NCT04966884

The Efficacy and Safety of JAK Inhibitor in the Treatment of Anti-MDA5 Antibody-positive Dermatomyositis Patients

• Status: Unknown
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 20 (estimated)
• Sponsor: First Affiliated Hospital Xi'an Jiaotong University · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

Anti-melanoma differentiation-associated gene5 (Anti-MDA5) antibody positive Dermatomyositis (DM) is a subtype of DM that is more frequent in East Asia, which is often exhibit skin lesion, clinically amyopathic and interstitial lung disease. About 42%-100% of patients with Anti-MDA5+ DM develop rapidly progressive interstitial lung disease (RPILD) and result in respiratory failure. The mortality is as high as 40% within 6 months. In addition, not every patient with Anti-MDA5+ DM respond to traditional treatment strategy and most of the patients are resistant to immunosuppressive therapy including a combination of high dose glucocorticoids (GCs) and immunosuppressants such as cyclosporine, tacrolimus, or cyclophosphamide. However, RP-ILD is still the main cause of death due to fatal respiratory failure. Therefore, treatment of Anti-MDA5+ DM patients is challenging.Blocking multiple cytokines may become a new target for the treatment of this disease.Jakinibs is a Janus kinase (JAK) inhibitor that blocks a variety of cytokines, such as type I and type II interferon. Few studies have reported a positive response to JAK inhibitor for Anti-MDA5+ DM. Kazuhiro et al. reported in 2018 that JAK inhibitor tofacitinib may be an effective treatment option for high risk amyopathic dermatomyositis (ADM) -ILD patients after failure of conventional treatment, but the number of cases is too small. And a recent paper showed that great efficacy of tofacitinib for the improvement of survival of anti-MDA5-positive early-stage ADM-ILD patients.The aim of this study is to evaluate the efficacy and safety of JAK inhibitors in the treatment of anti-MDA5+ DM patients, and to evaluate the effect of JAK inhibitors on B cells of these patients, so as to provide a new target and theoretical basis for the treatment of anti-MDA5+ DM.

Detailed description

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by chronic inflammation in the skin and muscle. Anti-melanoma differentiation-associated gene5 (Anti-MDA5) antibody positive DM is a subtype of DM that is more frequent in East Asia, which is often exhibit skin lesion, clinically amyopathic and interstitial lung disease. About 42%-100% of patients with Anti-MDA5+ DM develop rapidly progressive interstitial lung disease (RPILD) and result in respiratory failure. The mortality is as high as 40% within 6 months. In addition, not every patient with Anti-MDA5+ DM respond to traditional treatment strategy and most of the patients are resistant to immunosuppressive therapy including a combination of high dose glucocorticoids(GCs) and immunosuppressants such as cyclosporine, tacrolimus, or cyclophosphamide. However, RP-ILD is still the main cause of death due to fatal respiratory failure. Therefore, treatment of Anti-MDA5+ DM patients is challenging.The excessive production of multiple cytokines plays a crucial role in the development of Anti-MDA5+ DM patients complicated with ILD. Hyperferritinemia is a predictor of poor prognosis. Other abnormalities included lymphopenia, increased erythrocyte sedimentation rate(ESR), and elevated serum interleukin-18 (IL-18).Moreover, compared with Anti-MDA5- DM patients, serum interferon--α(IFN-α) concentration increased in Anti-MDA5+ DM patients with RP-ILD. Therefore, blocking multiple cytokines may become a new target for the treatment of this disease.Jakinibs is a Janus kinase (JAK) inhibitor that blocks a variety of cytokines, such as type I and type II IFN. Few studies have reported a positive response to JAK inhibitor for Anti-MDA5+ DM. Kazuhiro et al. reported in 2018 that JAK inhibitor tofacitinib may be an effective treatment option for high risk amyopathic dermatomyositis (ADM) -ILD patients after failure of conventional treatment, but the number of cases is too small. And a recent paper showed that great efficacy of tofacitinib for the improvement of survival of anti-MDA5-positive early-stage ADM-ILD patients.The aim of this study is to evaluate the efficacy and safety of JAK inhibitors in the treatment of anti-MDA5+ DM patients, and to evaluate the effect of JAK inhibitors on B cells of these patients, so as to provide a new target and theoretical basis for the treatment of anti-MDA5+ DM.This was a single-arm open-label pilot observational study. Patients were received a glucocorticoids (0.8mg-1mg/kg/day) and a combination with tofacitinib (at a dose of 5 mg twice daily). Inactive disease was defined as meeting the following three criteria: CK≤200U/L, physician visual analogue scale(VAS) =0, and myositis disease activity assessment visual analog scales (MYOACT) scores =0. Otherwise, the disease condition was considered to be active.The primary endpoint was the number of responders by total improvement score (TIS) ,which defined according to 2016 American College of Rheumatology(ACR)-European League Against Rheumatism(EULAR) Criteria for clinical response for adult DM/polymyositis(PM), after treatment with tofacitinib for 12 months. A TIS (0-100), determined by summing scores in each International Myositis Assessment and Clinical Studies Group (IMACS) core set measures (CSM). Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the TIS. Secondary endpoints included safety measures and change from baseline in the following index: percentage of predicted FVC (FVC % predicted) and percentage of predicted DLCO (DLCO% predicted), the ferritin level, peripheral lymphocyte subsets.

Conditions

• Dermatomyositis, Adult Type

Interventions

Type	Name	Description
DRUG	JAK Inhibitor	1. Prednisone 0.8-1.0 mg/kg/d, the dose was gradually reduced, and after 4 weeks, the dose was reduced by 5mg every two weeks, and then reduced to 10mg/d for 4-6 months after oral administration for 3 months, and then reduced to 7.5mg/d for maintenance therapy until 12 months; 2. Tofacitinib 5 mg twice daily for 12 months.

Timeline

• Start date: 2020-04-02
• Primary completion: 2021-12-30
• Completion: 2021-12-30
• First posted: 2021-07-19
• Last updated: 2021-07-19

Locations

1 site across 1 country: China