Elderly-onset familial Mediterranean Fever Carrying MEFV Exon 10 Variants in a Japanese Patient: A Case Report.

Familial Mediterranean fever (FMF) is the most prevalent hereditary autoinflammatory disease and is caused by the MEFV gene. In patients carrying MEFV exon 10 variants, FMF usually develops at an early age. A 76-year-old Japanese man presented with a periodic fever lasting 2-3 days, chest pain, and abdominal pain. An MEFV gene analysis revealed compoundheterozygous M694I/E148Q/L110P. Colchicine treatment (0.5 mg/day) improved the patient's symptoms. This is the first case report of an elderly Japanese patient with FMF onset in the 70s carrying the MEFV exon 10 variant.

Identification of novel cytokine to judge the diagnosis and clinical phenotype of adult-onset Still's disease.

This study aimed to identify biomarkers to distinguish adult-onset Still's disease (AOSD) and to predict disease phenotypes. In total, 49 patients diagnosed with AOSD and 200 patients with common diseases (controls) were included in the analysis. The levels of 69 cytokines were analyzed using a multi-suspension cytokine array. Cytokine cluster analysis was performed to identify specific molecular networks. Furthermore, random forest analysis and logistic regression analysis were used to rank cytokines based on their importance and to determine specific biomarkers for identification of AOSD patients and phenotypes. Patients with AOSD demonstrated significantly higher macrophage migration inhibitory factor (MIF) and interleukin (IL)-12(p40) serum levels than controls and patients with rheumatoid arthritis. Serum levels of chemokine (C-C motif) ligand (CCL) 8 and CCL22 were significantly lower in AOSD patients with a polycyclic systemic disease phenotype and could be differentiated with high accuracy from the other phenotypes (cutoff value for CCL8 = 122.7 pg/mL, CCL22 = 593.3 pg/mL, sensitivity 66.7%, specificity 87.1%, area under the curve 0.843). Combined MIF and IL-12(p40) levels may represent a biomarker for differentiating patients with AOSD from those with other diseases. The chemokine profiles of AOSD with a polycyclic systemic disease phenotype may differ from other phenotypes.

Inhibition of CEACAM1 expression in cytokine-activated neutrophils using JAK inhibitors.

OBJECTIVES: Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. METHODS: Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. RESULTS: We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. CONCLUSIONS: We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

Low remission rates and high incidence of adverse events in a prospective VEXAS syndrome registry.

OBJECTIVE: We aimed to gather real-world clinical evidence of detailed disease activity, treatments, remission rates, and adverse events (AEs) associated with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome in a prospective study. METHODS: Patients in Japan suspected of having VEXAS syndrome were enrolled in a registry study. A novel disease activity measure (VEXASCAF) assessing 11 symptoms associated with VEXAS syndrome was evaluated at enrolment and after 3 months. AEs, survival, CRP levels, and treatments were also recorded at enrolment and 3 months after enrolment. All exons of UBA1 were sequenced using a next-generation sequencer to determine the variant allele frequencies of pathogenic variants in the peripheral blood of all patients. RESULTS: Of the 55 registered patients, 30 patients were confirmed to have pathogenic variants of UBA1. All patients were male, with a median age of 73.5 years. VEXASCAF and CRP levels decreased significantly at 3 months post-enrolment, but the oral prednisolone dose did not change. Only two patients achieved complete remission according to FRENVEX at 3 months after enrolment. During the observation period of 6 months, 28 AEs were observed, including 3 deaths, 4 malignancies from two cases, 2 thromboses, and 13 infections (including 4 mycobacterial infections). Inflammation of the lung and cervical region (i.e. parotid and submandibular gland swelling, tonsillitis, cervical swelling, and pain) were the most common AEs. CONCLUSIONS: Patients with VEXAS syndrome required high-dose glucocorticoids to achieve remission, and complications-such as malignancy, thrombosis, and infection-occurred frequently within a short observation period.

