Dermatomyositis (DM) is a systemic autoimmune inflammatory disease characterized by proximal muscle weakness and cutaneous manifestations (1). Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+DM) is a distinct subtype of DM, frequently associated with rapidly progressive interstitial lung disease (RPILD) and high mortality (2). Emerging evidence indicates that the 6-month mortality rate for MDA5+DM patients with RPILD ranges from 50% to 70% (3–5).

The treatment strategies for MDA5+DM patients are determined based on disease severity, prognostic risk factors, and indicators of disease progression. The initial treatment for MDA5+DM commonly involves glucocorticoids combined with immunosuppressive agents, particularly calcineurin inhibitors, but its therapeutic efficacy remains rather limited (6). Currently, the recommended induction treatment protocol includes a combination therapy of high-dose systemic glucocorticoids and immunosuppressants (e.g., calcineurin inhibitors and cyclophosphamide). Administering this regimen at an early stage has shown the greatest potential to improve survival among patients with RPILD (7–9). However, a recent multicenter longitudinal cohort study of 115 MDA5+DM patients reported contradictory findings. The investigation failed to show improved survival with a triple-combination therapy consisting of high-dose corticosteroids, tacrolimus, and intravenous cyclophosphamide (10). Additionally, the triple-combination therapy increases infection risks (especially viral and fungal), with co-infections further exacerbating mortality (7, 11). Therefore, the initial triple-combination therapy may not be appropriate for all patients, necessitating careful evaluation of benefits and risks before initiation.

Despite aggressive immunosuppressive regimens, a certain group of patients still experience unremitting disease progression and premature death, highlighting the pressing need for alternative or supplementary therapeutic approaches. In recent studies, hyperactivation of the type I IFN signaling pathway has emerged as a key factor closely associated with the pathogenesis of MDA5+DM (2, 12). Tofacitinib, a potent inhibitor of the JAK-STAT signaling and interferon pathway, shows a promising treatment option for MDA5+DM-associated interstitial lung disease (ILD). A previous single-center trial showed that tofacitinib improved survival in MDA5+DM-ILD compared to historical controls (100% vs 78%) (13). These compelling results have firmly established the groundwork for the clinical application of tofacitinib, further supported by a large multicenter cohort showing greater benefits for 1-year lung transplantation-free survival versus calcineurin inhibitors (14). Another retrospective cohort of MDA5+DM patients demonstrated superior efficacy of combined calcineurin and tofacitinib therapy versus calcineurin inhibitor monotherapy (12).

At present, large-scale studies directly comparing the efficacy and safety of calcineurin inhibitor monotherapy, calcineurin inhibitor combined with tofacitinib or cyclophosphamide in the treatment of MDA5+DM are notably scarce. This research is designed to evaluate and contrast the 1-year mortality and infection risks among these regimens to inform more effective treatment strategies.

In this single-center retrospective study on MDA5+DM-ILD patients, combination therapy (calcineurin inhibitor and tofacitinib or cyclophosphamide) as initial immunosuppressive regimen was found to significantly reduce the 1-year mortality risk compared to calcineurin inhibitor monotherapy. However, the incidence of overall infection was the highest in the CNI+CTX group than the other groups. CNI monotherapy and co-infection were major mortality predictors, while CD8+T cells were protective.

The etiology of MDA5+DM remains unclear. Although environmental-genetic interactions are implicated, the underlying mechanisms remain incompletely understood, involving complex immune cell interactions (T cells, B cells, neutrophils, macrophages, natural killer cells). Notably, accumulating evidence has demonstrated that overactivation of the type I interferon (IFN) signaling pathway is strongly associated with the pathogenesis of MDA5+DM (12). Guided by the current understanding of its pathogenesis, the existing treatment for MDA5+DM-ILD typically involves a combination of high-dose glucocorticoids, calcineurin inhibitors, and intravenous cyclophosphamide (7). In parallel, researchers have explored alternative therapeutic modalities, notably the triple combination of glucocorticoids, calcineurin inhibitors, and tofacitinib (12). These clinical investigations have demonstrated that combined immunotherapeutic regimens confer a distinct advantage, markedly improving survival outcomes of MDA5+DM patients. Consistent with the previous studies, our results showed that the triple combination therapy can remarkably enhance the survival rates of these individuals.

