Although other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) are rare, they are important adverse effects of immunosuppressive therapies. Even though anti-melanoma differentiation association gene 5 (MDA5) antibody-positive dermatomyositis requires multidrug immunosuppressive therapy for interstitial pneumonia control, OIIA-LPD has rarely been reported. Moreover, central nervous system (CNS) OIIA-LPD has never been documented. Here, we report a case of CNS OIIA-LPD that may have been caused by treatment for MDA5 antibody-positive dermatomyositis. A 53-year-old woman was diagnosed with MDA5 dermatomyositis and treated for rapidly progressive interstitial lung disease using multidrug immunosuppressive therapy with prednisolone (PSL), tacrolimus, and intravenous cyclophosphamide pulse therapy. Seven months after treatment initiation, vomiting led to the discovery of a cerebellar tumour. The cerebellar tumour was histologically Epstein-Barr virus (EBV)-encoded small RNA-positive diffuse large B-cell lymphoma, with EBV-DNA being positive in the blood. The patient was diagnosed with OIIA-LPDs due to EBV reactivation. Chemotherapy, including high-dose methotrexate (MTX) and rituximab, prevented tumour recurrence without exacerbating interstitial lung disease. This is the first reported case of CNS OIIA-LPD with multidrug immunosuppression in a patient with MDA5 dermatomyositis. Chemotherapy, including high-dose MTX and rituximab, can be used for central OIIA-LPD without aggravating settled interstitial lung disease. The activity of MDA5 dermatomyositis during OIIA-LPD treatment may be managed with low-dose PSL.

INTRODUCTION:Clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) with rapidly progressive interstitial lung disease (RP-ILD) is often refractory for intensive immunosuppression. In this study, we verified the effectiveness and safety of plasma exchange (PEx) for this lethal disease.METHODS:We retrospectively examined the clinical course and adverse effect (AE) of 12 patients with anti-MDA5 Ab-positive CADM between January 2017 and December 2021 in our hospital.RESULTS:Five out of six patients treated with simple PEx using fresh frozen plasma or 5% albumin survived with or without home oxygen therapy. Multiple PEx (15-20 times) were required to achieve satisfactory improvement as well as remission of CADM. The AEs caused by PEx were resolved using conventional methods.CONCLUSION:PEx might be a promising option for controlling the disease activity of anti-MDA5 Ab-positive CADM with severe RP-ILD and may contribute to better survival.

Objective Antimelanoma differentiation–associated gene 5 (anti-MDA5)–positive dermatomyositis with interstitial lung disease (DM-ILD) progresses rapidly and has a poor prognosis. Previously, we reported the efficacy of a combination therapy comprising high-dose glucocorticoids (GCs), calcineurin inhibitors (CNIs), and intravenous cyclophosphamide (IV CYC) in a multicenter clinical trial (UMIN000014344). In the present study, we evaluated the long-term outcomes and effects of induction therapy on the maintenance of remission. Methods All participants from our previous trial were followed up for > 5 years. Seventy-three other patients with anti-MDA5–positive DM-ILD from our institute were retrospectively integrated into the previous trial for further analysis. Sixty-eight patients achieved remission and survived for > 6 months. Based on the induction treatment, we classified the patients into 2 groups: (1) group T (n = 56), with triple combination therapy (GCs, CNIs, and IV CYC), and (2) group C (n = 12), with monotherapy/dual therapy. The recurrence-free and drug-withdrawal rates of immunosuppressive agents were compared. Results The overall survival and recurrence-free survival rates at 5 years were 100% for the participants in the previous trial. The 5-year cumulative withdrawal rates for CNIs and GCs were 70% and 53%, respectively. In a comprehensive analysis, the recurrence-free rates in group T were higher than those in group C (90% vs 56%; P < 0.05). The drug-withdrawal rates of CNIs and GCs at 10 years in group T were also higher than those in group C (79% vs 0% and 43% vs 0%, respectively; P < 0.05). Conclusion Triple combination therapy in the induction phase can reduce the risk of recurrence and facilitate drug withdrawal in anti-MDA5–positive DM-ILD.