Association of rare single nucleotide variant MUC5B rs35705950 with interstitial lung disease in Japanese rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is sometimes complicated by interstitial lung disease (ILD) with a poor prognosis. A single nucleotide variant (SNV) in MUC5B was associated with ILD in European RA patients. However, associations of this SNV were not found in Japanese RA patients, because its frequency in Japanese populations is very low. We investigated the associations of candidate SNVs including the MUC5B variant with ILD in Japanese RA. METHODS: Genotyping of MUC5B rs35705950, MUC2 rs7934606, MAD1L1 rs12699415, and PPFIBP2 rs6578890 in Japanese RA patients was conducted for association analyses. RESULTS: MUC5B rs35705950 was associated with usual interstitial pneumonia (UIP) (p = 0.0039, Pc = 0.0156, odds ratio [OR] 10.66, 95% confidence interval [CI] 2.05-55.37) or ILD (p = 0.0071, Pc = 0.0284, OR 7.33, 95%CI 1.52-35.44) in Japanese RA under the allele model. MUC2 rs7934606 was associated with UIP (p = 0.0072, Pc = 0.0288, OR 29.55, 95%CI 1.52-574.57) or ILD (p = 0.0037, Pc = 0.0148, OR 22.95, 95%CI 1.27-416.13) in RA. Haplotype analyses suggested the primary association of MUC5B rs35705950 with UIP in Japanese RA. No significant association of MAD1L1 rs12699415 or PPFIBP2 rs6578890 with UIP, nonspecific interstitial pneumonia, or ILD in RA was observed. CONCLUSIONS: MUC5B rs35705950 is associated with, and might be involved in the pathogenesis of ILD, especially UIP, in Japanese RA.

Real-world comparative study of drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis.

BACKGROUND: Janus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA. METHODS: We retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model. RESULTS: Overall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001). CONCLUSIONS: In a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.

Increased serum caspase-1 in adult-onset Still's disease.

BACKGROUND: Caspase-1 is a crucial component in the inflammasome activation cascade. This study evaluated the potential of serum caspase-1 level as an inflammatory biomarker in patients with adult-onset Still's disease (AOSD). METHODS: The study included 51 consecutive patients diagnosed with AOSD based on the Yamaguchi criteria, 66 patients with rheumatoid arthritis (RA) as disease control, and 36 healthy controls (HCs). Serum caspase-1 concentrations were measured using enzyme-linked immunosorbent assay. The serum 69 cytokine levels were analyzed using a multisuspension cytokine array in patients with AOSD, and a cluster analysis of each cytokine was performed to determine specific molecular networks. RESULTS: Patients with AOSD had significantly increased serum caspase-1 levels versus patients with RA (p < 0.001) and HCs (p < 0.001). Additionally, serum caspase-1 demonstrated significant positive correlations with AOSD disease activity score (Pouchot score, r = 0.59, p < 0.001) and serum ferritin (r = 0.54, p < 0.001). Furthermore, among patients with AOSD, significant correlations existed between serum caspase-1 and inflammatory cytokines, including interleukin-18. Immunoblot analysis detected the cleaved form of caspase-1 (p20) in the serum of untreated patients with AOSD, not in those from patients with inactive AOSD receiving immunosuppressive treatments. CONCLUSIONS: Caspase-1 is a useful biomarker for AOSD diagnosis and monitoring. Caspase-1 activation could be correlated with the inflammatory component of AOSD, specifically through proinflammatory cytokine induction via inflammasome activation cascades.

Clinical features of flare in Japanese patients with new-onset SLE and risk factors for SLE flare in daily clinical practice: a single-center cohort study.

