Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: To update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology (JCR) clinical practice guidelines (CPG) for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, 2 independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to csDMARD. Rituximab with and without concomitant csDMARDs showed similar efficacy to other bDMARDs in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSION: This systematic review provides latest evidence for the 2024 update of the JCR CPG for RA management.

The 2023 Guidelines for the management and treatment of glucocorticoid-induced osteoporosis.

INTRODUCTION: Although synthetic glucocorticoids (GCs) are commonly used to treat autoimmune and other diseases, GC induced osteoporosis (GIOP) which accounts for 25% of the adverse reactions, causes fractures in 30-50% of patients, and markedly decreases their quality of life. In 2014, the Japanese Society for Bone and Mineral Research (JSBMR) published the revised guidelines for the management and treatment of steroid-induced osteoporosis, providing the treatment criteria based on scores of risk factors, including previous fractures, age, GC doses, and bone mineral density, for patients aged ≥18 years who are receiving GC therapy or scheduled to receive GC therapy for ≥3 months. MATERIALS AND METHODS: The Committee on the revision of the guidelines for the management and treatment of GIOP of the JSBMR prepared 17 clinical questions (CQs) according to the GRADE approach and revised the guidelines for the management and treatment of GIOP through systematic reviews and consensus conferences using the Delphi method. RESULTS: Bisphosphonates (oral and injectable formulations), anti-RANKL antibody teriparatide, eldecalcitol, or selective estrogen receptor modulators are recommended for patients who has received or scheduled for GC therapy with risk factor scores of ≥3. It is recommended that osteoporosis medication is started concomitantly with the GC therapy for the prevention of fragility fractures in elderly patients. CONCLUSION: The 2023 guidelines for the management and treatment of GIOP was developed through systematic reviews and consensus conferences using the Delphi method.

Biological/targeted synthetic DMARDs do not arrest bone loss in patients with rheumatoid arthritis: a multicenter prospective observational study.

OBJECTIVE: To elucidate the differential effects of biological/target synthesized DMARDs (b/tsDMARDs) on bone metabolism in patients with rheumatoid arthritis (RA) in a real-world cohort. METHODS: This was a multicentre prospective observational study of RA patients enrolled at the time of 1st b/tsDMARDs administration. Bone mineral density (BMD) and bone turnover markers (BTMs) were measured during the 52-week observation. The study was designed to enrol all eligible RA patients. The end-points were differences in changes in BMD according to b/tsDMARD type, and the correlation between BMD and BTMs. RESULTS: A total of 1,164 patients were enrolled in this study. b/tsDMARDs improved RA disease activity from mean CDAI 25.5 at baseline to 4.5 at week 26. Patients not receiving anti-osteoporotic agents (anti-OP) at baseline with no history of fracture experienced a significant decrease in both femoral neck (F: mean 0.666-0.655 g/cm3) and radial (R: 0.518-0.514) BMD at week 26. Despite maintaining low CDAI levels during weeks 26-52 (5.3-4.4), there was a continued decline in BMD (F: 0.653, R: 0.509. Weeks 52). None of b/tsDMARDs type preserved BMD. Conversely, patients receiving anti-OP at baseline maintained stable BMD throughout the study (Weeks 0/26/52. F: 0.551/0.551/0.555, R: 0.415/0.416/0.415). Although BTMs were changed by b/tsDMARDs, the changes were unrelated to those in BMD. CONCLUSION: Our study suggested the progression of osteoporosis in RA patients during b/tsDMARDs treatment without anti-OP. BTMs may not reflect BMD change. Regular monitoring of BMD in RA should be considered for early management of osteoporosis.

Safety and efficacy of anifrolumab therapy in systemic lupus erythematosus in real-world clinical practice: LOOPS registry.

