Three cases of relapsed eosinophilic sinusitis without eosinophilia during mepolizumab maintenance therapy for eosinophilic granulomatosis with polyangiitis.

We present three cases of eosinophilic granulomatosis with polyangiitis (EGPA) where patients experienced relapse of eosinophilic sinusitis without peripheral eosinophilia while on remission maintenance therapy with mepolizumab (MPZ), an anti-interleukin (IL)-5 monoclonal antibody. Despite the initial control of symptoms with high-dose prednisolone (PSL) and MPZ, patients experienced a relapse of nasal obstruction and eosinophilic infiltration in nasal mucosal biopsies. Notably, relapses occurred despite normal peripheral eosinophil counts, indicating the localized nature of eosinophilic inflammation. While IL-5 inhibitors effectively reduce peripheral blood eosinophils, eosinophilic sinusitis may persist due to local factors such as IL-4-mediated inflammation. IL-4 has been implicated in promoting eosinophil migration into nasal tissues, suggesting that IL-5 inhibitors alone may not sufficiently suppress eosinophilic infiltration in such cases. These findings highlight the importance of considering the possibility of eosinophilic sinusitis relapse in EGPA patients treated with IL-5 inhibitors and reduced glucocorticoid doses. Further research is warranted to elucidate the mechanisms underlying local eosinophilic inflammation and optimize treatment strategies for EGPA patients.

Real-world study comparing the efficacy of Janus kinase inhibitors in patients with difficult-to-treat rheumatoid arthritis.

OBJECTIVE: This study aimed to analyze the clinical efficacy of JAK inhibitors in difficult-to-treat rheumatoid arthritis (D2TRA) and non-D2TRA patients and evaluate the factors influencing their efficacy using real-world data. METHOD: Here, 159 JAK inhibitor-treated patients with rheumatoid arthritis were categorized into D2TRA and non-D2TRA groups. Data including the Clinical Disease Activity Index (CDAI) at initiation and 6 months after drug administration, drug retention months, and reason for discontinuation due to toxic adverse events were collected. RESULTS: The retention rates at 6 months were 64.0% (D2TRA) and 78.4% (non-D2TRA) and were significantly different between the two groups (p = 0.030). The discontinuation rate owing to toxic adverse events significantly differed between the two groups (p = 0.030). The CDAI-low disease activity (LDA) rates differed significantly between the two groups (non-D2TRA, 62.3%; D2TRA, 34%; p < 0.001). CDAI-LDA achievement at 6 months after drug introduction was significantly associated with the number of times that biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs were previously used and the CDAI at baseline in all patients treated with JAK inhibitors. However, no predictive factors were identified for D2TRA patients treated with JAK inhibitors. CONCLUSION: Compared to non-D2TRA patients, D2TRA patients demonstrated significantly lower drug retention rates, CDAI-LDA achievement rates, and safety of JAK inhibitors. No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients. Key Points • The retention of JAK inhibitors were significantly lower for the treatment of D2TRA patients in comparison with non-D2TRA patients. • The efficacy and safety of JAK inhibitors were significantly lower for the treatment of D2TRA patients. • Number of previous uses of b/tsDMARDs and CDAI at baseline were identified as the predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. • No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients.

Subarachnoid Hemorrhaging with Multiple Cerebral Artery Stenoses after Initiating Remission Induction Therapy for Eosinophilic Granulomatosis with Polyangiitis: a Case Report.

We encountered a 64-year-old Japanese woman who developed subarachnoid hemorrhaging (SAH) with multiple cerebral artery stenoses during remission induction therapy for eosinophilic granulomatosis and polyangiitis (EGPA). The treatment involved intensified steroid pulse therapy and continued intravenous cyclophosphamide pulse therapy, which led to beneficial effects. Given the rarity of multiple EGPA-associated cerebral artery stenoses and SAH, it is crucial to differentiate them from other diseases. The mortality rate of EGPA complicated by intracranial hemorrhagic lesions, including SAH, is high. When headache is present at the onset of EGPA, the possibility of SAH must be considered.

Association of large joint involvement at the start of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors with disease activity and drug retention in patients with rheumatoid arthritis: The ANSWER cohort study.

