High Incidence and Mortality of Pneumocystis Jiroveci Infection in Anti-MDA5-Antibody Positive Dermatomyositis: Experience From a Single Center

High Incidence and Mortality of Pneumocystis Jiroveci Infection in Anti-MDA5-Antibody Positive Dermatomyositis: Experience From a Single Center | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article High Incidence and Mortality of Pneumocystis Jiroveci Infection in Anti-MDA5-Antibody Positive Dermatomyositis: Experience From a Single Center Linlin Huang, Qiong Fu, Yan Ye, Yanwei Lin, Qingran Yan, Sheng Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-344084/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Idiopathic inflammatory myopathies (IIM) was associated with a significantly higher risk of opportunistic infections that including Pneumocystis jiroveci pneumonia (PJP), a potentially fatal opportunistic infection. However, no prior studies have evaluated the PJP infection in subtypes of IIM. Objectives To investigate the incidence rate and mortality rate of PJP infection in subgroups of Idiopathic inflammatory myopathies (IIM) patients according to myopathy specific antibodies. Methods In the first part, 463 consecutive patients with IIM were prospectively followed up for a period of at least one year to analyze incidence of PJP. In the next part, we enrolled 30 consecutive PJP patients with any rheumatic disease were to identify the mortality rate and risk factors by Cox regression. Kaplan-Meier curve with log-rank test was used to access differences in survival. Results We found that the incidence rate of PJP in IIM patients is 3.0/100 person-year, while in MDA5 + DM patients is 7.5/100 person-year and in MDA5 − IIM patients is 0.7/100 person-year. (P < 0.05). PJP typically happened in the first two months for MDA5 + DM patients who have a significant decrease in the CD4 + T cell counts and Lymphocyte counts (P < 0.05). In PJP + patients, the mortality was lethally higher in MDA5 + DM patients than those with other rheumatic diseases (83.3% VS. 38.9%, P < 0.05). Unlike patients with other rheumatic diseases, MDA5 + patients seemed not to benefit from prompt anti-PJP treatment. For patients with other rheumatic diseases, anti-PJP treatment within 6 days was confirmed to crucially increased the survival (P < 0.05). Conclusion PJP has alarming high incidence and mortality in MDA5 + DM patients. Timely treatment for PJP does not improve the prognosis of this particular subtype. Therefore, the necessity of further study of PJP prophylaxis treatment in MDA5 + DM patients is verified. Rheumatology anti-MDA5-antibody-positve dermatomyositis Pneumocystis jiroveci pneumonia incidence mortality treatment Figures Figure 1 Figure 2 Figure 3 Key Messages The incidence of PJP in IIM patients has significant MDA5 + subtype preference. The mortality of PJP with MDA5 + DM is lethally higher than that with other rheumatic diseases. Timely-anti-PJP-treatment can significantly improve the prognosis of PJP in other rheumatic disease yet has no benefit on the prognosis of MDA5 + DM patients. Our data suggest the necessity of further study of PJP prophylaxis treatment in MDA5 + DM patients, especially in the first three months treatment or in the situation of patients’ CD4 + T cell count < 200 cells. Introduction Patients with rheumatic diseases receiving intensive immunosuppression therapy, who are immunocompromised individuals, are often associated with opportunistic infections.[ 1 ] The risk of opportunistic infection was highest for dermatomyositis/polymyositis, followed by Systemic Lupus Erythematosus, systemic sclerosis, rheumatoid arthritis, and primary Sjogren's Syndrome[ 2 ]Pneumocystis jirovecii pneumonia(PJP) is a rare but potentially life-threatening opportunistic infection with a 30–60% mortality rate among immunocompromised (non-HIV) patients[ 3 ][ 4 ] In patients with rheumatic immune diseases, most PJP occurs in the first 3 months after the use of immunosuppressants.[ 2 ][ 5 ]. Idiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases characterized by myasthenia and typical skin rash, among which polymyositis (PM) and dermatomyositis (DM) are the most common. Myositis-specific antibodies have long been identified and their value for stratifying patients with different outcomes has been recognized. There are few reports on PJP in IIM subtypes. A recent study identified anti-melanoma differentiation associated gene 5 antibody (anti-MDA5) as the only myositis-specific antibody that associated with PJP in a multicenter juvenile DM cohort. [ 6 ] Unfortunately, MDA5 + DM is one of the subtypes with poor prognosis, which is mainly characterized by progressive interstitial lung disease, with or without muscle damage [ 7 ]. For adult MDA5 + patients, there is only a report on two PJP + cases who are dead. [ 8 ] The mortality of PJP in these patients are still unknown. Therefore, in this study, we first investigated the incidence of PJP in IIM patients with or without anti-MDA5, then we analyzed the outcomes of anti-PJP treatment and mortality risk factors of PJP infection in rheumatic diseases. Patients And Methods Patients In first part, we evaluated PJP incidence in an IIM cohort. All adult IIM patients clinically diagnosed fulfilling the 1997 classification criteria[9] were prospectively observed from May 2017 to January 2020 at department of Rheumatology, Renji Hospital, China. Patients were screened for myositis myositis-specific antibodies and myositis associated antibodies using a commercial immunoblot assay with 16 autoantigens. Baseline characteristics of patients in hospital, including demographic, clinical and laboratory data, were acquired from the Electronic Medical Record. Follow-up data were collected until January 2021.The occurrence of PJP was evaluated in these patients. In the second part, anti-PJP treatment outcomes were evaluated in all PJP patients with rheumatic diseases. 30 adult PJP patients with rheumatic diseases were recruited in a consecutive cohort study from May 2017 to January 2020 at department of Rheumatology, Renji Hospital, China, once the diagnosis of PJP was confirmed. Baseline characteristics of patients including demographic, clinical and laboratory data, were acquired at patients first admission in hospital. Follow-up data were collected a period of at least 3 months. The cumulative survival rates at 3-month were evaluated. Written informed consent was obtained from each study participant. The study was in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Renji Hospital, Shanghai, China. (ID: 2013-126) The diagnosis of PJP The diagnosis of PJP was based on comprehensive evaluation by clinical manifestations such as fever or acute dyspnea, characteristic radiographic findings, and etiology evidence data. A confirmed case needed to have positive microbiological tests such as next generation of sequencing and Grocott-Gomori methenamine-silver staining of bronchoalveolar lavage fluid. A probable case who had typical manifestations but failed to get etiology evidence needed confirmation by two infection specialists.However, a positive sequencing of PJP result while in the absence of clinical manifestations was not considered as PJP case. Statistical analysis Statistical analysis was performed using the SPSS 23.0 software package (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8.0(GraphPad Software). We used chi-square test or Fisher's exact test to compare the categorical variables and Student’s t test or the Mann-Whitney U test was applied to compare continuous variables. Cox proportional hazards regression was performed as multivariable analysis to identify independent risk factors for death and calculate their hazard ratios. The optimal cut-off value was determined by using receiver operating characteristic (ROC) analysis and Kaplan-Meier curve with log rank test was employed to access difference in survival. For all analysis, the two-tailed p-values less than 0.05 was considered