This study aimed to elucidate the clinical features, outcomes and risk factors of flares in patients with systemic lupus erythematosus (SLE). Data were collected from patients with newly diagnosed SLE at the Fukushima Medical University Hospital between 2011 and 2022. Patients who experienced a flare during the study period constituted the flare group, and their clinical features were compared with those of the no-flare group. The cumulative flare-free survival regarding several clinical items was compared between the two groups using Kaplan-Meier's curves. Among 387 patients with SLE, 83 patients with newly diagnosed SLE were included. Their mean age was 37.9 years, and 29 patients experienced flares during the study period. The general characteristics were similar between the two groups, with the exception of the observation period and anti-SS-A antibody positivity. Regarding therapy, a significantly increased frequency of hydroxychloroquine intake and combination with immunosuppressive agents were observed in the no-flare group. The Kaplan-Meier analysis revealed a significantly higher cumulative flare-free survival in the anti-SS-A negative group and combination immunosuppressive therapy group. In conclusion, anti-SS-A positivity may be a risk factor for SLE flare. In turn, combination immunosuppressive therapy may be beneficial for SLE treatment in daily clinical practice.

Long-term outcomes in patients with primary biliary cholangitis complicated with CREST syndrome.

Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the long-term outcomes of the affected patients have not been fully investigated. Herein, the long-term outcomes of PBC-CREST were evaluated. Next, the GLOBE and UK-PBC scores were validated and compared between the PBC alone and PBC-CREST groups. A total of 302 patients who were diagnosed with PBC between December 1990 and August 2021 at Fukushima Medical University Hospital were included. The liver transplantation (LT)-free survival rates were compared between patients with PBC alone (n = 245) and those with PBC-CREST (n = 57). Moreover, 173 patients, excluding those with liver-related death/LT within 1 year after ursodeoxycholic acid administration, were divided into two subgroups (PBC alone (n = 147) and PBC-CREST (n = 26)), and the GLOBE and UK-PBC scores were compared between the subgroups. The survival rates without LT (3/5/10 years) were 92/87/80% for the PBC-alone group and 98/96/96% for the PBC-CREST group, with a significantly better prognosis in the PBC-CREST group (log-rank P = 0.0172). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis. The predicted 5/10/15-year risks of liver-related death or LT based on the UK-PBC score were significantly lower in the PBC-CREST group (2.4/7.6/13.2%) than in the PBC-alone group (4.8/11.8/18.8%) (P < 0.05). The predicted 3/5-year LT-free survival rates based on the GLOBE score were significantly higher in the PBC-CREST group (93/88%) than in the PBC-alone group (88/81%) (P < 0.05). Patients with PBC-CREST may have better long-term outcomes than those with PBC alone.

Serum Mac-2 binding protein glycosylation isomer and galectin-3 levels in adult-onset Still's disease and their association with cytokines.

Background: Autoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still's disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD. Methods: We recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks. Results: Significant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p <0.001). There were significant positive correlations between serum Gal-3 levels and AOSD disease activity score (Pouchot score, r=0.66, p <0.001) and serum ferritin levels. However, no significant correlations were observed between serum M2BPGi levels and AOSD disease activity scores (Pouchot score, r = 0.32, p = 0.06) or serum ferritin levels. Furthermore, significant correlations were observed between the serum levels of Gal-3 and various inflammatory cytokines, including interleukin-18, in patients with AOSD. Immunosuppressive treatment in patients with AOSD significantly reduced serum Gal-3 and M2BPGi levels (p = 0.03 and 0.004, respectively). Conclusions: Although both Gal-3 and M2BPGi were elevated in patients with AOSD, only Gal-3 was a useful biomarker for predicting disease activity in AOSD. Our findings suggest that circulating Gal-3 reflects the inflammatory component of AOSD, which corresponds to proinflammatory cytokine induction through inflammasome activation cascades.

Successful Treatment of Ultrasound-confirmed Synovitis in Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis with Corticosteroid Therapy.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis without severe myositis but with characteristic cutaneous manifestations and severe interstitial lung disease. Joint symptoms can occur in patients with anti-MDA5 antibody-positive CADM. However, the treatment strategy and utility of ultrasound for treating joint symptoms remain unknown. We herein report an 85-year-old man with anti-MDA5 antibody-positive CADM who presented with ultrasound-confirmed synovitis that improved with medium-dose corticosteroid therapy.

