Subarachnoid Hemorrhaging with Multiple Cerebral Artery Stenoses after Initiating Remission Induction Therapy for Eosinophilic Granulomatosis with Polyangiitis: a Case Report.

We encountered a 64-year-old Japanese woman who developed subarachnoid hemorrhaging (SAH) with multiple cerebral artery stenoses during remission induction therapy for eosinophilic granulomatosis and polyangiitis (EGPA). The treatment involved intensified steroid pulse therapy and continued intravenous cyclophosphamide pulse therapy, which led to beneficial effects. Given the rarity of multiple EGPA-associated cerebral artery stenoses and SAH, it is crucial to differentiate them from other diseases. The mortality rate of EGPA complicated by intracranial hemorrhagic lesions, including SAH, is high. When headache is present at the onset of EGPA, the possibility of SAH must be considered.

Headache in systemic lupus erythematosus: The LUNA registry cross-sectional study.

OBJECTIVES: This study investigated the clinically relevant factors for headaches in patients with systemic lupus erythematosus (SLE) using a registry from a Japanese multicenter cohort. METHODS: This cross-sectional study analysed the clinical information of patients with SLE who experienced headache episodes using the Migraine Disability Assessment (MIDAS) questionnaire. Significant findings in the comparisons between patients with headache (HA patients) and those without headache (non-HA patients) and in the comparisons depending on the grades of headache-induced disability in daily life based on the MIDAS scores were evaluated. Multivariate logistic regression analyses were performed to identify the relevant factors for headache. RESULTS: We analyzed 369 patients (median age, 45 years; female, 90.8%), including 113 HA patients who were significantly younger than non-HA patients (p < .005). HA patients had significantly higher frequencies of photosensitivity, rashes, and mucosal ulcers than non-HA patients (p < .05). Age and photosensitivity were significantly associated with headache (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.95-0.99; OR 2.11, 95% CI 1.29-3.49, respectively). In the HA patients, hypocomplementemia was significantly associated with a disability of more than mild grade (OR 2.89, 95% CI 1.14-7.74), while rash was significantly observed in those presenting with moderate and severe disability. CONCLUSION: This study suggests that photosensitivity is a relevant manifestation of headache in patients with SLE. Persistent hypocomplementemia can contribute to headache-induced disability in daily life, whereas a rash may be a dominant manifestation in patients presenting with moderate/severe headache-induced disability.

Association of large joint involvement at the start of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors with disease activity and drug retention in patients with rheumatoid arthritis: The ANSWER cohort study.

AIM: To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease-modifying antirheumatic drug or Janus kinase inhibitor. METHODS: Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics. RESULTS: Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], p < .001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti-citrullinated peptide antibodies, and interleukin-6 receptor inhibitor (IL-6Ri) use. CONCLUSION: Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6Ri may be beneficial for patients with LJI.

Significant association of HLA-A26 with uveitis and gastrointestinal involvement in patients with Behçet's disease in a multicenter study.

OBJECTIVES: Specific HLA haplotypes are associated with Behçet's disease (BD). Because the effects of HLA-A26 and its combination with HLA-B51 on organ involvement in BD have not been well demonstrated, we aimed to examine them. METHODS: This multicenter, cross-sectional, observational study enrolled patients with BD who visited Kyoto University Hospital between 2018 and 2021 or Kurashiki Central Hospital between 2006 and 2016 (n = 200). Disease severity was evaluated using the Krause score. RESULTS: Uveitis and gastrointestinal involvement were observed in 95/196 and 57/167 patients, respectively. The HLA alleles identified were HLA-B51 (n = 52/106), HLA-A26 (n = 25/88), and HLA-B51 and HLA-A26 (n = 6/88). In patients harboring HLA-B51, the presence of HLA-A26 was associated with higher frequencies of uveitis (p = 0.03) and coexistence of uveitis and gastrointestinal involvement (p = 0.002), and higher Krause scores (p = 0.02). Furthermore, the presence of HLA-A26 was associated with a higher frequency of uveitis in patients with gastrointestinal involvement (p = 0.001) and gastrointestinal involvement in patients with uveitis (p = 0.001). CONCLUSIONS: Since specific HLA haplotypes and their combinations are associated with organ involvement, both HLA-A and HLA-B haplotypes should be confirmed when screening for affected organs.

