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CD4(+) T cells express IL-2 receptor complexes to the same level as CD8(+) T cells when the two T cell populations were stimulated simultaneously. However, the activation of downstream signaling molecules, such as Jaks, was increased in CD8(+) T cells. Although equivalent amounts of CD45, which acts as a Jak phosphatase, was expressed on the two T cell populations, those on the CD8(+) T cells have less protein tyrosine phosphatase activity than those on the CD4(+) T cells. Furthermore, we find that different CD45 isoforms dominate in the two populations; CD45RO on proliferating CD4(+) T cells and CD45RBC on proliferating CD8(+) T cells. In addition, NIH3T3 cells expressing the CD45RBC transgene had more phosphorylated Jak1 and grew faster than those with the CD45RO transgene. Thus, the expression of specific CD45 isoforms on T cells correlates with their proliferative response to IL-2, suggesting that controlling cells expressing specific CD45 isoforms could correct excessive or insufficient immune responses.

Among the heterogeneous antiphospholipid antibodies, many studies suggest that those directed to beta2-glycoprotein I (beta2GPI) are the major pathogenic antibodies in antiphospholipid syndrome (APS). They have been shown to activate the coagulation pathway via several mechanisms, activate platelets via thrombin formation, and suppress fibrinolysis. Additionally, we propose another possible mechanism that involves certain chemokines and results in platelet activation. This hypothesis is based on the observations that anti-beta2GPI antibodies stimulated monocytes to secrete inflammatory cytokines such as IL-1beta and TNF-alpha, which in turn stimulated vascular endothelial cells to express chemokines such as CX3CL1 and CCL5. CX3CL1 increased the ability of normal platelets to adhere to collagen at a high shear rate, while CCL5 induced platelet aggregation. Expression of tissue factor, IL-1beta, and TNF-alpha by monocytes stimulated with anti-beta2GPI antibodies, as well as CX3CL1 and CCL5 by vascular endothelial cells stimulated with IL-1beta or TNF-alpha were all suppressed by the NF-kappaB-specific inhibitor DHMEQ. These results suggest that the NF-kappaB pathway may be a potential therapeutic target relating to both the coagulation pathway and platelet activity.

We evaluated the efficacy and safety of tacrolimus in patients receiving glucocorticoid therapy for lupus nephritis. Patients with persistent nephritis were randomized to receive 28 weeks of double-blind treatment with tacrolimus (3 mg/day) or placebo. The primary endpoint was the change in the lupus nephritis disease activity index (LNDAI) calculated from scores for daily urinary protein excretion, urinary red cells, serum creatinine, anti-double-stranded DNA antibody, and serum complement. Statistical analysis was performed using the full analysis set. The LNDAI was decreased by 32.9 +/- 31.0% (mean +/- SD) in the tacrolimus group (n = 28) and was increased by 2.3 +/- 38.2% in the placebo group (n = 35) at final evaluation. There was significant improvement in the tacrolimus group. Daily urinary protein excretion showed a significant decrease in the tacrolimus group (p0.001). The complement (C3) level showed a significant increase in the tacrolimus group (p = 0.001). Treatment-related adverse events occurred in 92.9% of the tacrolimus group and 80.0% of the placebo group, but the difference was not significant. In patients on glucocorticoid therapy for lupus nephritis, addition of tacrolimus to basal therapy achieved significant improvement compared with placebo. Tacrolimus may therefore be a useful alternative treatment for lupus nephritis.

Objective To explore new molecular targets in the treatment of polymyositis (PM) by examining a recently established murine model of PM, C protein–induced myositis (CIM), for involvement of an interleukin-6 (IL-6)/IL-17A pathway. Methods CIM was induced by immunizing wild-type mice as well as IL-6–null and IL-17A–null C57BL/6 mice with recombinant mouse skeletal C protein fragments. Some mice were treated with anti–IL-6 receptor (anti–IL-6R) monoclonal antibodies or control antibodies. Muscle tissue samples were examined histologically and immunohistochemically. Results The syngeneic C protein fragments successfully induced inflammation in the skeletal muscles of wild-type mice. IL-6 was expressed by mononuclear cells, especially in macrophages, infiltrating in the muscles. IL-6–null mice developed myositis with significantly lower incidence and milder severity than wild-type mice. In contrast, IL-17A–null mice were as susceptible to CIM as wild-type mice. Intraperitoneal administration of anti–IL-6R monoclonal antibodies, but not of control monoclonal antibodies, ameliorated CIM both preventively and therapeutically. Conclusion Our findings indicate that IL-6 is critically involved in the development of CIM. Although many other autoimmune models require IL-6 for differentiation of pathogenic T cells producing IL-17A, IL-17A was dispensable in CIM. Nevertheless, treatment with anti–IL-6R antibodies was effective. IL-6 blockade is potentially a new approach to the treatment of autoimmune myositis, via processes distinct from interference in the IL-6/IL-17A pathway.

