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OBJECTIVE: To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA-4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy. METHODS: This was a 12-month, multicenter, randomized, double-blind, placebo-controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial. RESULTS: A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted. CONCLUSION: Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy. [ABSTRACT FROM AUTHOR]

An additional disorder in the spectrum of thyroid related muscle disease is presented. Hypothyroid and hyperthyroid disease are both associated with a variety of muscle abnormalities, from myalgias to myopathy. Polymyositis, however, has never been reported immediately after treatment for active hyperthyroidism. A patient is presented with typical hyperthyroidism, who developed a severe proximal muscle weakness and a raised creatine phosphokinase after treatment for hyperthyroidism with propylthiouracil (100 mg orally, three times a day). Electromyography, muscle biopsy, and the course of the patient's illness were consistent with polymyositis. Whether this represents a cause-effect association or a chance occurrence is unknown. Physician awareness of the occurrence of a variety of muscle disorders including polymyositis in thyroid disease is emphasised. A brief discussion of thyroid myopathy, thionamide drug reactions, and polymyositis is included. [ABSTRACT FROM PUBLISHER]

Background: The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis factor inhibitors (TNFis)., Objective: To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis., Design: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341)., Setting: Academic and community-based rheumatology, gastroenterology, and dermatology practices., Patients: Adults aged 50 years or older receiving TNFis for any indication., Intervention: Random assignment to ZVL versus placebo., Measurements: Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid., Results: Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL ( n = 310) or placebo ( n = 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively., Limitation: Potentially limited generalizability to patients receiving other types of immunomodulators., Conclusion: This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics., Primary Funding Source: The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.

Objective: Pegloticase is used for the treatment of severe gout, but its use is limited by immunogenicity. This study was undertaken to evaluate whether mycophenolate mofetil (MMF) prolongs the efficacy of pegloticase., Methods: Participants were randomized 3:1 to receive 1,000 mg MMF twice daily or placebo for 14 weeks, starting 2 weeks before receiving pegloticase and continuing while receiving intravenous pegloticase 8 mg biweekly for 12 weeks. Participants then received pegloticase alone from week 12 to week 24. The primary end points were the proportion of patients who sustained a serum urate level of ≤6 mg/dl at 12 weeks and the rate of adverse events (AEs). Secondary end points included 24-week durability of serum urate level ≤6 mg/dl. Fisher's exact test and Wilcoxon's 2-sample test were used for analyses, along with Kaplan-Meier estimates and log rank tests., Results: A total of 32 participants received ≥1 dose of pegloticase. Participants were predominantly men (88%), with a mean age of 55.2 years, mean gout duration of 13.4 years, and mean baseline serum urate level of 9.2 mg/dl. At 12 weeks, a serum urate level of ≤6 mg/dl was achieved in 19 (86%) of 22 participants in the MMF arm compared to 4 (40%) of 10 in the placebo arm (P = 0.01). At week 24, the serum urate level was ≤6 mg/dl in 68% of MMF-treated patients versus 30% of placebo-treated patients (P = 0.06), and rates of AEs were similar between groups, with more infusion reactions occurring in the placebo arm (30% versus 0%)., Conclusion: Our findings indicate that MMF therapy with pegloticase is well tolerated and shows a clinically meaningful improvement in targeted serum urate level of ≤6 mg/dl at 12 and 24 weeks. This study suggests an innovative approach to pegloticase therapy in gout., (© 2021, American College of Rheumatology.)

