Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Enthesitis as an initial presentation of vascular Behçet's syndrome: a case-based review.

Enthesitis is a characteristic manifestation of spondyloarthropathy (SpA). Historically, Behçet's syndrome (BS) was classified within SpA. Although they are now classified separately, the association between BS and SpA remains controversial. The concept of MHC-I (major histocompatibility complex class I)-opathy has been proposed based on the overlap in immunopathological mechanisms among diseases associated with human leukocyte antigen (HLA) class I. Enthesitis is a frequent complication in patients with BS who also have acne and arthritis. However, information regarding enthesitis in patients with BS without arthritis (BS-WA) is limited. Herein, we report a case of vascular BS complicated by enthesitis. In this case, heel pain was the dominant symptom at presentation. Laboratory tests revealed chlamydia antibody positivity, leading to a tentative diagnosis of reactive arthritis. Despite treatment, C-reactive protein (CRP) levels remained elevated. Imaging revealed numerous aneurysmal lesions in the large vessels. Based on these findings and other symptoms, patient was diagnosed with vascular BS. He tested positive for HLA-B15 and HLA-B46, which are associated with peripheral SpA. Subsequent remission induction therapy for BS was effective and the patient was discharged without complications. Our case and a literature review suggest that there exists a subgroup of BS-WA with a complication of enthesitis, possibly belonging to the spectrum of MHC-I-opathies. It is important to consider BS as a differential diagnosis in patients presenting with enthesitis and to conduct a precise medical history review regarding the symptoms of BS.

Establishing clinical remission criteria for giant cell arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis.

OBJECTIVE: To develop a proposal for giant cell arteritis remission criteria in order to implement a treat-to-target algorithm. METHODS: A task force consisting of 10 rheumatologists, 3 cardiologists, 1 nephrologist, and 1 cardiac surgeon was established in the Large-vessel Vasculitis Group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis to conduct a Delphi survey of remission criteria for giant cell arteritis. The survey was circulated among the members over four reiterations with four face-to-face meetings. Items with a mean score of ≥4 were extracted as items for defining remission criteria. RESULTS: An initial literature review yielded a total of 117 candidate items for disease activity domains and treatment/comorbidity domains of remission criteria, of which 35 were extracted as disease activity domains (systematic symptoms, signs and symptoms of cranial and large-vessel area, inflammatory markers, and imaging findings). For the treatment/comorbidity domain, ≤5 mg/day of prednisolone 1 year after starting glucocorticoids was extracted. The definition of achievement of remission was the disappearance of active disease in the disease activity domain, normalization of inflammatory markers, and ≤5 mg/day of prednisolone. CONCLUSION: We developed proposals for remission criteria to guide the implementation of a treat-to-target algorithm for giant cell arteritis.

Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

Intensive induction therapy combining tofacitinib, rituximab and plasma exchange in severe anti-melanoma differentiation-associatedprotein-5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated protein-5 (MDA5) autoantibodies (Abs) are associated with rapidly progressive interstitial lung disease (RP-ILD) in dermatomyositis (DM). Because the addition of plasma exchange (PE) and rituximab (RTX) to triple therapy is inadequate in severe cases, we treat such cases with intensive induction therapy (IIT) combining all these options with tofacitinib (TOF). In this study, we investigated the poor prognostic factors and the efficacy and safety of IIT. METHODS: Thirty-three patients diagnosed with anti-MDA5 Ab-positive DM in our institution between 2014 and 2021 were included. The clinical characteristics of poor prognosis were retrospectively analysed using principal component analysis (PCA), and the outcomes of IIT were analysed in terms of survival, assessed using the Kaplan-Meier test, and adverse events. RESULTS: Although triple therapy with RTX, PE, or intravenous immunoglobulin was administered before the introduction of IIT, eight of 12 RP-ILD cases with a ferritin level >400 ng/mL (mean, 2,342) died within a median of 2.5 months. PCA revealed distinct clusters for prognosis, and age and serum ferritin were leading predictors of the prognosis. IIT, consisting of combinations of triple therapy with higher doses of methylprednisolone, PE, RTX, and TOF, was applied to eight patients (mean ferritin, 3,558). Although two patients died even with these regimens, a significant improvement in survival was documented. Several IIT-related adverse events were observed, including viral and fungal infections and cytopenia. CONCLUSIONS: IIT significantly improved the survival of patients with severe anti-MDA5 Ab-positive RP-ILD. Although infections are noted, their benefits outweigh the risks in younger patients with high serum ferritin levels.