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.

This study is a prospective, randomized, double-blind study to compare the efficacy and safety of 10 mg/kg infliximab with those of 3 mg/kg infliximab treatment in methotrexate-refractory rheumatoid arthritis patients. After the patients received 3 mg/kg infliximab infusion at weeks 0, 2, and 6, they were randomly assigned to be administered 3, 6 or 10 mg/kg infliximab every 8 weeks from week 14 to 46. Mean American College of Rheumatology improvement (ACR-N) at week 54, the primary endpoint, was 51.3% and 58.3% for the 3 mg/kg and 10 mg/kg groups, respectively, with a statistically significant difference. Treatment with 10 mg/kg was found to be remarkably beneficial in patients who had not responded to three infusions with 3 mg/kg at week 10. The median changes in the modified Sharp score were 0.0 in the two groups. There were no significant differences in the incidences of adverse events between the groups. In patients who achieved better clinical response or greater inhibition of progression of joint damage, trough serum infliximab level was significantly higher than in patients who did not. The magnitudes of both efficacies were correlated with the trough serum infliximab level (ClinicalTrials.gov number: NCT00691028).

Objective Triggering receptor expressed on myeloid cells 1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in disease related to bacterial infections. Its blockade rescues the hosts in murine models of sepsis, to clear the bacteria without impairing the host defense. The aim of this study was to investigate the involvement of TREM-1 in an autoimmune, noninfectious disease. Methods Synovial tissue specimens from the joints of patients with rheumatoid arthritis (RA) and the joints of mice with collagen-induced arthritis (CIA) were examined for TREM-1 expression, using flow cytometric analysis. Expression of TREM-1 on macrophages was induced by lipopolysaccharide, with or without a cyclooxygenase inhibitor. Rheumatoid synovial cells were stimulated with agonistic anti–TREM-1 antibodies. Recombinant adenovirus encoding the extracellular domain of TREM-1 fused with IgG-Fc (AxCATREM-1 Ig) or synthetic TREM-1 antagonistic peptides were injected to treat CIA, and the clinical manifestations of the antigen-specific T cell and B cell responses were evaluated. Results TREM-1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with CIA. Unlike murine macrophages, human monocyte/macrophages did not depend on prostaglandin E2 for up-regulation of TREM-1. Agonistic anti–TREM-1 antibodies promoted tumor necrosis factor α production from rheumatoid synovial cells. Blockade of TREM-1 using AxCATREM-1 Ig and antagonistic peptides ameliorated CIA without affecting the serum levels of anti–type II collagen antibodies or the proliferative responses of splenocytes to type II collagen. Conclusion TREM-1 ligation contributes to the pathology of autoimmune arthritis. The results of this study implied that blockade of TREM-1 could be a new approach to rheumatic diseases that is safer than the presently available immunosuppressive treatments.

The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.

Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4+CD45RO+FoxP3+ regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-γ production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-κB ligand (RANKL), lack of IFN-γ response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity.

Objectives To evaluate the safety and efficacy of 5-year, long-term tocilizumab monotherapy for patients with rheumatoid arthritis. Methods In an open-label, long-term extension trial following an initial 3-month randomised phase II trial, 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy (8 mg/kg) every 4 weeks. Concomitant therapy with non-steroidal anti-inflammatory drugs and/or oral prednisolone (10 mg daily maximum) was permitted. All patients were evaluated with American College of Rheumatology (ACR) improvement criteria, disease activity score (DAS) in 28 joints, and the European League Against Rheumatism response, as well as for safety issues. Results 143 patients were enrolled in the open-label, long-term extension trial and 94 (66%) patients had completed 5 years as of March 2007. 32 patients (22%) withdrew from the study due to adverse events and one patient (0.7%) due to unsatisfactory response. 14 patients withdrew because of the patient's request or other reasons. The serious adverse event rate was 27.5 events per 100 patient-years, with 5.7 serious infections per 100 patient-years, based on a total tocilizumab exposure of 612 patient-years. Of the 88 patients receiving corticosteroids at baseline, 78 (88.6%) were able to decrease their corticosteroid dose and 28 (31.8%) discontinued corticosteroids. At 5 years, 79/94 (84.0%), 65/94 (69.1%) and 41/94 (43.6%) of the patients achieved ACR20, ACR50, and ACR70 improvement criteria, respectively. Remission defined as DAS28 less than 2.6 was achieved in 52/94 (55.3%) of the patients. Conclusion In this 5-year extension study, tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile.

