Dramatic improvement with colchicine in antihistamine- and omalizumab-resistant chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is defined as the presence of recurrent urticaria, angioedema or both without any specific triggers, which persists for ≥ 6 weeks. Refractory cases to standard therapeutic regimens including antihistamines, immunosuppressants and biologics have been reported. Therefore, it is crucial to evolve novel therapeutic strategies through accumulating refractory CSU cases, which are successfully treated. We here report a refractory case of CSU to antihistamines and omalizumab, which was dramatically improved with colchicine.

Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: No evidence has shown the efficacy of Sodium Risedronate (Risedronate) for glucocorticoid-induced osteoporosis (GIO) in patients with Rheumatoid arthritis (RA). The aim of this study was to explore the effectiveness and safety of Risedronate for GIO complicated with RA. METHODS: This was a six-month randomized, double-blind, placebo-controlled trial of 95 patients with GIO complicated with RA from 19 centers. The primary endpoint was the change from baseline in lumbar spine bone mineral density (L-BMD). Secondary endpoints included changes in femoral neck and total hip BMD and bone turnover markers, as well as rheumatoid arthritis Disease Activity Score with 28-joint counts. Incident of non-traumatic spine fractures and adverse events were tracked as safety endpoints. RESULTS: Increase in L-BMD was significantly greater in the Risedronate group compared to the Placebo group (Risedronate: 3.49% [95% CI: 1.92-5.05] vs Placebo: 0.12% [95% CI: -2.07 to 2.30], p < .0001). No significant difference was found in the femoral neck and total hip BMD. Although adverse events were observed in 28 patients, none were considered serious. Non-traumatic vertebral fractures were identified in 10 patients. CONCLUSION: Risedronate was effective in increasing L-BMD and was well tolerated in patients with GIO complicated with RA.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Calcineurin inhibitors for adult-onset Still's disease: a multicentre retrospective cohort study.

OBJECTIVES: To clarify the efficacy and safety of calcineurin inhibitors (CNI) for treating adult-onset Still's disease (AOSD). METHODS: This multicentre historical cohort study enrolled the consecutive patients with AOSD according to Yamaguchi classification criteria. The endpoints were set as the time from the initiation of treatment to events, the persistency rate of CNI and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We divided the events into two groups according to the treatment that included CNI or conventional therapy without CNI. RESULTS: One hundred seventy-eight patients with 247 events were analysed. CNI were predominantly used in 72 events with a recurrent history, typical skin rash, high ferritin levels, and/or severe complications such as macrophage activation syndrome, disseminated intravascular coagulation, serositis, meningitis. CNI led to a significantly longer event-free survival (hazard ratio: 0.57, 95% confidential interval: 0.32-0.99) after adjustment of concomitant medications. Subgroup analysis showed that CNI were effective for AOSD patients with high ALT level (hazard ratio: 0.11, 95% confidential interval: 0.02-0.59) and severe complications (hazard ratio: 0.11, 95% confidential interval: 0.01-0.94). The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI group (18% versus 8%, p=0.02); however, CNI did not involve in increased risk of adverse events, including nephrotoxicity, after adjustment (p=0.23). CONCLUSIONS: Our retrospective analysis suggested that CNI could be an effective and safe option for treating AOSD.

Crystalglobulinemia manifesting as chronic arthralgia and acute limb ischemia: A clinical case report.

