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Background: We aimed to reveal the effect of abatacept (ABT) on atherosclerosis in rheumatoid arthritis (RA) patients, 3-year efficacy for arthritis, and safety in a population of older vs. younger patients. Methods: In this open-label, prospective, observational study, patients were stratified into four groups: younger (20–64 years old) and older (≥ 65 years) patients taking ABT (AY and AO) and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (CY and CO). Primary endpoints were change from baseline in mean intima-media thickness (IMT) of the common carotid artery, IMT max (bulbus, bifurcation, and internal and common carotid artery), and plaque score at Week 156. Disease activity, retention rate, and adverse effects were also evaluated. Results: The ABT group (AY + AO) tended to have smaller increases in mean IMT, max IMT, and plaque score than the csDMARD group (CY + CO) at Week 156, although the differences between groups were not statistically significant. Multivariate analysis showed significantly lower increases in plaque score with ABT than with csDMARDs, only when considering disease activity at 156 weeks (p= 0.0303). Proportions of patients with good or good/moderate European League Against Rheumatism response were higher in the ABT group, without significant difference between older and younger patients. No significant differences were observed in ABT retention rates between older and younger patients. Serious adverse effects, especially infection, tended to be more frequent with ABT than with csDMARDs, although no significant differences were found. Conclusions: ABT may decelerate atherosclerosis progression and may be useful for patients with high risk of cardiovascular disease, such as older patients. Trial registration number:: UMIN000014913.

The role of programmed cell death, especially pyroptosis and apoptosis, in unfavorable immune responses in COVID-19 remains to be elucidated.

ETS proto-oncogene 1, transcription factor (ETS1) is involved in various immune responses. Genome-wide association studies on systemic lupus erythematosus in Chinese populations identified the association of ETS1polymorphism in 3′ untranslated region, rs1128334A, which was associated with lower ETS1expression. In view of substantial sharing of susceptibility genes across multiple autoimmune diseases, we examined whether ETS1is associated with a rare autoimmune rheumatic disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Association of rs1128334 was tested in 466 Japanese patients with AAV and 1099 healthy controls by logistic regression analysis under the additive model. AAV patients were classified into 285 microscopic polyangiitis (MPA), 92 granulomatosis with polyangiitis (GPA), 56 eosinophilic GPA, and 33 unclassifiable AAV, according to the European Medicines Agency (EMEA) algorithm. Among the patients, 376 were positive for MPO–ANCA and 62 for PR3–ANCA. When the patients were classified according to the EMEA classification, rs1128334A allele was significantly increased in GPA (P= 0.0060, Pc= 0.030, odds ratio (OR), 1.54; 95% confidence interval (CI), 1.13–2.10). With respect to the ANCA specificity, significant association was observed in PR3–ANCA positive AAV (P= 0.0042, Pc= 0.021, OR, 1.72; 95% CI, 1.19–2.49). In conclusion, ETS1polymorphism was suggested to be associated with GPA and PR3–ANCA positive AAV in a Japanese population.

Sulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystispneumonia (PJP) in immunosuppressed patients with systemic rheumatic diseases, but is sometimes discontinued due to adverse events (AEs). The objective of this non-blinded, randomized, 52-week non-inferiority trial was to quest an effective chemoprophylaxis regimen for PJP with a low drug discontinuation rate. Results at week 24 were reported. Adult patients with systemic rheumatic diseases who started prednisolone ≥0.6 mg/kg/day were randomized into three dosage groups: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, increasing incrementally to 200/40 mg daily). The primary endpoint was non-incidence rates (non-IR) of PJP at week 24. Of 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP. A total of 172 patients were included in the analysis. No cases of PJP were reported up to week 24. Estimated non-IR of PJP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8–100% using the exact confidence interval as a post-hoc analysis. The overall discontinuation rate was significantly lower with HS compared to SS (p= 0.007). The discontinuation rates due to AEs were significantly lower with HS (p= 0.006) and ES (p= 0.004) compared to SS. The IR of AEs requiring reduction in the dose of SMX/TMP (p= 0.009) and AEs of special interest (p= 0.003) were different among the three groups with significantly higher IR in SS compared to HS and ES. Although there were no PJP cases, the combined group of HS and ES had an excellent estimated non-IR of PJP and both were superior in safety to SS. From the perspective of feasibility and drug discontinuation rates, the daily half-strength regimen was suggested to be optimal for prophylaxis of PJP in patients with systemic rheumatic diseases. The University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727, registered 10 April 2012.

