BackgroundPatients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.ObjectivesTo evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide.MethodsStudy design: international, cross-sectional. Patients: consecutive RA patients. Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).ResultsOf 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)–erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.ConclusionsAmong RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.

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bcl-2 gene expression is induced by 17␤-estradiol (E2) in T47D and MCF-7 human breast cancer cells, and the mechanism of E2 responsiveness was further investigated by analysis of the bcl-2 gene promoter. The ؊1602 to ؊1534 distal region (bcl-2j) of the promoter was E2-responsive; however, in gel mobility shift assays, the estrogen receptor ␣ (ER ␣ ) did not bind [ 32 P]bcl-2j, whereas Sp1 protein formed a retarded band complex. Further analysis demonstrated that the upstream region (؊1603 to ؊1579) of the bcl-2 gene promoter contained two GC/GA-rich sites at ؊1601 (5-GGGCTGG-3) and ؊1588 (3-GGAGGG-5) that bound Sp1 protein. Subsequent studies confirmed that transactivation by E2 was dependent on ER ␣ /Sp1 interactions with both GCrich sites, and this was confirmed by in vitro footprinting. In contrast, a 21-base pair E2-responsive downstream region (؊1578 to ؊1534) did not bind Sp1 or ER ␣ protein; however, analysis of a complex binding pattern with nuclear extracts showed that ATF-1 and CREB-1 bound to this motif. These data coupled with results of transient transfection studies demonstrated that transcriptional activation by E2 of the ؊1578 to ؊1534 region of the bcl-2 gene promoter was dependent on induction of cAMP and subsequent activation through a cAMP response element. Thus, hormone regulation of bcl-2 gene expression in breast cancer cells involves multiple enhancer elements and E2-mediated transactivation does not require direct binding of the estrogen receptor with promoter DNA.

IntroductionWe investigated the clinical and serological features of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan using data from a nationwide, prospective, inception cohort study.MethodsIn total, 156 Japanese patients with newly diagnosed AAV were classified according to the European Medicines Agency (EMEA) algorithm with exploratory surrogate markers for AAV-related non-granulomatous pulmonary lesions, predefined as alveolar haemorrhage and interstitial lung disease (ILD), and their clinical and serological features were evaluated.ResultsUsing the EMEA algorithm, we identified 14 patients (9.0%) with eosinophilic granulomatosis with polyangiitis (EGPA), 33 (21.2%) with granulomatosis with polyangiitis (GPA), 78 (50.0%) with microscopic polyangiitis and renal-limited vasculitis (MPA/RLV), and 31 (19.9%) with unclassifiable vasculitis. The average ages of patients with EGPA (male/female, 5/9), GPA (12/21), and MPA/RLV (35/43) and unclassifiable (9/22) were 58.0, 63.6, 71.1, and 70.6 years, respectively. Myeloperoxidase (MPO)-ANCA and proteinase-3 ANCA positivity was 50.0% and 0% for EGPA, 54.6% and 45.5% for GPA, 97.4% and 2.6% for MPA/RLV, and 93.5% and 3.2% for unclassifiable, respectively. According to the Birmingham Vasculitis Activity Score (BVAS), cutaneous (71.4%) and nervous system (92.9%) manifestations were prominent in EGPA and ear, nose, and throat manifestations (84.9%) and chest manifestations (66.7%) in GPA. Renal manifestations developed frequently in MPA/RLV (91.0%) and GPA (63.6%). The average serum creatinine levels were 0.71 mg/dL for EGPA, 1.51 mg/dL for GPA, 2.46 mg/dL for MPA/RLV, and 0.69 mg/dL for unclassifiable. The percentages of patients with ILD were 14.3% for EGPA, 9.0% for GPA, 47.4% for MPA/RLV, and 61.3% for unclassifiable. Patients with ILD (n = 61) had significantly lower BVAS (P = 0.019) with fewer ear, nose, and throat and cardiovascular manifestations than patients without ILD (n = 95).ConclusionsMPO-ANCA-positive MPA/RLV is the most common form of AAV in Japanese patients, and one-half of patients with GPA were positive for MPO-ANCA. ILD is an important clinical manifestation in Japanese patients with AAV. Unclassifiable vasculitis with MPO-ANCA positivity and ILD may represent a novel variant of MPA.Trial RegistrationThe University Hospital Medical Information Network Clinical Trials Registry: UMIN000001648. Registered 28 February 2009.

