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BACKGROUND: Interleukin 6 (IL-6) inhibitors are the first-line treatment for idiopathic multicentric Castleman disease (iMCD); however, there is no established treatment for cases that are resistant to IL-6 inhibitors. Although sirolimus, a mammalian target of rapamycin inhibitor, has been suggested to be effective in patients with iMCD, the long-term safety and efficacy of sirolimus on individuals with IL-6 inhibitor-resistant iMCD have not been evaluated. METHODS/DESIGN: In this investigator-initiated, multicenter, open-label trial, the long-term safety of sirolimus will be evaluated in patients pating in a placebo-controlled, randomized, double-blind, parallel-group trial on tocilizumab (TCZ)-resistant iMCD. The study will be conducted in 7 centers in Japan. This trial will be promptly started after the evaluation and examination for 16 weeks in the preceding study. The trial will be completed by the time the drug is approved for iMCD treatment in Japan. The primary endpoint is the incidence of adverse events. The secondary endpoints include the following: the levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; physician global assessment (100-mm visual analog scale); patient global assessment (100-mm visual analog scale); and lymph node changes in subjects with lymphadenopathy. DISCUSSION: This clinical trial will provide evidence regarding the long-term safety of sirolimus as a potential novel therapeutic agent for patients with tocilizumab-resistant iMCD. TRIAL REGISTRATION NUMBER: jRCT2051200050., Medicine, 99(50), e23291; 2020

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) into clinical practice has dramatically improve the clinical outcomes of individuals with rheumatoid arthritis (RA). However, bDMARDs are associated with high costs, which has resulted in restricted treatment access and a burden on medical insurance finances. Although biosimilars offer cost-saving, their effectiveness and safety must be established in Post-Marketing Surveillance (PMS). Infliximab (IFX), a chimeric monoclonal antibody to TNF-alpha, is the first bDMARD; its biosimilar, CT-P13, is the first biosimilar DMARD approved for RA treatment in Japan. We will evaluate whether switching from originator IFX to CT-P13 is not inferior for maintaining non-clinical relapse to continued treatment with originator IFX in RA patients achieving clinical remission. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm against historical control and noninferiority clinical trial with a 24-week follow-up. Eighty RA patients who are treated by originator IFX for ?24 weeks and are achieving clinical remission will be included. Patients will be switched to CT-P13 with the unchanged dosing regimen. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the ratio of patients who experience a nonclinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of many biomarkers such as cytokines and chemokines.DISCUSSION: The study results are expected to show the noninferiority of switching to CT-P13 over the continuation of originator IFX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices but also MSUS to accurately and objectively evaluate disease activity at the joint, Medicine, 99(30), e21151; 2020

RATIONALE: Rare cases of reactive arthritis induced by active extra-articular tuberculosis (Poncet disease) have been reported. Complete response to antitubercular treatment and evidence of active extra-articular tuberculosis are the most important clinical features of Poncet disease. We report the case of successfully treated a patient with reactive arthritis induced by active extra-articular tuberculosis with a TNF inhibitor after sufficient antitubercular treatment. PATIENT CONCERNS: A 56-year-old Japanese man was admitted to our department with polyarthralgia, low back pain, and high fever. The results of rheumatoid factor, anti-citrullinated protein antibody, human leukocyte antigen B27, and the assays for the detection of infections (with an exception of T-SPOT.TB) were all negative. Fluoro-deoxy-D-glucose-positron emission tomography with CT (PET/CT) showed moderate uptake in the right cervical, right supraclavicular, mediastinal, and abdominal lymph nodes. As magnetic resonance imaging and power Doppler ultrasonography showed peripheral inflammation (tendinitis, tenosynovitis, ligamentitis, and enthesitis in the limbs). DIAGNOSIS: A diagnosis of tuberculous lymphadenitis was eventually established on the basis of lymph node biopsy results. There was no evidence of a bacterial infection including acid-fast bacteria in his joints, and the symptoms of polyarthralgia and low back pain were improved but not completely resolved with NSAID therapy; in addition, a diagnosis of reactive arthritis induced by active extraarticular tuberculosis was made. INTERVENTIONS: The patient experienced persistent peripheral inflammation despite antitubercular treatment for more than nine months and was then successfully treated with a tumor necrosis factor inhibitor (adalimumab 40 mg every 2 weeks). OUTCOMES: Finally, the patient responded to the treatment and has been in remission for over 4 months as of this writing. LESSONS: In patients who present with symptoms associated wit, Medicine, 98(49), e18008; 2019

