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Background: Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare., Methods: Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination., Results: Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05)., Conclusions: Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN., (© 2021. The Author(s).)

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways., (© 2021. The Author(s).)

Background: Juvenile idiopathic arthritis constitutes a significant cause of disability and quality of life impairment in pediatric and adult patients. The aim of this study was to ascertain clinical remission (CR) and subsequent relapse in juvenile idiopathic arthritis (JIA) patients, according to therapeutic approach and JIA subtype. Evidence in literature regarding its predictors is scarce., Methods: We conducted an observational, ambispective study. Patients diagnosed of JIA, treated with synthetic and/or biologic disease modifying antirheumatic drugs (DMARD) were included and followed-up to December 31st, 2015. Primary outcome was clinical remission defined by Wallace criteria, both on and off medication. In order to ascertain CR according to therapeutic approach, DMARD treatments were divided in four groups: 1) synthetic DMARD (sDMARD) alone, 2) sDMARD combined with another sDMARD, 3) sDMARD combined with biologic DMARD (bDMARD), and 4) bDMARD alone., Results: A total of 206 patients who received DMARD treatment were included. At the time the follow-up was completed, 70% of the patients in the cohort had attained CR at least once (144 out of 206), and 29% were in clinical remission off medication (59 out of 206). According to treatment group, CR was more frequently observed in patients treated with synthetic DMARD alone (53%). Within this group, CR was associated with female sex, oligoarticular persistent subtypes, ANA positivity, Methotrexate treatment and absence of HLA B27, comorbidities and DMARD toxicity. 124 DMARD treatments (62%) were withdrawn, 64% of which relapsed. Lower relapse rates were observed in those patients with persistent oligoarticular JIA (93%) when DMARD dose was tapered before withdrawal (77%)., Conclusions: More than two thirds of JIA patients attained CR along the 9 years of follow-up, and nearly one third achieved CR off medication. Females with early JIA onset, lower active joint count and ANA positivity were the ones achieving and sustaining remission more frequently, especially when receiving synthetic DMARD alone and in the absence of HLA B27, comorbidities or previous DMARD toxicity., (© 2021. The Author(s).)

Background: Childhood-onset systemic lupus erythematosus (cSLE) is a complex autoimmune disorder with multi-organ manifestations and can be associated with other rheumatic diseases including Sjögren's syndrome (SS). Salivary gland ultrasound (SGUS) represents a noninvasive tool to screen for salivary gland disease in rheumatic disease patients. The aims of this cross-sectional study were to determine feasibility of major SGUS in a clinic setting and to identify characteristics in a cohort of cSLE patients (without confirmed SS) that may be associated with salivary gland abnormalities consistent with secondary SS., Methods: Patients with SLE onset prior to age 18 were recruited. Patients completed questionnaires rating symptoms and underwent major SGUS examination. Disease and demographic differences were compared between cSLE patients with abnormal SGUS vs. cSLE patients with normal SGUS using t-tests and Fisher's exact tests., Results: Thirty-one cSLE patients were recruited, 84% were female, 55% were Caucasian. The average disease duration among all patients was 5 years. Average time to complete the SGUS examination and scoring protocol was 7 min. 35% of SGUS scores were abnormal and significantly associated with IgG level at diagnosis, and anti-Ro and anti-La antibodies., Conclusions: This is one of the first studies to our knowledge that assesses major SGUS in a cohort of patients with cSLE without prior diagnoses of SS. The SGUS protocol was feasible to perform by rheumatologists in a clinic setting. Although the sample size was small, SGUS abnormalities were identified in one-third of patients. IgG level at diagnosis and anti-Ro and anti-La antibodies may be associated with SGUS abnormalities.

