The muscle tissue transcriptome of idiopathic inflammatory myopathy reflects the muscle damage process by monocytes and presence of skin lesions.

OBJECTIVE: To investigate transcriptomic and immunophenotypic features of muscle specimens from patients with idiopathic inflammatory myopathy (IIM). METHODS: Bulk RNA-sequencing was performed on muscle biopsy samples from 16 patients with dermatomyositis (DM) and 9 patients with polymyositis (PM). Seven tested positive for anti-aminoacyl t-RNA synthetase antibodies in the DM patients (ARS-DM). We conducted weighted gene coexpression network analysis (WGCNA), differentially expressed gene (DEG) analysis, and gene set variation analysis (GSVA) to assess contributions of specific pathways. Cell proportions in muscle specimens were estimated using a deconvolution approach. RESULTS: WGCNA revealed significant positive correlations between serum creatine kinase (CK) levels and gene modules involved in cellular respiration, phagocytosis, and oxidative phosphorylation (OXPHOS). Significant positive correlations were also observed between CK levels and proportions of CD16-positive and -negative monocytes and myeloid dendritic cells. Notably, DM patients demonstrated enrichment of complement and interferon-α and -γ pathway genes compared to those with PM. Furthermore, ARS-DM demonstrated a higher proportion of Th1 cells and DEGs related to OXPHOS. Additionally, serum Krebs von den Lungen-6 levels correlated with gene modules associated with extracellular matrix and transforming growth factor-ß signaling pathway. CONCLUSION: Our study highlights a significant involvement of monocytes in muscle damage and delineates pathological differences among IIM subtypes. DM was characterized by complement, interferon-α and -γ signaling, whilst ARS-DM was associated with OXPHOS. Distinctive gene expression variations in muscle specimens suggest that different pathologic mechanisms underlie muscle damage in each IIM phenotype.

Machine learning-driven immunophenotypic stratification of mixed connective tissue disease corroborating the clinical heterogeneity.

OBJECTIVES: To stratify patients with mixed connective tissue disease (MCTD) based on their immunophenotype. METHODS: We analyzed the immunophenotype and transcriptome of 24 immune cell subsets from patients with MCTD, systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM), and systemic sclerosis (SSc) from our functional genome database, ImmuNexUT (https://www.immunexut.org/). MCTD patients were stratified by employing machine learning models including Random Forest, trained by immunophenotyping data from SLE, IIM, and SSc patients. Transcriptomes were analyzed with gene set variation analysis (GSVA) and clinical features of MCTD subgroups were compared. RESULTS: This study included 215 patients, including 22 patients with MCTD. Machine learning models, constructed to classify SLE, IIM, and SSc patients based on immunophenotyping, were applied to MCTD patients, resulting in 16 classified as SLE-immunophenotype and 6 as non-SLE-immunophenotype. Among MCTD patients, patients with the SLE-immunophenotype had higher proportions of Th1 cells [2.85% (interquartile range (IQR) 1.54-3.91) vs 1.33% (IQR 0.99-1.74) p= 0.027] and plasmablasts [6.35% (IQR 4.17-17.49) vs 2.00% (IQR 1.20-2.80) p= 0.010]. Notably, the number of SLE-related symptoms was higher in patients with the SLE-immunophenotype [2.0 (IQR 1.0-2.0) vs 1.0 (IQR1.0-1.0) p= 0.038]. Moreover, GSVA scores of interferon-α and -γ responses were significantly higher in patients with the SLE-immunophenotype in central memory CD8+ T cells, while hedgehog signalling was higher in non-SLE-immunophenotype patients in 5 cell subsets. CONCLUSION: This study describes the stratification of MCTD patients based on immunophenotyping, suggesting the presence of distinct immunological processes behind the clinical subtypes of MCTD.

Characteristics of anti-melanoma differentiation associated gene 5 antibody-positive dermatomyositis with thrombotic microangiopathy.