OBJECTIVES: To determine the safety and efficacy of anifrolumab in patients with systemic lupus erythematosus (SLE) classified based on the Lupus Low Disease Activity State (LLDAS) in real-world clinical practice. METHODS: This retrospective observational study involved SLE patients who started anifrolumab therapy. The primary end point was the retention rate over 26 weeks after initiating anifrolumab therapy; 45 patients followed up for 12 weeks or longer were analyzed in the following groups to determine the safety and efficacy up to week 12 after treatment initiation: 1) non-LLDAS achievement group and 2) minor flare group. Safety and efficacy were compared between the minor flare group and the standard of care (SoC) group (treated by adding glucocorticoids (GCs) or immunosuppressants) after adjustment with inverse probability of treatment weighting using propensity score (PS-IPTW). RESULTS: The retention rate of anifrolumab was 89.7% at week 26.The LLDAS achievement rates at week 12 were 42.9% and 66.7% in the non-LLDAS achievement and minor flare groups, respectively. In both groups, GC doses and SELENA-SLEDAI score significantly decreased. When the anifrolumab group with minor flare was compared with the SoC group or the GC dose increase group, the GC dose and SLEDAI score were significantly lower in the anifrolumab group than in both groups; there was no significant difference in LLDAS achievement. CONCLUSIONS: At week 26 after initiating anifrolumab therapy, ∼90% patients remained on therapy. Anifrolumab might lower disease activity without initiating GCs and reduce GC doses, especially in patients who experience minor flares after LLDAS achievement.

Generation-Dependent Retention Rates and Reasons for Discontinuation of Molecular Targeted Therapies in Patients with Rheumatoid Arthritis: From FIRST Registry.

INTRODUCTION: The study aimed to optimize medical care for elderly patients with rheumatoid arthritis (RA) by examining the 3-year continuation rate of different molecular targeted therapies across age groups in Japan, which has a significant elderly population. METHODS: The study included patients with RA who started molecular targeted therapies between 2013 and 2019 and divided them into three age groups. The primary outcome was to assess the 3-year continuation rate of each drug and analyze reasons for treatment discontinuation using inverse probability of treatment weighting. RESULTS: Among 2292 patients analyzed, tumor necrosis factor (TNF) inhibitors were most commonly used in those younger than 65 years of age (43.5%), while Janus kinase (JAK) inhibitors were also utilized (17.1%). In contrast, JAK inhibitors were less frequently used in patients aged 75 years and older (7.8%), with cytotoxic T lymphocyte antigen 4 immunoglobulin fusion proteins (CTLA4-Ig) being the most common (39.2%). JAK inhibitors and anti-interleukin-6 receptor (IL-6R) antibodies had higher continuation rates than other drugs in patients under 65 years (p < 0.001). For those aged 65-74 years, JAK inhibitors and CTLA4-Ig had higher continuation rates (p < 0.001), while among those aged 75 years and older, CTLA4-Ig and IL-6R antibodies had higher continuation rates (p < 0.001). Inadequate efficacy was the main reason for discontinuation in all age groups, while infection leading to discontinuation increased with age. CONCLUSIONS: The study highlights the need to consider different age groups separately in elderly RA care. Among patients aged 75 years and older, abatacept and anti-IL-6R antibodies showed the highest continuation rates, suggesting their potential suitability and efficacy for this specific age cohort.

TGF-ß3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: T peripheral helper (Tph) cells have major roles in pathological processes in SLE. We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. METHOD: Phenotypes and functions of Tph cell-related markers in human CD4+ T cells purified from volunteers or patients were analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. RESULTS: Among multiple cytokines, transforming growth factor (TGF)-ß3 characteristically induced programmed cell death protein 1 (PD-1)hi musculoaponeurotic fibrosarcoma (MAF)+, IL-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4 and CXCL13. The induction of Tph-like cells by TGF-ß3 was suppressed by the neutralization of TGF-ß type II receptor (TGF-ßR2). TGF-ß3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-ß3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. CONCLUSION: The induction of Tph-like cells by TGF-ß3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B-cell differentiation in patients with SLE.

