Systematic review for the treatment of older rheumatoid arthritis patients informing the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To update an evidence base informing the 2024 JCR clinical practice guidelines (CPGs) for the management of rheumatoid arthritis (RA) in older adults. METHODS: Four clinical questions (CQs) regarding efficacy and safety of drug treatment were evaluated, with CQ1 addressing methotrexate (MTX), CQ2 biological disease-modifying antirheumatic drugs (bDMARDs), CQ3 Janus kinase (JAK) inhibitors, and CQ4 glucocorticoids (GCs). Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: Observational studies confirmed a pivotal role of MTX in the treatment of older RA patients. The meta-analysis showed that tumor necrosis factor inhibitors and JAK inhibitors were unequivocally effective in older RA patients. No data indicated that bDMARDs were unsafe for older patients. No safety data for JAK inhibitor use in older patients were available. One randomized controlled trial demonstrated that long-term treatment with low-dose GCs increased risks of GC-associated adverse events. The certainty of overall evidence was very low for all CQs. CONCLUSION: This systematic review provides the necessary evidence for developing 2024 JCR CPGs for managing older patients with RA. Continued updates on the evidence of JAK inhibitors and GC are desired.

Comparison between rheumatoid arthritis with malignant lymphoma and other malignancies: Analysis of a National Database of Rheumatic Disease in Japan.

BACKGROUND: The background status and the current treatment options of patients with rheumatoid arthritis (RA) who develop malignant lymphoma (ML) and other malignancies are unclear. This study investigated the differences in background factors between ML and other malignancies that occur in RA patients and post-malignancy treatment. METHODS: We identified 935 RA patients with new-onset malignancies among 110,571 person-years registered in the National Database of Rheumatic Disease in Japan from 2012 to 2018. Analysis cohorts 1 and 2 included 597 and 490 patients with available data for 1 year before and after the development of malignancies, respectively. Factors associated with the development of ML were longitudinally evaluated by multiple logistic regression analyses. RESULTS: Of the 935 patients (mean age 70.5, standard deviation 9.9), 15.5% had ML; this was comparable to the rate of lung cancer (14.3%). In cohort 1, methotrexate (MTX), biological disease-modifying anti-rheumatic drugs (bDMARDs), and non-steroidal anti-inflammatory drugs (NSAIDs) were used in 74.4%, 23.4%, and 56.7% of ML and in 56.8%, 25.4%, and 35.3% of other malignancies 1 year before the occurrence of malignancies. Clinical disease activity index (CDAI) and C-reactive protein were similar between the two groups. Multivariable analysis showed that MTX use (odds ratio [OR]: 2.22, 95% CI [confidence interval]: 1.32-3.73, p=0.003) and NSAID use (OR: 2.51, 95% CI: 1.58-3.98, p <0.001) were significantly associated with the development of ML versus other malignancies. However, this association was not observed with bDMARDs. In cohort 2, one year after the development of malignancies, MTX was used in none of ML and 41.8% of patients who developed other malignancies. In both malignancy groups, approximately 15% of patients received bDMARDs and 50% received glucocorticoids. IL-6 inhibitors were preferentially prescribed in patients with ML versus those with other malignancies. At year 1, CDAI remission was achieved in 37.3% and 31.1% of patients in the ML and other malignancy groups, respectively. CONCLUSION: Patients receiving long-term treatment with MTX and NSAIDs may be at a relatively high risk of developing ML. The treatment landscape after developing malignancies differed considerably between patients with ML and other malignancies, and different treatment strategies should be established.

Granulomatosis with Polyangiitis Complicated by Severe Exudative Retinal Detachment and Orbital Granuloma Successfully Controlled with Rituximab: A Case Report.