Background: Coccidioides immitis is a dimorphic fungus endemic to the arid climates of the Southwest United States, Mexico and parts of Central and South America. Human infection occurs through inhalation of spores with less than half of exposures progressing to a symptomatic state that primarily consists of pulmonary manifestations. Disseminated coccidioidomycosis is exceedingly rare, occurring in fewer than 1 % of symptomatic infections. Through hematogenous spread, the fungus can infect most organ systems and may be fatal without systemic antifungal treatment. Individuals with impaired cell-mediated immunity either from primary immunodeficiency disorders or secondary to immunosuppression with medications such as tumor necrosis factor alpha (TNF-α) inhibitors have increased risk of disseminated coccidioidomycosis and previous cases of coccidioidomycosis have been reported with biologic therapy., Case Presentation: We present a case of disseminated coccidioidomycosis in a 16-year-old female with polyarticular juvenile idiopathic arthritis (JIA) being treated with prednisone, methotrexate, and infliximab. The patient presented with symptoms of meningeal irritation, bilateral choroidal lesions, and necrotizing peripheral pneumonia. Her infection was thought to be a reactivation of coccidioidomycosis given her history of resolved pneumonia that occurred after traveling to Arizona, New Mexico, and El Paso one year prior to presentation. Following diagnosis, she improved with discontinuation of her immunosuppressive medications and two weeks of intravenous amphotericin B and fluconazole with plans for lifetime treatment with fluconazole while immunosuppressed. Due to worsening arthritis, she will begin tofacitinib and continue close monitoring of chest x-rays and coccidioides antibody., Conclusions: Patients undergoing immunosuppressive therapy for rheumatological conditions are at increased risk of disseminated coccidioidomycosis and should be evaluated with high suspicion when presenting with atypical symptoms and history of travel to endemic regions.

Objectives: RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting., Methods: We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time., Results: Among the 27 583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction <0.001). The adjusted hazard ratios for seropositive compared with seronegative patients were 1.01 (95% CI 0.95, 1.07) for TNFis, 0.89 (0.78, 1.02)] for TCZ, 0.80 (0.72, 0.88) for ABA and 0.70 (0.59, 0.84) for RTX. Adjusted differences in remission and low disease activity rates between seropositive and seronegative patients followed the same pattern, with no difference in TNFis, a small difference in TCZ, a larger difference in ABA and the largest difference in RTX (Lundex remission difference +5.9%, low disease activity difference +11.6%)., Conclusion: Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Patients with rheumatologic diseases might be more susceptible to COVID-19 and carry a poorer prognosis. The aim of this study is to examine the incidence and outcomes of all COVID-19 patients with rheumatologic conditions in Hong Kong., Methods: This is a population-based retrospective study. All patients tested positive for SARS-CoV-2 by PCR with a previous diagnosis of rheumatologic diseases were reviewed. The incidence of COVID-19 in patients with rheumatologic conditions was calculated and compared to the general population in Hong Kong. Descriptive data of those rheumatologic patients with COVID-19 and the clinical course of the index infection were presented., Results: Up till 27 May 2020, there were 1067 cases of COVID-19 diagnosed in Hong Kong which had a population of 7.5 million. Out of the 39,835 patients with underlying rheumatologic diseases, we identified 5 PCR confirmed COVID-19 cases. The estimated incidence of COVID-19 was 0.0126% patients with rheumatologic diseases, compared to 0.0142% in the general population. All 5 patients had inflammatory arthropathies. One patient was on hydroxychloroquine and sulphasalazine, and one was on methotrexate. None of the 3534 patients on b/tsDMARDs was infected. Four patients had leucopenia/lymphopenia and stool viral PCR was positive in 3 patients. All patients made uneventful recovery without complications or flare of underlying diseases., Conclusions: We found no alarming signals of increased frequency or severity of COVID-19 in patients with rheumatologic diseases, although extrapolation of the results to other populations with different infection control strategies should be made with caution., Competing Interests: Declaration of Competing Interests None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To analyze clinical characteristics and outcome of COVID-19 patients with underlying rheumatic diseases (RD) on immunosuppressive agents., Method: A case series of COVID-19 patients with RD on disease modifying anti-rheumatic drugs (DMARDs) were studied by a retrospective chart review. A literature search identified 9 similar studies of single cases and case series, which were also included., Results: There were 4 COVID-19 inpatients with RD from our hospital, and the mean age was 57 ± 21 years. Two patients had a mild infection, and 2 developed severe COVID-19 related respiratory complications, including 1 patient on secukinumab requiring mechanical ventilation and 1 patient on rituximab developing viral pneumonia requiring supplemental oxygenation. All 4 patients had elevated acute phase reactants, 2 patients had mild COVID-19 with lymphopenia, and 2 patients had severe COVID-19 with normal lymphocyte counts, and high levels of IL-6. None of the patients exhibited an exacerbation of their underlying RD. In the literature, there were 9 studies of COVID-19 involving 197 cases of various inflammatory RD. Most patients were on DMARDs or biologics, of which TNFα inhibitors were most frequently used. Two tocilizumab users had a mild infection. Two patients were on rituximab with 1 severe COVID-19 requiring mechanical ventilation. Six patients were on secukinumab with 1 hospitalization. Of the total 201 cases, 12 died, with an estimated mortality of 5.9% CONCLUSION: Patients with RD are susceptible to COVID-19. Various DMARDs or biologics may affect the viral disease course differently. Patients on hydroxychloroquine, TNFα antagonists or tocilizumab may have a mild viral illness. Rituximab or secukinumab could worsen the viral disease. Further study is warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.