Efficacy and safety of guselkumab and adalimumab for pustulotic arthro-osteitis and their impact on peripheral blood immunophenotypes.

OBJECTIVES: We compared the treatment effectiveness between guselkumab and adalimumab in patients with pustulotic arthro-osteitis (PAO). In addition, we performed peripheral blood immunophenotyping to elucidate the immunological background and analyzed the impact of therapeutic drugs to verify the validity of immunological phenotypes as therapeutic targets. METHODS: Patients were treated with guselkumab 100 mg (guselkumab group; n = 12) and adalimumab 40 mg (adalimumab group; n = 13). Arthritis disease activity, skin lesion activity, and patient-reported outcomes (PROs) were evaluated and compared between the two groups. The retention rate and adverse events were evaluated. Comprehensive phenotyping of peripheral immune cells was performed in both groups, and phenotypes were compared before and after treatment. RESULTS: At 6 months, both groups showed significant improvement in arthritis disease activity and PROs. In the guselkumab group, skin symptoms significantly improved. The 6-month continuation rates were 91.7% (11/12) and 69.2% (9/13) in the guselkumab and adalimumab groups, respectively. Adverse events occurred in 2/12 and 5/13 patients in the guselkumab (16.7%) and adalimumab (38.5%) groups, respectively. Peripheral blood immunophenotyping showed that the proportion of activated T helper (Th) 1 cells was significantly lower in patients with PAO than in healthy controls and that the proportion of activated Th17 cells was significantly higher in patients with PAO, which significantly decreased after treatment with guselkumab. CONCLUSION: Although guselkumab and adalimumab have comparable efficacy for PAO, their impact on immunophenotypes varies.

Precision medicine based on the phenotypic differences in peripheral T helper cells in patients with psoriatic arthritis: One year follow-up outcomes.

Purpose: We validated the one-year effectiveness of strategic treatment with biological disease-modifying anti-rheumatic drugs (bDMARDs) based on peripheral T-lymphocytic phenotyping and explored the impact of treatment on T helper lymphocytic phenotypes. Methods: Ninety-seven patients were registered in this study. One-year treatment response was compared between the two groups: the strategic bDMARDs treatment group (n = 41), in which bDMARDs were selected based on peripheral blood lymphocyte analysis, and the standard bDMARDs treatment group (n = 56), in which the patients underwent no strategic selection of bDMARDs and phenotyping. Changes in helper T lymphocytic phenotypes were evaluated after 1-year post-treatment. Results: In the standard bDMARDs treatment group, 23 patients (42.6%) achieved disease activity in psoriatic arthritis (DAPSA)-remission (REM), and 23 of 46 (50.0%) achieved PASI 90. In the strategic bDMARDs treatment group, 22 (53.7%) achieved DAPSA-REM, and 26 of 35 (74.2%) achieved PASI90. The rate of achieving minimal disease activity (MDA) and DAPSA-REM at month 6, DAPSA-low disease activity (LDA) at months 6 and 12, and PASI 90 at month 12 were significantly higher in the strategic bDMARDs treatment group. After treatment with ustekinumab, the proportion of aTh1/CD4 (%) significantly decreased. The percent reduction in activated Th17 cells was significantly higher in IL-17-i cells than in UST/TNF-i cells. Conclusions: The results of this study demonstrate the 1-year effectiveness of precision medicine based on peripheral T-lymphocytic phenotyping in terms of DAPSA and MDA. Analysis of data from real-world clinical practice showed that the impact on the immune system varied among bDMARDs. However, because psoriatic arthritis has very high heterogeneity, it may be necessary to conduct studies with a larger sample size, perhaps drawing samples from multiple institutions.

Pentacyclic triterpenoid ursolic acid induces apoptosis with mitochondrial dysfunction in adult T-cell leukemia MT-4 cells to promote surrounding cell growth.