Comparison of retention of biologics in Japanese patients with elderly-onset rheumatoid arthritis-the ANSWER cohort study.

OBJECTIVES: This multicentre, retrospective study aimed to compare retention and reasons for discontinuation between Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs in patients with elderly-onset rheumatoid arthritis (EORA). METHODS: Patients with RA enrolled in a Japanese multicentre observational registry between 2015 and 2022 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding factors by indication for initiation of tumor necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), cytotoxic T-lymphocyte associated antigen 4 immunoglobulin (CTLA4-Ig) blockers, or JAKi, a propensity score based on baseline characteristics was used to compare drug retention. To assess the reasons for discontinuation, retention rates for ineffectiveness, adverse events, and remission were analyzed as secondary outcomes. RESULTS: A total of 572 patients with 835 treatment courses were identified (314 TNFi, 175 IL-6i, 228 CTLA4-Ig, and 118 JAKi). After adjusting for differences in baseline characteristics, drug retention was significantly higher for IL-6i (HR = 0.38, 95%CI = 0.27-0.55, p< 0.01) as compared with TNFi. Discontinuation due to lack of effectiveness was lower with the JAKi (HR = 0.38, 95%CI = 0.22-0.66, p< 0.01) and the IL-6i (HR = 0.29, 95%CI = 0.19-0.46, p< 0.01) as compared with the TNFi although the CTLA4-Ig had a similar HR to TNFi. The adjusted incidence of discontinuation due to adverse event was higher in the JAKi (HR = 2.86, 95%CI = 1.46-5.59, p< 0.01) than the TNFi. CONCLUSIONS: In EORA patients, IL-6i and JAKi had longer retention and less discontinuation due to ineffectiveness than TNFi. The potential risks of JAKi should be approached with an individualized perspective.

Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVE: This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. METHOD: The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. RESULTS: The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01-1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. CONCLUSION: The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.

Trends of disease activity in Japanese patients over 75 years with rheumatoid arthritis from 2014 to 2021- the ANSWER cohort study.

OBJECTIVES: To investigate if disease activity among elderly RA patients over 75 years has changed over time in the real-world clinical setting. METHODS: Data from an observational multicentre registry of RA patients in Japan were analyzed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (over 75 years) who achieved remission and low disease activity, from 2014 to 2021. The secondary outcome was to identify factors associated with remission and low disease activity by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression. RESULTS: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients over 75 years increased from 16.5% to 26.9%, with biologics and targeted-synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) usage increasing and glucocorticoids usage decreasing, while conventional-synthetic DMARDs usage remained relatively stable. The proportion of RA patients over 75 years achieving remission and low disease activity significantly increased from 62.2% to 78.2% (p for trend < 0.001). A negative factor associated with achieving remission and low disease activity was glucocorticoid usage, seropositivity, and history of previous b/tsDMARDs use while MTX usage was associated positively, independent of other predictors. CONCLUSIONS: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes.

Number of Attending Physicians and Accumulated Organ Damage in Patients with Systemic Lupus Erythematosus: LUNA Registry Cross-Sectional Study.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) frequently change attending physicians. The number of changes in attending physicians is related to the accumulated organ damage in patients with diabetes mellitus and inflammatory bowel disease, although similar results are not known for patients with SLE. This study investigated whether the number of attending physicians after the onset of SLE is associated with organ damage. METHODS: Patients with SLE were enrolled in a multicenter registry of 14 institutions (the Lupus Registry of Nationwide Institutions). Patients with a disease duration of 6 months to 10 years were included. Exposure was defined as the number of attending physicians. The primary outcome was the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The secondary outcomes were corticosteroid- and non-corticosteroid-related damage. Multiple logistic regression analysis was used to estimate the association between the number of attending physicians and SDI, adjusting for potential confounders, including age, sex, disease duration, number of hospitalizations due to SLE, disease activity at diagnosis, and emotional health. RESULTS: Of the 702 patients, 86.5% were women (median age 46 years, interquartile range 35-58). The disease duration was 7.3 years (4.3-11.3), the number of hospitalizations due to SLE was 1 (1-3), the number of attending physicians was 3 (2-4), and SDI was 0 points (0-1). The number of attending physicians was significantly associated with SDI [odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.26]. In the secondary outcome, the number of attending physicians was significantly associated with corticosteroid-related damage (OR 1.22, 95% CI 1.09-1.38). The number of attending physicians was not significantly associated with non-corticosteroid-related damage (OR 1.08, 95% CI 0.99-1.19). CONCLUSIONS: This study showed that SDI could increase as the number of attending physicians increases. The impact of changing attending physicians warrants greater attention for SLE and other diseases.