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.

Crk-associated substrate lymphocyte type (Cas-L) protein, also known as human enhancer of filamentation 1 (Hef1) or neural precursor cell-expressed, developmentally down-regulated gene 9 (Nedd9), belongs to the Cas family of adapter proteins, which are involved in integrin signaling. Previous reports showed that Cas-L is expressed preferentially in lymphocytes and epithelial cells. Cas-L mediates signals from integrins, T-cell receptors, B-cells receptors, and transforming growth factor beta, leading to cell movement and cell division. Here, we report the expression of Cas-L in neutrophils. Cas-L was tyrosine-phosphorylated when human neutrophils were stimulated by fMLP, tumor necrosis factor-alpha (TNF), or lipopolysaccharide. The tyrosine phosphorylation of Cas-L in fMLP- or TNF- stimulated neutrophils was further enhanced by adhesion of the cells to their substrates. Cas-L was found to be localized at focal adhesions in stimulated neutrophils based on immunofluorescence microscopy. These findings suggest that Cas-L is one of the targets of inflammatory cytokines and is also modulated by cell adhesion process in neutrophils.

Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis. Endogenous CDK inhibitors also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration of small molecules that inhibit CDK may or may not ameliorate arthritis. To address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and a newly synthesized CDK4/6-selective inhibitor were tested for antiarthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis mice with alvocidib suppressed synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed collagen-induced arthritis. Both small-molecule CDK inhibitors were effective in treating animal models of rheumatoid arthritis not by suppressing lymphocyte function. Thus, the two small-molecule CDK inhibitors ameliorated arthritis models in a distinctive way, compared with other immunosuppressive drugs.

p130Cas (Cas, Crk-associated substrate) is an adaptor molecule composed of a Src homology 3 (SH3) domain, a substrate domain (SD) and a Src binding domain (SBD). The SH3 domain of Cas associates with focal adhesion kinase (FAK), but its role in cellular function has not fully been understood. To address this issue, we established and analyzed primary fibroblasts derived from mice expressing a truncated Cas lacking exon 2, which encodes the SH3 domain (Cas Δexon 2). In comparison to wild-type cells, Cas exon 2Δ/Δ cells showed reduced motility, which could be due to impaired tyrosine-phosphorylation of FAK and Cas, reduced FAK/Cas/Src/CrkII binding, and also impaired localization of Cas Δexon 2 to focal adhesions on fibronectin. In addition, to analyze downstream signaling pathways regulated by Cas exon 2, we performed microarray analyses. Interestingly, we found that a deficiency of Cas exon 2 up-regulated expression of CXC Chemokine Receptor-4 and CC Chemokine Receptor-5, which may be regulated by IκBα phosphorylation. These results indicate that the SH3-encoding exon of Cas participates in cell motility, tyrosine-phosphorylation of FAK and Cas, FAK/Cas/Src/CrkII complex formation, recruitment of Cas to focal adhesions and regulation of cell motility-associated gene expression in primary fibroblasts.

Intravenous immunoglobulin (IVIG) therapy was administered to 15 patients who were refractory to traditional steroid therapy [eight with polymyosis (PM), seven with dermamyosis (DM)] to evaluate its efficacy. Serum creatine kinase (CK) significantly decreased from week 1, and manual muscle test scores (MMT) and activities of daily living (ADL) significantly increased from week 2. Efficacy rates were 93.3% (14/15 patients) as assessed using the MMT score, 80.0% (12/15 patients) using the ADL score, and 100% (15/15 patients) using the serum CK level. When changes in the serum CK level over two four-week periods, one before IVIG therapy (from week -4 to week 0) and one after IVIG therapy (from week 0 to week 4), were transformed to natural logarithms, the four-week change after IVIG therapy was significantly greater than that before IVIG therapy. The estimated duration of the serum CK level remaining normal in 50% of the patients after IVIG therapy was 334.5 days. Adverse reactions were observed in seven of 16 patients (43.8%) during the study period, but none of the adverse reactions were considered to be serious or required emergency treatment. In conclusion, the present study indicates that IVIG therapy is effective for steroid-resistant PM/DM.