OBJECTIVES: Anti-melanoma differentiation associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) is a representative of rapidly progressive interstitial pneumonia. However, its association with thrombotic microangiopathy (TMA), characterized by thrombocytopenia, haemolytic anaemia, and organ dysfunction, has not been defined. This study aimed to elucidate the characteristics of anti-MDA5 Ab-positive DM accompanied by TMA. METHODS: We reviewed our hospital records from November 2009 to September 2022. We included patients in accordance with the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria and the criteria of Bohan and Peter. TMA was diagnosed according to the criteria for transplantation-associated TMA proposed by the International Working Group. RESULTS: This study enrolled a total of 26 anti-MDA5 Ab-positive DM patients, four of whom developed TMA. The patients with TMA had an increased urine protein/creatinine ratio. In addition, these four of them showed significantly elevated levels of ferritin and anti-MDA5 Ab titers and were considered to have high disease activity; yet, all of them survived. CONCLUSIONS: Our study indicated that anti-MDA5 Ab-positive DM patients with hyperferritinemia, a high anti-MDA5 Ab titer, and an increased urine protein/creatinine ratio should be carefully managed, bearing in mind a complication of TMA.

Long-term risks of malignancy in myositis-specific antibody-positive idiopathic inflammatory myopathy.

To identify the long-term risks of malignancy in patients with myositis-specific antibody (MSA)-positive idiopathic inflammatory myopathy (IIM). This retrospective cohort study included 216 IIM patients (aged > 18 years). Of these, 109 patients were positive for antibodies against anti-aminoacyl-tRNA synthetase (ARS), melanoma differentiation-associated gene 5 (MDA5), Mi-2, and transcriptional intermediary factor 1-γ (TIF1-γ). Age- and sex-matched standardized incidence ratios (SIRs) were calculated to compare the incidence of malignancy in IIM patients to that of the general population. The malignancy-free survival rate was estimated by Kaplan-Meier methods. Our study included 109 patients, 64 with anti-ARS, 28 with anti-MDA5, 9 with anti-Mi-2, and 8 with anti-TIF1-γ antibodies; 16 and 5 patients were diagnosed with a malignancy within 3 years before or after and within 4 to 10 years after their IIM onset, respectively. The SIRs of malignancy within 3 years of IIM onset for each MSA were calculated as follows: 2.12 (95% confidence interval [CI] 0.98-4.35) for anti-ARS, 1.87 (95% CI 0.48-4.97) for anti-MDA5, 2.11 (95% CI 0.11-13.69) for anti-Mi-2, and 9.30 (95% CI 2.98-25.58) for anti-TIF1-γ antibodies. The SIR at 4 to 10 years after IIM onset in patients with an anti-MDA5 antibody was 4.62 (95% CI 1.19-14.72); other MSAs did not have statistically significant SIRs. The long-term SIR of malignancy in patients with an anti-MDA5 antibody was 4.62 (95% CI 1.19-14.72), and the SIR among patients with an anti-TIF1-γ antibody within 3 years of IIM onset was 9.30 (95% CI 2.98-25.58). Screening for malignancies in patients with late phase of IIM and an anti-MDA5 antibody may be beneficial.

Self-limited Polymyalgia Rheumatica-like Syndrome Following mRNA-1273 SARS-CoV-2 Vaccination.

Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease characterized by stiffness and aching mainly in the shoulders, neck and hip girdles. The underlying pathogenesis of PMR involves myeloid lineage activation with a high expression of pattern recognition receptors. In addition, vaccination against severe acute respiratory syndrome coronavirus 2 with mRNA-1273 functions as both an immunogen and intrinsic adjuvant. It leads to the activation of innate immunity, resulting in antibody production. We herein report the first case of PMR-like syndrome seven days after mRNA-1273 vaccination. Reassuringly, the symptoms, such as pain of the neck, shoulder girdle and pelvic girdle, as well as elevated inflammatory markers were resolved within a month without glucocorticoid or immunosuppressant administration.

Hypertrophic pachymeningitis in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is one of the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), which is characterised by systemic small vessels vasculitis with associated eosinophilia. Hypertrophic pachymeningitis (HP) is an inflammatory disease in which the cerebral or spinal dura mater is thickened. AAV other than EGPA may sometimes develop HP; however, patients with EGPA rarely develop HP. This is the case of myeloperoxidase-ANCA-positive EGPA that presented with headache and blurred vision and was diagnosed with HP. It was successfully treated with pulsed steroid therapy and intravenous cyclophosphamide without any relapse for more than 4 years.

Adverse drug reactions to trimethoprim-sulfamethoxazole in systemic lupus erythematosus.