To the Editor: We thank Mutoh et al1 for their interest in our study on antimelanoma differentiation-associated gene 5 antibody–positive interstitial lung disease (anti-MDA5-ILD) after vaccination with coronavirus disease 2019 (COVID-19) mRNA vaccines2 and for sharing their clinical experience. Mutoh et al1 reported a case of anti-MDA5-ILD that developed 8 weeks after COVID-19 mRNA vaccination in Japan. This case is similar to the cases that we have encountered. A recent literature review also reported 7 cases of anti-MDA5-ILD after COVID-19 vaccination.3 Collectively, these cases provide evidence of an association between vaccination with COVID-19 mRNA vaccines and anti-MDA5-ILD, and suggest the possibility of COVID-19 mRNA-vaccine-induced anti-MDA5-ILD. However, these cases do … Address correspondence to Dr. T. Kitajima, Respiratory Disease Center, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan. Email: m-kitajima{at}kita-no-hp.or.jp.

ObjectiveMelanoma differentiation-associated gene 5 (MDA5) is a viral RNA sensor induced by SARS-CoV-2. Similarities have been reported between the clinical presentations of coronavirus disease 2019 (COVID-19) pneumonia and anti-MDA5 antibody–positive interstitial lung disease (anti-MDA5-ILD). However, it is unknown whether COVID-19 mRNA vaccines are associated with anti-MDA5-ILD.MethodsWe retrospectively reviewed consecutive patients with anti-MDA5-ILD admitted to our hospital between April 2017 and March 2022. In addition, we investigated the clinical presentations of patients who developed anti-MDA5-ILD after vaccination with COVID-19 mRNA vaccines. We also examined the annual number of anti-MDA5-ILD cases before and after the COVID-19 vaccination campaign.ResultsNine patients with anti-MDA5-ILD were seen during the study period, of whom 4 developed anti-MDA5-ILD between August and October 2021, approximately 6 to 12 weeks after vaccination with a COVID-19 mRNA vaccine and a few months after the rapid mRNA COVID-19 vaccination campaign in Japan. None of the 4 patients had evidence of SARS-CoV-2 infection. The difference in the annual number of anti-MDA5-ILD cases before vs after the COVID-19 vaccination campaign (1.25 ± 0.96 cases/yr vs 4.0 cases/yr) was not statistically significant (P= 0.08).ConclusionWe encountered 4 cases of anti-MDA5-ILD after COVID-19 vaccination. Further large population studies are needed to clarify the relationship between anti-MDA5-ILD and vaccination with COVID-19 mRNA vaccines.

Objectives. To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. Methods. Treatment naive adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). Results. Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (S.E.M.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar. Conclusion. BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions.

Background The anti-cyclic citrullinated peptide (CCP) antibody is a diagnostic biomarker of rheumatoid arthritis (RA). However, some non-RA connective tissue disease (CTD) patients also test positive for the anti-CCP antibody and, thus, may ultimately develop RA. We retrospectively investigated whether anti-CCP-positive non-RA CTD patients developed RA and attempted to identify factors that may differentiate RA-overlapping CTD from pure CTD. Methods In total, 842 CTD patients with a primary diagnosis that was not RA were selected from our CTD database as of December 2012. Anti-CCP antibody titers were obtained from a retrospective chart review or measured using stored sera. RA was diagnosed according to the 1987 revised American College of Rheumatology classification criteria. Thirty-three anti-CCP-positive non-RA CTD patients were retrospectively followed up for the development of RA. Bone erosions on the hands and feet were assessed by X-ray. Citrullination dependency was evaluated by an in-house ELISA, the HLA-DRB1 allele was typed, and the results obtained were then compared between RA-overlapping and non-RA anti-CCP-positive CTD patients. Results Two out of 33 anti-CCP-positive CTD patients (6.1%) developed RA during a mean follow-up period of 8.9 years. X-rays were examined in 27 out of the 33 patients, and only one (3.7%) showed bone erosions. The frequency of the HLA-DRB1 shared epitope (SE) and anti-CCP antibody titers were both significantly higher in anti-CCP-positive RA-overlapping CTD patients than in anti-CCP-positive non-RA CTD patients, while no significant differences were observed in citrullination dependency. Conclusions Anti-CCP-positive non-RA CTD patients rarely developed RA. HLA-DRB1 SE and anti-CCP antibody titers may facilitate the differentiation of RA-overlapping CTD from anti-CCP-positive non-RA CTD.