statistically significant. Results PJP incidence analysis in IIM cohort 14 PJP patients was found in IIM cohort (n=463) after one-year follow-up. All IIM patients was divided by PJP+ group and PJP- group to compare the risk factors of PJP infection. (table 1) We found that anti-MDA5+ is a risk factors for PJP infection in IIM (85.7% VS. 33.0%, P<0.0001), We calculated the incidence rate of PJP in IIM cohort is 3.0/100 person-year, while in MDA5 + DM patients is 7.5/100 person-year and in MDA5 - IIM patients is 0.7/100 person-year. (Figure 1 7.5% VS. 0.7%, P<0.00001) Besides that, factors like shorter median course (2 months VS. 6 months); interstitial lung (92.9% VS. 70.4%); complicated with diabetes (42.9% VS. 13.6%); higher prednisone exposure (50mg VS. 30mg), and laboratory examination differences such as higher erythrocyte sedimentation rate and ferritin, lower serum albumin, CD4 + T lymphocytes counts, and lymphocytes (P < 0.05) may also contribute to PJP occurrence as well. In consideration that some of the factors mentioned above are characteristics of MDA5 + DM, we further divided MDA5 + DM patients into PJP+ group and PJP- group to confirm PJP infection factors. The Supplementary table S1(online) shows that PJP occurred in a median time of 2 months and with obvious decrease of CD4 + T cell counts and lymphocytes, which suggests that we may need to be on guard against the occurrence of PJP for MDA5 + DM patients in the first 2 months of the disease or in the time when lymphocytopenia occur or CD4 + T cell counts decreases. PJP+ cohort with rheumatic diseases To evaluate the impact of anti-MDA5 (+) phenotype on mortality of PJP, we further analyzed all PJP+ patients (n=30) admitted into our medical center during the same period of the IIM cohort. The clinical features between MDA5 + DM and other rheumatic disease were compared in Supplementary table S2(online), more details of 30 PJP+ patients in Supplementary table S3(online). As shown in Figure 2A, The MDA5 + DM (12, 39.60%) constituted the largest part of PJP+ patients, followed by Systemic Lupus Erythematosus (7, 22.70%), MDA5 - IIM (2, 6.93%), ANCA associated vasculitis (AAV; 2, 6.93%), and Adult-Onset Still’s disease (AOSD; 2, 6.93%), primary Sjogren's Syndrome (pSS; 2, 6.93%), Undifferentiated connective tissue disease (UCTD; 2, 6.93%) and rheumatoid arthritis (RA; 1, 2.97%). The heatmap Figure 2B shows the rheumatic disease duration when PJP infection occurred. For IIM, AAV, AOSD patients, PJP infection most happened within 6 months of disease duration; while a little unexpectedly for SLE patients, PJP seemed to occur at any stage of disease in this cohort. PJP mortality analysis in PJP cohort The mortality of anti-MDA5-ab-positive was lethally higher than that of other rheumatic diseases (83.3% versus 38.9% P=0.016) as shown in Figure 2C and D. For 3-month-mortality risk factors, we identified age, CD4 + T cell counts and MDA5 + DM with p values less than 0.10 in univariate analysis and then put the three factors in the cox regression model. It turned out that MDA5 + DM and CD4 + T cell counts were identified as independent risk factors for death by multivariate analysis. Notably in these two, though as traditional PJP mortality factor [10], CD4 + T cell counts only had hazard ratio of 0.994 (95% CI 0.989-1.000) while MDA5 + DM had HR of 3.254 (95% CI 1.209-8.756). (Table 2) Besides baseline risk factors, prompt anti-PJP treatment is critical for patient survival. It has been long noticed that early diagnosis and early treatment can improve the prognosis of PJP patients [11][12]. We try to find the period-limitation for PJP-treatment by ROC curve analysis, but the cut-off valve of was not statistically significant (Supplementary figureS1A, P=0.0983, cut-off valve=7days). When we further stratified all the patients by anti-MDA5, a similar ROC curve as previous reports showed in patients with rheumatic diseases other than MDA5 + DM. The time-to-PJP-treatment cut-off point of 6 days showed 85.7% sensitivity and 63.6% specificity, and with the Area Under Curve (AUC) 81.2% base on ROC curve. The time of six-day was the optimal cut-off point for timely treatment for PJP (Supplementary figureS1B, P=0.0297). However, in MDA5 + DM patients, the ROC curve did not show at all (Figure S1C). We then analyzed patient survival to confirm the cut-off value. Consistent with previous reports, patient with other rheumatic disease tended to have better survival if they received anti-PJP treatment within 6 days after initial symptoms (Figure 3A, 1-year survival rate: 87.5% VS. 40%, P=0.057); while in MDA5 + DM patients this phenomenon did not appear at all (Figure 3B, P=0.327). Timely-anti-PJP-treatment did not benefit the survival of MDA5 + DM patients in our center. Discussion Though early in 1996, a previous research reported that the prevalence of PJP in Systemic Lupus Erythematosus patients is 1.7%, while in DM patients is 37.5%, based on a small cohort. (n = 75)[ 13 ]. Our study is the first time to report the incidence of PJP in MDA5 + DM patients in an independent and the largest cohort study so far. Among rheumatic diseases, IIM has been noticed to have the highest PJP infection risk. Our data for the first time describe the different incidence of PJP between anti-MDA5 positive and negative IIM patients. The incidence rate of MDA5 + DM patients is up to 7.5/100 person-year in our cohort. Cockland review recommends prophylactic treatment should be taken when the risk of PJP infection in non-HIV Immunocompromised people is greater than 6.2/100 person-year. [ 14 ] The reason why MDA5 + DM is easy to be infected by Pneumocystis carshi is still unknown. According to previous reports, high risk factors for rheumatic disease complicated with PJP included granulomatosis with polyangiitis, microscopic polyangiitis, autoimmune interstitial pneumonia, high-dose glucocorticoid, cyclophosphamide [ 15 ] high-dose methotrexate, elderly, diabetes, nutritional deficiency, severe lymphocytopenia or low CD4 T cell count patients [ 16 ][ 17 ]. Our study shows that CD4 + T cell counts at admission, Lymphocyte counts at admission, the lowest lymphocyte count during hospitalization and rheumatic disease duration is significantly lower in 160 cases of MDA5 + DM than 303 cases of MDA5- IIM (Supplementary tableS4). These findings indicate us to pay more attention to PJP in MDA5 + DM patients, especially in the first three months of disease duration, or in the situation of patients’ CD4 T cell count < 200 cells. Further, our study first reported the 3-month mortality rate of MDA5 + DM patients was as high as 83.3% (all patients die in single hospitalization). MDA5 + DM and CD4 + T cell counts were identified as independent risk factors for death by multivariate analysis in our study. Since baseline lung involvement has been noticed as a possible factor leading to the progression of fatal interstitial pneumonia in RA patients when infected by pneumocystis jiroi [ 18 ], we speculate that the extremely high prevalence of ILD in MDA5 + DM patients may contribute the high mortality after pneumocystis jiroi infection. For CD4 + T cytopenia, a recent report by Freiwald et al supported that CD4 + T cell lymphopenia can predict mortality in kidney transplant patients with PJP. [ 19 ] Our study first found that timely PJP treatment could not improve the prognosis as other rheumatic diseases complicated with PJP. The risk of death is increased significantly once MDA5 + DM patient with PJP infection. It is very important to take measures to deal with such a dangerous disease, in which prophylaxis against PJP may be a good method. [ 20 ] It is proved that prophylaxis against PJP for rheumatic patients can significantly reduce the incidence of PJP without severe adverse event. [ 21 ] The prophylaxis rate was only 4%(n = 19) patients at admission in our IIM cohort, and merely 43(9.3%) patients had taken continuous anti-PJP prophylaxis since the treatment