OBJECTIVES: Trimethoprim-sulfamethoxazole (TMP-SMX), a prophylactic agent against pneumocystis pneumonia (PCP), can cause adverse drug reactions (ADRs), particularly in patients with systemic lupus erythematosus (SLE). However, the risk factors for ADRs remain unclear. Thus, we sought to examine the prevalence of TMP-SMX-related ADRs in patients with SLE and identify specific risk factors for ADR development in these patients. METHODS: We retrospectively reviewed data from patients with connective tissue disease (CTD) who were administered TMP-SMX as a PCP prophylactic. The prevalence of ADRs was compared between patients with SLE and those with other CTDs. Univariate and multivariate analyses were conducted to identify risk factors for ADRs in patients with SLE. RESULTS: Of the 424 patients with CTD included in our study (SLE, n = 162; other CTDs, n = 262), 22 with SLE (13.6%) developed ADRs, and this rate was significantly higher than that observed in patients with non-SLE CTDs (n = 18 [6.9%], p = 0.033). In patients with SLE, univariate analyses revealed direct associations of ADRs with anti-Sm (p < 0.001), anti-RNP (p = 0.02), and anti-Ro/SS-A antibodies (p = 0.042). Multivariate analysis identified a significant association between anti-Sm antibody levels and the development of ADRs (adjusted odds ratio 5.27, 95% confidence interval 1.80-15.40, p = 0.002). CONCLUSIONS: Patients with SLE who are prophylactically administered TMP-SMX are at high risk of ADRs. Among these patients, those who display a positive anti-Sm antibody should be carefully monitored for ADRs.

A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.

BACKGROUND: Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures. CASE PRESENTATION: A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously. CONCLUSIONS: Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.

Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: clinical features and prognosis.

OBJECTIVES: RA-associated interstitial lung disease (RA-ILD) is commonly associated with acute exacerbations (ILD-AE). This study examined the clinical characteristics and risk factors of ILD-AE and mortality of RA-ILD. METHODS: We retrospectively collected data on 165 RA-ILD patients who visited or were admitted to our hospital between January 2007 and December 2019. We compared the clinical characteristics of patients who did and did not develop ILD-AE and identified variables significantly associated with ILD-AE. We also compared the admission characteristics of those who survived and those who died after admission for ILD-AE. ILD-AE was defined using previously proposed criteria, modified slightly for application to RA-ILD. RESULTS: The mean patient age was 73.6 years (s.d. 9.7) and 97 (71.9%) patients were female. Thirty (22.2%) patients developed ILD-AE, 13 (43.3%) of whom died. In univariate analyses, neither the usual interstitial pneumonia (UIP) pattern nor MTX was associated with ILD-AE. In multivariate analyses, the UIP pattern was significantly associated with ILD-AE [odds ratio (OR) 2.55 (95% CI 1.05, 6.20), P = 0.038]. In the Cox proportional hazards model, the UIP pattern [hazard ratio (HR) 4.67 (95% CI 1.02, 21.45), P = 0.048] was significantly associated with death, while MTX use [HR 0.16 (95% CI 0.04, 0.72), P = 0.016] was significantly associated with survival. CONCLUSION: Our data suggest that the UIP pattern is related to ILD-AE. Furthermore, both the UIP pattern and non-use of MTX might be related to death from ILD-AE in RA-ILD.

Non-COVID-19 Patients with Life-threatening Diseases Who Visited a Fever Clinic: A Single-center, Observational Study in Tokyo, Japan.

Objective In fever clinics screening coronavirus disease (COVID-19), there could be patients with life-threatening diseases that physicians should not overlook. We exploratorily investigated the final diagnosis among non-COVID-19 hospitalized patients who visited the fever clinic. Methods This was a retrospective, observational, and single-centered study conducted in the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. We conducted a retrospective chart review of patients who visited the fever clinic in the NCGM from 11 March 2020 to 24 April 2020. Patients Patients who met the following clinical criteria visited the fever clinic in the NCGM: (1) body temperature >37.5°C, (2) any symptoms consistent with COVID-19 or (3) referral from local healthcare facilities. In the fever clinic, all patients who met the above criteria had severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test with nasopharyngeal swab specimens. Patients with severe symptoms or an unstable condition were sent to an outpatient clinic for infectious diseases for further evaluation and treatment. Results Among 1,470 patients who visited the fever clinic, 84 patients were hospitalized, and 45 of them were diagnosed as having COVID-19. Among the remaining 39 non-COVID-19 patients, there were nine patients with life-threatening diseases. The life-threatening diseases included acute heart failure, septic shock, pneumocystis pneumonia, peritonsillar abscess, and necrotizing fasciitis. Conclusion Physicians should evaluate each patient carefully while considering other life-threatening conditions even in such a COVID-19 pandemic era.