A. Tsuchiyama1,2, A. Takigawa3,4, T. Hirose3, H. Kawano3, Y. Imura3, S. Enju3, Y. Igami5, 1Research Organization of Science and Technology, Ritsumeikan University (atsuchi@fc.ritsunei.ac.jp), 2Guangzhou Institute of Geochemistry, 3Graduate School of Science, Kyoto University, 4The Hakubi Center for Advanced Research, Kyoto University. 5Institute of Materials and Systems for Sustainability, Nagoya University.

Background: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and infiltration of IgG4 plasma cells into multiple organs. It is not known whether serum IgG4 is autoreactive in IgG4-RD. Methods: We measured anti-nuclear antibody (ANA) in 19 IgG4-RD cases, determined IgG subclasses of the ANA, and compared them with those of other systemic autoimmune diseases (systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, and polymyositis), using subclass-based ANA test (indirect immunofluorescence). Results: 58 % of IgG4-RD cases were ANA-positive (cut-off: 1:40). Whereas their subclass of ANA was predominantly IgG2, we observed no IgG4-type ANA. In systemic autoimmune diseases, subclasses of ANA were mostly IgG1, 2, or 3, but IgG4-type ANA was very rarely detected. We also found several patients in whose serum ANA patterns differed among IgG subclasses, probably due to the difference of corresponding autoantigens. Conclusions: Although IgG4 is highly elevated in sera of IgG4-RD patients, their ANA do not include IgG4 subclass. These results offer new insight into the role of IgG4 and the pathogenesis of IgG4-RD, implying that each IgG subclass tends to cover its own spectrum of antigens, and IgG4 is not preferentially used to make ANA.

Abstract Objective: To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice. Patients and methods: RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde’s modified Total Sharp Score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined. Results: Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = .007) and slower radiographic progression (shown as ‘baseline mTSS/year <3’, OR = 3.727, p = .004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment. Conclusion: Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.

Interstitial lung disease (ILD) with dermatomyositis often requires intensive immunosuppressive therapy. Here, we report two cases of pulmonary alveolar proteinosis (PAP) in dermatomyositis with ILD. One case was secondary PAP, and the other was autoimmune PAP positive for the anti-granulocyte macrophage-colony-stimulating factor antibody. PAP arose during immunosuppressive therapy and symptoms ceased by attenuating immunosuppression. Exacerbation of pulmonary lesions during intensive immunosuppressive therapy may distinguish PAP from worsening ILD and attenuating immunosuppression should be considered.

Background Takayasu arteritis (TAK) is a type of large vessel vasculitis, which affects aorta and its main branches. We previously found a single nucleotide polymorphism (SNP), rs6871626 located in IL12B region, as a susceptible gene to TAK and reported that the risk allele at the SNP is associated with the risk of aortic regurgitation (AR)1). However, there have been no studies on the association of the SNP with the organ involvements other than AR in TAK patients. Objectives To investigate the association of the SNP with arterial and organ involvements except for AR. Methods We examined the medical records of 85 patients with TAK, stratified them into three groups according to the allele at the SNP, AA (n=26), AC (n=43) and CC (n=16) (A is a risk allele), and investigated the association of the SNP and organ involvements. Results There were no differences in the complication rates of carotid arterial lesions among the groups (AA 78.9%, AC 63.9% and CC 80.0%). The proportion of patients with lesions in descending aorta (Numano classification2) IIb∼V) was 75.0% in AA, 44.2% in AC 44.2% and 25.0% in CC and the proportion in AA was significantly higher than in CC (p=0.0096). Moreover, estimated glomerular filtration rate (eGFR) was significantly lower in AA than in CC (61.3±26.9ml/min/1.73m2 vs. 81.5±28.8 ml/min/1.73m2, p=0.042). Conclusions The SNP rs6871626 located in IL12B may influence on the occurrence of descending aortic lesions in TAK patients and this may lead to renal dysfunction. References Terao C et al. Am J Hum Genet. 2013; 93(2): 289–97. Hata A et al. Int J Cardiol. 1996; 54 Suppl: S155–163. Disclosure of Interest None declared