Successful management of interstitial lung disease in dermatomyositis complicated by malignancy: a case-based review.

Dermatomyositis (DM) is associated with interstitial lung disease (ILD) and malignancy. However, the coexistence of ILD and malignancy (DM-ILD-malignancy) is rare, and limited information exists regarding its management. Herein, we report the case of a 70-year-old man who developed DM with rapidly progressive ILD and advanced gastric cancer and provide a literature review of managing DM-ILD-malignancy. The patient presented with typical DM skin rashes and shortness of breath, which worsened within 1 month, without muscular symptoms. Additionally, the patient tested negative for myositis-specific autoantibodies (MSAs). Computed tomography revealed ILD and advanced gastric cancer, which was confirmed on endoscopic examination to be a poorly differentiated adenocarcinoma. Although the patient's ILD progressed rapidly, surgical treatment of the cancer was prioritized. Prednisolone (PSL) 0.5 mg/kg was initiated 3 days before surgery and increased to 1 mg/kg at 7 days postoperative. Remarkable improvement in the skin rash and ILD was observed, and the PSL dose was tapered without immunosuppressants. A literature review revealed that anti-melanoma differentiation-associated gene 5 and anti-aminoacyl transfer RNA synthetase antibodies are the predominant MSAs in DM-ILD-malignancy, and the optimal treatment should be determined based on several factors, including ILD patterns, and malignancy type and stage. In particular, lung cancer may be a risk factor for the acute exacerbation of ILD, and preceding immunosuppression would be useful. Furthermore, prioritizing surgery for gastric cancer is effective because of its paraneoplastic nature.

"Coexistence of IgA nephropathy and renal artery stenosis in Takayasu arteritis: case report and literature review".

Although Takayasu arteritis (TAK) is a form of large vessel vasculitis, complications of glomerulonephritis have occasionally been observed, with mesangial proliferative glomerulonephritis as the most common. The aim of this work was to present a case-based review regarding the association of glomerulonephritis and IgA nephropathy (IgAN) with TAK. A literature search was carried out using the PubMed and Scopus databases for articles published in English, and the Ichu-shi Web for Japanese. A 34-year-old Japanese man was evaluated for proteinuria, and IgAN was diagnosed by renal biopsy. Simultaneously, aortic wall thickening and right renal artery stenosis confirmed a coexisting TAK. Prednisolone and methotrexate improved both diseases, and percutaneous transluminal renal angioplasty resulted in right renal artery reopening. Our case and literature review revealed that membranous proliferative glomerulonephritis and IgAN are common in eastern Asia, while focal segmental glomerulosclerosis and mesangial proliferative glomerulonephritis are common in other regions. The incidence of IgAN is higher in TAK cases and is mostly reported in Asia. Abdominal aortic involvement and renal artery stenosis are common in cases with preceding TAK. IgAN could be related to the cytokine network involving interleukin-6, suggesting the usefulness of tocilizumab in patients with TAK accompanied by IgAN. The type of glomerulonephritis complicated with TAK differs among regions, and patients with TAK are more likely to experience IgAN than the healthy population.

Pharmacokinetics, pharmacodynamics, and safety of single-dose subcutaneous sarilumab with or without methotrexate in Japanese patients with rheumatoid arthritis: Two single-dose studies.

