Factors associated with drug retention of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis: A multicentre REVEAL cohort study.

OBJECTIVES: To determine the current retention rate of mepolizumab (MPZ) and identify factors associated with drug retention in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in the Kansai multicentre cohort (REVEAL cohort). METHODS: Sixty patients diagnosed with EGPA and treated with MPZ between December 2016 and June 2023 were enrolled. The clinical characteristics, including laboratory data, treatments administered, and disease course outcomes were collected retrospectively. The patients were stratified into MPZ continuation (n=53) and discontinuation (n=7) groups, and drug retention was statistically compared using the log-rank test. RESULTS: The median age of patients was 54.5 years, with 55% females, and 33% antineutrophil cytoplasmic antibody-positive at disease onset. MPZ exhibited a retention rate of 78.7% after five years. The reasons for discontinuation included treatment of coexisting diseases, inadequate response, and remission. Patient characteristics at disease onset were comparable between the groups. Patients receiving immunosuppressants (IS) before MPZ introduction demonstrated significantly higher retention rates (P = 0.038). During the final observation, the MPZ continuation group had a lower vasculitis damage index score (P = 0.027). CONCLUSIONS: MPZ exhibited a high 5-year retention rate, particularly in patients requiring IS. This study implies that long-term use of MPZ may mitigate irreversible organ damage.

Risk factors for serious infections and infection-related mortality in patients with microscopic polyangiitis: Multicentre REVEAL cohort study.

OBJECTIVE: Infections are a critical concern for patients with microscopic polyangiitis (MPA). This study aimed to identify the risk factors associated with serious infections (SIs) and infection-related mortality in patients with MPA, as well as the effect of glucocorticoid (GC) dose tapering on these outcomes. METHODS: This multicentre, retrospective, and observational study utilised data from a cohort of patients with MPA in Japan [Registry of Vasculitis Patients to Establish REAL World Evidence (REVEAL) cohort]. Patients were categorised based on the occurrence of SIs or infection-related deaths, and various characteristics were compared among the groups. RESULTS: Among 182 patients, 66 (36.2%) experienced 129 SIs and 27 (14.8%) developed infection-related deaths. Advanced age, elevated C-reactive protein (CRP) levels, and higher ratio of the GC dose at 3 months to the initial dose were identified as independent risk factors for SIs. Older age was also associated with infection-related deaths. Furthermore, the cumulative incidence of infection-related deaths was significantly higher in patients with a higher ratio of the GC dose at 24 months to the initial dose. CONCLUSION: Older age, elevated CRP levels, and slower GC dose tapering predispose patients to SIs and infection-related deaths. Strategies, such as rapid GC dose tapering, are anticipated to mitigate the risk of infections.

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling.

Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren's syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.

Risk prediction model for mortality in microscopic polyangiitis: multicentre REVEAL cohort study.

BACKGROUND: To establish refined risk prediction models for mortality in patients with microscopic polyangiitis (MPA) by using comprehensive clinical characteristics. METHODS: Data from the multicentre Japanese registry of patients with vasculitis (REVEAL cohort) were used in our analysis. In total, 194 patients with newly diagnosed MPA were included, and baseline demographic, clinical, laboratory, and treatment details were collected. Univariate and multivariate analyses were conducted to identify the significant risk factors predictive of mortality. RESULTS: Over a median follow-up of 202.5 (84-352) weeks, 60 (30.9%) of 194 patients died. The causes of death included MPA-related vasculitis (18.3%), infection (50.0%), and others (31.7%). Deceased patients were older (median age 76.2 years) than survivors (72.3 years) (P < 0.0001). The death group had shorter observation periods (median 128.5 [35.3-248] weeks) than the survivor group (229 [112-392] weeks). Compared to survivors, the death group exhibited a higher smoking index, lower serum albumin levels, higher serum C-reactive protein levels, higher Birmingham Vasculitis Activity Score (BVAS), higher Five-Factor Score, and a more severe European Vasculitis Study Group (EUVAS) categorization system. Multivariate analysis revealed that higher BVAS and severe EUVAS independently predicted mortality. Kaplan-Meier survival curves demonstrated lower survival rates for BVAS ≥20 and severe EUVAS, and a risk prediction model (RPM) based on these stratified patients into low, moderate, and high-risk mortality groups. CONCLUSIONS: The developed RPM is promising to predict mortality in patients with MPA and provides clinicians with a valuable tool for risk assessment and informed clinical decision-making.