We describe a case of systemic lupus erythematosus (SLE) complicated with multifocal leukoencephalopathy (PML). A 57-year old woman, who had a five-year history of SLE, was admitted to our hospital because of fever and multiple subcutaneous nodules. Diagnosis of disseminated cryptococcosis was made based on histological and bacteriological examinations, and she was successfully treated with anti-fungal drugs. Corticoteroids were increased for persistent lupus activities. One month later, however, she gradually developed disorientation and short-term memory loss. A brain magnetic resonance image (MRI) showed a focal lesion in the white matter of the right frontal lobe. Brain biopsy demonstrated demyelinating lesions with the presence of JC viral antigen. Polymerase chain reaction also revealed JC virus DNA in the cerebrospinal fluid. Her condition gradually progressed, and she died a year later due to pneumonia. Although acquired immunodeficiency syndrome is currently the most common disease associated with PML, patients with autoimmune diseases receiving immunosuppressive therapy also have risks for developing PML. In patients with SLE presenting with subacute neurological abnormalities and white matter lesions in the brain, PML should be considered in the differential diagnosis.

Application of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-alpha agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-alpha blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-alpha blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-alpha blocking agents and be alert to any adverse events for a better management of RA patients.

Here, we report a case of Muckle-Wells syndrome (MWS) caused by a novel mutation in the CIAS1/NALP3 gene. A 23-year-old woman had recurrent self-limited inflammatory episodes from childhood, with headache, abdominal pain, arthritis, and urticarial rash, associated with profound sensorineural hearing loss. The diagnosis was established on the basis of a typical clinical picture together with a missense mutation, which replaced an amino acid adjacent to one in an earlier reported case of MWS resembling this one.

Corticosteroids (CS) are the standard initial treatment for interstitial pneumonia (IP) associated with dermatomyositis (DM)/polymyositis (PM). However, many patients fail to respond and have significantly high mortality even if immunosuppressive drugs (ISDs) are subsequently added, while a more intensive initial approach using ISDs is suggested to improve their survival. We conducted a retrospective study to examine the association between initial therapeutic approaches and clinical outcomes of active IP in DM/PM patients. We reviewed medical records of 34 consecutive DM/PM patients who had active IP defined by the presence of pulmonary function abnormality or active symptoms, and compared clinical outcome between those patients to whom ISDs were added if CS alone did not result in a favorable response (a step-up approach) and those who were started on ISDs simultaneously with CS (a primary intensive approach). Clinical endpoints were death, pulmonary death, and progression or improvement of pulmonary function. The step-up approach was used in 20 patients, to 11 of whom ISDs were eventually added after a median of 2.0 weeks, while the primary intensive approach was used in 14 patients. The primary intensive approach group had significantly better survival than the step-up approach group (P = 0.030 by the log-rank test). These two groups did not differ significantly in demographic characteristics and baseline clinical and laboratory features. Intensive approach by starting ISDs simultaneously with CS in the initial treatment for active IP in DM/PM patients was associated with better survival, emphasizing the impact of initial treatment on their survival. Prospective clinical investigation of this approach is now needed, but the limited clinical utility of CS as an initial treatment might ethically challenge clinical-trial designing.

To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.

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. Histologic examination revealed a common pathologic feature of CIM and PM, involving abundant infiltration of CD8 and perforin-expressing cells in the endomysial site of the injured muscle. Suppression of myositis was achieved by depletion of both CD4 and CD8 T cells. Despite the development of serum anti-C protein antibodies in wild-type mice, severe myositis was induced in mice deficient in B cells. Induction of myositis was suppressed in interleukin-1alpha/beta (IL-1alpha/beta)-null mutant mice, but not in tumor necrosis factor alpha (TNFalpha)-null mutant mice. Use of IVIG, a treatment with proven efficacy in PM, suppressed CIM in the subgroup of treated mice. Conclusion CIM mimics PM pathologically and clinically. Infiltration of CD8 T cells is the most likely mechanism of muscle injury, and IL-1, but not B cells or TNFalpha, is crucial in the development of CIM. IVIG has therapeutic effects in CIM, suggesting that the effects of IVIG are not mediated by suppression of antibody-mediated tissue injury. This murine model provides a useful tool for understanding the pathologic mechanisms of PM and for developing new treatment strategies.

Objectives To evaluate, through a systematic review of the literature, the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and surgical site infection (SSI) or wound healing delay after orthopedic surgery in patients with rheumatoid arthritis (RA). Methods A systematic review of articles indexed in the Cochrane Library, PubMed, and Web of Science from 1992 to 2012 was performed. The search aimed to identify studies describing SSI or wound healing delay in patients with RA treated with or without bDMARDs. Articles fulfilling the predefined inclusion criteria were reviewed systematically and their quality was appraised. Results There was no Cochrane review on this subject. We found 75 articles through specific searches of PubMed and Web of Science, and hand searching. After inclusion and exclusion by full-text review, 10 articles were found for SSI, and 5 articles for delayed wound healing. The use of bDMARDs appeared to increase the rate of SSI slightly, especially in large joint-replacement surgery. Delayed wound healing was not increased by the use of bDMARDs. However, the definitions of SSI and delayed wound healing varied between the reviewed articles. Most of the articles focused on tumor necrosis factor-α inhibitors. Conclusion bDMARDs slightly increase the relative risk of SSI but not that of delayed wound healing after orthopedic surgery and should be used with appropriate caution.