Objectives: ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab., Methods: In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity., Results: A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies., Conclusions: Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA., Trial Registration Number: NCT01970475; Results., Competing Interests: Competing interests: SC reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Abbvie, Boehringer Ingelheim, Pfizer and Sandoz, outside the submitted work. MCG reports grants and personal fees from Amgen, AbbVie and Pfizer, and personal fees from Sandoz, FKb, Samsung BioEpis, Merck, Celltrion and Boehringer, during the conduct of the study. EC reports grants and personal fees from Amgen, during the conduct of the study; personal fees from Boehringer Ingelheim, Chelsea Therapeutics, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, Merck, Napp, Novartis, Regeneron, Sanofi-Aventis, Schering Plough, Synovate and Tonix and grants and personal fees from Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Pierre Fabre, Roche and UCB, outside the submitted work. FP-R reports grants from Amgen, during the conduct of the study; and personal fees from Amgen, outside the submitted work. AM reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from AbbVie, Pfizer and Bristol-Myers Squibb, grants from Takeda, Janssen, Gilead and UCB and personal fees from GlaxoSmithKline, outside the submitted work. JLP reports lecturing and consultancy fees from Roche, Novartis, Pfizer and Lilly, outside the submitted work. NZ and PK are employees of Amgen Inc., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To evaluate maintenance of response while reducing intravenous abatacept dose from ~10 mg/kg to ~5 mg/kg in patients with early rheumatoid arthritis (RA) who achieved disease activity score (DAS)28 (erythrocyte sedimentation rate, ESR) <2.6., Methods: This 1-year, multinational, randomised, double-blind substudy evaluated the efficacy and safety of ~10 mg/kg and ~5 mg/kg abatacept in patients with early RA with poor prognosis who had reached DAS28 (ESR) <2.6 at year 2 of the AGREE study. The primary outcome was time to disease relapse (defined as additional disease-modifying antirheumatic drugs, ≥2 courses high-dose steroids, return to open-label abatacept ~10 mg/kg, or DAS28 (C reactive protein) ≥3.2 at two consecutive visits)., Results: 108 patients were randomised (~10 mg/kg, n=58; ~5 mg/kg, n=50). Three and five patients, respectively, discontinued, and four per group returned to open-label abatacept. Relapse over time and the proportion of patients relapsing were similar in both groups (31% (~10 mg/kg) vs 34% (~5 mg/kg); HR: 0.87 (95% CI 0.45 to 1.69)). Mean steady-state trough serum concentration for the ~10 mg/kg group was 20.3-24.1 µg/mL, compared with 8.8-12.0 µg/mL for the ~5 mg/kg group., Conclusions: This exploratory study suggests that abatacept dose reduction may be an option in patients with poor prognosis early RA who achieve DAS28 (ESR) <2.6 after ≥1 year on abatacept (~10 mg/kg)., Trial Registration Number: NCT00989235., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To report results of subgroup analyses of bone mineral density (BMD) and bone turnover markers from a randomised, double-blind, placebo-controlled, phase II study of denosumab, an investigational RANKL inhibitor, in patients with rheumatoid arthritis (RA) concurrently receiving treatment with bisphosphonates or glucocorticoids., Methods: Patients received subcutaneous placebo (n=75), denosumab 60 mg (n=71) or denosumab 180 mg (n=72) at baseline and 6 months. Assessments included dual x-ray absorptiometry scans of the lumbar spine and hip, and determination of levels of serum type I C-telopeptide (sCTx-I) and serum procollagen 1N-terminal peptide (P1NP)., Results: Denosumab treatment increased mean lumbar spine and hip BMD and reduced sCTx-I and P1NP compared with placebo through 12 months, regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use., Conclusions: This study extends evidence that denosumab increases BMD and reduces bone turnover in patients with RA and may provide a new therapeutic option for reducing systemic bone loss in patients with RA.

Objective: T cells are involved in the pathogenesis of rheumatoid arthritis (RA). In animal models of autoimmune diseases, blockade of costimulatory molecules on antigen-presenting cells has been demonstrated to be effective in preventing or treating this disease by preventing T cell activation. To date, the effect of costimulatory blockade in patients with RA is unknown. The goal of this multicenter, multinational study was to determine the safety and preliminary efficacy of costimulatory blockade using CTLA-4Ig and LEA29Y in RA patients who have been treated unsuccessfully with at least 1 disease-modifying agent., Methods: CTLA-4Ig, LEA29Y (0.5, 2, or 10 mg/kg), or placebo was administered intravenously to 214 patients with RA. Patients received 4 infusions of study medication, on days 1, 15, 29, and 57, and were evaluated on day 85. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (ACR20). All patients were monitored for treatment safety and tolerability., Results: CTLA-4Ig and LEA29Y infusions were well tolerated at all dose levels. Peri-infusional adverse events were carefully monitored, and showed similar incidence across all dose groups with the exception of headaches, which were slightly more frequent in the 2 treatment groups. The incidence of discontinuations due to worsening of RA was 19%, 12%, and 9% at 0.5, 2, and 10 mg/kg, respectively, in the CTLA-4Ig-treated patients and 3%, 3%, and 6% at 0.5, 2, and 10 mg/kg, respectively, in the LEA29Y-treated patients (versus 31% in the placebo group). ACR20 responses on day 85 had increased in a dose-dependent manner (23%, 44%, and 53% of CTLA-4Ig-treated patients and 34%, 45%, and 61% of LEA29Y-treated patients at 0.5, 2.0, and 10 mg/kg, respectively, versus 31% of placebo-treated patients)., Conclusion: Both of the costimulatory blocking molecules studied were generally safe and well tolerated. As compared with placebo, both CTLA-4Ig and LEA29Y demonstrated efficacy in the treatment of RA.

