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Abstract: We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. "PD responder" was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept., Methods: We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change., Results: Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status., Conclusion: Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept., Trial Registration: Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000014657.

Background: Immunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4 + plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements., Methods: Serum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD., Results: In untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy., Conclusion: Serum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.

Objectives: To determine whether specific parameters contribute to clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis (RA) patients under the 'treat-to-target' strategy in clinical practice., Methods: We retrospectively analyzed 125 RA patients selected according to the following criteria; the patients' symptom duration was ≤6 months, and none had experience with DMARDs. We evaluated the patients' clinical disease activity at baseline and 1 year of treatment and the musculoskeletal ultrasound (MSUS)-detected synovitis activity at baseline. We performed an analysis to identify parameters that contribute to SDAI remission and the use of biologic/targeted synthetic (b/ts) DMARDs at 1 year post-diagnosis., Results: Forty-seven patients received b/tsDMARDs therapy, and 58 patients achieved SDAI remission at 1 year post-diagnosis. Rheumatoid factor positivity, low patient's/evaluator's global assessment at baseline, and methotrexate use at 1 year post-diagnosis were associated with SDAI remission. The baseline clinical disease activity and MSUS scores were not associated with SDAI remission. Anti-cyclic citrullinated peptide antibody positivity/high titer and high swollen joint counts or the presence of severe synovial hypertrophy at baseline were associated with the use of b/tsDMARDs therapy., Conclusion: The value of the expected poor-prognosis factors may be diminished by intensive therapy within the 'windows of opportunity'.

Abstract: We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers ( p  < .05). Although there was no significant difference, non-TNFi switchers tended to have a larger decrease than TNFi cyclers in efficacy indicators based on clinical disease activity index and PDUS. Multivariate logistic regression analysis identified a following independent factor associated with both EULAR good response and retention of a biologic agent: non-TNFi switch ( p  < .05 for both). Non-TNFi switchers were shown to have significantly higher percentage of EULAR good response and higher retention than TNFi cyclers. A non-TNFi biologic agent may hence be a preferential next-line treatment for TNF-IR patients.

A 71-year-old woman being treated with methotrexate (MTX) and tacrolimus (TAC) for rheumatoid arthritis (RA) was admitted to our hospital and underwent surgery for gastric perforation and peritonitis. An endoscopic examination six days post-surgery showed an extensive ulcer in the stomach, and a biopsy revealed diffused large B-cell lymphoma. We diagnosed her with immunodeficiency-associated lymphoproliferative disorder (LPD) and discontinued the MTX and TAC. She underwent gastrectomy due to stenosis approximately two months after the first operation, but the histopathological findings of lymphoma had disappeared. LPD should be considered as a potential cause of gastric perforation during RA treatment.

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-17 and 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.

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.

Objective: We evaluated the efficacy and safety of tofacitinib in patients with rheumatoid arthritis (RA) in a real-world setting., Methods: Seventy consecutive patients, for whom tofacitinib was initiated between November 2013 and May 2016, were enrolled. All patients fulfilled the 2010 ACR/EULAR classification criteria for RA. All patients received 5 mg of tofacitinib twice daily and were followed for 24 weeks. Clinical disease activity indicated by disease activity score (DAS)28-ESR, the simplified disease activity index, and the clinical disease activity index as well as adverse events (AEs) were evaluated. Statistical analysis was performed to determine which baseline variables influenced the efficacy of tofacitinib at 24 weeks., Results: Fifty-eight patients (82.9%) continued tofacitinib at 24 weeks. Clinical disease activity rapidly and significantly decreased, and this efficacy continued throughout the 24 weeks: i.e., DAS28-ESR decreased from 5.04 ± 1.33 at baseline to 3.83 ± 1.11 at 4 weeks and 3.53 ± 1.17 at 24 weeks (P<0.0001, vs. baseline). 15 AEs including 5 herpes zoster infection occurred during tofacitinib treatment. The efficacy of tofacitinib was not changed in patients without concomitant use of methotrexate (MTX) or patients whose treatment with tocilizumab (TCZ) failed. Multivariable logistic analysis showed that the number of biologic DMARDs (bDMARDs) previously used was independently associated with achievement of DAS-low disease activity., Conclusions: Our present study suggests that tofacitinib is effective in real-world settings even without concomitant MTX use or after switching from TCZ. Our results also suggest that its efficacy diminishes if started after use of multiple bDMARDs.