We report a rare case of severe exudative retinal detachment with orbital granuloma associated with granulomatosis with polyangiitis (GPA). A 42-year-old man developed bilateral conjunctival hyperemia and eye pain 15 months before presenting to us. Because vitreous cells and retinal detachment were detected in his left eye, he was referred to us for further evaluation. The left eye showed scleral edema, cells in the anterior chamber and anterior vitreous, exudative retinal detachment, and elevated white subretinal lesions from the nasal to the inferior parts of the eye fundus. Orbital contrast-enhanced magnetic resonance imaging revealed a granulomatous lesion, retinal detachment, and fluid retention in the left eyeball. Comprehensive rheumatological evaluation revealed proteinase 3 anti-neutrophil cytoplasmic antibody positivity and a history of otitis media, leading to a GPA diagnosis. Methylprednisolone 1,000 mg/day was administered intravenously for 3 days, followed by oral prednisolone and intravenous cyclophosphamide. Although the retinal detachment decreased, scleritis and choroidal detachment relapse were observed in the left eye after the fifth cyclophosphamide administration. After switching from cyclophosphamide to rituximab, the scleritis and choroidal detachment resolved. Remission was successfully maintained with biannual rituximab administration. In this case, we conclude that rituximab was important to re-induce and maintain remission after recurrence. Collaboration with a rheumatologist is essential for proper treatment in related cases. This is the first report of ultra-widefield and multimodal imaging for retinal detachment associated with GPA.

Nation-wide cohort study of remission induction therapy using rituximab in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis: Effectiveness and safety in the first 6 months.

OBJECTIVES: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan. METHODS: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome. RESULTS: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months. CONCLUSIONS: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated.

Non-drug and surgical treatment algorithm and recommendations for the 2020 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis-secondary publication.

OBJECTIVES: The aim of this study was to update the Japan College of Rheumatology (JCR) clinical practice guidelines (CPGs) for the management of rheumatoid arthritis (RA) and prepare an algorithm for non-drug and surgical treatments. This article is a digest version of the guidelines. METHODS: The Japanese Ministry of Health, Labour and Welfare's research group, in collaboration with the JCR, used the Grading of Recommendations, Assessment, Development, and Evaluation method to update the 2014 JCR CPG for RA. The consensus was formed by CPG panel members. RESULTS: We raised 19 clinical questions regarding non-drug and surgical treatments for RA and developed recommendations. The treatments included exercise therapy; occupational therapy; joint injection of corticosteroids; and orthopaedic surgeries including cervical spine surgery, wrist and foot arthroplasty, ankle arthrodesis, and replacement arthroplasty of the shoulder, elbow, finger, hip, knee, and ankle. Recommendations regarding the risks of surgery and perioperative discontinuation of medications have also been developed. Based on these recommendations, we created an original algorithm for the non-drug and surgical treatment of RA. CONCLUSIONS: These recommendations are expected to serve rheumatologists, health care professionals, and patients with RA as tools for shared decision-making to treat residual limb joint symptoms and functional impairment.

Chemoprophylaxis against Pneumocystis jirovecii pneumonia in Japanese patients with ANCA-associated vasculitis: An observational study.

OBJECTIVES: This study investigated the current practice of prophylactic treatment against Pneumocystis jirovecii pneumonia (PCP) and its effectiveness in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: This study included 319 patients registered from 53 institutions in Japan and newly diagnosed with AAV. During the 2-year observation period, we examined the frequency of usage, effectiveness and safety of prophylactic drugs against PCP. RESULTS: Most patients received prophylactic drugs against PCP with the initiation of immunosuppressive agents, and >50% of them remained on chemoprophylaxis against PCP at 2 years after. The initial daily dose of oral prednisolone and the proportion of cyclophosphamide administration were higher in patients who received chemoprophylaxis against PCP than in those who did not. PCP occurred in nine patients (3%) and resulted in the death of four. The incidence rate of PCP in patients who received chemoprophylaxis was 1.13/100 patient-years (95% confidence interval, 0.38-2.68) and that in those who did not was 2.74 (1.04-6.02). The incidence rate ratio was 0.41 (0.11-1.53). CONCLUSIONS: The markedly low incidence of PCP may be attributed to the continuous chemoprophylaxis against PCP received by >50% of Japanese patients with AAV, although the effectiveness of chemoprophylaxis against PCP was not statistically confirmed.