for IIM in our hospital. There is no recommendation for PJP management in MDA5 + DM patients. The data suggest the necessity of further study of PJP prophylaxis treatment in MDA5 + DM patients who may need a routine prophylaxis. The limitations of this study include were shown as following. First, the study of evaluating PJP occurrence in IIM was an observation study, a limitation inherent to observational studies; Second, the number of PCP cases in this study was rather small so we could not perform independent PJP occurrence factors in IIM or MDA5 + DM. Third, the number of patients who take a PJP prophylactic treatment is too small for us to assess the prophylactic effect of trimethoprim-sulfamethoxazole in MDA5 + DM patients. there may need a randomized controlled study to compare the prophylactic effect and the prevalence of adverse events. Conclusions In conclusion, we show here that MDA5 + DM patient is easy to be infected by pneumocystis jiroi which is hard to be cured than other background rheumatic disease. The reason related to the higher incidence and mortality may be associated with MDA5 + DM which characterized by lower CD4 T cell counts and progressive interstitial lung disease. The data suggests the necessity of further study of PJP prophylaxis treatment in MDA5 + DM patients. List Of Abbreviations Abbreviation Full name MDA5+ DM anti-melanoma differentiation associated gene 5 antibodies positive dermatomyositis MDA5-IIM anti-melanoma differentiation associated gene 5 antibodies negative Idiopathic inflammatory myopathy PJP pneumocystis jiroveci pneumonia IIM Idiopathic inflammatory myopathy PM polymyositis TMP-SMX trimethoprim/sulfamethoxazole Declarations Ethics approval and consent to participate The study was in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Renji Hospital, Shanghai, China.(2013-216). Consent for publication No individual person’s data were presented in any form in this study, and therefore, no consent to publish is required. Availability of data and materials All data generated or analysed during this study are included in this published article [and its supplementary information files] Competing interests: The authors declare that they have no competing interests Funding : This work was supported by National Natural Science Foundation of China (No.81771752). Authors’ contributions All authors discussed the results and contributed to the final manuscript. The authors read and approved the final manuscript. Acknowledgements The authors thank Dr. An Sun for statistical analysis consultation and Ping Ye and Shuiying Li for clinical lab technique and follow-up support. References Tasaka S. Recent Advances in the Diagnosis and Management of Pneumocystis Pneumonia. Tuberc Respir Dis. 2020;83:132–40. Hsu C-Y, Ko C-H, Wang J-L, Hsu T-C, Lin C-Y. Comparing the burdens of opportunistic infections among patients with systemic rheumatic diseases: a nationally representative cohort study. 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Tables Table 1 Comparison of risk factors in PJP and non-PJP cases for IIM patients PJP (n=14) Non-PJP (n=449) P value MDA5 + DM, n(%) 12(85.7%) 148(33.0%) 0.000 Non-MDA5 IIM, n(%) 2(14.3%) 301(67.0%) male gender, n(%) 6(42.9%) 135(30.1%) 0.376 assess age, mean ± SD 54±10 53±12 0.635 Disease duration, year, median 2 6 0.001 ILD(%) 13(92.9%) 316(70.4%) 0.077 Medications three month before PCP infection, n (%) Corticosteroid (≥20mg pred，≥1month) 10(71.4%) 226(50.4%) 0.12 Corticosteroid, mg, median 50 30 0.001 Cyclophosphamide 1(7.1%) 39(87.1%) 1.000 Methotrexate 0(0%) 43(9.6%) 0.630 Azathioprine 0(0%) 35(7.8%) 0.614 Cyclosporine 5(35.7%) 73(16.3%) 0.069 Tacrolimus 4(28.6%) 55(12.2%) 0.089 Mycophenolate Mofetil 1(7.1%) 28(6.2%) 0.601 hydroxychloroquine 5(35.7%) 104(23.2%) 0.334 Biologics 1(7.1%) 16(3.6%) 0.412 Others 1(7.1%) 83(18.5%) 0.482 Diabetes, n (%) 6(42.9%) 61(13.6%) 0.009 ESR, mm/h, median 34.5 21 0.085 CK, U/L, median 26.5 67.5 0.02 LDH, U/L, median 464.5 321 0.028 Ferritin, ug/ml,median 1122 341 0.001 Pre-albumin, g/L,median 208.5 214 0.832 Albumin, mg/L,median 29.4 32.5 0.005 CD4 + T cell counts at admission x10^9/L,median 113.4 350.4 0.000 Lymphocyte counts at admission x10^9/L,median 0.695 0.9 0.004 The lowest lymphocyte count x10^9/L,median（during hospitalization） 0.39 0.81 0.000 Table 2 Risk factors for 3-month mortality of PJP with rheumatic disease Univariable Multivariable Clinical factors HR(95%CI) P value HR(95%CI) P value Assessed age 0.981(0.951-1.012) 0.225 0.975(0.940-1.010) 0.158 Gender 0.437(0.207-0.923) 0.798 * * MDA5 + DM 2.830(1.067-7.505) 0.037 3.254(1.209-8.756) 0.02 AAV 0.674(0.089,5.099) 0.702 * * SLE 1.062(0.346,3.265) 0.916 * * CD4 + T cell counts 0.995(0.989-1.001) 0.083 0.994(0.989-1.000) 0.04 lymphocyte counts 0.142(0.025-0.808) 0.028 * * Interstitial lung disease 1.537(0.540-4.375) 0.421 * * Steroid dose 0.291(0.063,1.350) 0.115 * * Cyclophosphamide 1.807(0.586,5.568) 0.303 * * Rituximab 0.854(0.113,6.450) 0.878 * * Time to anti-PJP treatment 1.577(0.607-4.099) 0.35 * * CI, confidence interval; *Not included in the multivariable model due to lack of significant association in the univariable analysis; Supplementary Files OnlineSupplementary.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 18 May, 2021 Review # 1 received at journal 17 Apr, 2021 Review # 2 received at journal 17 Apr, 2021 Reviewer # 3 agreed at journal 04 Apr, 2021 Reviewer # 2 agreed at journal 02 Apr, 2021 Reviews received at journal 02 Apr, 2021 Reviewer # 1 agreed at journal 02 Apr, 2021 Reviewers invited by journal 01 Apr, 2021 Editor assigned by journal 21 Mar, 2021 Submission checks completed at journal 21 Mar, 2021 Editor invited by journal 21 Mar, 2021 First submitted to journal 18 Mar, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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11:34:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-344084/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-344084/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":7493745,"identity":"dbe42cdf-d8d0-416a-b120-c413e9439b89","added_by":"auto","created_at":"2021-03-30 17:43:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":110382,"visible":true,"origin":"","legend":"1-year PJP incidence rate","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-344084/v1/043e2ada2821618ab9b5497a.png"},{"id":7493365,"identity":"436e62cd-022f-4036-97ad-40b80f4e0b58","added_by":"auto","created_at":"2021-03-30 17:40:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74510,"visible":true,"origin":"","legend":"The risk of PJP infection and mortality in PJP cohort consists of all PJP patients with Rheumatic disease","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-344084/v1/9383f41191ba876ba72924c5.png"},{"id":7493367,"identity":"34aeb5cd-3f24-4043-aa4a-33c3477a4708","added_by":"auto","created_at":"2021-03-30 17:40:19","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1131365,"visible":true,"origin":"","legend":"Survival rates stratified by time-to-anti-PJP-treatment in PJP patients","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-344084/v1/87ba438b3632376c9070cdc5.png"},{"id":13682801,"identity":"1c4c18e2-c9fa-4bfc-9502-961ec6f4508f","added_by":"auto","created_at":"2021-09-17 11:59:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":511422,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-344084/v1/27da4079-c615-4867-bcf8-4498aa5e8479.pdf"},{"id":7493746,"identity":"83534ac1-22c1-4a47-ab31-d59c85dba07b","added_by":"auto","created_at":"2021-03-30 17:43:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1781609,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineSupplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-344084/v1/92317e96cfb261edf61cad49.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eHigh Incidence and Mortality of Pneumocystis Jiroveci Infection in Anti-MDA5-Antibody Positive Dermatomyositis: Experience From a Single Center\u003c/p\u003e","fulltext":[{"header":"Key Messages","content":"\u003col\u003e\n\u003cli\u003eThe incidence of PJP in IIM patients has significant MDA5\u003csup\u003e+\u003c/sup\u003esubtype preference.