Incidence Rates of Infections in Rheumatoid Arthritis Patients Treated with Janus Kinase or Interleukin-6 Inhibitors: Results of a Retrospective, Multicenter Cohort Study.

Objective: This study aimed to compare the incidence rates (IRs) of infections, including herpes zoster (HZ), in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) or interleukin-6 inhibitors (IL-6is). Methods: We retrospectively analyzed 444 RA patients treated using IL-6is (n = 283) or JAKis (n = 161). After adjusting for clinical characteristic imbalances by propensity score matching (PSM), we compared the IRs of infections including HZ between the JAKi and IL-6i groups. Results: Observational period: 1423.93 patient years (PY); median observational period: 2.51 years. After PSM, incidence rate ratios comparing JAKi with IL-6i were 3.45 (95% confidence interval [CI]: 1.48-9.04) for serious infections other than HZ indicating that the JAKi-treated group was more likely to develop serious infection than the IL-6i-treated group. Multivariate Cox regression analyses revealed that the use of prednisolone > 5.0 mg/day, coexisting interstitial lung disease (ILD), and diabetes mellitus (DM) were independent risk factors for serious infections. The crude IR for HZ was significantly higher in the JAKi group, but the difference between groups was not significant (IRR: 2.83, 95% CI: 0.87-10.96) in PSM analysis. Unadjusted and PSM analyses performed in our study showed increased IRs of serious infections in patients with RA treated with JAKis compared with those treated with IL-6is. Conclusions: The presence of ILD or DM and the use of prednisolone were found to be independent risk factors for serious infection in RA patients treated using JAKis. Whereas the IRs for HZ after PSM were not significantly different between the JAKi and IL-6i groups.

Post-renal acute kidney injury complicated by urinary tract obstruction due to massive blood clots and severe thrombocytopenia in a patient with systemic lupus erythematosus: A case report.

Systemic lupus erythematosus (SLE) is often seen with antiphospholipid antibody syndrome (APS), and these conditions may occur concurrently with severe immune thrombocytopenia (ITP) and even acute kidney injury (AKI); however, post-renal AKI due to bleeding is uncommon. Here, we describe a case of post-renal AKI and anuria in a patient with SLE and APS, which were attributable to urinary tract obstruction due to massive blood clots caused by secondary ITP. A 50-year-old Japanese woman was admitted to our hospital with anuria, abdominal tenderness, purpura in the trunk and in both legs, and severe thrombocytopenia. She had been receiving medical treatment for APS and SLE till the age of 45 years. Computed tomography revealed a blood clot without extravasation in both urinary tracts, and she was diagnosed with post-renal AKI due to complete obstruction of the urinary system. Additionally, based on her medical history, elevated platelet-associated Immunoglobulin G (IgG) levels, and increased megakaryocyte count, she was diagnosed with secondary ITP complicated by SLE and APS. She also had elevated APS-related autoantibodies, including antiphosphatidylserine/prothrombin Immunoglobulin M (IgM), and IgG. However, concomitant serositis such as lupus enteritis or cystitis was not seen. She was treated with a combination of glucocorticoids, intravenous immunoglobulin, and continuous haemodialysis/haemofiltration, which resulted in rapid improvement of her symptoms and renal dysfunction. Secondary ITP-induced massive bleeding of urinary tract can cause post-renal AKI. Appropriate diagnosis and aggressive treatment are necessary to improve prognosis in such patients.

New-onset Systemic Lupus Erythematosus Manifestation Following COVID-19: A Case Report and Literature Review.