RATIONALE: Crystalglobulinemia is a rare disease caused by monoclonal immunoglobulins, characterized by irreversible crystallization on refrigeration. It causes systemic symptoms including purpura, arthralgia, and vessel occlusive conditions to be exacerbated by exposure to cold. We report a patient with crystalglobulinemia associated with monoclonal gammopathy of undetermined significance (MGUS) manifesting as chronic arthralgia and recurrent acute arterial occlusion. PRESENTING CONCERNS: A 61-year-old man, who had been diagnosed with MGUS and who had arthralgia of unknown origin, presented with recurrent acute limb ischemia after surgical thromboembolectomy. Refrigeration of his serum formed precipitates that looked like needle-shaped crystals. These crystals did not dissolve with warming, which is not a characteristic of cryoglobulins. Skin biopsy results showed crystal-liked eosinophilic bodies in small vessels and we diagnosed crystalglobulinemia. INTERVENTION AND OUTCOMES: Although he underwent above-knee amputation, he was treated with a bortezomib and dexamethasone-based chemotherapeutic regimen, following lenalidomide maintenance therapy. Finally, he achieved complete remission and serum crystalglobulins diminished. LESSONS: Monoclonal gammopathy, previously diagnosed as MGUS, can cause systemic symptoms and thrombotic conditions by producing pathologic immunoglobulins, such as crystalglobulins. In such situations, MGUS, even when it has not progressed to multiple myeloma, can be a target of aggressive chemotherapy. Crystalglobulinemia should be considered for patients with monoclonal gammopathy manifesting as systemic and thrombotic symptoms exacerbated by cooling.

Maintenance treatment using abatacept with dose reduction after achievement of low disease activity in patients with rheumatoid arthritis (MATADOR) - A prospective, multicenter, single arm pilot clinical trial.

OBJECTIVES: To preliminarily evaluate the feasibility of maintenance therapy with reduced dose of intravenous abatacept (ABT) to 250 mg/body/month after achieving remission or low disease activity (LDA). PATIENTS AND METHODS: RA patients treated with ABT at 13 sites were enrolled in this prospective interventional pilot study during the period between March 2013 and March 2015. Inclusion criteria were (1) age at 20 years or older, (2) under treatment with monthly intravenous ABT at approved doses, (3) DAS28-CRP lower than 2.7 at least for 6 months, (4) agreed to join this trial with written informed consent and (5) body weight under 125 kg. Enrolled patients were maintained with intravenous monthly ABT at a reduced dose of 250 mg/body (MATADOR protocol). The primary end point was the proportion of the patients continued with MATADOR protocol at week 48. MATADOR protocol was discontinued upon disease flare or other reasons such as patients' request or severe adverse event (AE). Disease activities and structural changes were also evaluated. RESULTS: Fifty-three patients fulfilled the entry criteria and were followed for 1-year. MATADOR protocol was continued for 1-year in 43 (81%) of the evaluated patients. Three patients experienced severe AEs. Mean DAS28-CRP and remission rate were 1.56 and 88% when ABT reduced and 1.80 and 81% at 1-year, respectively. Structural remission was achieved in 34 out of 42 evaluated patients. CONCLUSIONS: Reduced dose of intravenous ABT was proposed as a feasible choice for maintenance therapy for RA after achievement of remission/LDA, although further randomized trials would be awaited.

Semi-Automated Quantification of Finger Joint Space Narrowing Using Tomosynthesis in Patients with Rheumatoid Arthritis.

The purpose of the study is to validate the semi-automated method using tomosynthesis images for the assessment of finger joint space narrowing (JSN) in patients with rheumatoid arthritis (RA), by using the semi-quantitative scoring method as the reference standard. Twenty patients (14 females and 6 males) with RA were included in this retrospective study. All patients underwent radiography and tomosynthesis of the bilateral hand and wrist. Two rheumatologists and a radiologist independently scored JSN with two modalities according to the Sharp/van der Heijde score. Two observers independently measured joint space width on tomosynthesis images using an in-house semi-automated method. More joints with JSN were revealed with tomosynthesis score (243 joints) and the semi-automated method (215 joints) than with radiography (120 joints), and the associations between tomosynthesis scores and radiography scores were demonstrated (P < 0.001). There was significant, negative correlation between measured joint space width and tomosynthesis scores with r = -0.606 (P < 0.001) in metacarpophalangeal joints and r = -0.518 (P < 0.001) in proximal interphalangeal joints. Inter-observer and intra-observer agreement of the semi-automated method using tomosynthesis images was in almost perfect agreement with intra-class correlation coefficient (ICC) values of 0.964 and 0.963, respectively. The semi-automated method using tomosynthesis images provided sensitive, quantitative, and reproducible measurement of finger joint space in patients with RA.

Tomosynthesis can facilitate accurate measurement of joint space width under the condition of the oblique incidence of X-rays in patients with rheumatoid arthritis.