Background: Immunoglobulin G4-related disease (IgG4-RD) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have different clinical and pathological features. However, differentiation between these 2 disorders is sometimes difficult.Objective: To report a case involving a patient with characteristics of both IgG4-RD and AAV.Methods: Case report with literature review.Results: We report a case of myeloperoxidase-ANCA–positive otitis media and rhinosinusitis with pathological features of IgG4-RD in a 73-year-old man. The patient was first clinically suspected to have granulomatosis with polyangiitis. All of the main characteristic pathological features of IgG4-RD were present: dense lymphoplasmacytic infiltration, increased numbers of IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis.Conclusions: The simultaneous presence of the characteristics of both IgG4-RD and AAV makes diagnosis and treatment difficult.

Background: High-dose glucocorticoids (GC) are first-line treatment for adult-onset Still’s disease (AOSD); however, some of the patients remain refractory to initial GC therapy, or rapidly relapse. The aim of this study was to identify prognostic factors for poor treatment response to initial GC therapy for AOSD. Methods: Data on newly diagnosed AOSD patients were extracted from our database (n=71, mean age 51.6 years). The primary outcome was a poor treatment outcome at 4 weeks, which was defined as failure to achieve remission or relapse after achieving remission within 4 weeks, followed by administration of two or more rounds of GC pulse therapy or of any other immunosuppressive drugs. Results: The initial mean dose ± standard deviation of prednisolone was 0.82 ± 0.23 mg/kg/day, and 34 (47.3%) patients received GC pulse therapy at week 0. Twenty-nine of 71 patients exhibited a poor treatment outcome at 4 weeks (40.8%). The second round of GC pulse therapy or immunosuppressive drugs was added in 17 or 24 of the 29 patients, respectively. These patients had higher baseline white blood cell (WBC) counts, serum ferritin levels, systemic feature score based on clinical symptoms (modified systemic feature score, mSFS), more hemophagocytic syndrome (HPS) over the 4 weeks, and the higher severity score based on modified Pouchot score or severity index of the Japanese Ministry of Health, Labour and Welfare, than the remaining 42 patients. Multivariable logistic regression model identified baseline WBC count as a prognostic factor for poor outcome (odds ratio per 1000/μl increment: 1.12, 95% CI 1.04–1.29), while thrombocytopenia, hyperferritinemia, and mSFS at baseline did not achieve statistical significance. Receiver-operating characteristic curve analysis showed that the optimal cut-off for WBC count was 13,050/μl. The Kaplan-Meier method showed the cumulative rate of poor treatment outcome to be 60.0% in patients with WBC ≥13,050/μl and 23.5% in those with WBC <13,050/μl. Conclusions: A higher WBC count but not thrombocytopenia, hyperferritinemia, and mSFS at baseline was a significant prognostic factor for poor treatment outcome at week 4 in this retrospective cohort of AOSD patients. Our findings provide important information for determining the initial treatment strategy of newly-diagnosed AOSD.

Objective.Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy.Methods.In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category.Results.During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22–6.74), ≥ 20 pack-years of smoking (2.63, 1.37–5.04), higher serum creatinine level (1.21, 1.05–1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35–5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36–17.01 per 1.0 mg/dl increase; 2.57, 1.28–5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not.Conclusion.Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.

The mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies.

Background: Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5Bvariant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5Bvariant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERTand DSPgenes are associated with susceptibility to AAV subsets and AAV-ILD. Methods: Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERTand DSPvariants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test. Results: When the frequencies of the IPF risk alleles TERTrs2736100A and DSPrs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P= 2.3 × 10−4, Pc= 0.0023, odds ratio [OR] 1.38; DSP P= 6.9 × 10−4, Pc= 0.0069, OR 1.32) and MPO-AAV (TERT P= 1.5 × 10−4, Pc= 0.0015, OR 1.33; DSP P= 0.0011, Pc= 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD. Conclusions: Unexpectedly, TERTand DSPIPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERTand DSPmay be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Background: Relapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA. Methods: We enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model. Results: Cranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52–8.24, p= 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes. Conclusion: The initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.

Chemerin is a chemotactic agonist identified as a ligand for ChemR23 that is expressed on macrophages and dendritic cells (DCs). In this study, we analyzed the expression of chemerin and ChemR23 in the synovium of rheumatoid arthritis (RA) patients and the stimulatory effects of chemerin on fibroblast-like synoviocytes (FLSs) from RA patients.