Coronavirus disease 2019 (COVID-19) is a respiratory viral disease, and several cases of autoimmune diseases have been reported after infection. This report presents the case of a 38-year-old Japanese woman who developed systemic lupus erythematosus (SLE) following COVID-19. Clinical manifestations included dermatological complications, joint pain, and positive autoantibodies. The patient met the SLE classification criteria, and renal involvement was observed. Her symptoms improved with immunosuppressive therapy. A literature review identified 10 similar cases, those with lymphopenia and renal involvement. SLE should be considered in patients with persistent nonspecific symptoms after COVID-19 infection, particularly when hematologic and renal involvement are present.

Human leucocyte antigens and Japanese patients with polymyalgia rheumatica: the protective effect of DRB1*09:01.

OBJECTIVE: The hallmarks of the chronic inflammatory disease polymyalgia rheumatica (PMR) include pain, and morning stiffness in areas of the neck, shoulder and pelvic girdle. The human leucocyte antigen (HLA) gene was reported to be an important risk factor for PMR, but it has not been analysed precisely, especially in populations other than Europeans. METHODS: Genotyping of DRB1 and DQB1 was performed in Japanese PMR patients (n=270) and controls (n=413). Associations between allele carrier and genotype frequencies were determined for PMR. RESULTS: DRB1*04:05 was associated with a predisposition to PMR (p=0.0006, Pc=0.0193, OR 1.85, 95% CI 1.31 to 2.62). DRB1*09:01 was associated with protection against PMR (p=1.46×10-5, Pc=0.0004, OR 0.40, 95% CI 0.26 to 0.61). A shared epitope (SE) associated with PMR (p=3.07×10-6, OR 2.11, 95% CI 1.54 to 2.88). DQB1*03:03 (p=0.0010, Pc=0.0140, OR 0.52, 95% CI 0.35 to 0.77) was associated with protection against PMR and DQB1*04:01 (p=0.0009, Pc=0.0140, OR 1.82, 95% CI 1.28 to 2.58) was associated with predisposition to PMR. A gene dosage effect was observed for DRB1*09:01 and DQB1*03:03, but not for DRB1*04:05, SE or DQB1*04:01. Haplotype and logistic regression analyses suggested a protective effect for DRB1*09:01. CONCLUSION: This study is the first to demonstrate predisposing associations of DRB1*04:05, SE, and DQB1*04:01, and protective associations of DRB1*09:01 and DQB1*03:03 with PMR in Japanese patients. Our data indicate HLA has predisposing and protective effects on the pathogenesis of PMR.

C5a stimulation induces caspase-1 activation and mature IL-1ß production in human peripheral blood mononuclear cells.

The complement component C5a contributes to the recruitment of immune cells to inflamed tissues and local inflammation. The proinflammatory cytokine interleukin (IL)-1ß is also related to inflammatory disorders through inflammasome activation. However, the association between inflammasome activation and C5a is unclear. Human peripheral blood mononuclear cells (PBMCs) were stimulated with C5a and measured for IL-1ß secretion by enzyme-linked immunosorbent assay (ELISA). The pro-IL-1ß expression in cell lysates was also examined by Western blot analysis. Similarly, magnetic bead-isolated CD14+ monocyte-depleted and lymphocyte-depleted PBMCs were stimulated with C5a, and immunoblot analysis was performed using an anti-cleaved-IL-1ß (p17) antibody. FACS was performed to detect caspase-1-activated cells. C5a-stimulated PBMCs produced IL-1ß in C5a concentration-dependent manner. The protein levels of pro-IL-1ß in the cell lysates were significantly increased. Furthermore, the cleaved-IL-1ß (p17) was faintly detected in the same lysates. Active caspase-1 was demonstrated in C5a-simulated CD14+ monocytes by FACS. Cleaved-IL-1ß (p17) was demonstrated in the supernatant of C5a-stimulated PBMCs. Lymphocyte-depleted PBMCs stimulated with C5a but monocyte-depleted PBMCs produced cleaved-IL-1ß (p17). C5a induced the production of mature IL-1ß in PBMCs. The IL-1ß production is mediated mainly by caspase-1 activation in CD14+ monocytes. These results suggest that C5a alone potentiates mature IL-1ß production mainly in monocytes.