OBJECTIVES: To assess the safety and pharmacokinetics (PK) of single-dose subcutaneous (SC) sarilumab or tocilizumab SC ± methotrexate (MTX) and to assess the pharmacodynamics (PD) of sarilumab SC or tocilizumab SC monotherapy in Japanese rheumatoid arthritis (RA) patients. METHODS: TDU13402 was a randomized, double-blind, placebo-controlled, single-ascending dose Phase 1 study (NCT01850680). Twenty-four patients (6 per treatment group) received sarilumab 50, 100, or 200 mg plus MTX or placebo (2 per cohort) on Day (D) 1; PK and safety were assessed through D57. PDY14191 was a randomized, open-label, single-dose study (NCT02404558). Thirty patients (15 per arm) received sarilumab 150 mg or tocilizumab 162 mg on D1; PK, PD, and safety were assessed through D43. RESULTS: TDU13402: mean serum sarilumab exposure increased in a greater than dose proportional manner from 50 to 200 mg dose with no clinically meaningful increase in treatment-emergent adverse events (TEAEs). PDY14191: PK profiles of single-dose sarilumab 150 mg or tocilizumab 162 mg were similar; some numerical differences in PD profiles and TEAEs were observed. Neutrophil count decrease/neutropenia was the most frequently reported TEAE with sarilumab treatment in both studies. CONCLUSIONS: PK, PD, and safety profiles of single-dose sarilumab SC with/without MTX were consistent with results anticipated in Japanese patients with RA.

Real-world safety and effectiveness of mepolizumab for patients with eosinophilic granulomatosis with polyangiitis (EGPA) in Japan: 48-week interim analysis of the MARS study.

OBJECTIVES: : Assess real-world, long-term safety/effectiveness of mepolizumab for eosinophilic granulomatosis with polyangiitis (EGPA) in Japan. METHODS: : MARS (GSK ID:213684/NCT04551989) is an ongoing 96-week study of patients with EGPA who received 4-weekly mepolizumab 300 mg subcutaneously for ≥96 weeks before study entry (baseline) and continued treatment. This interim analysis included safety from baseline to Week 48 (observation period) and clinical outcomes before mepolizumab and during the observation period. RESULTS: : Of 118 patients enrolled, 29% (34/118) experienced adverse events (AEs) of which 13% (15/118) experienced serious AEs; none were considered mepolizumab-related. Median oral corticosteroid (OCS) dose decreased from 6.9 (pre-mepolizumab) to 3.0 (baseline) and 2.0 mg/day (Weeks 45-48); the proportion of patients receiving no OCS increased from 8% to 32% and 38%, respectively. Patients experiencing clinical symptoms decreased from 94% (pre-mepolizumab) to 73% (baseline) and 67% (Week 48). During the observation period, 5% of patients experienced EGPA relapse; rates of EGPA-related hospitalisations, EGPA-related emergency room/unscheduled visits and asthma exacerbations were 0.05, 0.09 and 0.08 event/person-year, respectively. CONCLUSIONS: : Results of mepolizumab treatment for ≥144 weeks (before baseline plus observation) were consistent with the known safety profile and allowed OCS dose reduction while improving disease control versus pre-treatment among patients with EGPA.

The efficacy and safety of anifrolumab in Japanese patients with systemic lupus erythematosus: TULIP-2 subanalysis.

OBJECTIVES: Evaluate the efficacy and safety of anifrolumab in the subpopulation of Japanese patients with systemic lupus erythematosus (SLE) in phase 3 TULIP-2 trial. METHODS: TULIP-2 was a 52-week randomized placebo-controlled trial (N = 362) that evaluated efficacy and safety of anifrolumab 300 mg IV every 4 weeks vs. placebo in patients with moderate to severe SLE who were receiving standard therapy. We performed a post hoc analysis of the primary and key secondary endpoints, and safety, of TULIP-2 in the Japanese subpopulation. RESULTS: In the Japanese subpopulation (anifrolumab, n = 24; placebo, n = 19), the proportion of patients who achieved a British Isles Lupus Assessment Group-based Composite Lupus Assessment response at Week 52 (primary endpoint) was greater in the anifrolumab group vs. placebo [50.0% (12/24) vs. 15.8% (3/19); treatment difference: 34.2%, 95% confidence interval 6.9, 61.5; nominal p = .014]. Improvement in skin activity and flare rates (key secondary endpoints) were favourable for anifrolumab vs. placebo. Consistent with the overall population, anifrolumab had an acceptable safety and tolerability profile. CONCLUSIONS: The efficacy and safety of anifrolumab 300 mg in Japanese patients with SLE was consistent with the demonstrated clinical profile of anifrolumab for the overall TULIP-2 population.

The long-term safety and tolerability of anifrolumab for patients with systemic lupus erythematosus in Japan: TULIP-LTE subgroup analysis.