We investigated the antitumor effects of oleanolic acid (OA) and ursolic acid (UA) on adult T-cell leukemia cells. OA and UA dose-dependently inhibited the proliferation of adult T-cell leukemia cells. UA-treated cells showed caspase 3/7 and caspase 9 activation. PARP cleavage was detected in UA-treated MT-4 cells. Activation of mTOR and PDK-1 was inhibited by UA. Autophagosomes were detected in MT-4 cells after UA treatment using electron microscopy. Consistently, mitophagy was observed in OA- and UA-treated MT-4 cells by confocal microscopy. The mitochondrial membrane potential in MT-4 cells considerably decreased, and mitochondrial respiration and aerobic glycolysis were significantly reduced following UA treatment. Furthermore, MT-1 and MT-4 cells were sorted into two regions based on their mitochondrial membrane potential. UA-treated MT-4 cells from both regions showed high activation of caspase 3/7, which were inhibited by Z-vad. Interestingly, MT-4 cells cocultured with sorted UA-treated cells showed enhanced proliferation. Finally, UA induced cell death and ex vivo PARP cleavage in peripheral blood mononuclear cells from patients with adult T-cell leukemia. Therefore, UA-treated MT-4 cells show caspase activation following mitochondrial dysfunction and may produce survival signals to the surrounding cells.

Safety and effectiveness of mepolizumab therapy in remission induction therapy for eosinophilic granulomatosis with polyangiitis: a retrospective study.

OBJECTIVES: To investigate the safety and effectiveness of mepolizumab (MPZ), an anti-interleukin-5 antibody, as remission induction therapy for severe eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: The clinical courses of patients with severe EGPA over 6 months were retrospectively investigated and compared between patients treated with high-dose corticosteroid (CS) plus MPZ therapy (MPZ group, n = 7) and those treated with high-dose CS plus intravenous cyclophosphamide (IVCY) pulse therapy (IVCY group, n = 13). The primary endpoints were the MPZ retention rate and the IVCY completion rate. The secondary endpoints were adverse events and changes in the Birmingham Vasculitis Activity Score (BVAS), Vascular Damage Index (VDI), eosinophil counts, and concomitant CS doses, and the extent and rates of these changes were compared between the MPZ and IVCY groups. RESULTS: Regarding the primary endpoints, the MPZ retention rate was 100%, and the IVCY completion rate was 61.5%. Regarding the secondary endpoints, adverse events were detected in 2/7 patients (28.6%) in the MPZ group and 7/13 patients (53.8%) in the IVCY group. BVAS and eosinophil counts significantly decreased in both groups at and after month 1, but there was no significant difference in the magnitude of changes between the two groups. VDI scores did not significantly increase in either group, and the degree of changes did not significantly differ between the two groups. Although concomitant CS doses significantly decreased at and after month 1 in both groups, the rates of decrease in CS doses at and after month 3 were significantly higher in the MPZ group. CONCLUSIONS: This study suggested that the use of MPZ as remission induction therapy for severe EGPA might be safe and effective for controlling disease activity and reducing CS doses.

A patient with eosinophilic granulomatosis with polyangiitis successfully weaned from corticosteroids through remission induction therapy with mepolizumab.

The patient was a 74-year-old man who was admitted to our hospital for fever, purpura, abdominal pain, and bilateral numbness. Although the patient tested negative for anti-neutrophil cytoplasmic antibody (ANCA), he presented with an elevated peripheral eosinophil count, increased inflammatory responses, duodenitis, cholecystitis, lung lesions, renal disorder, and peripheral neuropathy. The skin biopsy findings revealed vasculitis. Thus, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Given the advanced age of the patient, in addition to the poor general condition and hepatic and renal dysfunction, administration of immunosuppressants was considered to pose a high risk. After obtaining informed consent, remission induction therapy was initiated with mepolizumab (MPZ; 300 mg/M) in combination with high-dose corticosteroid therapy (equivalent to 70 mg/day of prednisolone). After treatment initiation, eosinophil counts and inflammatory responses decreased. Moreover, the abdominal pain and purpura resolved, and renal/hepatic dysfunction and peripheral neuropathy also improved. While the corticosteroid dose was subsequently reduced, no relapse was observed. Approximately 2 years later, the corticosteroid was discontinued. After the discontinuation of the corticosteroid, the patient continued treatment with MPZ alone and has remained in remission for approximately 6 months. Therefore, MPZ may be useful as a remission induction therapy in ANCA-negative EGPA resistant to steroids.

