Interleukin 21 (IL-21) has recently been identified as a multifunctional cytokine that induces the proliferation of T cells and B cells and differentiation of natural killer cells. To determine whether IL-21 regulates IL-4–mediated immune responses, we examined the effect of IL-21 on antigen-specific IgE production in mice. We also examined the effect of IL-21 on IL-4–induced IgE production from B cells and antigen-induced T-helper 2 (Th2) cell differentiation. The in vivo injection of IL-21 prevented antigen-specific IgE but not IgG2a production on immunization. IL-21 did not affect Th2 cell differentiation or IL-4 production from CD4+ T cells but directly inhibited IL-4–induced IgE production from B cells at single-cell levels. Moreover, IL-21 inhibited IL-4–induced germ line Cε transcription in B cells without the inhibition of signal transducer and activator of transcription 6 (Stat6) activation. Taken together, these results indicate that IL-21 down-regulates IgE production from IL-4–stimulated B cells through the inhibition of germ line Cε transcription and thus suggest that IL-21 may be useful for the treatment of IgE-dependent allergic diseases.

No abstract

Infliximab NRs comprise subtypes with distinct CRP patterns. Failure to suppress the CRP at week 2 identified the majority of patients who were NRs at week 12. CRP suppression at week 12 in the NRs was associated with a late clinical improvement with infliximab treatment (24 weeks), whereas failure to suppress the CRP at week 12 was associated with a good response on switching to etanercept.

To clarify the impact of comorbidities on treatment strategies and outcomes in patients with rheumatoid arthritis (RA) using a large observational RA cohort, the presence of comorbidities was assessed using the Charlson Comorbidity Index (CCI). Changes in medication, disease activity by Disease Activity Score-28 joint count (DAS28) over 6 months, disability assessed by the Japanese version of the Health Assessment Questionnaire (J-HAQ), and quality of life by EuroQOL-5-Dimensions (EQ-5D) over 1 year in patients with high disease activity (DAS28 > 5.1) at baseline were assessed according to age-adjusted CCI (CCI(A)) and categorized into four groups (CCI(A) 0, 1-2, 3-4, and ≥5). Among 5,317 patients, 975 patients (18.3%) had at least one comorbidity listed by CCI. DAS28, J-HAQ, and EQ-5D increased in severity with increased CCI(A) levels. Among patients with high disease activity (n = 267), treatment with methotrexate and/or biologics and improved DAS28 scores, shown by attenuated intensity, were associated with increased CCI(A) levels. J-HAQ improved from 1.29 ± 0.31 to 0.87 ± 0.37 in 1 year in the CCI(A) 0 group. The adjusted difference (standard error) in J-HAQ at 1 year in CCI(A) 1-2, 3-4, and ≥5 groups was worse than J-HAQ in the CCI(A) 0 group by 0.32 (0.09, p < 0.001), 0.45 (0.10, p < 0.001), and 0.45 (0.15, p < 0.01), respectively. The magnitude of improvement of EQ-5D was significantly attenuated with increasing CCI(A) levels. Thus, patients with comorbidities may not experience the same degree of benefit from recent RA treatments compared with patients without comorbidities in daily practice.

Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans.

Allergic inflammation is mediated by Th2 cell-derived cytokines, including IL-4, IL-5, and IL-13, and down-regulated by IFN-γ and IL-12. Tyk2 is a member of the Janus family of protein tyrosine kinases and is activated by a variety of cytokines: IFN-αβ, IL-6, IL-10, IL-12, and IL-13. In this study, we investigated the role of Tyk2 in the regulation of Ag-induced Th cell differentiation and Ag-induced allergic inflammation in the airways using Tyk2-deficient (Tyk2−/−) mice. When splenocytes were stimulated with antigenic peptide, IL-12-mediated Th1 cell differentiation was decreased, but IL-4-mediated Th2 cell differentiation was increased in Tyk2−/− mice. In vivo, Ag-specific IgE and IgG1 production was increased, but Ag-specific IgG2a production was decreased in Tyk2−/− mice as compared with those in control mice. In addition, Ag-induced eosinophil and CD4+ T cell recruitment, as well as the production of Th2 cytokines in the airways, was increased in Tyk2−/− mice. Adoptive transfer experiments revealed that CD4+ T cells were responsible for the enhanced Ag-induced eosinophil recruitment in Tyk2−/− mice. In contrast, although the level of IL-13 was increased in the airways of Tyk2−/− mice after Ag inhalation, the number of goblet cells, as well as Muc5ac mRNA expression, was decreased in Tyk2−/− mice. Together, these results indicate that Tyk2 plays a bilateral role in the regulation of allergic inflammation in the airways: Tyk2 plays a role in the down-regulation of Th2 cell-mediated Ab production and eosinophil recruitment in the airways by regulating Th1/Th2 balance toward Th1-type, while Tyk2 is necessary for the induction of IL-13-mediated goblet cell hyperplasia in the airways.

Management of rheumatoid arthritis (RA) has improved over the last 10 years. These changes have been monitored in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) observational cohort, and clinical remission has become a realistic goal. However, we should recognize that the ultimate goal of treatment is to improve long-term outcomes. These improvements have been achieved not only by new drugs, but also by the overall approach toward treating patients. Biologics in RA have been successful; however, safety concerns and pharmacoeconomical issues are still debated. Protein kinase inhibitors have been developed, and can be called "molecular-targeting antirheumatic drugs" (MTARDs), as opposed to "disease-modifying antirheumatic drugs." In comparison with biologics, oral MTARDs should be less expensive; however, their safety profile should be confirmed. Considering the limitations of randomized trials, it is encouraged to conduct studies based on daily practice. It is time to consider the application of the evidence generated from "our" patients to patients in daily practice, namely institute-based medicine as opposed to evidence-based medicine, of which "IORRA-based medicine" would be representative. Finally, there remains much for us rheumatologists to do for our patients, including patient-perspective approaches.

Objective. In patients with rheumatoid arthritis (RA) treated with tumor necrosis factor ␣ (TNF␣)-blocking therapy, there is heterogeneity of response. This raises the possibility that in certain circumstances, cytokines such as interleukin-1 (IL-1) may dominate the drive toward joint inflammation. This study was undertaken to investigate whether blocking the action of IL-1 with an IL-1 receptor antagonist (IL-1Ra) is efficacious in patients with disease that did not respond to TNF␣ blockade.Methods. We identified 26 RA patients whose disease had failed to respond to TNF␣-blocking therapy, defined as failure to achieve or sustain a 20% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR20 response). These patients were then treated with anakinra (100 mg/day subcutaneously) for 12 weeks, and their levels of response were assessed.Results. After 3 months of anakinra therapy, only 2 of 26 patients (8%) achieved an ACR20 response; none achieved an ACR50 or ACR70 response. A rise in the mean C-reactive protein level and an increase in the mean swollen joint count were noted during the study period.Conclusion. This study demonstrates that patients with disease that fails to respond to TNF␣ blockade also do not respond to IL-1Ra. These data do not provide evidence of a dominant role for IL-1 in patients who do not respond to TNF␣ blockade, but they do not exclude a role for other proinflammatory mediators.