OBJECTIVES: Evaluate the long-term safety and tolerability of anifrolumab 300 mg, alongside standard therapy, in patients from Japan with systemic lupus erythematosus (SLE) in the TULIP-LTE trial (NCT02794285). METHODS: TULIP-LTE was a 3-year, randomized, double-blind, placebo-controlled long-term extension (LTE) of the TULIP trials. The primary safety outcome included serious adverse events (SAEs) and AEs of special interest (AESIs) during the LTE period. Exploratory efficacy outcomes included SLE Disease Activity Index 2000 (SLEDAI-2K) scores and glucocorticoid use. We performed a post hoc subgroup analysis of patients who enrolled in Japan. RESULTS: Exposure-adjusted incidence rates of SAEs during the LTE and follow-up for patients receiving anifrolumab 300 mg (n=21) were 8.7 per 100 patient-years; AESIs included influenza (6.9) and herpes zoster (3.5). One of three patients receiving placebo had an SAE (13.9). One patient per group discontinued due to an AE. There were no deaths. During the TULIP+LTE period, patients receiving anifrolumab 300 mg (n=24) had sustained reduction from baseline in mean SLEDAI-2K scores and cumulative glucocorticoid dosage. CONCLUSIONS: Anifrolumab 300 mg showed a favourable benefit-risk profile for the long-term treatment of adult patients with moderate to severe SLE from Japan, with safety, tolerability, and efficacy profiles consistent with the overall population.

Branched chain amino acids in the treatment of polymyositis and dermatomyositis: a phase II/III, multi-centre, randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. METHODS: Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). RESULTS: Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s.e.m.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar. CONCLUSION: BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/, UMIN000016233.

Multi-targeted therapy for refractory eosinophilic granulomatosis with polyangiitis characterized by intracerebral hemorrhage and cardiomyopathy: a case-based review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disorder classified under anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, predominantly affecting small- to medium-sized vessels, characterized by asthma, eosinophilia, and necrotizing granulomatous inflammation. Most patients with EGPA experience peripheral neuropathy, whereas intracerebral hemorrhage is rare as EGPA-related presentation in central nervous system involvement, causing severe morbidity and mortality. Here, we present a 45-year-old man with refractory EGPA who developed intracerebral hemorrhage as the first manifestation, followed by cardiac involvement. This patient with a history of bronchial asthma developed a right putaminal hemorrhage caused by EGPA. Although intravenous cyclophosphamide (IVCY) and mepolizumab (MPZ) induced remission, relapse was frequently observed. Subsequently, he developed cardiomyopathy despite administration of rituximab (RTX) substituted from IVCY and MPZ. Combined immunosuppressive therapy, including IVCY, MPZ, and RTX was required to inhibit vascular inflammation, leading to sustained remission. We review previously published literature while focusing on the clinical features of patients with intracerebral hemorrhage caused by EGPA and describe clinical characteristics for detecting EGPA in patients with intracerebral hemorrhage, emphasizing rapid evaluation and recognition of EGPA and adequate intervention in the early vasculitic phase of this disease. We also refer to the immunological aspects of this case. It is important to consider "multi-targeted therapy" through interleukin-5 suppression and B cell depletion in the management of refractory EGPA.

Association of various myositis-specific autoantibodies with dermatomyositis and polymyositis triggered by pregnancy.

Although pregnancy is an important risk factor for autoimmune rheumatic diseases, little is known regarding the association between pregnancy and dermatomyositis (DM) or polymyositis (PM). Herein, we present two patients with DM that developed during the perinatal period. The first patient was positive for anti-aminoacyl synthetase (ARS) antibody and developed DM in the 14th week of pregnancy. Despite treatment, her foetus died of intrauterine growth restriction in the 27th week. The second patient was positive for anti-melanoma differentiation-associated gene 5 (MDA-5) antibody and developed DM 1 week after miscarriage at 9 weeks of gestation. The patient developed severe interstitial pneumonia, and intensive therapy including tofacitinib and rituximab administration was required. Our cases and a literature review revealed that various myositis-specific autoantibodies, including anti-ARS, anti-Mi-2, anti-TIF-1γ, and anti-MDA-5, are associated with DM and PM triggered by pregnancy. We also found that delay in commencing treatment in case of active disease including myositis and interstitial pneumonia, and poor response to corticosteroids were related to poor foetal outcomes in DM and PM. Although rare in pregnant women, it is critical to consider the possibility of DM and PM in patients presenting with rash, fever, weakness, and cough, and testing for myositis-specific autoantibodies is recommended.