AIM: To investigate the association of large joint involvement (LJI) with disease activity and drug retention in patients with rheumatoid arthritis (RA) who started receiving a biological disease-modifying antirheumatic drug or Janus kinase inhibitor. METHODS: Patients with RA from a Japanese multicenter observational registry were enrolled. Our definition of large joints included the shoulder, elbow, hip, knee, and ankle joints. Linear mixed-effects models were used to examine changes in the clinical disease activity index (CDAI) score at Week 24 as the primary outcome, and drug retention rates were compared between patients with and without LJI using Cox proportional hazards models. We examined the potential effect modifications of changes in the CDAI by baseline characteristics. RESULTS: Overall, 2507 treatment courses from 1721 patients were included (LJI, 1744; no LJI, 763). Although LJI was associated with significantly higher changes in CDAI from baseline at Week 24 (difference in change in CDAI: -5.84 [-6.65 to -5.03], p < .001), CDAI was significantly higher in patients with LJI over time. Retention rates were similar in both groups. The association of LJI with changes in disease activity was more prominent in patients with a short disease duration, negative anti-citrullinated peptide antibodies, and interleukin-6 receptor inhibitor (IL-6Ri) use. CONCLUSION: Although LJI was associated with a greater reduction in disease activity from baseline, higher disease activity at baseline was not offset over time in patients with LJI, demonstrating that LJI is an unfavorable predictor. An early treat-to-target strategy using an IL-6Ri may be beneficial for patients with LJI.

Comparison of retention of biologics in Japanese patients with elderly-onset rheumatoid arthritis-the ANSWER cohort study.

OBJECTIVES: This multicentre, retrospective study aimed to compare retention and reasons for discontinuation between Janus kinase inhibitors (JAKi) and biologic disease-modifying antirheumatic drugs in patients with elderly-onset rheumatoid arthritis (EORA). METHODS: Patients with RA enrolled in a Japanese multicentre observational registry between 2015 and 2022 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding factors by indication for initiation of tumor necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), cytotoxic T-lymphocyte associated antigen 4 immunoglobulin (CTLA4-Ig) blockers, or JAKi, a propensity score based on baseline characteristics was used to compare drug retention. To assess the reasons for discontinuation, retention rates for ineffectiveness, adverse events, and remission were analyzed as secondary outcomes. RESULTS: A total of 572 patients with 835 treatment courses were identified (314 TNFi, 175 IL-6i, 228 CTLA4-Ig, and 118 JAKi). After adjusting for differences in baseline characteristics, drug retention was significantly higher for IL-6i (HR = 0.38, 95%CI = 0.27-0.55, p< 0.01) as compared with TNFi. Discontinuation due to lack of effectiveness was lower with the JAKi (HR = 0.38, 95%CI = 0.22-0.66, p< 0.01) and the IL-6i (HR = 0.29, 95%CI = 0.19-0.46, p< 0.01) as compared with the TNFi although the CTLA4-Ig had a similar HR to TNFi. The adjusted incidence of discontinuation due to adverse event was higher in the JAKi (HR = 2.86, 95%CI = 1.46-5.59, p< 0.01) than the TNFi. CONCLUSIONS: In EORA patients, IL-6i and JAKi had longer retention and less discontinuation due to ineffectiveness than TNFi. The potential risks of JAKi should be approached with an individualized perspective.

Associations of disease duration and anti-citrullinated peptide antibody status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis: Post hoc analysis of a multicentre, real-world observational study in Japan (ORIGAMI).

OBJECTIVES: The aim of the article is to investigate the associations of disease duration and anti-cyclic citrullinated peptide antibody (ACPA) status with the effectiveness of abatacept in biologic-naïve patients with rheumatoid arthritis (RA). METHODS: We performed post hoc analyses of the Orencia® Registry in Geographically Assembled Multicenter Investigation (ORIGAMI) study of biologic-naïve RA patients aged ≥20 years with moderate disease activity who were prescribed abatacept. Changes in the Simplified Disease Activity Index (SDAI) and Japanese Health Assessment Questionnaire (J-HAQ) at 4, 24, and 52 weeks of treatment were analysed in patients divided according to ACPA serostatus (positive/negative), disease duration (<1/≥1 year), or both. RESULTS: SDAI scores decreased from baseline in all groups. SDAI scores tended to decrease more in the ACPA-positive group and disease duration <1-year group than in the ACPA-negative group and disease duration ≥1-year group, respectively. In the disease duration <1-year group, SDAI tended to decrease more in the ACPA-positive group than in the ACPA-negative group. Disease duration was independently associated with the change in SDAI and SDAI remission at Week 52 in multivariable regression models. CONCLUSIONS: These results suggest that starting abatacept within 1 year of diagnosis was associated with greater effectiveness of abatacept in biologic-naïve patients with RA and moderate disease activity.

