Pneumocystis jirovecii pneumonia (PJP) is a common opportunistic infection among immunocompromised individuals, including those with HIV infection, malignancy, and autoimmune diseases, posing significant morbidity and mortality risks (1). Dermatomyositis (DM) is a systemic autoimmune disorder characterized by muscle weakness and skin rash (2). Recent research has revealed an association between DM and increased susceptibility to infections, including PJP (3). Moreover, a longitudinal study spanning 13 years was conducted in patients with five rheumatic diseases, found that PM/DM patients have the highest risk of opportunistic infections, with an incidence rate of 61.3 per 1000 person-years, while, the incidence rate of PJP reaching 1.76 per 1000 person-years (4).

Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+DM) is a distinct subtype of DM, typically associated with rapidly progressive interstitial lung disease (RPILD), often leading to a poor prognosis (5). Patients with anti-MDA5+DM typically undergo aggressive immunosuppressive therapy, increasing their vulnerability to opportunistic infections, especially PJP (6, 7). The incidence of infections, including opportunistic ones, in anti-MDA5+ DM patients has attracted attention, underscoring the need for a deeper understanding of infectious complications in this population.

Recently, studies employing metagenomic next-generation sequencing (mNGS) techniques have provided valuable insights into the pathogenesis and epidemiology of infections in organ transplantation, hematologic malignancies, and solid tumors (8, 9). However, their application in anti-MDA5+ DM has been limited (10). Chen et al. found that the mNGS showed a satisfying diagnostic performance with a sensitivity of 100% in detecting PJP (11). In this study, we utilized mNGS technology to identify and compare clinical characteristics, risk factors, and survival status among anti-MDA5+DM patients with PJP infection.

Although guidelines have been published for the use of PJP prophylaxis in patients with HIV and cancer and transplant patients, there is no consensus concerning whether patients with rheumatic diseases should receive PJP prophylaxis. 2022 EULAR recommendations provide some general guidance on PJP prophylaxis in patients with autoimmune inflammatory rheumatic diseases. Daily doses >15-30mg of prednisolone or equivalent for more than 2-4 weeks, concomitant immunosuppressants, older age, underlying lung disease and persistent lymphopenia were recognized as risk factors of PJP infection, which was quite common in MDA5+DM patients (15). In this study, we offer valuable insights into the characteristics, risk factors, and mortality rates associated with PJP in patients with anti-MDA5+ DM.

PJP+ group has more fever, lower lymphocyte counts, and higher levels of CRP, and further multivariable logistic analysis suggested elevated NLR and CRP levels were independent risk factors for PJP infection, but TMP/SMZ prophylaxis was an independent protective role. However, in our study, only a small proportion of patients received TMP/SMZ prophylaxis in anti-MDA5+DM patients. The limited use of TMP/SMZ prophylaxis was manly attributed to nearly one-third of these patients being newly diagnosed. While, definitive guidelines are lacking to aid clinicians in appropriately administering prophylactic treatment. There is an urgent need for evidence-based guidelines to help healthcare providers identify specific risk factors for PJP development and initiate timely PJP prophylaxis, thus minimizing the occurrence of PJP (16).

We found that the mortality rate in the PJP+ group was significantly higher in the first 3 months compared to the PJP- group among anti-MDA5+DM patients. However, the overall mortality rate was similar at 6 months. This suggests that the primary mortality risk for PJP+ patients is concentrated in the first 3 months, which was is generally consistent with the previous report (6, 16). Therefore, for anti-MDA5+ patients, it is crucial to actively prevent PJP infection in the early stages of the disease, especially within the first 3 months. Our multivariable analysis identified elevated NLR and CRP levels as independent risk factors for PJP infection. Conversely, effective TMP/SMZ prophylaxis was shown to significantly reduce the incidence of PJP (1). Therefore, for anti-MDA5+DM patients with markedly decreased lymphocyte counts and significantly elevated inflammatory markers, early implementation of TMP/SMZ prophylaxis is recommended. Once anti-MDA5+DM patients developed PJP infection in the first 3 months, the concomitant RPILD appears to become the primary risk factor for mortality, given its significantly elevated HR. Similarity, Yoshida et al. reported that baseline lung involvement was a possible factor leading to fatal interstitial pneumonia in PJP+ rheumatoid arthritis patients (17). It is thought that the presence of underlying lung disease might create a conducive environment for opportunistic pathogens, as studies have indicated a disproportionate impact of PJP on patients with non-rheumatic pulmonary conditions (7, 18).

However, once the disease course extends beyond 3 months, the mortality risk for PJP+ patients become comparable to that of PJP- patients, and RPILD was no longer an independent risk factor for mortality, which could be linked to the stabilization of lung conditions following intensive treatment. It is worth noting that the use of corticosteroids (mean value: 30mg) can reduce the mortality rate of anti-MDA5+ patients with PJP+ at both 3 and 6 months. The debate over the use of GCs in PJP began early in the HIV epidemic (19). In 1990, several RCTs demonstrated a benefit when GCs were used in HIV patients with moderate to severe PJP (20, 21). These studies reported significant reductions in respiratory failure and death in the early stages of the disease. In non-HIV patients, the data on GCs is less clear, although some guidelines have recommended the use of GCs in PJP infection (22, 23). Retrospective studies have contradictory outcomes (24, 25); however, our results supported the use of GCs in anti-MDA5+DM patients with PJP infection. Theoretically, GCs could reduce the inflammatory response associated with PJP cell death. Some in-vivo studies also showed GCs had been shown to decrease cytokine release from alveolar macrophages, thereby reducing lung inflammation (26). Also, as RPILD was identified to be an independent risk factor of mortality in the MDA5+DM patients with PJP, the potential observed benefit with GCs might be contributed by therapeutic effect on RPILD.

Data concerning the effects of immunosuppressant therapy on PJP development in patients with rheumatic diseases are limited. Some IS have been reported as risk factors for PJP in some rheumatic diseases (27, 28). However, our results suggested IS were neither a risk factor for PJP infection nor do they affect the mortality rate in anti-MDA5+ DM patients with PJP infection. Recent studies have shown that early aggressive treatment is often needed, and multiagent immunosuppression is potentially more effective than traditional treatment (GC plus a single IS) (5, 29). Therefore, we suggested that the urgency of treating the primary disease should be balanced against the risk of PJP infection. When intensified treatment for the primary disease was urgently required, IS can be used without undue concern about PJP infection. Nonetheless, further large-scale cohort studies are necessary to elucidate the impact of IS on PJP infection more comprehensively.

Our study has several limitations. Firstly, it was a single-center study conducted in one hospital with a focus on a specific population, thus single-center effects cannot be ruled out. Conducting a multicenter experiment is necessary to further validate our results. Secondly, the sample size of our cohort was relatively small, which might have restricted the detection of certain potential positive outcomes. Thirdly, we only revealed risk factors for PJP occurrence in anti-MDA5+ DM patients only at one time. This is far from enough, we are conducting prospective study to explore the occurrence of PJP, and analyze the effect of PJP on anti-MDA5+ DM patients. Lastly, the high overall mortality of these patients might be attributed to more serious condition and high proportion of ICU admission. Further prospective studies with larger cohorts are warranted to confirm our findings.

In this retrospective cohort study, we found that there was a high incidence and mortality in anti-MDA5+DM patients with PJP, while TMP/SMZ prophylaxis significantly reduces PJP risk. Mortality in PJP+ patients is primarily concentrated within the first 3 months, associated with RPILD. Early intervention with corticosteroids and prophylactic measures are crucial in reducing mortality.