C protein-induced myositis (CIM) is a mouse model of polymyositis in which activated antigen-specific CD8+ T cells injure the muscles. Animal models of autoimmunity that have been examined in the past for the effects of the type 1 cytokine interferon-γ (IFNγ) and the type 2 cytokine interleukin-4 (IL-4) are all mediated by pathogenic CD4+ T cells. In those models, the disruption of IFNγ leads to up-regulation of IL-17A, exacerbating the disease with neutrophil infiltration into sites of inflammation. This study was undertaken to investigate the roles of IFNγ and IL-4, as well as IL-17A in the absence of IFNγ, in CD8+ T cell-mediated CIM.IFNγ(-/-) mice, anti-IL-17A antibody-treated IFNγ(-/-) mice, IFNγ(-/-) IL-17A(-/-) mice, IL-4(-/-) mice, and wild-type C57BL/6 mice were immunized with skeletal muscle C protein fragments to induce CIM. Muscle tissue specimens were examined histologically.IFNγ(-/-) mice developed myositis at a higher incidence and with greater severity than wild-type mice. Unlike wild-type mice, IFNγ(-/-) mice had infiltration of neutrophils into the endomysial sites of the affected muscles. IFNγ(-/-) mice treated with anti-IL-17A antibodies and IFNγ(-/-) IL-17A(-/-) mice developed myositis with an incidence and severity comparable to those in IFNγ(-/-) mice and showed neutrophil infiltration similar to that in IFNγ(-/-) mice. IL-4(-/-) mice developed CIM comparable to that in wild-type mice.Our findings indicate that IFNγ, but not IL-4, plays a suppressive role in the development of CIM. Unlike in CD4+ T cell-mediated autoimmune disease models, IFNγ prevents factors other than IL-17A from exacerbating myositis and neutrophil infiltration in CD8+ T cell-mediated CIM.

In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases.

We describe two cases of leflunomide-related interstitial pneumonia (IP). A 75-year-old woman with rheumatoid arthritis (RA) developed rapidly progressing IP 45 days after institution of leflunomide. She died of respiratory failure, and an autopsy revealed a mixed pattern of acute and organizing diffuse alveolar damage. A 69-year-old woman with RA also developed acute IP 3 months after institution of leflunomide. Methylprednisolone pulse therapy and cholestyramine ameliorated her IP. The implication of leflunomide in the pathogenesis of IP was suggested.

Rheumatoid arthritis (RA) affects approximately 1% of the population, resulting in disturbances of daily activity and quality of life. Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of RA, and the blockade of TNF-α with anti-TNF-α monoclonal antibodies (infliximab and adalimumab) and the soluble TNF-α receptor (etanercept) has caused a dramatic paradigm shift in the treatment of RA. Etanercept is a safe, highly effective biological agent in the treatment of RA. It can be used alone or with methotrexate, but the combination of the two is highly efficacious compared with monotherapy using etanercept. The most significant benefit of etanercept is to inhibit the progression of joint destruction. Although etanercept is well tolerated, its long-term safety, including the occurrence of malignant lymphoma, remains to be elucidated.

Application of biological agents targeting inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) dramatically caused a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-TNF-alpha monoclonal antibody, has initially been introduced to Japan in 2003 and shown to be dramatically effective in alleviating arthritis refractory to conventional treatment. However, serious adverse events such as bacterial pneumonia, tuberculosis, and Pneumocystis jiroveci pneumonia were reported to be in relatively high incidence; i.e., 2%, 0.3%, and 0.4%, respectively, in a strict postmarketing surveillance of an initial 4000 cases in Japan. Etancercept, a recombinant chimeric protein consisting of p75 TNF-alpha receptor and human IgG, was subsequently introduced to Japan in March of 2005. We therefore drew up treatment guidelines for the use of etanercept to avoid potential serous adverse events, since only approximately 150 cases have been included in the clinical study of etanercept in Japan. The guidelines were initially designed by the principal investigators (N.M, T.T., K.E.) of rheumatoid arthritis study groups of the Ministry of Health, Labor and Welfare (MHLW), Japan, and finally approved by the board of directors of the Japan College of Rheumatology. The MHLW assigned a duty to the pharmaceutical companies to perform a complete postmarketing surveillance of an initial 3000 cases to explore any adverse events, and this was performed according to the treatment guidelines shown in this article.

