Evolution of diagnostic criteria and new insights into clinical testing in mixed connective tissue disease; anti-survival motor neuron complex antibody as a novel marker of severity of the disease.

Mixed connective tissue disease (MCTD) is an autoimmune disorder characterized by a combination of clinical features from systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease, along with the presence of positive anti-U1-ribonucleoprotein (U1-RNP) antibodies. The exact etiology of the disease remains unclear, but it is believed to involve vascular damage within the context of heightened autoimmune responses. Consequently, Raynaud's phenomenon and pulmonary arterial hypertension are observed in patients with MCTD. While specific biomarkers for MCTD have not yet been identified, the recent study of the utility of anti-survival motor neuron complex (SMN) antibodies in MCTD suggests a promising avenue for further research and the accumulation of additional evidence.

GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway.

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.

Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases by cohort-wide immunophenotyping.

OBJECTIVE: Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine. METHODS: We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS). RESULTS: Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease. CONCLUSION: Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.

Oral glucocorticoid use in patients with rheumatoid arthritis initiating TNF-inhibitors, tocilizumab or abatacept: Results from the international TOCERRA and PANABA observational collaborative studies.

OBJECTIVE: To evaluate and compare the use of oral glucocorticoids with three classes of bDMARDs in patients with rheumatoid arthritis (RA). METHODS: We included patients from 13 observational registries treated with a TNF-inhibitor, abatacept or tocilizumab and with available information on the use of oral glucocorticoids. The main outcome was oral glucocorticoid withdrawal. A McNemar test was used to analyse the change in the use of glucocorticoids after 1 year. Kaplan-Meier estimates and Cox regressions, adjusted for patient, treatment, and disease characteristics, were used to evaluate glucocorticoid discontinuation in patients with glucocorticoids at baseline. Because of heterogeneity, analyses were done by registers and pooled using random-effects meta-analysis. RESULTS: A total of 12,334 participants treated with TNF-inhibitors, 2100 with tocilizumab and 3229 with abatacept were included. At one-year, oral glucocorticoid use decreased in all treatment groups (odds ratio for stopping vs. starting of 2.19 [95% CI 1.58; 3.04] for TNF-inhibitors, 2.46 [1.39; 4.35] for tocilizumab; 1.73 [1.25; 2.21] for abatacept). Median time to glucocorticoid withdrawal was ≈2 years or more in most countries, with a gradual decrease over time. Compared to TNF-inhibitors, crude hazard ratios of glucocorticoid discontinuation were 0.65[0.48-0.87] for abatacept, and 1.04 [0.76-1.43] for tocilizumab, and adjusted hazard ratios were 1.1 [0.83-1.47] for abatacept, and 1.30 [0.96-1.78] for tocilizumab. CONCLUSION: After initiation of a bDMARD, glucocorticoid use decreased similarly in all treatment groups. However, glucocorticoid withdrawal was much slower than advocated by current international guidelines. More effort should be devoted to glucocorticoid tapering when low disease activity is achieved.

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.

Anti-survival motor neuron complex antibodies as a novel biomarker for pulmonary arterial hypertension and interstitial lung disease in Mixed connective tissue disease.

OBJECTIVE: The presence of anti-U1 RNP antibodies (Abs) is critical for diagnosing mixed connective tissue disease (MCTD). Aim of this study is to evaluate the clinical relevance of anti-survival motor neuron (SMN) complex Abs, which often coexist with anti-U1 RNP Abs. METHODS: 158 newly diagnosed consecutive cases of systemic lupus erythematosus (SLE), systemic sclerosis (SSc) or MCTD with anti-U1 RNP Abs were enrolled in this multicentre observational study between April 2014 and August 2022. Serum anti-SMN complex Abs were screened by immunoprecipitation of 35S-methionine-labelled cell extracts, and associations between anti-SMN complex Abs positivity and clinical characteristics were analyzed. RESULTS: Anti-SMN complex Abs were detected in 36% of MCTD patients, which was significantly higher than that in SLE (8%) or SSc (12%). Among MCTD patients classified based on the combination of the clinical features of SLE, SSc, and idiopathic inflammatory myopathies (IIM), anti-SMN complex Abs showed the highest prevalence in a subset with clinical features of all three components. Anti-SMN complex Abs-positive MCTD had a higher prevalence of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), which are related to poor prognosis, than negative patients. Moreover, all three cases of death within 1 year of the treatment were positive for anti-SMN complex Abs. CONCLUSIONS: Anti-SMN complex Abs is the first biomarker of a typical subset of MCTD which bears organ damages such as PAH and ILD.

Sustained remission following the discontinuation of tofacitinib in patients with rheumatoid arthritis (XANADU study): an open-label randomised study.