Expression and immunological significance of IFN-γ, a pivotal cytokine in murine lupus, have not been clearly demonstrated in human systemic lupus erythematosus (SLE). In the present study we investigated the expression of IFN-γ in peripheral blood T cells from patients with SLE and its role in the production of the soluble B lymphocyte stimulator (sBLyS). Peripheral blood T cells from patients with SLE expressed significantly larger amounts of IFN-γ in response to stimulation with anti-CD3 mAb plus anti-CD28 mAb than those from normal controls as shown by three analytical methods, including ELISA, flow cytometry, and quantitative RT-PCR. The ratio of IFN-γ-producing T cells to effector memory T cells in CD3+CD4+ and CD3+CD8+ populations in patients with SLE was significantly higher than that of normal controls. The T-box expressed in T cells (T-bet) mRNA/GATA-binding protein-3 (GATA-3) mRNA ratio was significantly higher in patients with SLE than in normal controls. T cell culture supernatants from patients with SLE contained significantly higher sBLyS-inducing activity than normal controls; this was almost completely inhibited by the addition of anti-human IFN-γ mAb. Percentages of BLyS-expressing peripheral blood monocytes in patients with SLE were significantly higher than those of normal controls. Monocytes from patients with SLE produced significantly larger amounts of sBLyS in response to IFN-γ than those from normal controls. Taken together, these data strongly indicate that the overexpression of IFN-γ in peripheral blood T cells contributes to the immunopathogenesis of SLE via the induction of sBLyS by monocytes/macrophages, which would promote B cell activation and maturation.

Objective.An all-patient postmarketing surveillance program was conducted to evaluate the safety and effectiveness of tocilizumab (TCZ) for rheumatoid arthritis (RA) in the real-world clinical setting in Japan.Methods.Patients received 8 mg/kg TCZ every 4 weeks and were observed for 28 weeks. Data were collected on patient characteristics, and drug safety and effectiveness.Results.A total of 7901 patients were enrolled. Percentages of total and serious adverse events (AE) were 43.9% and 9.6%, respectively. The most common serious AE were infections (3.8%). Logistic regression analysis identified the following risk factors for the development of serious infection: age ≥ 65 years, disease duration ≥ 10 years, previous or concurrent respiratory disease, and concomitant corticosteroid dose > 5 mg/day (prednisolone equivalent). The incidence rate of serious infections in patients with ≥ 3 risk factors was 11.2%, compared with 1.2% for patients without risk factors. The Week 28 rates of 28-joint Disease Activity Score–erythrocyte sedimentation rate remission, Boolean remission, and European League Against Rheumatism (EULAR) Good Response were 47.6%, 15.1%, and 59.4%, respectively. Contributing factors for effectiveness were body weight ≥ 40 kg, less advanced RA, no previous biologics, no concomitant corticosteroids or nonsteroidal antiinflammatory drugs, and low disease activity at baseline. From the benefit-risk balance analysis, patients with a high probability of remission and a low probability of developing serious infection were most likely to have less advanced RA and to have not received biologics previously.Conclusion.These data confirm the safety and effectiveness of TCZ in patients with RA in the real-world clinical setting in Japan and identify factors that contribute to the successful use of TCZ for RA.

To facitinib and baricitinib are two of the currently available Janus kinase (JAK) inhibitors for the treatment of patients with RA. Randomized controlled trials have shown that these JAK inhibitors are as efficacious as biological DMARDs. Safety profiles of these JAK inhibitors in randomized controlled trials and their long-term extension studies have been demonstrated; however, real world evidence remains to be established to bridge the gap between randomized controlled trials and rheumatology clinics. Fundamentally, no difference in the screening, prevention, and monitoring of infections between JAK inhibitors and biological DMARDs exists. However, increased risk of herpes zoster is probably common to all JAK inhibitors. No indication of increased risk for malignancy in patients with RA treated with JAK inhibitors has been reported. To evaluate risks of relatively rare serious adverse events such as thromboembolic events, gastrointestinal perforation, and interstitial lung disease in clinical settings, accumulation of cases with these events are needed. Continuous pharmacovigilance activity is absolutely warranted to establish the safety of JAK inhibitors in patients with RA and other rheumatic diseases.

Objective. To establish a new murine model of polymyositis (PM) for the understanding of its pathologic mechanisms and the development of new treatment strategies.Methods. C protein-induced myositis (CIM) was induced by a single immunization of recombinant human skeletal C protein in C57BL/6 mice, as well as in CD4-depleted, CD8-depleted, and mutant mice as controls. Some mice were treated with high-dose intravenous immunoglobulin (IVIG) after disease induction. Muscle tissues were examined histologically.Results. In mice with CIM, inflammation was confined to the skeletal muscles. Polymyositis (PM) is a chronic autoimmune inflammatory myopathy affecting striated muscles (1). Damage of muscles results in varying degrees of muscle weakness. Dysphagia with choking episodes and respiratory muscle weakness can occur in acute cases of PM. Currently, the pathogenesis of PM is unknown, and patients are therefore treated with nonspecific immunosuppressants. High-dose corticosteroids are the first-line treatment but are not effective in all patients. Improvement of disease often depends on the dosage of corticosteroids, making a dosage reduction difficult and thus, in many cases, necessitating administration of methotrexate or other immunosuppressants as adjunctive treatment. Because these medications can elicit a wide variety of adverse drug reactions, new therapies to address the specific pathologic features of PM are needed.In affected muscles of patients with PM, infiltration of mononuclear cells leads to muscle fiber necrosis. These cells are found in the endomysial site, where non-necrotic muscle fibers are damaged, and also in the perimysial and perivascular sites of the muscles. Immunohistochemical studies have disclosed that CD8 T cells are most abundant in the endomysial site and invade