The tumor suppressor p53 has been shown to be essential in apoptosis induced by irradiation, deregulated c-Myc expression and anti-cancer drugs. The protein level of p53 was moderately increased when the B cell line WEHI-231 undergoes apoptosis by B cell receptor (BCR) crosslinking. However, overexpression of a dominant negative form of p53, p53DD, abolished DNA binding activity of p53 almost completely but failed to block BCR-mediated death of WEHI-231, suggesting that p53-mediated transactivation is not required for BCR-mediated apoptosis of WEHI-231. Moreover, B cells of p53-deficient mice underwent cell death upon BCR crosslinking as efficiently as those of normal littermates, indicating that p53 is not essential for BCR-mediated apoptosis of normal B cells. Although a previous report suggested that p53 is required for BCR-mediated apoptosis through its transactivation, our data strongly argue that p53 is not required for BCR-mediated apoptosis.

Systemic lupus erythematosus (SLE) is an autoimmune-mediated collagen disease that results in multiorgan failure. It is the collagen disease most frequently associated with neuropsychiatric symptoms, which have been hypothesized to stem from certain types of cognitive dysfunction. Subjects were 21 patients with SLE (one man, 20 women; aged 16-55 years; mean age, 35.1 ± 10.7 years) who were undergoing treatment in the rheumatology unit of a general hospital, and 17 healthy control subjects matched to the patient group with respect to age and gender (two men, 15 women; mean age, 35.9 ± 6.3 years). They were administered various tests of cognitive function including verbal reasoning, non-verbal reasoning, verbal memory, non-verbal memory, attention and mental flexibility, psychomotor speed and frontal lobe function. In addition, the SLE patients were tested for antiphospholipid antibodies. The SLE patients performed worse than the control group on immediate, delayed and interference of the Rey verbal test and paired associate tests of Wechsler Memory Scale, and their reaction time was slower in Trail A and Trail B tests. Moreover, these findings were more pronounced in the group with major neuropsychiatric symp- toms. However, no relationship was apparent between these deficits in cognitive function and the presence or absence of antiphospholipid antibodies. The results suggest that verbal memory and psychomotor speed underlie the neuropsychiatric symptoms seen in SLE patients.

Objective: Single-photon emission computed tomography (SPECT) studies have demonstrated decreased regional cerebral blood flow (rCBF) in systemic lupus erythematosus (SLE) patients. However, no study has done voxel-based analysis using statistical parametric mapping (SPM) that can evaluate rCBF objectively, and the relationship between rCBF and psychiatric symptoms has not been well investigated. Using L,L-ethyl cysteinate dimer ( 99m Tc ECD) SPECT and SPM, we aimed to clarify the association of rCBF changes with psychiatric symptoms in SLE patients whose magnetic resonance imaging (MRI) showed no morphological abnormalities. Method: Twenty SLE patients and 19 healthy volunteers underwent 99m Tc ECD SPECT. Data were collected from August 2000 to March 2003. SLE was diagnosed according to American College of Rheumatology criteria, and psychiatric symptoms were diagnosed according to ICD-10 criteria. On the basis of the modified Carbotte, Denburg, and Denburg method, the patients were classified into 3 groups: a group with major psychiatric symptoms (hallucinosis, delusional disorder, and mood disorder), a group with minor psychiatric symptoms (anxiety disorder, dissociative disorder, and emotionally labile disorder), and a group without psychiatric symptoms. Gross organic lesions were ruled out by brain MRI. Group comparisons of rCBF were performed with analysis using SPM99. Results: SLE patients without MRI lesions showed decreased rCBF in the posterior cingulate gyrus and thalamus. The reduction in rCBF was overt in patients with major psychiatric symptoms. Conclusion: Our study indicated that SLE patients may have dysfunction in the posterior cingulate gyrus and thalamus and that this may be associated with the severity of psychiatric symptoms.

Differences in ethnic backgrounds as well as in medical and socioeconomic status often affect both the efficacy and adverse effects of medications. Recent data suggest an increased risk of opportunistic infections, especially tuberculosis (TB), among rheumatoid arthritis (RA) patients receiving infliximab, a chimeric monoclonal anti-tumor necrosis factor alpha (TNF-alpha) antibody. In this regard, the annual incidence of TB is approximately five times higher in Japan than in the United States. Furthermore, since Bacillus Calmette-Guerin vaccination is mandatory in childhood when the skin test for purified protein derivative (PPD) is negative, a high incidence of false-positive PPD skin tests is observed among the Japanese population. In addition, the upper limit of methotrexate dosage to be used for RA is lower in Japan. We have therefore established official guidelines for the proper use of infliximab in Japanese RA patients. In this review, an algorithm for the diagnosis and management of TB in RA is presented in an evidenced-based form.

Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive T cell infiltration into the synovium. The accumulated T cells express type 1 cytokines, such as interferon-γ (IFNγ) and tumor necrosis factor α, and activated markers of inflammation, such as CD154 and inducible costimulator (ICOS). It is thought that chemokines contribute to T cell accumulation in the synovium. In this study, we examined the role of CXCL16 and CXCR6 in T cell migration and stimulation in RA synovium. Methods Expression of CXCL16 and CXCR6 was analyzed by immunohistochemistry, reverse transcription–polymerase chain reaction, Western blotting, and/or flow cytometry. Migration activity was assessed using a chemotaxis chamber. IFNγ production was analyzed by enzyme-linked immunosorbent assay. The effect of anti-CXCL16 monoclonal antibody on murine collagen-induced arthritis (CIA) was evaluated. Results CXCL16 was expressed in RA synovium. CXCR6 was expressed more frequently on synovial T cells than in peripheral blood. Moreover, CXCR6-positive synovial T cells more frequently expressed CD154 and ICOS than did CXCR6-negative T cells. Stimulation with interleukin-15 (IL-15) up-regulated the expression of CXCR6 on peripheral blood T cells, and then stimulation with CXCL16 induced migration of IL-15–stimulated T cells and enhanced IFNγ production. Furthermore, anti-CXCL16 monoclonal antibody significantly reduced the clinical arthritis score and reduced infiltration of inflammatory cells and bone destruction in the synovium of mice with CIA. Conclusion Our results indicate that CXCL16 plays an important role in T cell accumulation and stimulation in RA synovium and suggest that CXCL16 could be a target molecule in new therapies for RA.

Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA-positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population.

Serum C reactive protein (CRP) is generally elevated by infection. We encountered two patients with severe bacterial infections without increases in CRP. Patient 1: A 67-year-old man developed thoracic empyema by Escherichia coli and Streptococcus intermedius . His body temperature was 36.6°C, his leukocyte count was elevated (9960/μl) and he was negative for CRP (0.01 mg/dl). Despite antibiotic treatment, he died of respiratory failure. Patient 2: A 56-year-old woman developed multiple subcutaneous abscesses by Staphylococcus aureus . She had rheumatoid arthritis (RA) for 30 years and was treated with sodium aurothiomalate. Her body temperature was 37.4°C, and leukocyte count (5600/μl) and CRP (0.05 mg/dl) were not elevated. She recovered with antibiotics. Neither patient had a past history of severe bacterial infection. Since serum CRP is mainly controlled by interleukin (IL)-6,1 the lack of IL-6 function was suggested. Serum IL-6 was not detected by ELISA in either patient, although it is known to increase with severe infection.2 ,3 However, IL-6 production from peripheral blood monocytes with/without lipopolysaccharide stimulation was similar between Patient 1 and healthy controls (data not shown). Soluble IL-6 receptor (IL-6R) and IL-6 signal transducer (IL-6ST) serum levels were also …

The Japanese criteria for diagnosing Sjögren's syndrome (SS) were revised in 1999, and consist of four major areas: histopathology, oral examination, ocular examination, and serological examination. A diagnosis of SS can be made when the patient meets at least two of these four criteria. This report describes how the revised Japanese criteria were established. After the publication of the revised Japanese criteria (1999), a research study which focused on evaluating its availability and validity was carried out in 2001 using funds from Grant-in-Aids for Scientific Research supported by the Japan Society for the Promotion of Science. The availability of the revised criteria was investigated by a questionnaire study through the Japanese Medical Society for Sjögren's Syndrome, and the use of the revised criteria for diagnosing SS in these medical facilities was found to be 76%. To evaluate the validity of the revised criteria, the records of 900 patients, including SS patients and non-SS controls, from 54 clinical centers were registered and analyzed to calculate the accuracy of the criteria. The revised Japanese criteria were found to have 96.0% sensitivity, 90.5% specificity, and 94.5% accuracy for diagnosing SS.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with massive infiltration of inflammatory cells in the synovium of multiple joints. We and others have shown that fractalkine (FKN/CX3CL1), a chemokine expressed on fibroblast-like synoviocytes and endothelial cells in RA synovium, may contribute to the accumulation of T cells, macrophages, and dendritic cells, which express CX3CR1, the receptor for FKN. This interaction might be involved in adhesion of the inflammatory cells to endothelial cells, migration into the synovium, and cytokine production. In this study, we examined the effect of FKN inhibition on murine collagen-induced arthritis. Anti-FKN mAb significantly lowered clinical arthritis score compared with control Ab, and reduced infiltration of inflammatory cells and bone erosion in the synovium. However, anti-FKN mAb did not affect the production of either serum anti-collagen type II (CII) IgG or IFN-γ by CII-stimulated splenic T cells. Furthermore, treatment with anti-FKN mAb inhibited migration of adoptively transferred splenic macrophages into the inflamed synovium. Our results suggest that anti-FKN mAb ameliorates arthritis by inhibiting infiltration of inflammatory cells into the synovium. Thus, FKN can be a new target molecule for the treatment of RA.

