Treatment Response in Immune-mediated Myositis Associated Rapidly-progressing Interstitial Lung Disease

Interstitial Lung Disease, Myositis

Idiopathic inflammatory myopathies (IIM) are a group of autoimmune conditions characterized by inflammation of muscles with possible extra-muscular manifestations which can include skin and interstitial lung disease (ILD). IIM-associated ILD carries poor prognosis. Particular subtypes of IIM such as anti-melanoma differentiation-associated protein 5 positive (anti-MDA5+) dermatomyositis with ILD are most commonly associated with rapidly progressive-interstitial lung disease (RP-ILD). RP-ILD is defined as worsening dyspnoea on exertion, hypoxaemia, and presence of newly emerging or expanding ground glass opacities on radiographic or computed topography of chest imaging excluding drug or infectious cause. Particularly, patients with anti-MDA5+ dermatomyositis often have RP-ILD with high mortality of over 60% in the first six months of diagnosis. The mainstay of treatment is immunosuppression though there has been no highly efficacious therapy proven to date. Therefore, the overall goal is to improve patient outcomes in IIM-associated RP-ILD including those with anti-MDA5+ dermatomyositis through the development of better treatment regimens. The objective of this research study is to evaluate the efficacy and safety of a combined immunosuppressive regime in patients with IIM-associated RP-ILD. The investigators hypothesize that the simultaneous inhibition of particular targets in the innate and adaptive immune system will improve efficacy and patient survival. The approach involves a combination of four immunosuppressive medications targeting different pathways implicated in IIM associated ILD. If successful, this study could contribute significantly to improving clinical outcomes for patients with IIM-associated RP-ILD.

The primary feature of idiopathic inflammatory myopathies (IIM) is inflammation of muscles, yet extra-muscular manifestations are common such as interstitial lung disease (ILD). Based on both muscular and extra-muscular features, patients can fall into different types of IIMs, including broad subtypes of dermatomyositis (DM), polymyositis (PM), inclusion-body myositis (IBM) and immune-mediating necrotizing myopathies (IMNM). Particular subtypes such as dermatomyositis patients positive for anti-melanoma differentiation-associated protein 5 (anti-MDA5) are most commonly associated with rapidly progressive lung involvement and high mortality, with survival at 1 year being less than 60% despite current available treatment. Treatment for IIM patients involves immunosuppression, though there is no consensus or treatment guidelines available for different subtypes, particularly for myositis-associated RP-ILD. Despite several trials having shown increased efficacy with more aggressive immunosuppressive regimes, mortality still remains high. There is thus an unmet need with regards to treatment of patients with IIM, particularly for myositis-associated RP-ILD. There is an urgent need to improve outcomes in myositis-associated RP-ILD. Till date, there are no randomised controlled trials that investigate therapy of myositis-associated RP-ILD likely due to the low incidence of the disease. Current best level of evidence for therapies come from single-arm prospective cohort studies with comparison with historical controls. Recent studies using combination therapy to target different aspects of these pathological processes have demonstrated increased efficacy compared to single target alone. This shows that appropriate selection of targets with subsequent combination blockade will be beneficial in treatment of patients with myositis associated RP-ILD. Hence, the investigators propose the utilization of rituximab to block the B-cell involvement, tacrolimus to target T-cells, tofacitinib to block interferon signaling with steroids due to their effects on both the innate and adaptive system in the treatment of myositis-associated RP-ILD. Such combination therapy allows precise targeting of pathways responsible for pathophysiology of the disease, without high individual dosages and hence reducing potential side effects. Till date there are no prospective studies that look into current combination of steroids, tacrolimus, tofacitinib and rituximab in the patients with myositis-associated RP-ILD. However, a drawback for increased immunosuppression is infection, particularly with cytomegalovirus (CMV). The investigators will employ a prophylactic treatment strategy to mitigate the risk of increased infection following higher intensity immunosuppression. The primary end point will be survival rate at 6 months from initiation of treatment. Secondary end points include improvement of clinical status, biochemical markers, radiological appearance and parameters on lung function test. Secondary end points also include adverse events rate including side effects from treatment and infection rates.

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