\u003c/li\u003e\n\u003cli\u003eThe mortality of PJP with MDA5\u003csup\u003e+\u003c/sup\u003eDM is lethally higher than that with other rheumatic diseases.\u003c/li\u003e\n\u003cli\u003eTimely-anti-PJP-treatment can significantly improve the prognosis of PJP in other rheumatic disease yet has no benefit on the prognosis of MDA5\u003csup\u003e+\u003c/sup\u003eDM patients.\u003c/li\u003e\n\u003cli\u003eOur data suggest the necessity of further study of PJP prophylaxis treatment in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients, especially in the first three months treatment or in the situation of patients\u0026rsquo; CD4\u003csup\u003e+\u003c/sup\u003e T cell count \u0026lt; 200 cells.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Introduction","content":" \u003cp\u003ePatients with rheumatic diseases receiving intensive immunosuppression therapy, who are immunocompromised individuals, are often associated with opportunistic infections.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The risk of opportunistic infection was highest for dermatomyositis/polymyositis, followed by Systemic Lupus Erythematosus, systemic sclerosis, rheumatoid arthritis, and primary Sjogren's Syndrome[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]Pneumocystis jirovecii pneumonia(PJP) is a rare but potentially life-threatening opportunistic infection with a 30\u0026ndash;60% mortality rate among immunocompromised (non-HIV) patients[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] In patients with rheumatic immune diseases, most PJP occurs in the first 3 months after the use of immunosuppressants.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIdiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases characterized by myasthenia and typical skin rash, among which polymyositis (PM) and dermatomyositis (DM) are the most common. Myositis-specific antibodies have long been identified and their value for stratifying patients with different outcomes has been recognized. There are few reports on PJP in IIM subtypes. A recent study identified anti-melanoma differentiation associated gene 5 antibody (anti-MDA5) as the only myositis-specific antibody that associated with PJP in a multicenter juvenile DM cohort. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eUnfortunately, MDA5\u003csup\u003e+\u003c/sup\u003eDM is one of the subtypes with poor prognosis, which is mainly characterized by progressive interstitial lung disease, with or without muscle damage [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. For adult MDA5\u0026thinsp;+\u0026thinsp;patients, there is only a report on two PJP\u0026thinsp;+\u0026thinsp;cases who are dead. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] The mortality of PJP in these patients are still unknown. Therefore, in this study, we first investigated the incidence of PJP in IIM patients with or without anti-MDA5, then we analyzed the outcomes of anti-PJP treatment and mortality risk factors of PJP infection in rheumatic diseases.\u003c/p\u003e "},{"header":"Patients And Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn first part, we evaluated PJP incidence in an IIM cohort. All adult IIM patients clinically diagnosed fulfilling the 1997 classification criteria[9] were prospectively observed from May 2017 to January 2020 at department of Rheumatology, Renji Hospital, China. Patients were screened for myositis myositis-specific antibodies and myositis associated antibodies using a commercial immunoblot assay with 16 autoantigens. Baseline characteristics of patients in hospital, including demographic, clinical and laboratory data, were acquired from the Electronic Medical Record. Follow-up data were collected until January 2021.The occurrence of PJP was evaluated in these patients.\u003c/p\u003e\n\u003cp\u003eIn the second part, anti-PJP treatment outcomes were evaluated in all PJP patients with rheumatic diseases. 30 adult PJP patients with rheumatic diseases were recruited in a consecutive cohort study from May 2017 to January 2020 at department of Rheumatology, Renji Hospital, China, once the diagnosis of PJP was confirmed. Baseline characteristics of patients including demographic, clinical and laboratory data, were acquired at patients first admission in hospital. Follow-up data were collected a period of at least 3 months. The cumulative survival rates at 3-month were evaluated. Written informed consent was obtained from each study participant. The study was in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Renji Hospital, Shanghai, China.\u0026nbsp;(ID: 2013-126)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe diagnosis of PJP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnosis of PJP was based on comprehensive\u0026nbsp;evaluation by clinical manifestations such as fever or acute dyspnea, characteristic radiographic findings, and etiology evidence data. A confirmed case needed to have positive microbiological tests such as next generation of sequencing and Grocott-Gomori methenamine-silver staining of bronchoalveolar lavage fluid. A probable case who had typical manifestations but failed to get etiology evidence needed confirmation by two infection specialists.However, a positive sequencing of PJP result while in the absence of clinical manifestations was not considered as PJP case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using the SPSS 23.0 software package (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8.0(GraphPad Software). We used chi-square test or Fisher's exact test to compare the categorical variables and Student\u0026rsquo;s t test or the Mann-Whitney U test was applied to compare continuous variables. Cox proportional hazards regression was performed as multivariable analysis to identify independent risk factors for death and calculate their hazard ratios. The optimal cut-off value was determined by using receiver operating characteristic (ROC) analysis and Kaplan-Meier curve with log rank test was employed to access difference in survival. For all analysis, the two-tailed p-values less than 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePJP incidence analysis in IIM cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e14 PJP patients was found in IIM cohort (n=463) after one-year follow-up. All IIM patients was divided by PJP+ group and PJP- group to compare the risk factors of PJP infection. (table 1) We found that anti-MDA5+ is a risk factors for PJP infection in IIM (85.7% VS. 33.0%, P\u0026lt;0.0001), We calculated the incidence rate of PJP in IIM cohort is 3.0/100 person-year, while in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients is 7.5/100 person-year and in MDA5\u003csup\u003e-\u003c/sup\u003eIIM patients is 0.7/100 person-year. (Figure 1 7.5% VS. 0.7%, P\u0026lt;0.00001) Besides that, factors like shorter median course (2 months VS. 6 months); interstitial lung (92.9% VS. 70.4%); complicated with diabetes (42.9% VS. 13.6%); higher prednisone exposure (50mg VS. 30mg), and laboratory examination differences such as higher erythrocyte sedimentation rate and ferritin, lower serum albumin, CD4\u003csup\u003e+\u003c/sup\u003eT lymphocytes counts, and lymphocytes (P \u0026lt; 0.05) may also contribute to PJP occurrence as well. In consideration that some of the factors mentioned above are characteristics of MDA5\u003csup\u003e+\u003c/sup\u003eDM, we further divided MDA5\u003csup\u003e+\u003c/sup\u003eDM patients into PJP+ group and PJP- group to confirm PJP infection factors. The Supplementary table S1(online) shows that PJP occurred in a median time of 2 months and with obvious decrease of CD4\u003csup\u003e+\u003c/sup\u003e T cell counts and lymphocytes, which suggests that we may need to be on guard against the occurrence of PJP for MDA5\u003csup\u003e+\u003c/sup\u003eDM patients in the first 2 months of the disease or in the time when lymphocytopenia occur or CD4\u003csup\u003e+\u003c/sup\u003e T cell counts decreases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePJP+ cohort with rheumatic diseases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the impact of anti-MDA5 (+) phenotype on mortality of PJP, we further analyzed all PJP+ patients (n=30) admitted into our medical center during the same period of the IIM cohort. The clinical features between MDA5\u003csup\u003e+\u003c/sup\u003eDM and other rheumatic disease were compared in Supplementary table S2(online), more details of 30 PJP+ patients in Supplementary table S3(online).