Although diffuse idiopathic skeletal hyperostosis generally affects the lumbar spine, any segment of the spine may be involved. When the cervical spine is affected, dysphagia may occur. Diabetes mellitus is commonly present. A history of previous cervical trauma is an indication to obtain cervical spine radiographs. Barium swallow and endoscopy provide confirmation of etiology. Surgery is curative.

Purpose: Beginning in the 1980s, methotrexate has been used successfully to treat rheumatoid arthritis. The magnitude and severity of short- and long-term methotrexate toxicity, however, have not been adequately investigated. Our study was performed to determine the prevalence of hepatotoxicity in patients with rheumatoid arthritis receiving long-term methotrexate therapy., Patients and Methods: We conducted a retrospective, computer-assisted review of all Duke University Medical Center patients undergoing liver biopsy for methotrexate monitoring from January 1979 to January 1988. A total of 538 biopsies were performed in 399 patients, 259 of whom had inflammatory arthritis (210 with rheumatoid arthritis, 47 with psoriatic arthritis, and two with seronegative spondyloarthropathy)., Results: No evidence of cirrhosis was defined in the cohort with rheumatoid arthritis; however, six patients with rheumatoid arthritis had histologic changes of fibrotic liver disease (prevalence of 2.9 percent in the group with rheumatoid arthritis) while taking methotrexate. Five of the six patients were obese and three had glucose intolerance or overt diabetes mellitus, and one person admitted to alcohol usage. Only one patient with fibrotic liver disease had elevated liver function test results, and no person showed a declining serum albumin level at the time of biopsy. Sixty-one patients with rheumatoid arthritis underwent multiple samplings (44 with two, 13 with three, and four with four biopsies). Fourteen of these patients showed progressive hepatic disease, whereas four patients improved., Conclusion: Although the prevalence of methotrexate hepatotoxicity in this large cohort of patients with rheumatoid arthritis was low, a small but definite risk of hepatic fibrosis, not predictable by laboratory screening, still exists.

We have described a patient in whom an erosive arthropathy of the right wrist developed three years after insertion of a silicone lunate prosthesis. The clinical picture of silicone synovitis is being recognized more frequently after bone and joint implants, but the diagnosis may be delayed because initial suspicions focus on infection or crystal-induced arthropathy rather than foreign body reaction.

To characterize patterns of autoantibody expression in pediatric and adult systemic lupus erythematosus (SLE), IgG and IgM antibodies to cardiolipin (aCL) and single-stranded DNA (anti-DNA) were measured in sera from 32 pediatric and 36 adult patients. Antibody levels were assessed by isotype-specific ELISA and compared with 15 pediatric disease controls and 36 healthy adult controls. These determinations revealed significant differences in the pattern of IgG and IgM autoantibody expression in adult and pediatric patients. IgM aCL were more common in the pediatric than adult SLE population with 11 of 32 pediatric patients being positive compared to only 4 of 36 in the adult group (p less than 0.05). Conversely, enhanced IgG autoantibody production was observed in the adult group as 27 of 36 adult patients were positive for IgG anti-DNA compared to only 16 of 32 children (p less than 0.05). Analysis of sequential sera showed differences in the temporal expression of IgG and IgM autoantibodies as well as variability between anti-DNA and aCL responses over time. Our data suggest differences in the isotype profile of autoantibody responses in pediatric and adult SLE and provide further evidence for heterogeneity in the mechanisms of autoantibody production.

To determine the prevalence of anticardiolipin antibodies (aCL) in pediatric systemic lupus erythematosus (SLE) and their possible association with clinical manifestations, aCL were measured in sera of 32 patients with the onset of SLE before age 16. IgM and IgG aCL were determined by ELISA and values compared to those of 12 patients with juvenile rheumatoid arthritis (JRA), 15 age matched asthmatics, and 32 adult controls. aCL were demonstrated in sera of 16 of 32 (50%) children with SLE, 5 of 12 (42%) patients with JRA, 1 of 15 (7%) asthmatics, and in none of the 32 adult controls. Serial samples on 11 patients with SLE showed fluctuations in aCL levels that often corresponded to disease activity; the highest levels occurred in patients during periods of seizure activity and other neurologic events. The antibodies were not crossreactive anti-DNA antibodies as shown by the failure of DNA to inhibit binding to cardiolipin. These data suggest that the prevalence of aCL is similar in pediatric and adult SLE and that aCL levels may vary with disease activity, especially neurologic disease.