The treat-to-target principle of controlling inflammatory disease activity by means of disease-modifying antirheumatic drugs or immunosuppressive drugs also pertains to systemic lupus erythematosus (SLE). However, in SLE, intensifying immunosuppression with higher-dose glucocorticoids may worsen outcomes. Therefore, all current recommendations favor better disease control while limiting daily glucocorticoid doses to a maximum of 5 or 7.5 mg of prednisolone daily. Hydroxychloroquine and other prophylactic measures are added, and antiphospholipid syndrome is treated with anticoagulation and not with immunosuppression, which makes the approach of treat to target slightly more complex, mirroring the complexity of the disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although many treatment options exist for the initial management of rheumatoid arthritis, there has long been discussion about whether initial treatment should be with methotrexate (MTX) as monotherapy or in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Although studies initially showed additional benefit from combining MTX with other csDMARDs, this benefit disappears when glucocorticoids are added to MTX, a strategy recommended in current guidelines as a short-term bridging approach until MTX therapy exhibits its full efficacy. Also concomitant use of glucocorticoids, with MTX may not be inferior to combination therapy of MTX with TNF-inhibitors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction : Spondyloarthritis (SpA) refers to a group of disorders sharing common clinical, genetic and imaging characteristics. Axial (ax) SpA corresponds to a subgroup that mainly affects the axial skeleton, leading to inflammatory back pain and progressive radiographic changes of the sacroiliac joints and the spine. axSpA are currently subdivided into two forms, namely the radiographic and nonradiographic form, and are associated with musculoskeletal pain, restriction of spinal mobility, specific extra-articular features and overall, altered quality of life. The therapeutic management of axSpA has considerably progressed and is now well standardized. Areas covered : Herein, the author reviews the pharmacological treatments that may be used in axSpA, including radiographic and nonradiographic forms in addition to the role of nonsteroidal anti-inflammatory drugs (NSAIDs), TNF alpha (TNFi), and IL-17A (IL-17Ai) inhibitors. Expert opinion : NSAIDs remain the mainstay of initial therapy and biological agents may be then envisaged. TNFi and IL-17Ai may be used in axSpA, but physicians have more experience with TNFi. Only TNFi are licensed for the treatment of nonradiographic axSpA. IL-17Ai may be used as first or second line biologic disease modifying antirheumatic drugs (bDMARDs) and further results are needed to better define their position in the therapeutic management of axSpA.