Prediction model for respiratory-related mortality in microscopic polyangiitis with interstitial lung disease: multicenter REVEAL cohort study.

OBJECTIVE: This study aimed to establish prediction models for respiratory-related mortality in microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using clinical characteristics. METHODS: We enrolled patients with MPA with ILD between May 2005 and June 2021 in a multicentre cohort of Japanese patients with MPA (REVEAL cohort). We evaluated the demographic, clinical, laboratory, radiological findings, treatments, and the presence of honeycombing 1 cm above the diaphragm using chest high-resolution computed tomography (HRCT) on admission. We explored the risk factors predictive of respiratory-related mortality. RESULTS: Of 115 patients, 26 cases died of respiratory-related diseases during a median follow-up of 3.8 years. Eighteen patients (69%) died due to respiratory infection, three (12%) had diffuse alveolar hemorrhage (DAH), and five (19%) had exacerbation of ILD. In univariate analysis, older age, lower percent forced vital capacity (%FVC), lower percent diffusing capacity of carbon monoxide (%DLco), and the presence of honeycombing in the right lower lobe were identified as risk factors. Additionally, in multivariate analysis adjusted for age and treatment, %FVC, %DLco, and the presence of honeycombing in the right lower lobe were independently associated with respiratory-related mortality. We created prediction models based on the values of %FVC, %DLco, and presence of honeycombing on chest HRCT (MPF model). The 5-year respiratory-related death-free rate was significantly different between patients with MPA with ILD stratified by the number of risk factors based on the MPF model. CONCLUSIONS: Our study indicates that the MPF model may help predict respiratory-related death in patients with MPA with ILD.

CD8+ Regulatory T Cell Deficiency in Elderly-Onset Rheumatoid Arthritis.

Elderly-onset rheumatoid arthritis (EORA) is associated with higher disease activity and accelerated joint destruction compared with young-onset RA (YORA). However, the underlying immunological mechanism remains unclear. Regulatory T cells (Tregs) are an immunosuppressive T cell subset, and CD4+ Tregs are deficient and/or dysfunctional in RA; however, CD8+ Tregs have not been fully examined in RA. Here, we aimed to determine the role of CD8+ Tregs, particularly in EORA. A total of 40 patients (EORA, n = 17; YORA, n = 23) were cross-sectionally enrolled. Current disease activity and treatment were comparable between the two groups; however, levels of multiple cytokines, including IL-1ß, TNFα, interferon (IFN)-γ, IL-2, and IL-10, were significantly increased in EORA. The number of CD4+ Tregs did not differ between the groups (p = 0.37), but those of CD8+ Tregs were significantly decreased in EORA (p = 0.0033). The number of CD8+ Tregs were inversely correlated with plasma matrix metalloprotease (MMP)-3 levels (r = -0.3331, p = 0.036). Our study results revealed an intrinsic deficiency of CD8+ Tregs in patients with EORA, which leaves synovitis unchecked with excessive MMP-3 release. A therapeutic approach to restore CD8+ Tregs may provide a new avenue for the treatment of EORA.

Clinical profile and outcome of large-vessel giant cell arteritis in Japanese patients: A single-centre retrospective cohort study.

OBJECTIVES: Recent advances in imaging revealed that giant cell arteritis (GCA) is frequently associated with large vessel involvement (LVI), but they may also contribute to earlier diagnosis and treatment of LV-GCA. We aimed to compare the clinical characteristics of GCA with or without LVI and evaluate its association with clinical outcomes. METHOD: We retrospectively reviewed the medical records of 36 patients with GCA in Kyoto University Hospital. RESULTS: Eighteen patients each were assigned to the LVI(+) and LVI(-) groups. Five-year survival rates in the LVI(+) group were better than in the LVI(-) group (p = .034), while five-year relapse-free survival rates were similar between the groups (p = .75). The LVI(+) group required lower doses of glucocorticoid at month 6 (p = .036). Disease activity evaluated with the Birmingham Vasculitis Activity Score at disease onset was higher in the LVI(-) group (p = .014), and the Vasculitis Damage Index score examined at the last visit was higher in the LVI(-) group (p = .011). CONCLUSION: GCA without LVI had more active disease, severer vascular damage, and worse survival, possibly because of ophthalmic complications and their greater glucocorticoid requirement. Our results revisit the impact of cranial manifestations on disease severity and morbidity.

A case of intestinal amoebiasis mimicking intestinal Behçet's disease.