Objective Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti–IL-6 receptor antibody, MRA, in patients with RA. Methods In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. Results Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. Conclusion Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

Forced expression of a cyclin-dependent kinase inhibitor gene, p21Cip1 in the synovial tissues was effective in treating animal models of rheumatoid arthritis. Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21Cip1 on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21Cip1 gene transferred. We have found that p21Cip1 gene transfer down-regulates expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of rheumatoid arthritis. These molecules included IL-6, -8, type I IL-1R (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, and matrix metalloproteinases-1 and -3. Down-regulation of IL-1R1 by p21Cip1 resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21Cip1 was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21Cip1, and inactivation of NF-κB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitor gene and inflammatory molecules.

Inducible costimulator (ICOS)-B7 homologous protein (B7h) is a new member of the CD28-B7 family of costimulatory molecules that regulates T cell-dependent humoral immune responses. In this study, we examined the involvement of this costimulatory pathway in the development and progression of lupus in NZB/W F1 mice. Expression of ICOS on T cells was enhanced with disease progression, whereas B7h expression on B cells was down-regulated. Administration of anti-B7h mAb before the onset of renal disease significantly delayed the onset of proteinuria and prolonged survival. Blockade of B7h effectively inhibited all subclasses of IgG autoantibody production and accumulation of both Th1 and Th2 cells. Hypercellularity and deposition of IgG and C3 in glomeruli were significantly reduced. B7h blockade after the onset of proteinuria prevented the disease progression and improved the renal pathology. Our results demonstrated the involvement of the ICOS-B7h costimulatory pathway in the pathogenesis of lupus nephritis, and the blockade of this pathway may be beneficial for the treatment of human systemic lupus erythematosus.

We have molecularly cloned TPP36, a novel 36 kDa protein with 281 amino acids that was identified as a protein phosphorylated in B progenitor cells following stimulation with pervanadate/H2O2. Analysis with anti-TPP36 antiserum revealed that TPP36 was expressed ubiquitously and had an isoform with 236 amino acids, designated TPP32. TPP36/32 were localized mainly in cytoplasm despite the presence of a typical nuclear localization signal sequence. These proteins were phosphorylated preferentially by Abl among a panel of tyrosine kinases examined. Phosphorylation of tyrosine 120 in TPP36/32 led to an apparent mobility shift in sodium dodecyl sulfate–polyacrylamide gel electrophoresis, suggesting conformational change in the phosphorylated protein. Thus, TPP36/32 appear to be novel substrates of Abl tyrosine kinase.

To the Editor: Granulomatosis with polyangiitis (GPA; formerly Wegener’s granulomatosis) is a small to medium-size vessel vasculitis involving various organs, with the classic triad of upper airway, lung, and kidney involvement. GPA can be accompanied by chronic hypertrophic pachymeningitis (CHP), characterized by inflammatory thickening of the cerebral or spinal dura mater1. Although the pathology of CHP does not depend on the contiguous spread of granulomatous lesions from the nasal or paranasal sinuses, GPA with CHP has been reported to present mostly with limited organ involvement2,3. Specifically, antimyeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive GPA with CHP has been reported to lack renal involvement1,2,4. We describe a case of MPO-ANCA-positive GPA, which presented with CHP-related central nervous system (CNS) symptoms and with renal abnormalities, with a discussion of the incidence of renal involvement in MPO-ANCA-positive GPA accompanied by CHP. A previously healthy 48-year-old Japanese man presented to the otolaryngology department with a 3-month history of fever, bilateral temporal headaches, left facial nerve paralysis, dysphagia, and hoarseness, which occurred sequentially. … Address correspondence to Dr. H. Kohsaka, Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: kohsaka.rheu{at}tmd.ac.jp