Objective : To identify predictors of sick leave and improved worker productivity in patients with early rheumatoid arthritis (RA) treated for 52 weeks with intensive combination strategies. Methods : Patients with early RA were included in the COmbinatietherapie Bij Reumatoïde Artritis (COBRA)-light trial and followed for 52 weeks. As the COBRA-light strategy proved to be non-inferior to the COBRA strategy, all patients were pooled. Predictors for sick leave and improved worker productivity were assessed through a 3 month time-lag multivariable logistic generalized estimating equations model. Results : At baseline, 97 patients had a paid job, 59 had no job, and for six patients the work status was unknown. During the trial, 13 patients stopped working (8%) and six started working (4%). Only sick leave in the past 3 months predicted sick leave. By excluding this variable, patient global assessment and actual hours of sick leave became predictors. Increased worker productivity was predicted by higher patient global assessment levels, Sharp van der Heijde score ≥ 1, actual hours on sick leave, and higher worker productivity in the past 3 months. Conclusion : Sick leave and improved worker productivity were mainly predicted by non-disease-specific variables. Both outcomes can be predicted on a 3 month basis, using the outcome over the past 3 months for the next 3 months. By applying this model in daily practice, decisions for therapy change could be based not solely on disease activity but also taking into account a possible high risk for sick leave in the upcoming 3 months.

Background/objective: Many individuals with juvenile idiopathic arthritis (JIA) have persistent disease into adulthood. Polyarticular JIA (pJIA) is often mislabeled as rheumatoid arthritis (RA) in adult rheumatology clinics, and treatment for adult pJIA patients is not well defined. We aimed to describe clinical features and medication use in the adult pJIA population in relation to an RA control cohort., Methods: We performed a cross-sectional study of 45 adults with pJIA and 94 with RA seen from 2013 to 2017. Clinical characteristics including RA classification criteria were compared using χ and McNemar tests. Medication use was analyzed focusing on tumor necrosis factor inhibitor (TNFi) survival, and an accelerated failure-time model was developed for time to methotrexate initiation., Results: Polyarticular JIA patients were less likely to be rheumatoid factor or cyclic citrullinated peptide antibody positive; fewer than half of pJIA subjects met the RA 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria. Time from diagnosis to methotrexate initiation was associated with longer disease duration in both groups (p < 0.01). Current TNFi use was more prevalent in pJIA patients (49% vs. 18%, p < 0.01), and TNFi use, particularly for etanercept, was sustained longer with a median drug survival of 4.41 years compared with 0.70 years in RA patients (p < 0.01)., Conclusions: Although often considered together in adult rheumatology practice, adults with pJIA are distinct from patients with RA. Medication use markedly differed between the 2 populations with greater prevalence and duration of TNFi use in pJIA patients. Further study is needed to improve outcomes in this unique population.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We performed a comprehensive review of phase 3 studies of tofacitinib 5 mg twice daily (BID) (approved dose in many countries) in patients with moderate to severe RA and inadequate response to prior disease-modifying antirheumatic drugs., Methods: A search of PubMed and ClinicalTrials.gov identified 5 studies: ORAL Solo (NCT00814307), ORAL Sync (NCT00856544), ORAL Standard (included adalimumab 40 mg once every 2 weeks; NCT00853385), ORAL Scan (NCT00847613), and ORAL Step (NCT00960440). Efficacy and safety data for tofacitinib 5 mg BID, placebo, and adalimumab were analyzed., Results: Across the 5 studies, 1216 patients received tofacitinib 5 mg BID, 681 received placebo, and 204 received adalimumab. At month 3, tofacitinib demonstrated significantly higher 20%, 50%, and 70% improvement in American College of Rheumatology response criteria (ACR20, ACR50, and ACR70, respectively) response rates, greater improvement in Health Assessment Questionnaire-Disability Index, and a higher proportion of Disease Activity Score-defined remission than placebo. Frequencies of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar for tofacitinib and placebo at month 3; serious infection events were more frequent for tofacitinib. In ORAL Standard, although not powered for formal comparisons, tofacitinib and adalimumab had numerically similar efficacy and AEs; serious AEs and serious infection events were more frequent with tofacitinib., Conclusions: Tofacitinib 5 mg BID reduced RA signs and symptoms and improved physical function versus placebo in patients with inadequate response to prior disease-modifying antirheumatic drugs. Tofacitinib 5 mg BID had a consistent, manageable safety profile across studies, with no new safety signals identified.