Intestinal amoebiasis is caused by Entamoeba histolytica (E. histolytica) and is characterised by cecal lesions, multiple lesions, aphthae, and multiple exudative erosions. Intestinal Behçet's disease (BD) is a chronic inflammatory disorder that is characterised by multiple ulcers. Although the aetiologies of these two bowel diseases are unrelated, they are difficult to distinguish because they present similarly with inflammation and ulcers, especially if evidence of specific pathogens is not detected. Herein, we report a case of intestinal amoebiasis in a patient with BD. The patient underwent colonoscopy four times before intestinal amoebiasis was diagnosed. As intestinal BD was initially suspected, she received high-dose glucocorticoid therapy, which exacerbated her condition. Following exacerbation, she underwent colonoscopy, and E. histolytica was revealed. Deliberate care should be taken to distinguish between intestinal amoebiasis and intestinal BD, as the appropriate treatments for these diseases are entirely different.

A susceptibility locus in the IL12B but not LILRA3 region is associated with vascular damage in Takayasu arteritis.

HLA-B*52 is an established genetic factor in Takayasu arteritis (TAK). Recently, single nucleotide polymorphisms (SNPs) in IL12B (rs6871626) and LILRA3 (rs103294) were newly identified as non-HLA susceptibility loci in TAK. Here, we examined how these SNPs contribute to clinical characteristics and vascular damage in TAK. We retrospectively reviewed the medical records of 99 TAK patients enrolled in our previous genome-wide association study, and whose genotypes for IL12B rs6871626, LILRA3 rs103294, and HLA-B*52 were available. Incidence of aortic regurgitation (AR) was significantly associated with the A allele (risk allele) of IL12B rs6871626 (CC 42%, AC 61%, AA 81%; p = 0.0052; odds ratio [OR] 2.45), as well as with the incidence of hypertension (p = 0.049; OR 1.82) and the proportion of patients who underwent aortic valve replacement (p = 0.023; OR 3.64). Regarding vascular damage, there was positive correlation between the Takayasu Arteritis Damage Score and the A allele of IL12B rs6871626 (CC 3.42 ± 2.71, AC 4.06 ± 3.25, AA 6.00 ± 2.81; p = 0.0035; ß = 1.35) and between the Vasculitis Damage Index and the A allele (CC 3.47 ± 1.98, AC 4.33 ± 2.40, AA 5.37 ± 2.22; p = 0.0054; ß = 0.96). Contrarily, no correlation was found between LILRA3 rs103294 and vascular damage. In the present study, IL12B rs6871626 was associated with vascular damage in TAK, whereas LILRA3 rs103294 was not. Genotyping of IL12B rs6871626 may help to identify patients at risk of disease progression.

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.

Acute onset systemic lupus erythematosus interstitial lung disease: A case report.

A 40-year-old Japanese man was diagnosed with systemic lupus erythematosus. Chest computed tomography showed patchy consolidation in both lungs. A cryobiopsy and bronchoalveolar lavage showed organizing pneumonia, not acute lupus pneumonia or diffuse alveolar hemorrhage. This case demonstrates the usefulness of cryobiopsy for the management of systemic lupus erythematosus interstitial lung disease.

Annual variation rate of KL-6 for predicting acute exacerbation in patients with rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: This study evaluated the prognostic factors for acute exacerbation (AE), including sequential changes in Krebs von den Lungen-6 (KL-6) levels, in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. METHODS: This was a retrospective observational study. We reviewed 125 patients diagnosed with RA-ILD between 2010 and 2019. We defined ΔKL-6 as the annual variation rate of KL-6 one visit before AE onset (or the last visit). The Cox regression analysis was used for evaluating significant variables associated with AE. We analysed the overall survival and respiratory-related death-free survival. RESULTS: Thirty-three patients (26.4%) developed AE during the observation period. The univariate analysis revealed that KL-6 levels at RA-ILD diagnosis [hazard ratio (HR), 1.11; 95% confidence interval (CI), 1.05-1.15; p < .01) and ΔKL-6 (HR: 3.69; 95% CI: -1.36 to 7.96; p = .01] were significantly associated with AE. ΔKL-6 was an independent prognostic factor for AE in the multivariate analysis (HR: 3.37; 95% CI: -1.16 to 8.87; p = .03). Patients with AE had a significantly higher overall mortality rate (p = .02) and respiratory-related mortality rate (p < .01) than those without AE. CONCLUSION: ΔKL-6 can be a prognostic marker for detecting AE in RA-ILD patients.