\u003c/p\u003e\n\u003cp\u003eAs shown in Figure 2A, The MDA5\u003csup\u003e+\u003c/sup\u003eDM (12, 39.60%) constituted the largest part of PJP+ patients, followed by Systemic Lupus Erythematosus (7, 22.70%), MDA5\u003csup\u003e-\u003c/sup\u003eIIM (2, 6.93%), ANCA associated vasculitis (AAV; 2, 6.93%), and Adult-Onset Still\u0026rsquo;s disease (AOSD; 2, 6.93%), primary Sjogren's Syndrome (pSS; 2, 6.93%), Undifferentiated connective tissue disease (UCTD; 2, 6.93%) and rheumatoid arthritis (RA; 1, 2.97%). The heatmap Figure 2B shows the rheumatic disease duration when PJP infection occurred. For IIM, AAV, AOSD patients, PJP infection most happened within 6 months of disease duration; while a little unexpectedly for SLE patients, PJP seemed to occur at any stage of disease in this cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePJP mortality analysis in PJP cohort \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mortality of anti-MDA5-ab-positive was lethally higher than that of other rheumatic diseases (83.3% versus 38.9% P=0.016) as shown in Figure 2C and D. For 3-month-mortality risk factors, we identified age, CD4\u003csup\u003e+\u003c/sup\u003e T cell counts and MDA5\u003csup\u003e+\u003c/sup\u003eDM with p values less than 0.10 in univariate analysis and then put the three factors in the cox regression model. It turned out that MDA5\u003csup\u003e+\u003c/sup\u003eDM and CD4\u003csup\u003e+\u003c/sup\u003e T cell counts were identified as independent risk factors for death by multivariate analysis. Notably in these two, though as traditional PJP mortality factor [10], CD4\u003csup\u003e+\u003c/sup\u003e T cell counts only had hazard ratio of 0.994 (95% CI 0.989-1.000) while MDA5\u003csup\u003e+\u003c/sup\u003eDM had HR of 3.254 (95% CI 1.209-8.756). (Table 2)\u003c/p\u003e\n\u003cp\u003eBesides baseline risk factors, prompt anti-PJP treatment is critical for patient survival. It has been long noticed that early diagnosis and early treatment can improve the prognosis of PJP patients [11][12]. We try to find the period-limitation for PJP-treatment by ROC curve analysis, but the cut-off valve of was not statistically significant (Supplementary figureS1A, P=0.0983, cut-off valve=7days). When we further stratified all the patients by anti-MDA5, a similar ROC curve as previous reports showed in patients with rheumatic diseases other than MDA5\u003csup\u003e+\u003c/sup\u003eDM. The time-to-PJP-treatment cut-off point of 6 days showed 85.7% sensitivity and 63.6% specificity, and with the Area Under Curve (AUC) 81.2% base on ROC curve. The time of six-day was the optimal cut-off point for timely treatment for PJP (Supplementary figureS1B, P=0.0297). However, in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients, the ROC curve did not show at all (Figure S1C). We then analyzed patient survival to confirm the cut-off value. Consistent with previous reports, patient with other rheumatic disease tended to have better survival if they received anti-PJP treatment within 6 days after initial symptoms (Figure 3A, 1-year survival rate: 87.5% VS. 40%, P=0.057); while in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients this phenomenon did not appear at all (Figure 3B, P=0.327). Timely-anti-PJP-treatment did not benefit the survival of MDA5\u003csup\u003e+\u003c/sup\u003eDM patients in our center.\u003c/p\u003e"},{"header":"Discussion","content":" \u003cp\u003eThough early in 1996, a previous research reported that the prevalence of PJP in Systemic Lupus Erythematosus patients is 1.7%, while in DM patients is 37.5%, based on a small cohort. (n\u0026thinsp;=\u0026thinsp;75)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Our study is the first time to report the incidence of PJP in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients in an independent and the largest cohort study so far. Among rheumatic diseases, IIM has been noticed to have the highest PJP infection risk. Our data for the first time describe the different incidence of PJP between anti-MDA5 positive and negative IIM patients. The incidence rate of MDA5\u003csup\u003e+\u003c/sup\u003eDM patients is up to 7.5/100 person-year in our cohort. Cockland review recommends prophylactic treatment should be taken when the risk of PJP infection in non-HIV Immunocompromised people is greater than 6.2/100 person-year. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe reason why MDA5\u003csup\u003e+\u003c/sup\u003eDM is easy to be infected by Pneumocystis carshi is still unknown. According to previous reports, high risk factors for rheumatic disease complicated with PJP included granulomatosis with polyangiitis, microscopic polyangiitis, autoimmune interstitial pneumonia, high-dose glucocorticoid, cyclophosphamide [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] high-dose methotrexate, elderly, diabetes, nutritional deficiency, severe lymphocytopenia or low CD4 T cell count patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e][\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Our study shows that CD4\u003csup\u003e+\u003c/sup\u003e T cell counts at admission, Lymphocyte counts at admission, the lowest lymphocyte count during hospitalization and rheumatic disease duration is significantly lower in 160 cases of MDA5\u003csup\u003e+\u003c/sup\u003eDM than 303 cases of MDA5- IIM (Supplementary tableS4). These findings indicate us to pay more attention to PJP in MDA5\u0026thinsp;+\u0026thinsp;DM patients, especially in the first three months of disease duration, or in the situation of patients\u0026rsquo; CD4 T cell count\u0026thinsp;\u0026lt;\u0026thinsp;200 cells.\u003c/p\u003e \u003cp\u003eFurther, our study first reported the 3-month mortality rate of MDA5\u003csup\u003e+\u003c/sup\u003eDM patients was as high as 83.3% (all patients die in single hospitalization). MDA5\u003csup\u003e+\u003c/sup\u003eDM and CD4\u003csup\u003e+\u003c/sup\u003e T cell counts were identified as independent risk factors for death by multivariate analysis in our study. Since baseline lung involvement has been noticed as a possible factor leading to the progression of fatal interstitial pneumonia in RA patients when infected by pneumocystis jiroi [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], we speculate that the extremely high prevalence of ILD in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients may contribute the high mortality after pneumocystis jiroi infection. For CD4\u003csup\u003e+\u003c/sup\u003e T cytopenia, a recent report by Freiwald et al supported that CD4 \u003csup\u003e+\u003c/sup\u003e T cell lymphopenia can predict mortality in kidney transplant patients with PJP. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOur study first found that timely PJP treatment could not improve the prognosis as other rheumatic diseases complicated with PJP. The risk of death is increased significantly once MDA5\u003csup\u003e+\u003c/sup\u003eDM patient with PJP infection. It is very important to take measures to deal with such a dangerous disease, in which prophylaxis against PJP may be a good method. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] It is proved that prophylaxis against PJP for rheumatic patients can significantly reduce the incidence of PJP without severe adverse event. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] The prophylaxis rate was only 4%(n\u0026thinsp;=\u0026thinsp;19) patients at admission in our IIM cohort, and merely 43(9.3%) patients had taken continuous anti-PJP prophylaxis since the treatment for IIM in our hospital. There is no recommendation for PJP management in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients. The data suggest the necessity of further study of PJP prophylaxis treatment in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients who may need a routine prophylaxis.\u003c/p\u003e \u003cp\u003eThe limitations of this study include were shown as following. First, the study of evaluating PJP occurrence in IIM was an observation study, a limitation inherent to observational studies; Second, the number of PCP cases in this study was rather small so we could not perform independent PJP occurrence factors in IIM or MDA5\u003csup\u003e+\u003c/sup\u003eDM. Third, the number of patients who take a PJP prophylactic treatment is too small for us to assess the prophylactic effect of trimethoprim-sulfamethoxazole in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients. there may need a randomized controlled study to compare the prophylactic effect and the prevalence of adverse events.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eIn conclusion, we show here that MDA5\u003csup\u003e+\u003c/sup\u003eDM patient is easy to be infected by pneumocystis jiroi which is hard to be cured than other background rheumatic disease. The reason related to the higher incidence and mortality may be associated with MDA5\u003csup\u003e+\u003c/sup\u003eDM which characterized by lower CD4 T cell counts and progressive interstitial lung disease. The data suggests the necessity of further study of PJP prophylaxis treatment in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients.\u003c/p\u003e "},{"header":"List Of Abbreviations","content":"\u003ctable\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003eAbbreviation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003eFull name\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003eMDA5+ DM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003eanti-melanoma differentiation associated gene 5 antibodies positive dermatomyositis\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003eMDA5-IIM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003eanti-melanoma differentiation associated gene 5 antibodies negative Idiopathic inflammatory myopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003ePJP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003epneumocystis\u0026nbsp;jiroveci\u0026nbsp;pneumonia\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003eIIM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003eIdiopathic inflammatory myopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003ePM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003epolymyositis\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"218\"\u003e\n\u003cp\u003eTMP-SMX\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"374\"\u003e\n\u003cp\u003etrimethoprim/sulfamethoxazole\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Renji Hospital, Shanghai, China.(2013-216).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo individual person\u0026rsquo;s data were presented in any form in this study, and therefore, no consent to publish is required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article [and its supplementary information files]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u003c/strong\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This work was supported by National Natural Science Foundation of China (No.81771752).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors discussed the results and contributed to the final manuscript. The authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Dr. An Sun for statistical analysis consultation and Ping Ye and Shuiying Li for clinical lab technique and follow-up support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTasaka S. Recent Advances in the Diagnosis and Management of Pneumocystis Pneumonia. Tuberc Respir Dis. 2020;83:132\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu C-Y, Ko C-H, Wang J-L, Hsu T-C, Lin C-Y. Comparing the burdens of opportunistic infections among patients with systemic rheumatic diseases: a nationally representative cohort study. Arthritis Res Ther. 2019;21:211.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas CF, Limper AH. Pneumocystis Pneumonia. N Engl J Med. 2004;350:2487\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCa M, Ac DS. G, L C-S. Pneumocystis jiroveci pneumonia in rheumatic disease: a 20-year single-centre experience. Clin Exp Rheumatol. 2017;35:671\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhellaf M, Godeau B. Pneumocystis pneumonia among patients with systemic diseases. Presse M\u0026eacute;dicale. 2009;38:251\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSabbagh SE, Neely J, Chow A, DeGuzman M, Lai J, Lvovich S, et al. Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America. Rheumatology. 2021;60:829\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsuji H, Nakashima R, Hosono Y, Imura Y, Yagita M, Yoshifuji H, et al. Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti\u0026ndash;Melanoma Differentiation\u0026ndash;Associated Gene 5\u0026ndash;Positive Dermatomyositis. Arthritis Rheumatol. 2020;72:488\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAymonier M, Abed S, Boy\u0026eacute; T, Barazzutti H, Fournier B, Morand J-J. Dermatomyositis associated with anti-MDA5 antibodies and pneumocystis pneumonia: Two lethal cases. Ann Dermatol V\u0026eacute;n\u0026eacute;r\u0026eacute;ologie. 2017;144:279\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTargoff IN, Miller FW, Medsger TA, Oddis CV. Classification criteria for the idiopathic inflammatory myopathies. Curr Opin Rheumatol. 1997;9:527\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKumar SD, Krieger BP. CD4 Lymphocyte Counts and Mortality in AIDS Patients Requiring Mechanical Ventilator Support due to Pneumocystis carinii Pneumonia. Chest. 1998;113:430\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAsai N, Motojima S, Ohkuni Y, Matsunuma R, Nakashima K, Iwasaki T, et al. Early diagnosis and treatment are crucial for the survival of Pneumocystis pneumonia patients without human immunodeficiency virus infection. J Infect Chemother. 2012;18:898\u0026ndash;905.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKo R-E, Na SJ, Huh K, Suh GY, Jeon K. Association of time-to-treatment with outcomes of Pneumocystis pneumonia with respiratory failure in HIV-negative patients. Respir Res. 2019;20:213.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA K, J O, Y I, H K. Risk factors for Pneumocystis carinii pneumonia in patients with polymyositis/dermatomyositis or systemic lupus erythematosus. J Rheumatol. 1996;23:1186\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group, editor. Cochrane Database Syst Rev [Internet]. 2014 [cited 2021 Mar 10]; Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://doi.wiley.com/10.1002/14651858.CD005590.pub3\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Zheng Y. Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases. Rheumatol Int. 2014;34:1765\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolfe RM, Peacock JE. Pneumocystis Pneumonia and the Rheumatologist: Which Patients Are At Risk and How Can PCP Be Prevented? Curr Rheumatol Rep. 2017;19:35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerrou J, De Lastours V. Predictive factors of pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids. Ann Rheum Dis. 2020;79:e23\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida Y, Takahashi Y, Minemura N, Ueda Y, Yamashita H, Kaneko H, et al. Prognosis of pneumocystis pneumonia complicated in patients with rheumatoid arthritis (RA) and non-RA rheumatic diseases. Mod Rheumatol. 