Anti-centromere antibody (ACA) is one of the classical anti-nuclear antibody (ANA) staining patterns. However, characteristics of ACA in comparison with the other ANA patterns and clinical features of ACA-positive subjects have not been elucidated. Here, we examined all ANA patterns by indirect immunofluorescence for 859 rheumatoid arthritis (RA) patients. Together with the ANA data of 9,575 healthy volunteers, we compared distributions of the ANA levels. ACA was the only ANA that demonstrated a definite bimodal distribution of levels. ACA showed significantly higher levels than the other ANA staining patterns in both RA and healthy population (p < 0.0001). ACA-positivity was associated with old age and was observed more in females. We further recruited another cohort of 3,353 RA patients and confirmed the findings. ACA was also associated with Raynaud’s phenomenon (p = 6.8 × 10−11) in RA. As a conclusion, ACA displays a specific ANA staining pattern with a bimodal distribution, and ACA-positive RA may constitute a distinct subset with specific clinical features.

A 63-year-old male visited our hospital after bilateral apical lung masses were detected on medical check-up chest X-ray. Histopathology of the resected mass revealed storiform fibrosis with an increased number of immunoglobulin G4 (IgG4)-positive plasma cells, compatible with IgG4-related disease (IgG4-RD). The patient was subsequently followed up without treatment for 3 years. Later, at age 66, he revisited our hospital because of scleritis, proteinuria, and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) positivity (179 U/ml). A renal biopsy revealed pauci-immune necrotising crescentic glomerulonephritis. After high-dose prednisolone (PSL) was started, the patient's scleritis subsided and his MPO-ANCA level and proteinuria were decreased. Subclass-based indirect immunofluorescence revealed that the patient's serum was positive for IgG1-type ANCA but negative for IgG4-type ANCA. Including the present case, there have been nine reported cases involving both biopsy-proven IgG4-RD and ANCA-associated vasculitis (AAV). In all these concomitant cases of IgG4-RD and AAV, PSL and immunosuppressants were used to control AAV. Deliberate care should be taken to distinguish between IgG4-RD and AAV at diagnosis as they have overlapping features and can, though very rarely, occur concomitantly.

BACKGROUND:Interstitial lung disease (ILD) is strongly associated with polymyositis (PM), dermatomyositis (DM), and clinically amyopathic dermatomyositis (CADM). It is also related to mortality. Previous studies have highlighted that the acute form of PM/DM/CADM-associated ILD (PM/DM/CADM-ILD) has a poor short-term prognosis. However, little is known about the long-term clinical features of patients with PM/DM/CADM-ILD. The aim of the present study is to clarify the clinical characteristics and the predictive factors for long-term outcomes in patients with PM/DM/CADM-ILD. METHODS:Thirty-four patients with PM/DM/CADM-ILD who were followed up for more than 12 months were analyzed retrospectively. The patients were classified as "stable" or "deterioration" according to respiratory symptoms, serial changes in forced vital capacity (FVC) or arterial oxygen pressure, and radiologic findings during the follow-up period. RESULTS:Twenty-six patients (76%) were in the stable group and eight patients (24%) were in the deterioration group. Home oxygen therapy was performed in six cases in the deterioration group because of chronic respiratory failure due to progression of ILD. The deterioration group, in comparison to the stable group, had a significantly lower %FVC and a higher positive rate for the anti-PL-7 antibody. Multivariate logistic regression analysis revealed that a positive anti-PL-7 antibody test and a lower %FVC were independently associated with deterioration during long-term follow-up. CONCLUSIONS:Patients with PM/DM/CADM-ILD are at risk for chronic respiratory failure due to the deterioration of ILD during long-term follow-up. The presence of anti-PL-7 antibody and a lower %FVC at initial diagnosis may predict long-term deterioration in patients with PM/DM/CADM-ILD.