Impact of serum interleukin-22 as a biomarker for the differential use of molecular targeted drugs in psoriatic arthritis: a retrospective study.

BACKGROUND: We explored whether serum cytokines could be used as biomarkers for optimal use of tumor necrosis factor inhibitors (TNF-i) and interleukin (IL)-17 inhibitors (IL-17-i) in patients with psoriatic arthritis (PsA). METHODS: In cohort 1 (47 patients treated with IL-17-i [n=23] or TNF-i [n=24] for ≥1 year), we identified serum cytokines that predicted the achievement of Disease Activity in Psoriatic Arthritis-remission (DAPSA-REM), Psoriasis Area and Severity Index (PASI) 90, and Minimal Disease Activity after 1 year of TNF-i or IL-17-i therapy. Subsequently, we developed treatment strategies based on the identified cytokines; initiation of IL-17-i therapy in patients with low IL-22 concentrations (IL-22 <0.61376 pg/ml) and TNF-i therapy in patients with high IL-22 concentrations (0.61376< IL-22 pg/ml). In cohort 2 (34 patients), treatment responses were compared between the strategic treatment group (n=17), which was treated based on the treatment strategies, and the mismatched treatment group (n=17) to verify the validity of the treatment strategies developed using serum cytokines as biomarkers. RESULTS: In cohort 1, serum IL-22 concentration was identified as a predictor of DAPSA-remission after 1 year of IL-17-i therapy. Regarding treatment strategies, we selected TNF-i for patients with high IL-22 concentrations and IL-17-i for those with low IL-22 concentrations. There were no significant differences in the baseline characteristics between the strategic and mismatched treatment groups. Regarding treatment effects, activity significantly improved at 1 year in both groups. Upon comparison of the treatment effects, the rate of achieving DAPSA-REM and Minimal Disease Activity at month 12 was significantly higher in the strategic treatment group. CONCLUSIONS: The results of this pilot study suggest that IL-22 may be a biomarker of treatment response to TNF-i and IL-17-i in patients with PsA. Further large-scale studies in independent, prospectively collected datasets are required to verify that IL-22 is indeed a biomarker of treatment response in these patients.

Nailfold microvascular abnormalities are associated with a higher prevalence of pulmonary arterial hypertension in patients with MCTD.

OBJECTIVE: MCTD manifests with microvasculopathy and overlapping clinical features of SLE, SSc and idiopathic inflammatory myopathies (IIM). The aim of this study was to investigate the clinical significance of microvasculopathy in patients with MCTD using nailfold videocapillaroscopy (NVC). METHODS: Fifty patients with newly diagnosed and untreated MCTD were enrolled in this multicentre, prospective and observational study. Clinical features and NVC findings were assessed at baseline and after 1 year post-intervention, along with disease controls [SLE (n = 40), SSc (n = 70) and IIM (n = 50)]. RESULTS: All MCTD patients presented Raynaud's phenomenon and were positive for anti-U1 RNP antibodies, and 22.0% (11/50) had pulmonary arterial hypertension (PAH). The prevalence of NVC scleroderma patterns in MCTD was 38.0%, which was lower than SSc (88.6%) but higher than SLE (10.0%). In addition, when we divided MCTD patients into two groups by presence or absence of NVC scleroderma patterns, we found a higher prevalence of PAH in patients with NVC scleroderma patterns. Namely, NVC scleroderma patterns were observed in all MCTD patients with PAH, and in 21.0% of those without PAH. After intensive immunosuppressive therapy, NVC scleroderma patterns disappeared in half of the MCTD patients but were not changed in SSc patients. CONCLUSIONS: MCTD differed from SLE, SSc and IIM in terms of the prevalence and responsiveness of NVC scleroderma patterns to immunosuppressive therapy. Detection of nailfold microvascular abnormalities in MCTD could contribute to predicting PAH and help us to understand further aspects of the pathogenesis of MCTD.

