Upfront combination therapy in anti‐melanoma differentiation‐associated gene 5 (MDA5) associated rapidly progressive interstitial lung disease

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis-associated interstitial lung disease (DM-ILD) is recognized as a rheumatological emergency, potentially requiring aggressive upfront combination therapies to prevent respiratory failure due to rapidly progressive ILD (RP-ILD).1 Infectious complications due to immunosuppression are a major concern.1 Interstitial lung disease (ILD) in patients diagnosed with idiopathic inflammatory myositis (IIM) has a global prevalence of approximately 41%.2 A recent meta-analysis reported that the prevalence of RP-ILD is 8.9%, with rates being higher in Asian populations—reaching up to 20% in some studies.3-5 Although no consensus exists on the time frame for RP-ILD, it is typically characterized by worsening symptoms, hypoxemia, and declines in radiological or lung function over 1–3 months.6-8 It is crucial to acknowledge that different time frames (1 or 3 months) are used for defining RP-ILD in different studies, which could lead to significant variability in the prevalence and outcomes of RP-ILD in anti-MDA5 DM-ILD among studies.3-8 This heterogeneity among studies highlights the pressing need for shared criteria for defining RP-ILD. Given the rarity of anti-MDA5 antibody-positive dermatomyositis (anti-MDA5 DM), evidence-based treatments are limited to small, uncontrolled series.9 Hata et al., using the conventional treatment as historical controls, explored the efficacy of a new treatment strategy implemented after April 2015.10 In addition to conventional triple combination therapy with high-dose steroids, calcineurin inhibitor, intravenous cyclophosphamide, their new treatment implementation includes mycophenolate mofetil, rituximab, plasma exchange, or polymyxin B immobilized fiber column hemoperfusion. In cases where aggressive immunosuppressive therapy is used, the authors also advocate for proactive prophylaxis against pneumocystis pneumonia (PCP) and routine monitoring for cytomegalovirus (CMV) infection as opportunistic infections are the major concerns during the treatment of anti-MDA5 DM; however, the risk is considered largely owing to the use of high-dose glucocorticoid and combined immunosuppressive agents.10 Considering the high mortality rate associated with RP-ILD, whether due to the progression of ILD or infectious complications, it is essential to actively seek and implement methods that enhance patient stability.11 Notably, new treatment methods have shown a 64% survival rate at 48 weeks, significantly higher than the traditional methods with only a 33% survival rate.10 While the proposed upfront combination therapy might offer advantages for patients with severe conditions, the variability in clinical progression and outcomes among patients with anti-MDA5 DM-ILD warrants caution. Since a significant portion of anti-MDA5 DM patients do not experience RP-ILD, initiating combination therapy could lead to unnecessary overtreatment. This increases the risk of adverse effects such as infections, which in turn, may deteriorate patient outcomes. Consequently, appropriate mortality risk stratification is crucial for managing of anti-MDA5 DM-ILD. The MCK model, utilizing serum C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6) levels along with anti-MDA-5 antibody status, effectively predicts mortality risk in Japanese patients with polymyositis/dermatomyositis-associated ILD.12 The FLAIR risk score model, comprising ferritin, lactate dehydrogenase levels, anti-MDA5 antibody status, high-resolution CT imaging scores, and the presence of RP-ILD, effectively predicts survival and guides treatment in Chinese patients with amyopathic dermatomyositis-associated ILD.13 The CROSS model, consisting of CRP levels, anti-Ro52 antibody positivity, short disease duration, and male sex, predicts the development of RP-ILD in anti-MDA5 DM.14 Using these risk models to stratify patients with anti-MDA5 DM can guide physicians to use proactive strategies in high-risk groups. As anti-MDA5 DM-ILD often develops within the context of dermatomyositis, it has been categorized as part of connective tissue disease (CTD)-related ILD, which is at risk for progressive pulmonary fibrosis (PPF).15-17 PPF is an extension of the concept of Progressive Fibrotic Interstitial Lung Disease (PF-ILD).15 It serves as a