Real-world comparative study of the efficacy of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVE: This multicentre, retrospective study compared the efficacy and safety of tofacitinib, baricitinib, peficitinib and upadacitinib in real-world clinical settings after minimizing selection bias and adjusting the confounding patient characteristics. METHOD: The 622 patients were selected from the ANSWER cohort database and treated with tofacitinib (TOF), baricitinib (BAR), peficitinib (PEF) or upadacitinib (UPA). The patient's background was matched using propensity score-based inverse probability of treatment weighting (IPTW) among four treatment groups. The values of Clinical Disease Activity Index (CDAI), C-reactive protein (CRP), and modified Health Assessment Questionnaire (mHAQ) after drug initiation and the remission or low disease activity (LDA) rates of CDAI at 6 months after drug initiation were compared among the four groups. Further, the predictive factor for TOF and BAR efficacy was analysed. RESULTS: The retention and discontinuation rates until 6 months after drug initiations were not significantly different among the four JAK inhibitors treatment groups. Mean CDAI value, CDAI remission rate, and CDAI-LDA rate at 6 months after drug initiation were not significantly different among treatment groups. Baseline CDAI (TOFA: OR 1.09, P < 0.001; BARI: OR 1.07, P < 0.001), baseline CRP (TOFA: OR 1.32, P = 0.049), baseline glucocorticoid dose (BARI: OR 1.18, 95% CI 1.01-1.38, P = 0.035), a number of previous biological or targeted synthetic disease-modifying antirheumatic drugs (biological/targeted synthetic DMARDs) (BARI: OR 1.36, P = 0.004) were predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. CONCLUSION: The efficacy and safety of TOF, BAR, PEF and UPA were not significantly different for the treatment of patients with rheumatoid arthritis.

Trends of disease activity in Japanese patients over 75 years with rheumatoid arthritis from 2014 to 2021- the ANSWER cohort study.

OBJECTIVES: To investigate if disease activity among elderly RA patients over 75 years has changed over time in the real-world clinical setting. METHODS: Data from an observational multicentre registry of RA patients in Japan were analyzed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (over 75 years) who achieved remission and low disease activity, from 2014 to 2021. The secondary outcome was to identify factors associated with remission and low disease activity by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression. RESULTS: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients over 75 years increased from 16.5% to 26.9%, with biologics and targeted-synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) usage increasing and glucocorticoids usage decreasing, while conventional-synthetic DMARDs usage remained relatively stable. The proportion of RA patients over 75 years achieving remission and low disease activity significantly increased from 62.2% to 78.2% (p for trend < 0.001). A negative factor associated with achieving remission and low disease activity was glucocorticoid usage, seropositivity, and history of previous b/tsDMARDs use while MTX usage was associated positively, independent of other predictors. CONCLUSIONS: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes.

Association of anti-ß2-glycoprotein I/HLA-DR complex antibody with arterial thrombosis in female patients with systemic rheumatic diseases.

BACKGROUND: ß2-glycoprotein I (ß2GPI) complexed with human leukocyte antigen DR (ß2GPI/HLA-DR) was found to be a major autoantibody target in antiphospholipid syndrome (APS). This study aimed to reveal the association between anti-ß2GPI/HLA-DR antibodies and vascular thromboses in women with systemic rheumatic diseases. METHODS: We conducted a retrospective longitudinal study. We measured anti-ß2GPI/HLA-DR antibodies and compared them with anti-phospholipid antibody (aPL) profiles and the adjusted global antiphospholipid syndrome score (aGAPSS). Using receiver operating characteristic (ROC) analysis, we determined the best cut-off value for arterial thrombosis. We also evaluated the validity of anti-ß2GPI/HLA-DR antibodies by adding to conventional cardiovascular risk factors in multivariate logistic analysis. RESULTS: We evaluated 704 patients, including 66 (obstetric or thrombotic) APS, 13 primary APS, and 78 asymptomatic aPL carriers. Seventy-seven patients had a history of arterial thrombosis, and 14 patients had both arterial and venous thrombosis. These 14 patients, as well as patients with aGAPSS > 10 or triple-positive aPL profiles, displayed high anti-ß2GPI/HLA-DR antibody titers. The ROC curve showed a sensitivity, specificity, and area under the curve (AUC) for arterial thrombosis of 33.8%, 91.4%, and 0.6009, respectively, with a cut-off value of 172.359 U/mL. The anti-ß2GPI/HLA-DR antibody positivity using this cut-off value yielded an odds ratio of 5.13 (95%CI: 2.85-9.24), significantly improving the AUC from 0.677 to 0.730. CONCLUSION: Anti-ß2GPI/HLA-DR antibodies are associated with arterial thrombosis in female patients with systemic rheumatic diseases.