Development of severe thrombocytopenia with TAFRO syndrome-like features in a patient with rheumatoid arthritis treated with a Janus kinase inhibitor: A case report.

RATIONALE: Thrombocytepenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a novel disease entity characterized by a constellation of symptoms (thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly). Here, we describe the development of TAFRO syndrome-like features during the treatment of rheumatoid arthritis with a Janus kinase (JAK) inhibitor. PATIENT CONCERNS: In this report, a 74-year-old woman treated with a JAK inhibitor (tofacitinib) for rheumatoid arthritis was admitted because of fever and thrombocytopenia. DIAGNOSES: On laboratory examination, marked thrombocytopenia and elevated creatinine and C-reactive protein levels were present. A computed tomography scan revealed lymphadenopathy, hepato-splenomegaly, and anasarca. A left axillary lymph node biopsy revealed Castleman's disease-like features. These clinical features satisfied the proposed diagnostic criteria for TAFRO syndrome. Since autoimmune disorders should be excluded when diagnosing TAFRO syndrome, it is not strictly correct to diagnose her as TAFRO syndrome. Therefore, we diagnosed her as rheumatoid arthritis complicated by TAFRO syndrome-like features. INTERVENTIONS: The patient was treated with high-dose glucocorticoid, tacrolimus, eltrombopag, intravenous immunoglobulin, and rituximab. OUTCOMES: Her condition was refractory to the above-mentioned treatment, and she eventually died because of multi-organ failure 6 months after the first admission. LESSONS: TAFRO syndrome-like features can develop during treatment with a JAK inhibitor for rheumatoid arthritis. Patients with autoimmune diseases complicated by TAFRO syndrome-like features can follow a fatal clinical course, and thus, an intensive combined treatment is warranted for such patients, especially in cases refractory to glucocorticoid.

Initial high-dose corticosteroids and renal impairment are risk factors for early severe infections in elderly patients with antineutrophil cytoplasmic autoantibody-associated vasculitis: A retrospective observational study.

Recent large observational studies of antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) show that severe infection is a major cause of death and that the majority of infections occur during the early phase of initiating remission-induction therapy. Many risk factors for severe infection have been suggested, but these have been inconsistent. Nevertheless, infectious risk factors in elderly patients with AAV have not been adequately investigated in previous studies.In this retrospective observational study, we examined potential predictors of severe infection within 90 days (early severe infections) after remission-induction therapy in patients with AAV aged 65 years or older. We included 167 consecutive elderly patients with AAV admitted to our hospital. Data from medical history and remission-induction therapy were analyzed for predictive risk factors associated with early severe infections. The relationship between initial doses of corticosteroids and cumulative incidence of severe infections was also analyzed. A multivariate analysis of risk factors for early severe infections was performed using logistic regression analysis. The Kaplan-Meier method was used to estimate the overall survival, and the log-rank test was used to evaluate the differences between patients with and without early severe infections. Gray method was used to compare the cumulative incidence of severe infections in patients who did and did not receive initial high-dose corticosteroids.Logistic regression analysis showed that initial high-dose corticosteroid administration (prednisolone ≥0.8 mg/kg/d) (odds ratio [OR] 3.86, P = .030) and serum creatinine levels at diagnosis ≥1.5 mg/dL (OR 5.13, P = .003) were independent predictors of early severe infection although administration of cyclophosphamide or rituximab was not. The cumulative incidence of severe infections was also significantly higher in patients who received initial high-dose corticosteroids (P = .042), and patients with early severe infections exhibited a high mortality rate within 6 months (P < .001).Our findings suggest that initial high-dose corticosteroids and renal impairment at diagnosis are associated with a higher risk of early severe infections and early death in elderly patients with AAV.

Efficacy of Plasma Exchange in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

We aimed to investigate the efficacy of plasma exchange on severe anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Of 182 patients with AAV in our hospital, 12 patients with life-threatening organ damage (rapidly progressive glomerulonephritis and/or diffuse alveolar hemorrhage) underwent centrifuge-based therapeutic plasma exchange and immunosuppressive therapy. Twenty-four patients matched for age, serum creatinine, and severity of vasculitis, who received high-dose glucocorticoids with or without immunosuppressants, were included in the nonplasma exchange group. Renal survival rate at 2 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.524). Mortality rate at 5 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.631). In this retrospective study, we could not show the significant differences in the renal survival rate and survival rate between the two groups.