Pulmonary Cryptococcosis Diagnosed by a Transbronchial Lung Cryobiopsy in a Patient with Rheumatoid Arthritis.

A 77-year-old woman with seronegative rheumatoid arthritis who was being treated with prednisolone (8 mg/day) and methotrexate (12 mg/week) visited our hospital with an 11-day history of a fever and dyspnea. Chest computed tomography showed infiltration in the right lower lobe. A transbronchial lung cryobiopsy (TBLC) showed cryptococcal cells, and bronchoalveolar lavage fluid later showed growth of Cryptococcus neoformans. She was treated with amphotericin B and flucytosine for about four weeks, and the pulmonary shadows improved. The treatment was then changed to fluconazole as outpatient consolidation and maintenance therapy. A rare case of pulmonary cryptococcosis diagnosed by a TBLC is reported.

Severe Lupus Myocarditis Preceded by Mesalazine-induced Lupus.

In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.

HLA-B52 allele in giant cell arteritis may indicate diffuse large-vessel vasculitis formation: a retrospective study.

BACKGROUND: This study aimed to identify new characteristics of elderly onset large-vessel vasculitis (EOLVV) by focusing on human leucocyte antigen (HLA) genotype, polymyalgia rheumatica (PMR), and affected vascular lesions observed on positron emission tomography/computed tomography (PET/CT) imaging. METHODS: We retrospectively studied 65 consecutive Japanese patients with large-vessel vasculitis (LVV) who had extracranial vasculitis lesions and underwent PET/CT imaging. PET/CT images were assessed using the semi-quantitative PET visual score of each affected vessel, and the PET vascular activity score (PETVAS) and number of affected vessels were calculated. Subjects were subsequently grouped based on age at onset, superficial temporal artery (STA) involvement, and presence of PMR and compared each group according to HLA genotype. Unsupervised hierarchical cluster analysis was used to identify the patients with similar characteristics in terms of affected vascular lesions detected through PET/CT imaging. The clinical characteristics and PET/CT findings of the population newly identified in this study were examined. RESULTS: Twenty-seven patients with EOLVV did not meet the American College of Rheumatology 1990 criteria for giant cell arteritis (GCA) and Takayasu arteritis and were considered as unclassified EOLVV (UEOLVV). The unsupervised hierarchical cluster analysis revealed that UEOLVV with PMR and large-vessel GCA (LV-GCA) formed a cluster of LVV with GCA features (i.e., PMR and/or STA involvement) when restricted to patients who were HLA-B52-positive. Patients who were HLA-B52-positive with LVV and GCA features had similar clinical characteristics and patterns of affected vessels and presented with diffuse LVV lesions. HLA-B52-positive patients who had LVV with GCA features also presented with higher PETVAS, more affected vessels, and lower rates of biologics usage and relapse compared to HLA-B52-positive patients with TAK. CONCLUSIONS: Patients who had UEOLVV with PMR had similar characteristics to patients with LV-GCA. Patients who were HLA-B52-positive and had LVV with GCA features presented with diffuse vascular lesions and may comprise a core population of Japanese patients with EOLVV. The findings of HLA-B52 positivity and diffusely affected vessels in patients with EOLVV can be considered as suspicious findings of LV-GCA.

Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants.