OBJECTIVE: To investigate sustained remission following the discontinuation of tofacitinib in patients with rheumatoid arthritis. METHODS: Patients who had an inadequate response to methotrexate (MTX) with or without biological disease-modifying antirheumatic drugs were randomly divided into two groups at baseline, and tofacitinib treatment in combination with MTX was administered to both groups. Either MTX or tofacitinib was then withdrawn if patients achieved Clinical Disease Activity Index remission at week 52. The primary outcome was the proportion of patients who sustained clinical remission at week 104. RESULTS: A total of 113 patients participated in this study. Among them, a total of 48 patients achieved remission at week 52. After discontinuation of tofacitinib, only 29.2% (7/24) of patients remained remission, while 50.0% (10/20) of patients, which was numerically higher but not statistically significant, sustained remission after MTX discontinuation. A greater proportion of bio-naïve patients achieved remission at week 52 and sustained low disease activity with tofacitinib discontinuation at week 104. Additionally, the patients who were able to discontinue tofacitinib without flares had lower rheumatoid factor (p=0.04) and lower anti-cyclic citrullinated peptide antibody (p=0.051) before discontinuation of tofacitinib. No severe adverse events were recorded after discontinuation of tofacitinib or MTX. In patients who relapsed after tofacitinib discontinuation, 71.4% achieved remission with resumption of tofacitinib. CONCLUSIONS: This study implies that a blanket cessation of tofacitinib may not be suitable for all patients, given that 58% of the participants experienced relapse. However, the withdrawal of tofacitinib is unlikely to result in the acquisition of treatment-resistance.

JAK inhibitors for rheumatoid arthritis.

INTRODUCTION: JAK (Janus kinase) is a type of non-receptor tyrosine kinase that includes JAK1, JAK2, JAK3, and Tyk2. Currently, there are five JAK inhibitors approved for treating rheumatoid arthritis. These inhibitors vary in their selectivity for different JAK isoforms. AREA COVERED: This review outlines the mode of actions and the results of Phase III trials of the JAK inhibitors which have been approved for the treatment of rheumatoid arthritis. EXPERT COMMENTARY: JAK inhibitors have the potential to finely tune immunity and inflammation in patients with rheumatoid arthritis. The in vitro data indicates that IL-6 signaling is suppressed by all JAK inhibitors, while tofacitinib exhibits the most extensive suppression of cytokines via the JAK pathway. Peficitinib suppresses common gamma cytokines, and filgotinib suppresses interferon. Furthermore, baricitinib and upadacitinib appear to be inclined toward suppressing interferon and the IL-12 family. Despite their specific target profiles, any of these drugs can inhibit other JAKs if their blood levels surpass a certain threshold. As a result, predicting in vivo selectivity remains a challenging task. JAK inhibitor seems to be a vital treatment option for difficult-to-treat rheumatoid arthritis patients, and it is expected that precision medicine approaches will enhance its effectiveness in the future.

Possible involvement of CXCR3-CXCR6 + CD4 + T cells in Langerhans cell histiocytosis.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a condition characterized by proliferation of Langerhans cells and wide-range pathologies, ranging from single granulomatous lesions to multi-organ involvement, associated with tissue destruction. LCH pathogenesis remains obscure although association with interleukin (IL)-17A has been reported. We report here a case that illustrates the potential pathogenic role of helper T17 (Th17) cells in LCH-related bone destruction. MATERIALS AND METHODS: The patient was a 66-year-old woman. The clinical course included craniectomy and bone mass excision in X-9, diagnosis of LCH confirmed by histopathology, followed by 26-month chemotherapy. In August X, the patient was diagnosed with complete central diabetes insipidus. Symptoms improved after treatment with desmopressin. Pituitary magnetic resonance imaging showed swelling extending from the suprasellar region to the pituitary stalk, suggestive of LCH recurrence. This was followed by chemotherapy combined with mercaptopurine hydrate.  RESULTS: Subsequent peripheral blood lymphocyte analysis showed marked increase in activated Th17 cells (CXCR3-CXCR6+ CD4+ T cells). Double staining for CD4 and IL-17 by immunofluorescence of pathological tissue samples obtained during temporal bone mass excision, which confirmed the diagnosis of LCH in X-9, showed areas of combined presence of CD4-positive cells and IL-17-positive cells. Chemotherapy resulted in size reduction of the pituitary lesion and decrease in peripheral blood-activated Th17 cells. CONCLUSIONS: We found abundant peripheral blood-activated Th17 cells and high percentages of IL-17-producing cells in osteolytic bone lesions in LCH. This finding, together with the decrease in peripheral blood-activated Th17 cells following chemotherapy, suggests the potential involvement of activated Th17 cells in LCH-related osteolysis.

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.

Comprehensive immunophenotypic analysis reveals the pathological involvement of Th17 cells in Graves' disease.