Serum gasdermin D levels are associated with the chest computed tomography findings and severity of COVID-19.

BACKGROUND: The role of programmed cell death, especially pyroptosis and apoptosis, in unfavorable immune responses in COVID-19 remains to be elucidated. METHODS: We conducted a cross-sectional analysis to investigate the association between the serum gasdermin D (GSDMD) levels, a pyroptotic marker, and caspase-cleaved cytokeratin 18 fragment (M30), an apoptotic marker, and the clinical status and abnormal chest computed tomography (CT) findings in patients with COVID-19. RESULTS: In this study, 46 patients diagnosed with COVID-19 were divided into the following three groups according to the disease severity: mild to moderate group (n = 10), severe group (n = 14), and critical group (n = 22). The serum GSDMD levels were higher in the critical group than in the mild to moderate group (P = 0.016). In contrast, serum M30 levels were lower in the critical group than in the severe group (P = 0.048). Patients who required mechanical ventilation or died had higher serum GSDMD levels than those who did not (P = 0.007). Area of consolidation only and of ground glass opacity plus consolidation positively correlated with serum GSDMD levels (r = 0.56, P < 0.001 and r = 0.53, P < 0.001, respectively). CONCLUSION: Higher serum GSDMD levels are associated with critical respiratory status and the consolidation area on chest CT in patients with COVID-19, suggesting that excessive activation of pyroptosis may affect the clinical manifestations in patients with COVID-19.

Systematic review for the treatment of older rheumatoid arthritis patients informing the 2020 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To provide an evidence base for clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA) in older adults. METHODS: PubMed, Cochrane library, and Japan Centra Revuo Medicina databases were searched for articles published between 1990 and 2019. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system, with some modifications. RESULTS: Among 702 identified articles, there were 5 post-hoc analyses of randomized controlled trials and 10 observational studies. Meta-analysis of the former yielded a mean difference of the van der Heijde-modified total Sharp score of -2.79 (95% confidence interval [CI] - 3.74 to -1.84) for treatment with tumor necrosis factor inhibitors. The risk ratio (RR) for the American College of Rheumatology 50% response rate, and for serious adverse events was 2.83 (95%CI 1.90-4.21) and 1.32 (95%CI 0.53-3.31), respectively, for Janus kinase inhibitors. Meta-analysis of the observational studies yielded an RR for disease activity score-28 remission and serious infections of 0.76 (95%CI 0.64-0.91) and 1.92 (95%CI 1.31-2.81) for older-versus-younger patients receiving biological disease-modifying antirheumatic drugs, respectively. CONCLUSION: This systematic review provides the necessary evidence for developing CPG for the management of RA in older adults.

Comprehensive risk analysis of postoperative complications in patients with rheumatoid arthritis for the 2020 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To examine the risk factors of surgical site infection (SSI), delayed wound healing, and death after orthopedic surgery in patients with rheumatoid arthritis (RA). METHODS: We identified articles indexed in the Cochrane Library, PubMed, and Japan Centra Revuo Medicina Web published from 2013 to 2019 and other articles. Articles fulfilling the predefined inclusion criteria were reviewed systematically and their quality was appraised according to the Grading of Recommendations Assessment, Development, and Evaluation system with some modifications. RESULTS: After inclusion and exclusion by full-text review, 29 articles were analyzed. Use of biological disease modifying antirheumatic drugs was a risk factor of SSI (risk ratio 1.66, 95% confidence interval 1.25-2.19), but not of delayed wound healing. RA itself was a risk factor of SSI, and oral glucocorticoid use was a risk factor of SSI in three of the four studies analyzed and of postoperative death. Age, male sex, comorbidities such as diabetes mellitus and chronic obstructive pulmonary disease, surgical factors such as foot/ankle and spine surgery and longer operative time were risk factors of those postoperative complications. CONCLUSION: Patients with those factors should be dealt with appropriate cautions to strike a risk-benefit balance of orthopedic surgeries.