Drug retention of biologics and Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study.

OBJECTIVES: This multicentre retrospective study in Japan aimed to assess the retention of biological disease-modifying antirheumatic drugs and Janus kinase inhibitors (JAKi), and to clarify the factors affecting their retention in a real-world cohort of patients with rheumatoid arthritis. METHODS: The study included 6666 treatment courses (bDMARD-naïve or JAKi-naïve cases, 55.4%; tumour necrosis factor inhibitors (TNFi) = 3577; anti-interleukin-6 receptor antibodies (aIL-6R) = 1497; cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig) = 1139; JAKi=453 cases). The reasons for discontinuation were divided into four categories (ineffectiveness, toxic adverse events, non-toxic reasons and remission); multivariate Cox proportional hazards modelling by potential confounders was used to analyse the HRs of treatment discontinuation. RESULTS: TNFi (HR=1.93, 95% CI: 1.69 to 2.19), CTLA4-Ig (HR=1.42, 95% CI: 1.20 to 1.67) and JAKi (HR=1.29, 95% CI: 1.03 to 1.63) showed a higher discontinuation rate due to ineffectiveness than aIL-6R. TNFi (HR=1.28, 95% CI: 1.05 to 1.56) and aIL-6R (HR=1.27, 95% CI: 1.03 to 1.57) showed a higher discontinuation rate due to toxic adverse events than CTLA4-Ig. Concomitant use of oral glucocorticoids (GCs) at baseline was associated with higher discontinuation rate due to ineffectiveness in TNFi (HR=1.24, 95% CI: 1.09 to 1.41), as well as toxic adverse events in JAKi (HR=2.30, 95% CI: 1.23 to 4.28) and TNFi (HR=1.29, 95%CI: 1.07 to 1.55). CONCLUSIONS: TNFi (HR=1.52, 95% CI: 1.37 to 1.68) and CTLA4-Ig (HR=1.14, 95% CI: 1.00 to 1.30) showed a higher overall drug discontinuation rate, excluding non-toxicity and remission, than aIL-6R.

Demographic, Physical, and Psychological Determinants of Patient Experience with Subcutaneous Self-Injection in Patients with Rheumatoid Arthritis: Structural Equation Modeling Approach.

Purpose: To achieve a better patient experience with self-injection, an assessment of potential demographic, physical, and psychological barriers is necessary. The aim of this study was to examine the demographic, physical, and psychological characteristics associated with the experiences of self-injection in patients with rheumatoid arthritis (RA). Patients and Methods: In this study, overall patient experience with subcutaneous self-injection was assessed using the Self-Injection Assessment Questionnaire. Upper limb function was assessed using the three domains of the Health Assessment Questionnaire associated with upper extremity disability (dressing and grooming, eating, and grip). Structural equation modeling was used to estimate the association between the demographic and clinical characteristics of patients with RA and their experiences with self-injection in the theoretical model. Results: Data from 83 patients with RA were analyzed. Compared with younger patients, elderly patients were more likely to experience lower self-confidence, self-image, and ease of use. Female patients had lower ease of use than male patients. In terms of upper limb function, patients with more difficulty in performing activities of daily living were more likely to have a lower self-image. Self-injection perceptions before learning the method of injection, such as fear of needles and anxiety about self-injection, were associated with post-injection feelings, injection site reactions, self-confidence, and ease of use. Conclusion: To optimize patients' experiences with self-injection, healthcare workers should assess each patient's age, sex, upper limb function, and pre-self-injection perceptions as demographic, physical, and psychological barriers.

Prognostic Factors Affecting Death in Patients with Rheumatoid Arthritis Complicated by Pneumocystis jirovecii Pneumonia and One-Year Clinical Course: The ANSWER Cohort Study.

This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP (median age, 69 years; 73% female), chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention.

Severe Lupus Myocarditis Preceded by Mesalazine-induced Lupus.

In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.

Effect of resolvin D5 on T cell differentiation and osteoclastogenesis analyzed by lipid mediator profiling in the experimental arthritis.