Real-world results with IgPro20 for hypo- or agammaglobulinemia in Japan.

BACKGROUND: Subcutaneous immunoglobulin is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra® ; l-proline-stabilized 20% human subcutaneous immunoglobulin) is approved for agammaglobulinemia or hypogammaglobulinemia due to PID or secondary immunodeficiency (SID); however, its safety and effectiveness has not previously been assessed in a real-world setting. METHODS: This multicenter, open label post-marketing surveillance study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions, and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose. RESULTS: Of 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n = 28, SID n = 11). At least one adverse drug reaction was observed in 27 patients (31.8%; PID n = 21, SID n = 6), and the most common were injection site reactions (n = 17, 20.0%). Four patients (PID n = 3, SID n = 1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n = 2; SID n = 4) but in only one patient with SID during IgPro20 treatment (1.2%). CONCLUSIONS: In Japan, IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID.

Hypertrophic Pachymeningitis Development in Eosinophilic Granulomatosis with Polyangiitis at Relapse of Disease: A Case-Based Review.

Hypertrophic pachymeningitis (HP) presents with thickening of the dura mater in the cerebrum and spine, and its symptoms vary depending on the affected location. The association of HP with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis has been recognized, and most cases are complicated by granulomatosis with polyangiitis. We report the case of a 47-year-old man who presented with HP upon relapse of eosinophilic granulomatosis with polyangiitis (EGPA), with literature review. He presented with disturbance of consciousness, and magnetic resonance imaging (MRI) revealed thickening of the dura mater around the left parietal lobe. Although myeloperoxidase (MPO)-ANCA was positive on EGPA diagnosis, the elevation of MPO-ANCA was not documented at the onset of HP. Brain perfusion scintigraphy showed an increase in blood flow in the left parietal lobe and temporal lobe, and electroencephalogram (EEG) revealed slow waves in the left parietal lobe. He was treated with a high dose of corticosteroid and rituximab, and the slow waves on EEG and brain perfusion were normalized. Although the most frequent symptom of HP is headache, disturbance of consciousness can be the manifestation of HP, and inflammation of HP could affect the cerebral parenchyma, which can be documented as abnormal EEG and perfusion scintigraphy. Literature review revealed that most of the HP in EGPA developed when EGPA relapsed, and was observed in patients with MPO-ANCA positivity. HP develops without evidence of other clinical features of EGPA; therefore, adequate imaging, including contrast-enhanced MRI, is necessary. Rituximab may be effective for treating HP complicated with EGPA.

Sjögren's Syndrome Presenting with Temporary Hemiplegia Mimicking Transient Ischemic Attack.

Sjögren's syndrome manifests with a wide variety of neurologic symptoms. This case report presents a 53-year-old woman with Sjögren's syndrome associated with temporal hemiplegia, which was suspected to be a transient ischemic attack. After induction of immunosuppressive therapies [high-dose prednisolone (1 mg/kg/day) and intravenous cyclophosphamide (total 5 g)], the hemiplegia did not reappear and the blood flow abnormalities remarkably improved as depicted on electroencephalography and single photon emission computed tomography. This case suggests that temporal hemiplegia presenting with transient ischemia-like attack symptoms may be a neurologic manifestation of Sjögren's syndrome and responsive to immunosuppressive therapy.

Establishing clinical remission criteria and the framework of a treat-to-target algorithm for Takayasu arteritis: Results of a Delphi exercise carried out by an expert panel of the Japan Research Committee of the Ministry of Health, Labour and Welfare for intractable vasculitis.

OBJECTIVES: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). METHODS: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 paediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over four reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with three patients. RESULTS: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0-5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including positron emission tomography-computed tomography, and two on treatment intensification. CONCLUSIONS: We developed a T2T algorithm and proposals for standardised remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis.

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.