An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.

OBJECTIVE: To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. METHODS: We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. RESULTS: The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. CONCLUSIONS: Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.

mTOR activation in CD8+ cells contributes to disease activity of rheumatoid arthritis and increases therapeutic response to TNF inhibitors.

OBJECTIVE: This study aimed to understand the role of mammalian target of rapamycin (mTOR) in CD8+ cells in the pathogenicity of RA and the changes after treatment with biologic drugs. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 17 healthy controls and 86 patients with RA. Phosphorylation of mTOR (p-mTOR) and its clinical relevance were evaluated. The role of mTOR in CD8+ cells was also examined in vitro. RESULTS: Patients with RA who had a moderate or high disease activity, were biologic-naïve, and were refractory to MTX were enrolled in this study. The p-mTOR levels in CD8+ cells were higher in patients with RA than in healthy controls, and they positively correlated with the disease activity in such patients. However, after one year of treatment with TNF inhibitors, the p-mTOR levels in CD8+ cells were suppressed and showed a positive correlation with the treatment response, which was not observed in the abatacept-treatment group. In vitro stimulation of CD8+ cells with anti-CD3 and anti-CD28 antibodies induced mTOR phosphorylation and increased the production of granzyme B, granulysin, TNF-α and IFN-γ but decreased the production of granzyme K. However, on treatment with TNF inhibitors, p-mTOR levels in CD8+ cells and granzyme B production decreased, while granzyme K production increased. The production of granulysin and IFN-γ was not affected by the TNF inhibitors. CONCLUSION: These results suggested that mTOR activation in CD8+ cells may be a novel evaluation marker for RA disease activity and a predictive marker of therapeutic response to TNF inhibitors.

Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis.

OBJECTIVES: B cells play an important pathological role in RA. In this study, we investigated the role of metabolic regulator mTOR in B cells and its relevance to the pathology of RA. METHODS: Peripheral blood mononuclear cells were isolated from 31 normal subjects and 86 RA patients and the gated B cells were assessed for mTOR phosphorylation and chemokine receptor expression. In vitro studies on peripheral blood B cells isolated from the control and RA patients investigated the molecular mechanisms. RESULTS: Higher concentrations of CXCL10 (CXCR3 ligands) and lower percentages of CXCR3+ memory B cells were present in the peripheral blood of RA patients relative to the control. RA patients with high CXCL10 concentrations had smaller percentage of CXCR3+ memory B cells and high disease activity. One-year treatment with TNF inhibitors increased the percentage of CXCR3+ memory B cells and reduced serum CXCL10 concentrations. mTOR phosphorylation in B cells was further enhanced in RA patients, compared with the control, and was selectively enhanced in CXCR3+ memory B cells. mTOR phosphorylation in CXCR3+ memory B cells correlated with disease activity. In vitro, mTOR phosphorylation in B cells enhanced IL-6 production and increased RANKL expression. CONCLUSION: mTOR activation in CXCR3+ memory B cells of RA patients is associated with disease activity, mediated through IL-6 production and RANKL expression. The obtained results also suggest that TNF inhibitors mediate an impact on the association between CXCL10 and mTOR activated CXCR3+ memory B cells.