Real-World Effectiveness of Belimumab in Patients with Active Lupus.

This study evaluated the real-world effectiveness of belimumab (BLM) in the treatment of systemic lupus erythematosus (SLE) patients with moderate to high disease activity. This retrospective cohort study enrolled 129 Japanese patients with moderate to high SLE disease activity who received BLM between January 2013 and March 2023. The clinical outcomes, including the flare-free survival, SLE Disease Activity Index 2000 (SLEDAI-2K) score, and prednisone-equivalent dose, in the BLM and mycophenolate mofetil (MMF) treatment groups were compared before and after treatment. Safety data for BLM were collected. Additionally, we compared the effectiveness of BLM and intravenous cyclophosphamide (IV-CY) treatment using the stabilized inverse probability of treatment weighting (IPTW) method based on the propensity scores. This observational study enrolled 129 patients with moderate/severe SLE: 48 patients received belimumab, 45 received IV-CY, and 36 received MMF and prednisolone for remission induction therapy. The median follow-up for the BLM group was 17.0 months. Among them, 19 received BLM plus MMF. BLM significantly reduced the mean SLEDAI-2K (from mean baseline to 52 weeks: 49.2% reduction from 12.8 to 6.5) and prednisone daily dose (from mean baseline to 52 weeks: 21.9% reduction from 12.8 to 10.0 mg/day). The flare-free survival at 52 weeks was not significantly different between the BLM and MMF groups. There was no significant difference in the flare-free survival rates or reduction rates of the SLEDAI-2K between the patients treated with BLM and those treated with BLM plus MMF. In the propensity score-matched comparative analyses, there was no significant difference in the flare-free survival rates or an estimated decline in the SLEDAI-2K scores between the patients with lupus treated with BLM and IV-CY. BLM may be a promising alternative treatment option for lupus patients with moderate or high disease activity who do not respond to conventional treatments.

Association of a Single Nucleotide Variant in TERT with Airway Disease in Japanese Rheumatoid Arthritis Patients.

Interstitial lung disease and airway disease (AD) are often complicated with rheumatoid arthritis (RA) and have a poor prognosis. Several studies reported genetic associations with interstitial lung disease in RA. However, few genetic studies have examined the susceptibility to AD in RA patients. Here, we investigated whether single nucleotide variants susceptible to idiopathic pulmonary fibrosis might be associated with interstitial lung disease or AD in Japanese RA patients. Genotyping of rs2736100 [C/A] in TERT and rs1278769 [G/A] in ATP11A was conducted in 98 RA patients with usual interstitial pneumonia, 120 with nonspecific interstitial pneumonia (NSIP), 227 with AD, and 422 without chronic lung disease using TaqMan assays. An association with AD in RA was found for rs2736100 (p = 0.0043, Pc = 0.0129, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.11-1.77). ATP11A rs1278769 was significantly associated with NSIP in older RA patients (>65 years, p = 0.0010, OR 2.15, 95% CI 1.35-3.40). This study first reported an association of rs2736100 with AD in RA patients and ATP11A rs1278769 with NSIP in older RA patients.

Effectiveness of Colchicine or Canakinumab in Japanese Patients with Familial Mediterranean Fever: A Single-Center Study.

