Relapsing Polychondritis following PD-1 Blockade by an Immune Checkpoint Inhibitor.

Immune-related adverse events (irAEs) mimicking rheumatic diseases are observed in 1.5%-22% of patients receiving cancer therapy with immune checkpoint inhibitors (ICIs). Relapsing polychondritis (RP) is a rare autoimmune disease mainly involving auricle, nose, and airway cartilage inflammation. However, knowledge regarding RP as an irAE is scarce. Pembrolizumab, a type of ICI that regulates the programmed cell death protein-1 (PD-1), is used in patients whose cancer cannot be cured with surgery or radiation therapy. We report the first case of pembrolizumab-induced RP with isolated auricular lesions resolved without immunosuppressants. A 49-year-old man with lower lip cancer underwent surgical resection followed by reconstruction. Histopathological investigation confirmed the diagnosis of squamous cell carcinoma. Since multiple metastases 6 months post-surgery rendered the carcinoma inoperative, pembrolizumab was initiated, improving lymph node involvement. However, 4 months later, the patient developed rapidly progressive swelling and pain in both auricles. While no pathogen was detected, C-reactive protein levels were elevated (11.21 mg/dL). Computed tomography (CT) showed swelling of the bilateral auricles; the biopsy of the right auricle revealed cartilage destruction by infiltration of surrounding granulation tissue. Since these characteristic findings were not observed before pembrolizumab was initiated, we clinically diagnosed the patient with RP induced by pembrolizumab. The swelling of the auricles resolved spontaneously 1 month after pembrolizumab discontinuation. 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/CT revealed no 18F-FDG uptake in reduced auricular lesions. On re-administration of pembrolizumab to maintain antitumor immunity, both auricles swelled again, and pembrolizumab was switched to paclitaxel, considering the risk of tracheobronchial chondritis. Although no recurrence of auricular chondritis was observed, the patient died from cancer progression 8 months after paclitaxel administration. RP can occur as a rheumatic irAE in patients receiving anti-PD-1 therapy, and a literature review with retrospective analysis indicates that PD-1 inhibition-induced RP is unusual and atypical.

Systematic review and meta-analysis for 2023 clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVES: The objective of this study is to provide evidence for the revision of clinical practice guidelines for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society databases were searched for articles published between 2015 and 2020 to update the systematic review for existing clinical questions, while PubMed, CENTRAL, EMBASE, and the Japan Medical Abstracts Society were searched for articles published between 2000 and 2020 to conduct a systematic review for newly developed clinical questions. The certainty of evidence was assessed with the GRADE approach. RESULTS: For remission induction, when used in conjunction with cyclophosphamide or rituximab, reduced-dose glucocorticoid lowered the risk of serious adverse events compared to standard-dose glucocorticoid. Avacopan improved sustained remission at 12 months compared to high-dose glucocorticoid. Addition of plasma exchange to remission induction therapy did not reduce the risk of death, end-stage kidney disease, or relapse. For remission maintenance, rituximab reduced the risk of relapse compared to azathioprine. Long-term rituximab or azathioprine reduced the risk of relapse compared to short-term rituximab or azathioprine, respectively. CONCLUSIONS: This systematic review provided evidence required to develop the 2023 clinical practice guideline for the management of ANCA-associated vasculitis.

Upfront rituximab therapy for thrombotic thrombocytopenic purpura in systemic lupus erythematosus: a case-based review.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes on tissues. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematological disorder that rarely develops in SLE, mainly caused by inhibitory or clearing autoantibody against ADAMTS13. Although B cells play critical roles in the pathogenesis of two diseases, the role of B-cell depletion therapy using rituximab (RTX), a chimeric monoclonal antibody targeting CD20, in the management of TTP associated with SLE remains unclear. We present a 27-year-old woman who manifested TTP and nephritis simultaneously at diagnosis of SLE. This patient successfully responded to high-dose glucocorticoids combined with plasma exchange, and early administration of RTX-induced sustained remission of TTP without relapse over 16 months. This literature review in light of our case demonstrates relationship between early intervention with RTX and better treatment response despite the degree of ADAMTS13 activity. Moreover, we discuss the clinical features in TTP associated with SLE, risk factors for the development of TTP in SLE, and possible outcomes based on RTX dose. It is important to consider upfront RTX as a promising treatment strategy for SLE-associated secondary TTP to improve short-term response and long-term prognosis.

Predictive factors for retention of golimumab over a median 4-year duration in Japanese patients with rheumatoid arthritis in a real-world setting: A retrospective study and literature review.

OBJECTIVES: To investigate 6-year drug survival (median: 48.5 months) of golimumab and predictors for lack of efficacy leading to golimumab discontinuation in Japanese patients with rheumatoid arthritis (RA) in routine practice. METHODS: This retrospective single-center study included 60 patients with RA treated with golimumab from November 2011 to August 2020. Patients were divided into 2 groups (retention, n = 28; withdrawal due to lack of efficacy, n = 24). The retention rate was assessed using the Kaplan-Meier method, and variables associated with golimumab discontinuation were identified using the Cox proportional hazard model. RESULTS: The prevalence of concomitant methotrexate and no biologics use was significantly higher in the retention than in the withdrawal group. Overall drug survival of golimumab was 66.3%, 48.3%, and 24.5% at 12, 36, and 72 months, respectively. There were statistical differences in retention rates among groups stratified by initiation dose, methotrexate, and biologics use. Multivariate analysis revealed the factor associated with golimumab discontinuation as history of 1 (hazards ratio: 4.42, 95% CI: 1.35-19.93, P = .012) and ≥2 biologics use (7.49, 1.97-36.27, P = .003). CONCLUSIONS: Prior exposure of increasing number of biologics was identified as the most important factor negatively affecting long-term golimumab retention in Japanese patients with RA.