BACKGROUND:A previous study revealed the association between susceptibility to Takayasu arteritis (TAK) and a single nucleotide polymorphism (SNP) rs6871626 located in IL12B, which encodes interleukin (IL)-12p40, a common component of IL-12p70 and IL-23. We investigated the expression of these cytokines in patients with TAK, stratifying them into those with or without the risk allele at the rs6871626 SNP.METHODS:Plasma levels of IL-12p40, IL-12p70, and IL-23 were quantified in 44 patients with TAK and 19 healthy controls (HCs) by enzyme-linked immunosorbent assays. Monocytes were obtained from 20 patients with TAK and 14 HCs, treated with interferon-γ (IFN-γ) and lipopolysaccharide, and then supernatant cytokines were quantified. In addition, the ratio of IFN-γ+ or IL-17A+ cells to CD4+ T cells was measured by flow cytometric analysis of peripheral blood mononuclear cells.RESULTS:The levels of plasma IL-12p40, plasma IL-12p70, and supernatant IL-12p70 were significantly higher in patients with TAK than in HCs, whereas there were no significant differences in the levels of plasma IL-23, supernatant IL-23, or supernatant IL-12p40. The levels of plasma IL-12p70, supernatant IL-12p40, and supernatant IL-12p70 were significantly higher in patients with the risk allele than in those without. The ratio of CD4+IFN-γ+ cells was significantly higher in patients with the risk allele, whereas CD4+IL-17A+ cells showed no differences.CONCLUSIONS:The rs6871626 SNP in IL12B may influence the increased expression of IL-12p40 and IL-12p70. These enhanced cytokines might play roles in the pathophysiology of TAK.

Background Previously it has been described that lipid and lipid mediators are present in synovial fluid from patients with rheumatoid arthritis (RA). It is, however, currently unknown to what extent these lipid mediators are involved in disease pathophysiology. Objectives The aim of this study is to clarify which lipid mediators in plasma correlate with disease activity of RA. Methods We obtained blood from RA patients registered in the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) cohort. None of the patients was treated with glucocorticoids or NSAIDs, both of which could affect lipid metabolism. Targeted lipidomics, using a LC–MS/MS (liquid chromatography–tandem mass spectrometry) platform was used for the identification of lipids present in the patients9 plasma. SDAI (simplified disease activity index) was examined in this cohort and lipidomics profiling and disease status were combined. Data were statistically analyzed by Spearman9s rank correlation coefficient test or multivariate regression analysis. Results Twenty-six RA patients were enrolled; female ratio: 84%, mean age: 63.0 years old, mean disease duration: 18.7 years and mean SDAI 5.26. In this group, patients age was significantly correlated with SDAI (p value =0.005, Spearman9s rho =0.552). By LC-MS/MS analyses, 23 lipid components were identified and quantified. Multivariative regression analysis (Standard Least Squares) revealed that 19,20-diHDPA (Dihydroxydocosapentaenoic acid) and 14,15-diHETE (Dihydroxyeicosatetraenoic acid) significantly explained SDAI score independently of sex and age. Among the composite measure for SDAI, the best correlated component with TJC (tender joint count) was LA (Linoleic acid, p=0.002, rho = -0.611), that with patient VAS (visual analogue scale) was 19,20-diHDPA (p=0.032, rho =0.440), and that with CRP was DHA (Docosahexaenoic acid, p=0.021, rho = -0.452). Additionally, principal component analysis was carried out. In the first primary component (PC1), absolute eigenvecotor values of AdA (Adrenic acid), ALA (Alpha-linolenic acid), DHA, DPA (Docosapentaenoic acid) and LA are more than 0.25, among which DHA was strongly correlated with PC1 (p<0.0001, rho =0.902). PC1 positively and significantly explained TJC count independent of sex and age. Conclusions Since 19, 20-diHDPA (metabolized from DHA) and 14,15-diHETE (from EPA, eicosapentaenoic acid) are both generated by cytochrome P450-catalyzed epoxidation followed by conversion to the vicinal diols by epoxide hydrolase, such kind of enzymes might be key molecules connecting lipid metabolism and RA. Although a replication study is inevitable, a certain kinds of lipid and lipid mediator profiles may be associated with disease activity, especially analgesic descriptors such as tender joint count. References Giera M, et al. Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. Biochim Biophys Acta. 2012, 1821(11):1415–24. Acknowledgements None. Disclosure of Interest None declared