Graves' disease (GD) is an organ-specific autoimmune disease, but there are a few studies that have evaluated how immunophenotypes are related to clinical symptoms and intractable pathology, or the effects of treatment on immunophenotypes. We performed peripheral blood immunophenotyping in GD. We assessed the proportion of functional subsets of T helper cells (such as Th1, Th17, Treg and Tfh cells), B cells (Naïve, IgM memory, Class-switched, IgD-CD27- double negative and Plasmablasts cells), Monocytes, Dendritic cells and NK cells, and evaluated the relationship of immunophenotypes with clinical indices, disease activity, risk of relapse, and changes in immunophenotypes after treatment with antithyroid drugs. The activated Th17 cells, activated T follicular helper (Tfh) cells, and IgD-CD27- double-negative B cells were higher in newly onset GD compared with healthy participants. Th17 cells were associated with thyroid autoantibodies, thyroid function, thyroid enlargement, and Graves' Recurrent Events After Therapy (GREAT) score; while double-negative B cells were associated with thyroid autoantibodies. Treatment with antithyroid drugs decreased the activated Tfh cells in parallel with the improvement in thyroid function. However, activated Th17 cells were not associated with clinical improvement and remained unchanged. Peripheral blood immunophenotyping identified the differential involvement of T and B cell subsets in the pathogenesis of GD. Abnormalities in the differentiation of Th17, Tfh, and double-negative B cells reflected the clinical pathology associated with autoantibody production and excess thyroid hormones. And Th17 cells are significantly associated with the marker for resistance to treatment. These results suggest the involvement of Th17 cell activation in the intractable pathology associated with potential immune abnormalities in GD. Clinical trial registration: #UMIN000017726 (Date: June 1st, 2015).

Early B cell factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells.

Apoptosis is a genetically regulated program of cell death that plays a key role in immune disease processes. We identified EBF4, a little-studied member of the early B cell factor (EBF) family of transcription factors, in a whole-genome CRISPR screen for regulators of Fas/APO-1/CD95-mediated T cell death. Loss of EBF4 increases the half-life of the c-FLIP protein, and its presence in the Fas signaling complex impairs caspase-8 cleavage and apoptosis. Transcriptome analysis revealed that EBF4 regulates molecules such as TBX21, EOMES, granzyme, and perforin that are important for human natural killer (NK) and CD8+ T cell functions. Proximity-dependent biotin identification (Bio-ID) mass spectrometry analyses showed EBF4 binding to STAT3, STAT5, and MAP kinase 3 and a strong pathway relationship to interleukin-2 regulated genes, which are known to govern cytotoxicity pathways. Chromatin immunoprecipitation and DNA sequencing analysis defined a canonical EBF4 binding motif, 5'-CCCNNGG/AG-3', closely related to the EBF1 binding site; using a luciferase-based reporter, we found a dose-dependent transcriptional response of this motif to EBF4. We also conducted assay for transposase-accessible chromatin sequencing in EBF4-overexpressing cells and found increased chromatin accessibility upstream of granzyme and perforin and in topologically associated domains in human lymphocytes. Finally, we discovered that the EBF4 has basal expression in human but not mouse NK cells and CD8+ T cells and vanishes following activating stimulation. Together, our data reveal key features of a previously unknown transcriptional regulator of human cytotoxic immune function.

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.

Preclinical Characterization of ASP2713, a Novel Igß and FcγRIIB Cross-Linking Antibody, for Prediction of Human Pharmacokinetics and Clinically Effective Dose.

Previously, we reported the fundamental pharmacological characteristics of a novel Igß and Fc gamma receptor IIB cross-linking antibody, ASP2713, as a new treatment option for systemic lupus erythematosus. The aims of the present study were to investigate ASP2713's characteristics with regard to pharmacological effect, pharmacokinetics (PK), and receptor occupancy, and to predict its human PK and clinically effective dose. The relationship between the concentration and receptor occupancy of ASP2713 for Igß of B cell receptors was examined using whole blood B cells. Calculated EC50 values in cynomolgus monkeys and healthy volunteers were 0.35 and 0.058 µg/mL, respectively. Dose-dependent inhibition of anti-tetanus toxoid (TTx) antibody production, PK, and receptor occupancy of ASP2713 in TTx-sensitized cynomolgus monkeys suggested a minimally effective dose of 1 mg/kg by single intravenous (IV) administration. Scaling-up of monkey PK parameters to humans by allometric scaling predicted a clinically effective dose of 0.4 mg/kg IV administration at 4-week intervals to maintain a trough concentration in humans which achieved the same receptor occupancy expected at the effective dose in monkeys. This study aids in understanding the characteristics of ASP2713 and can be used as a basis for clinical dose setting.

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.

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans.

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6-/- mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.