However, for such MDA5+DM patients, intensive immunosuppressive regimens may increase the risk of opportunistic infections. In our research, the overall infection incidence among these patients was strikingly high, reaching 37.5%. Notably, the infection rate in the CNI + CTX group was even more pronounced, surging to 51%. Among these infectious cases, specific pathogens emerged as the most common culprits, prominently including Aspergillus, PJP, and CMV, which is consistent with previous studies (7, 18, 19). Specifically, for patients undergoing combined immunosuppressive regimens, the CMV infection rate reached a staggering 85% (7). Analogously, the incidence of PJP among MDA5+DM is equally concerning, soaring to 48.4% (20). Moreover, these infections often served as a catalyst, precipitating the exacerbation of ILD activity, thereby increasing the risk of mortality.

As expected, infection proved to be a pivotal risk factor for mortality among MDA5+DM patients in our study. This finding aligns closely with the results reported in prior studies (19, 20). Notably, a staggering 62.5% of the patients who succumbed to the disease had concurrent infections. Prophylactic medications and careful monitoring for opportunistic infections should be considered as a routine in the management of MDA5+DM. Previous evidence has demonstrated that prophylactic trimethoprim- sulfamethoxazole(TMP-SMZ) treatment was associated with a reduced incidence of PJP and a lower mortality rate among MDA5+DM patients (21). This intervention holds significant promise in enhancing patient outcomes and improving long-term prognosis for this vulnerable population.

It is noteworthy that peripheral lymphopenia is a unique laboratory feature of MDA5+DM. This condition is characterized by simultaneous decreases in both CD4+ and CD8+ T cells, with the reduction being especially pronounced in patients with RPILD, and indicates that T cells play an important role in the development of MDA5+DM. Additionally, lymphopenia has emerged as a significant risk factor for patient mortality. Previous research has postulated that lymphocytes migrate to the lungs to engage in the local immune response, thereby leading to a reduction in peripheral blood lymphocytes (22, 23). This redistribution of lymphocytes may represent an adaptive immune mechanism, where immune cells are mobilized to the site of inflammation, yet it simultaneously results in lymphocytopenia in the circulatory system. The roles of CD4+T lymphocytes in MDA5+DM have been widely studied and are well recognized. Emerging evidence also suggests that CD8+ T cells play a critical role in MDA5+DM (24). In our study, we also found that CD4+T cells and CD8+T cells in the death group were lower via the univariable analysis, and further multivariable analysis revealed that more CD8+T cells might improve survival prognosis in MDA5+DM patients. It is a well-established fact that CD8+T cells, also known as cytotoxic T cells, possess the remarkable ability to directly identify and eliminate virus-infected cells. Through the release of potent cytotoxic agents, including perforin and granzymes, these cells initiate a cascade of events that culminate in the apoptosis of target cells, effectively purging the body of invading pathogens. CD8+T cells from patients with MDA5+DM showed significant exhausted phenotype, and increased exhausted CD8+T cells were associated with high risk of pulmonary fungal infection (25). An increased number of circulating CD8+T lymphocytes acts as a formidable bulwark, significantly bolstering the overall defense mechanisms against various infectious agents. This enhanced immunological surveillance and response capacity translate into a substantial decrease in mortality rates associated with infectious diseases. Evidently, CD8+ T cells play a central and indispensable role in ensuring survival in the face of infectious threats. The mechanism for CD8+T cells in MDA5+DM is complex and warrants further investigation.

Our study has several limitations. Firstly, it was a retrospective study conducted in one hospital, and the sample size of the cohort was relatively small, which might have restricted the detection of certain potential positive outcomes. In the future, randomized controlled trials with larger samples are needed to explore the therapeutic value of triple therapy in MDA5+DM. Secondly, the pulmonary function, which serve as crucial indicator of the severity of lung lesions, was not routinely recorded in this real-world cohort. Thirdly, adverse events might not be completely recorded. Lastly, the study only involved a Chinese population, potentially limiting its generalizability. Further prospective studies with larger cohorts are warranted to confirm our findings.

In this retrospective cohort study, we discovered that combination therapy may enhance the survival prognosis of patients with MDA5+ DM. Nevertheless, vigilant monitoring for opportunistic infections during treatment is essential. This comprehensive approach ensures both the therapeutic efficacy and the overall safety of patients, striking a crucial balance between treatment benefits and potential complications.