Rationale:The pathology of gouty arthritis and reactive arthritis (ReA) partially overlaps, and both diseases are characterized by the production of inflammatory cytokines associated with the activation of monocytes and macrophages. However, the precise cytokine profile of cases with a coexistence of both diseases is unknown, and there are few reports on the course of treatment in patients with both gouty arthritis and ReA.Patient concerns:A 39-year-old man with a recurrent episode of gouty arthritis presented prednisolone-resistant polyarthritis with high level of C-reactive protein (CRP). He had the features of gouty arthritis such as active synovitis of the first manifestation of metatarsophalangeal (MTP) joints and the presence of monosodium urate (MSU) crystals from synovial fluid. But he also had the features of ReA such as the presence of tenosynovitis in the upper limb, the positivity of human leukocyte antigen (HLA)-B27, a history of sexual contact and positive findings of anti-Chlamydia trachomatis-specific IgA and IgG serum antibodies.Diagnoses:He was diagnosed with HLA-B27 associated Chlamydia-induced ReA accompanied by gout flares.Interventions:He was treated with 180 mg/day of loxoprofen, 1 mg/day of colchicine, and 10 mg/day of prednisolone for gout flares. However, his polyarthritis worsened with an increased level of CRP (23.16 mg/dL). Accordingly, we added 500 mg/day of salazosulfapyridine followed by adalimumab (ADA) 40 mg once every 2 weeks.Outcomes:After starting ADA, the patient's symptoms and laboratory findings showed rapid improvement and he achieved clinical remission 1 month after initiation of ADA treatment. As of this writing, the patient's clinical remission has been maintained for >1 year.Lessons:This case suggests that with exacerbation of arthritis during gouty arthritis, coexistence with other pathologies such as peripheral spondyloarthritis should be considered, and early intensive treatment including tumor necrosis factor inhibito, Medicine, 98(40), e17233; 2019

RATIONALE: Idiopathic multicentric Castleman disease (iMCD) is a systemic disease with multiple regions of lymphadenopathy and systemic symptoms and associated with rheumatoid arthritis (RA) and collagen diseases. However, few reported have described the coexistence of iMCD and RA and the mechanisms by which iMCD induces arthritis remain elusive. We experienced a rare case of iMCD, wherein the patient exhibited symptoms of polyarthritis with high-grade fever. PATIENT CONCERNS: A 34-year-old woman was admitted to our hospital for further evaluation of a high fever with polyarthritis. The levels of both rheumatoid factor and anticitrullinated protein antibody were negative.F-fluorodeoxyglucose/positron emission tomography-computed tomography showed lymphadenopathy with increased fluoro-2-deoxy-D-glucose uptake. Magnetic resonance imaging and musculoskeletal ultrasonography revealed active synovitis in the hands which was consistent with RA. DIAGNOSES: We diagnosed iMCD based on human herpesvirus 8 negativity, HIV negativity, systemic lymphadenopathy, and pathologic findings of the lymph nodes. The patient did not satisfy the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for RA. Cytokine assay showed elevated serum levels of interleukin-17and CXCL10, comparable to those in patients with RA. INTERVENTIONS: We administered 15?mg/d of predonisolone. OUTCOMES:After this treatment, the patient's symptoms showed improvement. As of this writing, we tapered the prednisolone to 7.5?mg/d,and the patient's remission has been maintained for >4 months. LESSONS: The present case suggests that RA-like active synovitis may coexist in iMCD, resulting from aberrant T-cell activation and histologic examination using lymph node biopsy may help enable early diagnosis of iMCD., Medicine, 98(18), e15237 ;2019

RATIONALE: Power Doppler ultrasonography (PDUS) in musculoskeletal ultrasound (MSUS) is a sensitive and reliable method for the assessment of rheumatoid arthritis (RA). The association between ultrasound-detectable forefoot bursae and the development of RA has gained attention. However, a few studies have evaluated the utility of PDUS for examining forefoot bursae in early RA. We report the case of an RA patient who developed reduced foot mobility and had detectable intermetatarsal bursitis with remarkable power Doppler (PD) signals in MSUS at the onset of RA. PATIENT CONCERNS: A 40-year-old Japanese woman diagnosed with palindromic rheumatism visited our department due to sustained forefoot pain and difficulty walking. The levels of both rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA) were high. She had opening toes with swelling in metatarsophalangeal (MTP) joints. PDUS showed intermetatarsal bursitis with mild MTP synovitis. DIAGNOSES: We diagnosed RA by comprehensive judgment based on the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for RA. INTERVENTIONS:We administered 6.0?mg/wk of methotrexate (MTX) and 2.0?mg/d of prednisolone (PSL) followed by an increase of MTX to 10?mg/wk. OUTCOMES: After those treatments, the patient's symptoms showed improvement. As of this writing,the patient's remission has been maintained for >2 months. LESSONS: Her case suggests that PDUS is useful for the detection of forefoot bursitis, and the detection of forefoot bursitis by PDUS may provide the opportunity to make an early diagnosis of RA., Medicine, 97(51), e13295; 2018

PATIENT CONCERNS: A 31-year-old Japanese woman suffered high fever and arthralgia lasting for 2 to 3 days after each menstrual period's start. She was admitted to our hospital, and colchicine was administered immediately after her next period's start, and the febrile attack was completely prevented.DIAGNOSES: We eventually diagnosed typical FMF.INTERVENTIONS: Her remission has been maintained by intermittent colchicine therapy. RATIONALE: Because most patients with familial Mediterranean fever (FMF) have attacks without any prodromal symptoms, and since it is suggested that patients with FMF have subclinical inflammation even during remission, a daily continuous administration of colchicine is recommended for patients with FMF even during remission. However, it is possible that intermittent colchicine therapy only during FMF attacks prevents the attacks completely in patients with FMF with expectable attacks.OUTCOMES: The genetic analysis revealed the G304R heterozygous mutation in exon 2 of the MEFV gene. Cytokine analysis suggested subclinical inflammation during the remission period.LESSONS: This case suggests that taking an extensive medical history (including the relationship between fever attack and menstruation) is important in the diagnosis of female patients with FMF. This case also suggests that a continuous administration of colchicine may have to be considered to regulate subclinical inflammation even in patients with FMF with completely expectable attacks., Medicine, 97(38), e12305; 2018