Resolvins, are specialized pro-resolving mediators (SPMs) derived from n-3 polyunsaturated fatty acids. They contribute actively to the resolution of inflammation, but little is known concerning their role in chronic inflammation, such as in rheumatoid arthritis (RA). Here, we performed lipid mediator (LM) profiling in tissues from the paws of SKG arthritic mice using lipid chromatography (LC)/mass spectrometry (MS)/MS-based LM metabololipidomics. We found elevated levels of SPMs including resolvin D5 (RvD5) in these tissues. Moreover, RvD5 levels were significantly correlated with arthritis disease activity. From experiments to assess the role of RvD5 in the pathology of RA, we concluded that RvD5 suppressed Th17 cell differentiation and facilitated regulatory T cell differentiation, as well as inhibiting CD4+ T cell proliferation. Furthermore, RvD5 attenuated osteoclast differentiation and interfered with osteoclastogenesis. Targeting the resolution of inflammation could be promising as a novel treatment for RA.

Soluble guanylate cyclase stimulator reduced the gastrointestinal fibrosis in bleomycin-induced mouse model of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. METHODS: Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance × (duodenum - appendix)] - 1 × 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. RESULTS: Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. CONCLUSIONS: These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion.

Subjective well-being among rheumatoid arthritis patients.

AIM: Subjective well-being (SWB) is a psychological construct that is synonymous with happiness. Many variables including age, sex, income, employment, and marital status are related to SWB. Health is also an important determinant of SWB that can be adversely affected in patients with chronic conditions such as rheumatoid arthritis (RA). In this study, we evaluate the SWB of RA patients and compare it with that of healthy controls. METHODS: We obtained the original dataset from the "Quality of Life Survey, 2013", which was conducted by the Economic and Social Research Institute, Cabinet Office, Government of Japan. In this survey, SWB was determined by asking participants to rate their happiness between 0 (very unhappy) and 10 (very happy). The survey also included a 56-point questionnaire regarding well-being-related variables. This questionnaire was administered to RA patients recruited from Kobe University Hospital, and clinical and treatment data were simultaneously collected. RESULTS: Multivariate analysis revealed that RA patients with high or moderate disease activity had SWB scores that were similar to those of controls. However, the SWB scores of RA patients in remission or with low disease activity were higher than those of controls (P = .013). SWB was associated with household income, self-assessment of living costs, self-assessment of health, depression/ anxiety, and social connection. CONCLUSIONS: For RA patients, achieving the therapeutic target can result in better SWB than that of healthy controls. Financial status, self-assessment of health, psychological stress, and social network are also important determinants for the SWB of RA patients.

Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice.

Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4+ T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G+ granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4+ T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4+ T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4+ T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis.

Immunometabolism in rheumatoid arthritis.

Recent studies have revealed a relationship between cellular metabolism and cell function in immune cells. Cellular metabolism not only provides supplemental ATP, but also supports dynamic changes in cell proliferation and differentiation. For example, T cells exhibit subset-specific metabolic profiles, and require certain types of metabolism for their functions. Determining the metabolic profiles that support inflammatory immune responses may lead to novel treatment strategies for chronic inflammatory diseases such as rheumatoid arthritis (RA). However, the mechanisms by which metabolism modulates cell function have been unclear. Recent studies have begun to unveil unexpected non-metabolic functions for metabolic enzymes in the context of inflammation, including roles in signaling and gene regulation. Here we describe recent findings related to immunometabolism, the metabolome of RA patients, and the metabolically independent functions of glycolytic enzymes. We discuss how metabolic processes impact immune cells, especially T cells and fibroblast like synoviocytes, which are considered the orchestrators of autoimmune arthritis.

3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation.

Recent studies have shown that cellular metabolism plays an important role in regulating immune cell functions. In immune cell differentiation, both interleukin-17-producing T (Th17) cells and dendritic cells (DCs) exhibit increased glycolysis through the upregulation of glycolytic enzymes, such as hexokinase-2 (HK2). Blocking glycolysis with 2-deoxyglucose was recently shown to inhibit Th17 cell differentiation while promoting regulatory T (Treg) cell generation. However, 2-DG inhibits all isoforms of HK. Thus, it is unclear which isoform has a critical role in Th17 cell differentiation and in rheumatoid arthritis (RA) pathogenesis. Here we demonstrated that 3-bromopyruvate (BrPA), a specific HK2 inhibitor, significantly decreased the arthritis scores and the histological scores in SKG mice, with a significant increase in Treg cells, decrease in Th17 cells, and decrease in activated DCs in the spleen. In vitro, BrPA facilitated the differentiation of Treg cells, suppressed Th17 cells, and inhibited the activation of DCs. These results suggested that BrPA may be a therapeutic target of murine arthritis. Although the role of IL-17 is not clarified in the treatment of RA, targeting cell metabolism to alter the immune cell functions might lead to a new therapeutic strategy for RA.