Although anti-tumor necrosis factor (TNF) agents have greatly improved the management of rheumatic diseases, their cost limits access to many patients throughout the world. As a result, patients and clinicians have turned to biosimilars to provide similar efficacy at a lower cost. Many of the regulatory guidelines in the Asia Pacific region are largely based on those of the European Medicines Agency and the World Health Organization; however, there are variations between countries. Additionally, in some countries, intended copies are available that were approved prior to the development of guidelines and have not fulfilled the requirements of a biosimilar. We review the various regulatory requirements for biosimilars in the Asia Pacific region, the anti-TNF biosimilars and intended copies approved in the region, and whether clinical data are available for these agents. We discuss concerns about the need for additional regulations and education, and we provide recommendations for a multidisciplinary pharmacovigilance approach that closely monitors the safety of biosimilar use., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing-remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation., Methods: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued., Results: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n = 62, 24%) or on injectable (n = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences., Conclusion: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS.

Objective: The aims of this study were to evaluate the prevalence of metabolic syndrome (MetS) in psoriatic arthritis (PsA) patients according to the most recent definition in a Mediterranean population and to determine its association with biomarkers of inflammation and serum adipocytokine levels., Methods: Demographic, clinical, and laboratory data were collected on 74 patients with PsA and 82 control subjects. The presence of MetS was determined according to the current "harmonization" definition. Serum adipocytokines were analyzed. Continuous variables were compared by t test and discrete variables by χ test. Multivariate regression models compared the association between the presence of MetS and the blood levels of adipocytokines., Results: The prevalence of MetS was higher in PsA patients compared with the control group: 54.8% versus 36.6%, respectively (P = 0.02; odds ratio, 2.33; 95% confidence interval, 1.16-4.69). The main difference between the 2 groups was waist circumference. No association was found between MetS and parameters of articular and skin disease activity or treatment. Leptin levels and leptin/adiponectin ratio were higher in PsA patients compared with control subjects: 83.4 versus 51.7 ng/mL (P = 0.001) and 6.3 × 10 versus 4.1 × 10 (P = 0.015), respectively. There was no significant difference in the adiponectin levels between the groups., Conclusions: The prevalence of MetS was higher in PsA patients compared with non-PsA control subjects in this Mediterranean population. Clinicians caring for PsA patients ought to be aware of the increased risk of MetS in PsA patients, confirmed in different regions worldwide. The increased MetS seems to be linked to central obesity in these patients, and appropriate treatment recommendations are advised.

Rheumatoid arthritis is the most commonly diagnosed systemic inflammatory arthritis, with a lifetime prevalence of up to 1% worldwide. Women, smokers, and those with a family history of the disease are most often affected. Rheumatoid arthritis should be considered if there is at least one joint with definite swelling that is not better explained by another disease. In a patient with inflammatory arthritis, the presence of a rheumatoid factor and/or anti-citrullinated protein antibody, elevated C-reactive protein level, or elevated erythrocyte sedimentation rate is consistent with a diagnosis of rheumatoid arthritis. Rheumatoid arthritis may impact organs other than the joints, including lungs, skin, and eyes. Rapid diagnosis of rheumatoid arthritis allows for earlier treatment with disease-modifying antirheumatic drugs, which is associated with better outcomes. The goal of therapy is to initiate early medical treatment to achieve disease remission or the lowest disease activity possible. Methotrexate is typically the first-line agent for rheumatoid arthritis. Additional disease-modifying antirheumatic drugs or biologic agents should be added if disease activity persists. Comorbid conditions, including hepatitis B or C or tuberculosis infections, must be considered when choosing medical treatments. Although rheumatoid arthritis is often a chronic disease, some patients can taper and discontinue medications and remain in long-term remission.