Multi-targeted therapy for refractory eosinophilic granulomatosis with polyangiitis characterized by intracerebral hemorrhage and cardiomyopathy: a case-based review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disorder classified under anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, predominantly affecting small- to medium-sized vessels, characterized by asthma, eosinophilia, and necrotizing granulomatous inflammation. Most patients with EGPA experience peripheral neuropathy, whereas intracerebral hemorrhage is rare as EGPA-related presentation in central nervous system involvement, causing severe morbidity and mortality. Here, we present a 45-year-old man with refractory EGPA who developed intracerebral hemorrhage as the first manifestation, followed by cardiac involvement. This patient with a history of bronchial asthma developed a right putaminal hemorrhage caused by EGPA. Although intravenous cyclophosphamide (IVCY) and mepolizumab (MPZ) induced remission, relapse was frequently observed. Subsequently, he developed cardiomyopathy despite administration of rituximab (RTX) substituted from IVCY and MPZ. Combined immunosuppressive therapy, including IVCY, MPZ, and RTX was required to inhibit vascular inflammation, leading to sustained remission. We review previously published literature while focusing on the clinical features of patients with intracerebral hemorrhage caused by EGPA and describe clinical characteristics for detecting EGPA in patients with intracerebral hemorrhage, emphasizing rapid evaluation and recognition of EGPA and adequate intervention in the early vasculitic phase of this disease. We also refer to the immunological aspects of this case. It is important to consider "multi-targeted therapy" through interleukin-5 suppression and B cell depletion in the management of refractory EGPA.

Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis.

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.

Insufficient Use of Corticosteroids without Immunosuppressants Results in Higher Relapse Rates in Takayasu Arteritis.

OBJECTIVE: Although prednisolone (PSL) and immunosuppressants are key drugs for Takayasu arteritis (TA) treatment, there is limited evidence on the optimal PSL dose. The aim of this study was to investigate the correlation between the initial PSL dose and relapse in TA. METHODS: We enrolled 105 patients with TA who satisfied the criteria of the Japanese Circulation Society and American College of Rheumatology from 1990 to 2015. The clinical characteristics and outcomes of patients with TA were retrospectively evaluated. The relapse-free period was assessed according to the difference in initial treatments. RESULTS: Relapse was observed in 57 (59.4%) of 96 patients treated with immunosuppressive therapy at diagnosis during a median followup of 56 months. Male sex and younger age of onset were significantly associated with relapse. Although ≤ 30 mg/day PSL monotherapy was preferably prescribed for patients with lower inflammatory markers, compared with > 30 mg/day (87.2% vs 52.6%), a significantly higher relapse rate was observed in the ≤ 30 mg/day group (HR 1.78; p = 0.047). Further, the relapse-free period was longer in patients treated with ≥ 50 mg/day PSL compared with those treated with ≤ 40 mg/day PSL. Combination therapy improved the relapse-free period compared with PSL monotherapy in the short term. The initial PSL dose was not associated with adverse events. CONCLUSION: A higher dose of PSL was associated with a significant decrease in the relapse rate. The effect of combination therapy on relapse needs to be further investigated. Lower-dose PSL monotherapy is an undesirable strategy for remission induction in TA, despite low disease activity.

Refractory Takayasu arteritis successfully treated with rituximab: case-based review.

Takayasu arteritis (TAK) is a subtype of the large-vessel vasculitis, affecting the aorta and its major branches. Although T cell-mediated autoimmunity is mainly involved in vascular inflammation, in recent years, accumulating evidence suggests the important role of B cells in the pathogenesis and effectiveness of B-cell-targeted therapy with rituximab (RTX), a chimeric anti-CD20 monoclonal antibody in refractory TAK. Herein, we report for the first time a case involving a 34-year-old man with TAK who was refractory to four different biologic agents, such as one selective T-cell co-stimulation modulator (abatacept), one anti-interleukin-6 receptor monoclonal antibody (tocilizumab), and two tumor necrosis factor-α inhibitors (infliximab and etanercept), but eventually achieved remission with RTX. He received a total of six courses of RTX, and doses of prednisolone and methotrexate were tapered without relapse. The current case provided further evidence to the potential role of RTX therapy in patients with refractory TAK, and its efficacy needs to be validated in a controlled trial.

Study on the frequency and risk factors of moderate-to-severe sleep apnea syndrome in rheumatoid arthritis.

OBJECTIVES: We aimed to investigate the frequency of moderate-to-severe sleep apnea syndrome (SAS) that possibly influences long-term prognosis in patients with rheumatoid arthritis (RA), and to analyze the risk factors for this group. METHODS: We examined respiratory disturbance index (RDI) by polysomnography in 62 hospitalized RA patients. Risk factors of moderate-to-severe SAS (RDI ≥20) were analyzed using a multivariate logistic regression analysis. RESULTS: RA was complicated by moderate-to-severe SAS in 13/62 (20.9%) cases. The highest stage of temporomandibular joint abnormality (TMJA) and a high value of health assessment questionnaire-disability index (HAQ-DI) were significant risk factors, according to the results of the multivariate logistic regression analysis (p < 0.0001 and p = 0.010, respectively). Contrary to these results, RDI was not related to the disease activity indexes of RA and other clinical characteristics. CONCLUSION: We clarified that the highest TMJA stage and a high value of HAQ-DI are novel important risk factors for moderate-to-severe SAS in RA patients.