OBJECTIVE: Accurate evaluation of joint space width (JSW) is important in the assessment of rheumatoid arthritis (RA). In clinical radiography of bilateral hands, the oblique incidence of X-rays is unavoidable, which may cause perceptional or measurement error of JSW. The objective of this study was to examine whether tomosynthesis, a recently developed modality, can facilitate a more accurate evaluation of JSW than radiography under the condition of oblique incidence of X-rays. METHODS: We investigated quantitative errors derived from the oblique incidence of X-rays by imaging phantoms simulating various finger joint spaces using radiographs and tomosynthesis images. We then compared the qualitative results of the modified total Sharp score of a total of 320 joints from 20 patients with RA between these modalities. RESULTS: A quantitative error was prominent when the location of the phantom was shifted along the JSW direction. Modified total Sharp scores of tomosynthesis images were significantly higher than those of radiography, that is to say JSW was regarded as narrower in tomosynthesis than in radiography when finger joints were located where the oblique incidence of X-rays is expected in the JSW direction. CONCLUSION: Tomosynthesis can facilitate accurate evaluation of JSW in finger joints of patients with RA, even with oblique incidence of X-rays. ADVANCES IN KNOWLEDGE: Accurate evaluation of JSW is necessary for the management of patients with RA. Through phantom and clinical studies, we demonstrate that tomosynthesis may achieve more accurate evaluation of JSW.

AP-VAS 2012 case report: an atypical case of microscopic polyangiitis presenting with acute tubulointerstitial nephritis without glomerular change.

Renal involvement in myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis is frequently characterized by focal segmental crescentic and/or necrotizing glomerulonephritis. However, a few cases of only tubulointerstitial nephritis (TIN) involvement without any apparent glomerular lesions have been reported. Here we report just such a case. A 74-year-old woman was admitted to a nearby hospital with a 2-week history of pitting edema, fever and anemia. She developed acute renal failure without proteinuria and microscopic hematuria. The urinary excretion of N-acetyl-beta-D-glucosaminidase and beta2-microglobulin concentration were 30.3 U/ml and 42270 µg/ml, respectively. Gallium-67 scintigraphy revealed abnormal concentrations on both sides of her kidneys. Her MPO-ANCA titer was 92 EU (normal range <10 EU). Skin and renal biopsies demonstrated fibrinoid vasculitis, necrotizing angiitis and TIN without glomerular change. Microscopic polyangiitis was diagnosed based on clinical and pathological criteria. No other factor that could induce TIN was detected. This case illustrates an unusual renal presentation of acute renal failure due to necrotizing arteritis and TIN, consistent with MPO-ANCA-associated vasculitis lacking crescentic glomerulonephritis. The pathogenesis is currently unclear, but the low-affinity type of MPO-ANCA was identified.

Antigenic structures recognized by anti-beta2-glycoprotein I auto-antibodies.

Beta2-glycoprotein I (beta2-GPI) is a major antigen for anti-cardiolipin antibodies and their epitopes are cryptic. Conformation of each domain of beta2-GPI was optimized from its crystal structure by energy minimization and by molecular dynamics simulation. Three electrostatic interactions, i.e. D193-K246, D222-K317 and E228-K308, were observed between domains IV and V in the optimized structure that was constructed based on the consensus sequences obtained by the phage-displayed random peptide library. Antigenic structures determined by the epitope mapping mainly consisted of hydrophobic amino acids located on two discontinuous sequences in domain IV. These amino acid clusters, as an epitope, were covered by domain V and were of a hidden nature. A similar but incomplete counterpart to the epitopic clusters was found in domain I but was not in domains II or III. Binding of anti-beta2-GPI auto-antibodies to solid-phase beta2-GPI was significantly reduced either by L replacement for W235, a common amino acid component for the epitopes, or by V replacement for all of D193, D222 and E228. Structural analysis indicated a hypothesis that these electrostatic interactions between domains IV and V retained exposure to W235 and that epitope spreading occurred in the region surrounding W235. Thus, epitopic structures recognized by anti-beta2-GPI auto-antibodies are cryptic and inter-domain electrostatic interactions are involved in their in exposure.