2012;22:509\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFreiwald T, B\u0026uuml;ttner S, Cheru NT, Avaniadi D, Martin SS, Stephan C, et al. CD4(+) T cell lymphopenia predicts mortality from Pneumocystis pneumonia in kidney transplant patients. Clin Transplant. 2020;34:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmajuk G, Jafri K, Evans M, Shiboski S, Gianfrancesco M, Izadi Z, et al. Pneumocystis jirovecii pneumonia (PJP) prophylaxis patterns among patients with rheumatic diseases receiving high-risk immunosuppressant drugs. Semin Arthritis Rheum. 2019;48:1087\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark JW, Curtis JR, Moon J, Song YW, Kim S, Lee EB. Prophylactic effect of trimethoprim-sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids. Ann Rheum Dis. 2018;77:644\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Comparison of risk factors in PJP and non-PJP cases for IIM patients\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003ePJP\u003c/p\u003e\n\u003cp\u003e(n=14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003eNon-PJP\u003c/p\u003e\n\u003cp\u003e(n=449)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eMDA5\u003csup\u003e+\u003c/sup\u003eDM, n(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e12(85.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e148(33.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"57\"\u003e\n\u003cp\u003e0.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eNon-MDA5 IIM, n(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2(14.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e301(67.0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003emale gender, n(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e6(42.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e135(30.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.376\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eassess age, mean \u0026plusmn; SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e54\u0026plusmn;10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e53\u0026plusmn;12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.635\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eDisease duration, year, median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eILD(%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e13(92.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e316(70.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.077\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" width=\"575\"\u003e\n\u003cp\u003eMedications three month before PCP infection, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eCorticosteroid (\u0026ge;20mg pred，\u0026ge;1month)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e10(71.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e226(50.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003e\u003cstrong\u003eCorticosteroid, \u003c/strong\u003emg, median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eCyclophosphamide\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1(7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e39(87.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eMethotrexate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e0(0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e43(9.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.630\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eAzathioprine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e0(0%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e35(7.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.614\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eCyclosporine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5(35.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e73(16.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.069\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eTacrolimus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4(28.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e55(12.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.089\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eMycophenolate Mofetil\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1(7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e28(6.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.601\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003ehydroxychloroquine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5(35.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e104(23.2%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.334\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eBiologics\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1(7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e16(3.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.412\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"331\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1(7.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e83(18.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.482\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eDiabetes, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e6(42.9%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e61(13.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eESR, mm/h, median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e34.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.085\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eCK, U/L, median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e26.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e67.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eLDH, U/L, median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e464.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e321\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.028\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eFerritin, ug/ml,median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1122\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e341\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003ePre-albumin, g/L,median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e208.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e214\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.832\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eAlbumin, mg/L,median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e29.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e32.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eCD4\u003csup\u003e+\u003c/sup\u003e T cell counts at admission x10^9/L,median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e113.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e350.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eLymphocyte counts at admission x10^9/L,median\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e0.695\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"1\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"330\"\u003e\n\u003cp\u003eThe lowest lymphocyte count x10^9/L,median（during hospitalization）\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"95\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"57\"\u003e\n\u003cp\u003e0.