Patient satisfaction with total joint replacement surgery for rheumatoid arthritis: a questionnaire survey for the 2020 update of the Japan college of rheumatology clinical practice guidelines.

OBJECTIVE: This study aimed to evaluate satisfaction with total joint replacement (TJR) surgery among patients with rheumatoid arthritis (RA). METHODS: We mailed questionnaires to randomly selected members of the Japan Rheumatism Friendship Association, stratified by age and prefecture, throughout Japan. The questionnaire collected demographic and clinical characteristics as well as patients' satisfaction with TJR and their current therapy. RESULTS: Of the 1156 patients who returned the questionnaire, 339 (29.3%) responded that they had had TJR of any type. The mean age was 66.6 years, and 94.4% were women. The mean time period from the hip and knee TJR was 14-15 years. Over half of the patients who had had TJR were satisfied with the results, especially those who had had hip (89.6%) and knee TJR (87.3%), who reported a high level of satisfaction. Multivariable linear regression analysis revealed that, in patients with knee TJR, satisfaction with current therapy was significantly related to whether they were satisfied with the results of the surgery. CONCLUSION: Most patients with RA who had undergone TJR were satisfied with the results even after a long period of time, and their level of satisfaction was associated with their satisfaction with current therapy.

Treatment strategies for elderly-onset rheumatoid arthritis in the new era.

Elderly-onset rheumatoid arthritis (EORA) is characterized by acute onset and clinical features of high disease activity. Anti-cyclic citrullinated peptide antibody (ACPA) positivity or the presence of bone erosions predicts a radiological joint destruction of EORA, but ACPA-negative EORA with a polymyalgia rheumatica (PMR) phenotype may also present. Biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors were beneficial both in older and in younger patients in terms of risk-benefit balance. Implementation of a treat-to-target strategy could improve EORA outcomes, but older patients have more age-related comorbidities and interstitial lung disease than younger patients. Baseline comorbidities, more frequent methotrexate dose-dependent adverse events, serious infections, cardiovascular disease events, and malignancy all influence the choice of treatment and the treatment goals for older patients. Based on articles reviewed here, it is suggested that current treatment strategies for younger patients are also useful for ACPA-positive EORA and for ACPA-negative EORA with bone erosion. Differential diagnosis of ACPA-negative EORA without erosive arthritis and PMR with peripheral manifestations is challenging, and the treatment strategy of patients presenting with this overlap phenotype remained unclear. An appropriate treatment strategy for all patients with EORA still needs to be developed.

Associated factors of poor treatment outcomes in patients with giant cell arteritis: clinical implication of large vessel lesions.

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

Association Between Reappearance of Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Subgroup Analysis of Nationwide Prospective Cohort Studies.

OBJECTIVE: To evaluate clinical links between levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and relapse in patients with ANCA-associated vasculitis (AAV) using a data set from 2 nationwide prospective cohort studies. METHODS: From the cohort studies, MPO-ANCA-positive patients who achieved remission during the 6 months after remission induction therapy were enrolled. We measured MPO-ANCA levels at months 0, 3, 6, 12, 18, 24, and at the time of relapse. The primary outcome measure was relapse. A nested case-control analysis and multivariable analysis were performed to investigate the relationship between ANCA reappearance and relapse. RESULTS: Of 271 patients, 183 were classified as having microscopic polyangiitis, 34 as having granulomatosis with polyangiitis, 15 as having eosinophilic granulomatosis with polyangiitis, and 39 were unclassifiable. The median age was 73 years, and 165 (61%) were female. In 195 patients (72%), MPO-ANCA levels decreased to normal levels within 6 months after commencement of treatment, and MPO-ANCA reappeared in 73 of 181 patients (40%) with complete follow-up data. Reappearance of MPO-ANCA was more frequent in patients with relapse than in 75 age- and sex-matched control patients without relapse (odds ratio 26.2 [95% confidence interval 8.2-101], P < 0.0001) after adjustment for confounding factors. CONCLUSION: Reappearance of MPO-ANCA could be a clinically useful biomarker for predicting relapse in patients with MPO-ANCA-positive AAV in remission. This suggests that routine MPO-ANCA monitoring should be implemented in this patient population.

Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population.

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

Presence of Citrullinated Histone H3-Positive Neutrophils in Microscopic Polyangiitis from the Early Phase: An Autopsy Proven Case.

A 76-year-old man was admitted with general fatigue, weight loss, fever, headache, renal failure, and a high serum level of myeloperoxidase-antineutrophil cytoplasmic antibody. Biopsy revealed citrullinated histone H3 (citH3)-positive neutrophils adherent to the temporal artery endothelium. Three days after completing pulse steroid therapy, he suffered from a sudden disturbance of consciousness and died. On autopsy, the kidneys showed the most severe vasculitis with dense infiltration of citH3-positive neutrophils. The lungs showed intra-alveolar hemorrhage due to capillaritis. Severe brain hemorrhage was found in the left frontal lobe and putamen with uncal herniation. No vasculitis or thrombi was observed in the brain. The right dura mater was thickened due to fibrosis and inflammation. In conclusion, autopsy revealed systemic vasculitis with infiltration of abundant citH3-positive neutrophils, suggesting that the neutrophil extracellular trap formation and citH3 might play important roles in the early phases and development of microscopic polyangiitis.

Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study.

OBJECTIVE: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. RESULTS: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. CONCLUSIONS: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009.

Targeting Low Disease Activity in Elderly-Onset Rheumatoid Arthritis: Current and Future Roles of Biological Disease-Modifying Antirheumatic Drugs.

Elderly rheumatoid arthritis (RA) is classified into two clinical subsets, elderly-onset RA (EORA) and younger-onset elderly RA. With the improvement of life expectancy in the general population and advent of the super-aging society, the number of patients with EORA is anticipated to increase. Both large and small joints are affected initially at onset, and individuals with early EORA have higher scores of disease activity and levels of acute-phase reactants than those with early younger-onset RA. EORA is a progressive disease similar to younger-onset RA. Tumor necrosis factor (TNF) inhibitors are equally or slightly less effective in elderly patients than in younger patients with RA, and disease duration may have a greater impact on disease outcomes than age. Evidence of non-TNF biological disease-modifying antirheumatic drug use in EORA is limited. TNF inhibitors may not increase the risk for infection in elderly patients any more than methotrexate; however, increasing age is an independent and strong risk factor for serious infections in patients with RA. Treatment choice in patients with EORA is strongly influenced by comorbidities, especially cardiovascular disease, chronic lung disease, and frailty. To prevent progression to irreversible geriatric syndromes, non-frail patients with EORA, who are aging successfully should undergo intensive treatment using the treat-to-target strategy, and pre-frail and frail patients with EORA should be treated with the aim of returning to a non-frail or pre-frail stage, respectively. An appropriate treatment strategy for EORA and younger-onset elderly RA should be developed in the next decade using a multi-disciplinary approach.

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody-Positive Otitis Media and Rhinosinusitis With Pathological Features of Immunoglobulin G4-Related Disease: A Case Report.

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

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry.

INTRODUCTION: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. METHODS: This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. RESULTS: Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). CONCLUSIONS: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

Assessment of risks of pulmonary infection during 12 months following immunosuppressive treatment for active connective tissue diseases: a large-scale prospective cohort study.

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