rationale for the use of anti-fibrotic treatments.17 A recent study with a one-year follow-up on patients with idiopathic inflammatory myopathies-associated interstitial lung disease (IIM-ILD) found that 18% developed progressive fibrotic ILD, underscoring that fibrotic changes can manifest early in the course of IIM-ILD.18 Predictors of PF-ILD by univariate analysis included anti-MDA5 antibodies, heliotropic rash, xerostomia, and xerophthalmia.18 Due to lack of evidence supporting upfront combination with immunosuppressive agents, a sequential addition of anti-fibrotic treatment is recommended in CTD-ILD.15-17 It has been shown that combining pirfenidone with immunosuppressive agents can improve the prognosis of clinically amyopathic dermatomyositis patients with subacute ILD.19 The early use of anti-fibrotic agents along with immunosuppressive treatments should be tested in a well-structured randomized controlled trial. A recent retrospective cohort study by Chen et al. shed light on the complex pathology underlying these conditions. Organizing pneumonia (OP) was identified as the predominant radiological pattern in anti-MDA5 DM-ILD, with a corresponding histological pattern of non-specific interstitial pneumonia (NSIP) or NSIP+OP. Moreover, the presence of radiological patterns indicating NSIP+OP or diffuse alveolar damage (DAD) was linked to RP-ILD and increased mortality.20 A notable observation in this retrospective cohort study was the identification of a case of acute fibrinous and organizing pneumonia (AFOP), which is considered in the differential diagnosis for DAD in patients with acute respiratory distress syndrome.20-22 Here, we present a case to show that early fibrosis can be found in patients with RP-ILD. This 62-year-old woman was diagnosed in 2016 with anti-MDA5 DM. The presence of anti-MDA5 antibody was confirmed by line immunoassay, enzyme-linked immunosorbent assay, and immunoprecipitation. High-resolution computed tomography (HRCT) showed subpleural consolidation and bilateral ground-glass opacity, featuring a mix of NSIP plus OP pattern. Within a month after diagnosis with only glucocorticoid use, she developed RP-ILD and respiratory failure. The postmortem lung tissues revealed AFOP. The presence of intraluminal plugs, composed of proliferative fibroblasts and known as Masson bodies, within the airspaces, is pathognomonic of organizing pneumonia (Figure 1). In such cases, using anti-fibrotic drugs to slow or inhibit fibroblasts might be beneficial. Although fibroblast proliferation is a part of this process, it does not always result in long-term or irreversible fibrosis. Early and proactive use of anti-fibrotic and aggressive immunosuppressive agents may be advantageous for managing this life-threating condition. The pathological features observed in this case bear striking similarities to those seen in severe acute respiratory syndrome (SARS) and the recent COVID-19 pandemic, where numerous diagnoses of OP and AFOP have been reported.23, 24 During the SARS outbreak in Toronto, autopsy samples from 20 patients revealed that eight predominantly showed a diffuse alveolar damage (DAD) pattern, while six exhibited a primary AFOP pattern, and the others had a combination of both.23 Additionally, two of these cases involved complications from invasive aspergillosis, and CMV.23 The latter findings support the validity of preventative measures against opportunistic infections in patients with RP-ILD, especially under intensive immunosuppressive treatments. The recent study also confirms that preventive administration of sulfamethoxazole–trimethoprim is effective and safe, enhancing the prognosis of anti-MDA5 DM patients.25 Ongoing research is expected to further refine these strategies and provide more detailed guidance in the future. CWT is responsible for the conceptulization, data acquisition, manuscript preparation, and visualization. Gratitude is extended to the Department of Pathology and Laboratory Medicine at Taichung Veterans General Hospital for assisting with and interpretating the pathology images. All authors had no conflicts of interest to declare. Informed consent was obtained and the study was approved by Institutional Review Board of Taichung Veterans General Hospital (CE17037B). The data that support the findings of this study are available from the corresponding author upon reasonable request.

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