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr /\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Risk factors for 3-month mortality of PJP with rheumatic disease\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"236\"\u003e\n\u003cp\u003eUnivariable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"218\"\u003e\n\u003cp\u003eMultivariable\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eClinical factors\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eHR(95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003eHR(95%CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eAssessed age\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.981(0.951-1.012)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.225\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e0.975(0.940-1.010)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e0.158\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eGender\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.437(0.207-0.923)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.798\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eMDA5\u003csup\u003e+\u003c/sup\u003eDM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e2.830(1.067-7.505)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.037\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e3.254(1.209-8.756)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eAAV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.674(0.089,5.099)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.702\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eSLE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e1.062(0.346,3.265)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.916\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eCD4\u003csup\u003e+\u003c/sup\u003e T cell counts\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.995(0.989-1.001)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.083\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e0.994(0.989-1.000)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003elymphocyte counts\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.142(0.025-0.808)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.028\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eInterstitial lung disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e1.537(0.540-4.375)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.421\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eSteroid dose\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.291(0.063,1.350)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.115\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eCyclophosphamide\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e1.807(0.586,5.568)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.303\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eRituximab\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e0.854(0.113,6.450)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.878\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003eTime to anti-PJP treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"186\"\u003e\n\u003cp\u003e1.577(0.607-4.099)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"50\"\u003e\n\u003cp\u003e0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"74\"\u003e\n\u003cp\u003e*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;CI, confidence interval;\u003c/p\u003e\n\u003cp\u003e*Not included in the multivariable model due to lack of significant association in the univariable analysis;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"arthritis-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arrt","sideBox":"Learn more about [Arthritis Research \u0026 Therapy](http://arthritis-research.biomedcentral.com/)","snPcode":"13075","submissionUrl":"https://submission.nature.com/new-submission/13075/3","title":"Arthritis Research \u0026 Therapy","twitterHandle":"@ArthritisRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"anti-MDA5-antibody-positve dermatomyositis, Pneumocystis jiroveci pneumonia, incidence, mortality, treatment","lastPublishedDoi":"10.21203/rs.3.rs-344084/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-344084/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eIdiopathic inflammatory myopathies (IIM) was associated with a significantly higher risk of opportunistic infections that including Pneumocystis jiroveci pneumonia (PJP), a potentially fatal opportunistic infection. However, no prior studies have evaluated the PJP infection in subtypes of IIM.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo investigate the incidence rate and mortality rate of PJP infection in subgroups of Idiopathic inflammatory myopathies (IIM) patients according to myopathy specific antibodies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn the first part, 463 consecutive patients with IIM were prospectively followed up for a period of at least one year to analyze incidence of PJP. In the next part, we enrolled 30 consecutive PJP patients with any rheumatic disease were to identify the mortality rate and risk factors by Cox regression. Kaplan-Meier curve with log-rank test was used to access differences in survival.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe found that the incidence rate of PJP in IIM patients is 3.0/100 person-year, while in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients is 7.5/100 person-year and in MDA5\u003csup\u003e\u0026minus;\u003c/sup\u003eIIM patients is 0.7/100 person-year. (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). PJP typically happened in the first two months for MDA5\u0026thinsp;+\u0026thinsp;DM patients who have a significant decrease in the CD4\u003csup\u003e+\u003c/sup\u003e T cell counts and Lymphocyte counts (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In PJP\u0026thinsp;+\u0026thinsp;patients, the mortality was lethally higher in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients than those with other rheumatic diseases (83.3% VS. 38.9%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Unlike patients with other rheumatic diseases, MDA5\u0026thinsp;+\u0026thinsp;patients seemed not to benefit from prompt anti-PJP treatment. For patients with other rheumatic diseases, anti-PJP treatment within 6 days was confirmed to crucially increased the survival (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePJP has alarming high incidence and mortality in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients. Timely treatment for PJP does not improve the prognosis of this particular subtype. Therefore, the necessity of further study of PJP prophylaxis treatment in MDA5\u003csup\u003e+\u003c/sup\u003eDM patients is verified.\u003c/p\u003e","manuscriptTitle":"High Incidence and Mortality of Pneumocystis Jiroveci Infection in Anti-MDA5-Antibody Positive Dermatomyositis: Experience From a Single Center","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-30 17:40:18","doi":"10.21203/rs.3.rs-344084/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-05-19T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-04-18T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-04-18T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-04-05T00:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-04-03T01:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-04-03T00:00:00+00:00","index":0,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-04-03T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-04-02T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-03-22T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-03-21T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-03-21T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Arthritis Research \u0026 Therapy","date":"2021-03-19T03:28:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"arthritis-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arrt","sideBox":"Learn more about [Arthritis Research \u0026 Therapy](http://arthritis-research.biomedcentral.com/)","snPcode":"13075","submissionUrl":"https://submission.nature.com/new-submission/13075/3","title":"Arthritis Research \u0026 Therapy","twitterHandle":"@ArthritisRes","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4de5ccb9-fba5-4eb5-a5cd-37f6c5666080","owner":[],"postedDate":"March 30th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":3295298,"name":"Rheumatology"}],"tags":[],"updatedAt":"2021-08-16T08:35:48+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-30 17:40:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-344084","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-344084","identity":"rs-344084","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}