PURPOSE: Pathogenic MEFV variants cause pyrin-associated autoinflammatory diseases (PAADs), which include familial Mediterranean fever (FMF), FMF-like disease, and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). The diagnosis of PAADs is established by clinical phenotypic and genetic analyses. However, the pathogenicity of most MEFV variants remains controversial, as they have not been functionally evaluated. This study aimed to establish and validate a new functional assay to evaluate the pathogenicity of MEFV variants. METHODS: We transfected THP-1 monocytes with 32 MEFV variants and analyzed their effects on cell death with or without stimulation with Clostridium difficile toxin A (TcdA) or UCN-01. These variants were classified using hierarchical cluster analysis. Macrophages were obtained from three healthy controls and two patients with a novel homozygous MEFVP257L variant, for comparison of IL-1ß secretion using a cell-based assay and a novel THP-1-based assay. RESULTS: Disease-associated MEFV variants induced variable degrees of spontaneous or TcdA/UCN-01-induced cell death in THP-1. Cell death was caspase-1 dependent and was accompanied by ASC speck formation and IL-1ß secretion, indicating that pathogenic MEFV variants induced abnormal pyrin inflammasome activation and subsequent pyroptotic cell deaths in this assay. The MEFV variants (n = 32) exhibiting distinct response signatures were classified into 6 clusters, which showed a good correlation with the clinical phenotypes. Regarding the pathogenicity of MEFVP257L variants, the results were consistent between the cell-based assay and the THP-1-based assay. CONCLUSION: Our assay facilitates a rapid and comprehensive assessment of the pathogenicity of MEFV variants and contributes to a refined definition of PAAD subtypes.

Protective effect of different doses of trimethoprim-sulfamethoxazole prophylaxis for early severe infections among patients with antineutrophil cytoplasmic autoantibody-associated vasculitis.

OBJECTIVES: To analyse the protective effect of different doses of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for early severe infections in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), considering time-varying changes. METHODS: In this retrospective observational study, we assessed the protective effect of TMP/SMX within the first 6 months of diagnosis among Japanese patients with AAV. We included 250 consecutive patients with AAV who were admitted to our hospital. The protective effect of TMP/SMX against early severe infections was verified using Cox regression analysis along with potential confounding factors. Cox regression with inverse probability treatment weights for early severe infections was also performed as a sensitivity analysis. RESULTS: Cox regression analysis showed that the reduced TMP/SMX exposure group had a significant protective effect against early severe infections (standard-dose group versus no TMP/SMX group: hazard ratio [HR] 0.393, 95% confidence interval [CI]: 0.139-1.11, p=0.077; reduced-dose group versus no TMP/SMX group: HR 0.418, 95%CI: 0.216-0.807, p=0.009), even when considering time-dependent changes. In the sensitivity analysis, the reduced-dose group still had a significantly lower risk of early severe infections than the no TMP/SMX group (HR = 0.393, 95%CI: 0.177-0.873, p=0.022). During follow-up, 18.0% of the patients discontinued TMP/SMX due to side effects. CONCLUSIONS: TMP/SMX is highly effective in preventing severe infections among patients with AAV despite the high incidence of side effects. Further studies are needed to determine the optimal dose of TMP/SMX for preventing severe infections, especially considering renal impairment.

Age-related Epstein-Barr Virus-associated Lymphoproliferative Disorder Masquerading as Systemic Lupus Erythematosus.

Age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder (LPD) occurs in elderly patients without immunodeficiency. An 81-year-old woman without any known immunodeficiency was examined for fever, rash, arthritis, thrombocytopenia, pleural and pericardial effusions, lymphadenopathy, and positive autoantibodies, which satisfied the classification criteria for systemic lupus erythematosus (SLE). However, a lymph node biopsy revealed EBV-LPD, and she was diagnosed with age-related EBV-LPD. In young individuals, EBV infection is a major differential diagnosis of SLE, but to our knowledge, this is the first reported case of age-related EBV-LPD mimicking SLE. We should therefore consider EBV-related disorders in the differential diagnosis of SLE even in elderly individuals.

Black-blood magnetic resonance imaging suggesting central nervous system vasculitis in moyamoya syndrome associated with systemic lupus erythematosus.

Moyamoya syndrome is a cerebrovascular disorder characterized by bilateral stenosis and occlusion of the internal carotid arteries and their branches. A 45-year-old woman with a history of systemic lupus erythematosus was admitted for recurrent ischemic strokes. Magnetic resonance (MR) angiography revealed moyamoya-like vasculopathy. Black-blood gadolinium-based contrast-enhanced MR images showed strong, concentric enhancement along the occluded arteries, which suggested vasculitis as the etiology of moyamoya-like vasculopathy. Intensive immunosuppressive therapy combined with anticoagulation therapy and rehabilitation led to a favorable outcome in this case. Black-blood MR imaging can be a non-invasive and prompt imaging modality when central nervous system vasculitis is suspected.