Background: To investigate the clinical features of Japanese patients with Familial Mediterranean Fever (FMF), we evaluated the frequency of attacks, treatment responses, and adverse effects in 27 patients with FMF treated with colchicine or canakinumab in a real-world clinical setting. Methods: We retrospectively reviewed 27 Japanese patients with FMF treated at our institute between April 2012 and June 2023. All patients were diagnosed with FMF according to the Tel-Hashomer criteria. We performed genetic analyses of the MEFV gene using targeted next-generation sequencing. The clinical response was monitored through the number of attacks, and inflammatory markers were monitored through the C-reactive protein (CRP), and serum amyloid A (SAA) concentrations. Colchicine resistance was defined as the presence of at least one attack/month despite administration of the maximum tolerated dose of colchicine for at least 6 months, and C-reactive protein and serum amyloid A levels above the normal range between attacks. Results: A total of 27 patients diagnosed with FMF were enrolled in this study and the median follow-up period was 36.4 months. The median attack frequency was 1.0 (interquartile range: 0.33-1.0) every 3 months before treatment initiation. All the patients (n = 27) were treated with colchicine. Among the 27 patients, 20 (71.8%) showed a clinical response and 7 (25.9%) showed an incomplete response with sufficient doses of colchicine (n = 5) and non-sufficient doses (n = 2). Two patients on non-sufficient doses were unable to increase colchicine to the maximum dose due to diarrhea and liver dysfunction. All seven patients achieved a reduction in attack frequency after the initiation of canakinumab. No serious adverse events associated with canakinumab treatment were observed. In these seven patients with colchicine-resistant FMF (crFMF), the MEFV exon 10 variant was not detected, and the absence ratio of the MEFV variant was significantly higher compared to those without crFMF. Conclusions: Colchicine was effective in 71.8% (20/27) of Japanese patients with FMF; however, the remaining patients (7/27) had crFMF. Canakinumab effectively controlled febrile attacks in crFMF, even in the absence of pathogenic MEFV exon 10 variants.

Safety of JAK and IL-6 inhibitors in patients with rheumatoid arthritis: a multicenter cohort study.

Background: The ORAL Surveillance trial showed a potentially higher incidence of malignancy and major adverse cardiovascular events (MACEs) associated with tofacitinib than those associated with tumor necrosis factor (TNF) inhibitors (TNFis). However, few studies have compared the safety of non-TNFis or other Janus kinase (JAK) inhibitors (JAKis). This study was aimed at comparing the incidence rates (IRs) of malignancies and MACEs in patients with rheumatoid arthritis (RA) treated using interleukin-6 (IL-6) inhibitors (IL-6is) or JAKis. Methods: We retrospectively analyzed 427 patients with RA who were treated using an IL-6i (n = 273) or a JAKi (n = 154). We determined the IRs of malignancy and MACEs, and the standardized incidence ratio (SIR) of malignancies and investigated factors related to malignancy and MACEs. After adjusting the clinical characteristic imbalance by propensity score matching (PSM), we compared the IRs of adverse events between the JAKi and IL-6i groups. Results: After PSM, the observational period was determined to be 605.27 patient-years (PY), and the median observational period was determined to be 2.28 years. We identified seven cases of malignancy (IR: 2.94 per 100 PY) in the JAKi-treated group and five cases (IR: 1.36 per 100 PY) in the IL-6i-treated group after PSM. The IR of MACEs was 2.56 and 0.83 (per 100 PY) in the JAKi- and IL-6i-treated groups. The IRRs of JAKi-treated patients versus IL-6i-treated patients were 2.13 (95% confidence interval (CI): 0.67-7.42) for malignancy and 3.03 (95% CI: 0.77-15.21) for MACE. There were no significant differences in IRR for malignancy and MACE between both groups after PSM. Univariate and multivariable Cox regression analyses revealed that older age and JAKi use were independent risk factors for malignancy, while older age, hypertension, and JAKi use were independent risk factors for MACEs. The overall malignancy SIR was significantly higher in the JAKi-treated group compared to the general population (2.10/100 PY, 95% CI: 1.23-2.97). Conclusion: The IRs of malignancy and MACE in patients with RA after PSM were comparable between IL-6i-treated and JAKi-treated patients. However, the SIR of malignancy in JAKi treatment was significantly higher than in the general population; therefore, further safety studies comparing JAKi to non-TNFi biologic disease-modifying antirheumatic drugs (bDMARDs) are needed.