with experienced myositis researchers upon request to PI.

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