Effectiveness and safety of mepolizumab in combination with corticosteroids in patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Mepolizumab (MPZ), an anti-interleukin-5 antibody, is effective for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). However, its effectiveness has not been adequately evaluated in real-world clinical practice. In this study, we assessed the effectiveness and safety of MPZ (300 mg) for relapsing/refractory EGPA resistant to corticosteroids (CS) for 1 year in real-world settings. METHODS: We administered MPZ (300 mg) to 16 patients with relapsing/refractory EGPA resistant to CS (Post-MPZ). We also retrospectively collected data from the same patients for the 12 months before the administration of MPZ (Pre-MPZ). The primary endpoint was the 12-month remission rate after MPZ administration and the secondary endpoints were the Birmingham vasculitis activity score (BVAS), vasculitis damage index (VDI), eosinophil counts, changes in concomitant CS doses/concomitant immunosuppressant use, MPZ retention rate, and incidence of adverse events. The clinical course was compared between Pre-MPZ and Post-MPZ. RESULTS: The 12-month remission rate after the initiation of MPZ was 75%. No change was observed in BVAS, eosinophil count, or concomitant CS dose over time in the Pre-MPZ group, whereas all these parameters were significantly decreased over time in the Post-MPZ group. The number of patients using concomitant immunosuppressant also decreased over time in the Post-MPZ group. VDI did not increase in either group. The MPZ retention rate was 100% and only three patients (18.8%) had infections. Changes in BVAS, eosinophil count, and cumulative concomitant CS dose were significantly lower in the Post-MPZ group than in the Pre-MPZ group. There was no significant difference in the changes in VDI between the groups. CONCLUSION: This study demonstrated that MPZ is effective and safe for EGPA. Furthermore, MPZ decreases disease activity, increases remission rate, and has a CS-sparing effect.

Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells.

Recent reports have shown the importance of IFN-γ and T-bet+ B cells in the pathology of SLE, suggesting the involvement of IFN-γ-producing T-bet+ CD4+ cells, i.e., Th1 cells. This study determined the changes in Th1 subsets with metabolic shift and their potential as therapeutic targets in SLE. Compared with healthy donors, patients with SLE had higher numbers of T-bethiCXCR3lo effector cells and T-bet+Foxp3lo non-suppressive cells, which excessively produce IFN-γ, and lower number of non-IFN-γ-producing T-bet+Foxp3hi activated-Treg cells. These changes were considered to be involved in treatment resistance. The differentiation mechanism of Th1 subsets was investigated in vitro using memory CD4+ cells obtained from healthy donors and patients with SLE. In memory CD4+ cells of healthy donors, both rapamycin and 2-deoxy-D-glucose (2DG) suppressed T-bet+Foxp3- cells, and induced T-bet+Foxp3+(lo/hi) cells. Rapamycin induced IFN-γ-producing T-bet+Foxp3lo cells accompanied with enhanced lipid metabolism, whereas 2DG induced IFN-γ-non-producing T-bet+Foxp3hi cells. In memory CD4+ cells of SLE patients, inhibition of fatty acid synthesis, but not ß-oxidation, suppressed IFN-γ production, and up-regulated of Foxp3 expression in T-bet+Foxp3+ cells. Metabolic regulators such as fatty acid synthesis inhibitors may improve the pathological status by correcting Th1 subset imbalance and overproduction of IFN-γ in SLE.

Systemic lupus erythematosus with repeated protein-losing enteropathy resulting from different pathological conditions: a case report.

Protein-losing enteropathy (PLE) is a rare organ disorder that can develop as a complication of systemic lupus erythematosus (SLE). Here, we report the case of a 59-year-old woman with SLE who experienced recurrent PLE resulting from different pathological conditions. The patient was diagnosed with SLE in X-14. In X-12, she was hospitalised due to persistent diarrhoea, generalised oedema, abdominal distension, dyspnoea on exertion, and hypoalbuminemia. A thrombus was noted in the superior mesenteric vein extending from the main trunk of the portal vein. She was diagnosed with PLE resulting from portal vein thrombosis caused by SLE, and her condition improved with anticoagulant therapy. In X-1, she developed diarrhoea and hypoalbuminemia again and was diagnosed with PLE associated with SLE. The symptoms promptly ameliorated with immunosuppressive therapy. Because PLE associated with SLE can be caused by various pathological conditions, appropriate therapeutic intervention based on the underlying condition is crucial.