Objective: The aim of this study was to systemically review the efficacy and safety of inhibitors of interleukin 6 (IL-6): clazakizumab, IL-12/23: ustekinumab, and IL-17A: secukinumab, brodalumab, and ixekizumab in psoriatic arthritis (PsA)., Methods: The literature search was conducted using MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science. We included randomized controlled trials that assessed the efficacy of IL inhibitors and reported American College of Rheumatology 20 response at 24 weeks. Meta-analysis was done using random-effects model utilizing the DerSimonian and Laird method. Quality assessment was done using RobotReviewer Cochrane Risk-of-Bias Assessment Tool. Heterogeneity was assessed with Q statistic and quantified with I. Publication bias was assessed with a funnel plot., Results: Eight studies including 2722 subjects demonstrate the efficacy of IL inhibitors clazakizumab, secukinumab, ixekizumab, brodalumab, and ustekinumab in the treatment of PsA. The American College of Rheumatology 20/50/70 risk ratios were 2.02 (95% confidence interval [CI], 1.65-2.47; P = 0.000), 2.95 (95% CI, 2.32-3.73; P = 0.00), and 5.14 (95% CI, 3.28-8.06; P = 0.00), respectively, in favor of treatment versus placebo. There was no evidence of significant heterogeneity between trials. Subgroup analysis showed efficacy in patients who were tumor necrosis factor naive, as well as tumor necrosis factor nonresponders or inadequate responders. The number of adverse events was higher in the treatment groups versus placebo, the majority were mild and did not require treatment adjustment (risk ratio, 1.17; 95% CI, 1.06-1.28; P = 0.001). There was no significant difference in drug withdrawals., Conclusions: Our meta-analysis shows that the inhibitors of IL-6 (clazakizumab), IL-12/23 (ustekinumab), and IL-17A (secukinumab, brodalumab, ixekizumab) are efficacious and generally well tolerated when used to treat patients with PsA.

Background: There is limited information about the factors related with the development of long-term permanent work disability (PWD) in rheumatoid arthritis (RA) treated with a combination of conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs)., Objective: The aim of this study was to evaluate incidence and factors associated with the development of PWD in RA treated with combination therapy using conventional synthetic cs-DMARDs., Methods: We assessed in multivariate models the effect of clinical and demographic factors in the development of PWD in a long-term retrospective cohort of 180 workers with RA who were treated with a combination of cs-DMARDs., Results: Incidence rates of PWD were 2.2% at 1 year, 7.7% at 5 years, 24.9% at 10 years, 34.9% at 15 years, and 45% at 20 years. In the adjusted Cox regression analysis, factors associated with PWD development were the first failure with combination of cs-DMARDs (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.05-5.46; P = 0.03), poor functioning at time of cohort onset (HR, 2.2; 95% CI, 1.05-4.70; P = 0.03), and requirement for joint replacement (HR, 3.3; 95% CI, 1.28-8.79; P = 0.01)., Conclusions: Around 25% of workers with combination therapy with cs-DMARDs developed PWD in 10 years following the diagnosis of RA. Some factors increase the risk of disability. Permanent work disability generates a relevant society burden and increases health care costs. Therefore, indicators predicting failure of combination therapies with cs-DMARDs might provide clinicians of useful tools for modifying treatments avoiding the disease progression.

The category of disease-modifying anti-rheumatic drugs (DMARDs) emerged in the 1970s to describe drugs capable of altering the long-term destructive course of arthritis. It became a core concept in rheumatology's reorientation towards pharmaceuticals in the late twentieth century. By examining the earliest use of the term "disease-modifying" in scientific publications, this paper identifies the drugs that the category described when it first emerged. Leaning on systematic reviews of each of these drugs towards the end of their career in rheumatology, it then establishes that posterity would not recognize any of these early DMARDs as capable of altering the long-term course of the disease. The notion of disease-modifying drugs was thus originally used to categorize drugs that were not disease-modifying. Instead of interpreting this inconsistency as an anomaly, the paper argues that the DMARD category may have gained currency because it allowed a number of actors to respond pragmatically to an ongoing crisis in the pharmacological approach to treating arthritis. The term offered to conjure prospects of disease-modifying effects regardless of drugs' actual capacities, and thus to semantically solve the tensions between needs and means that characterized rheumatology at the time. While shedding light on a pivotal moment in the history of rheumatology, the paper also models an approach to understanding drug categories as meaning-making mechanisms by which people can mediate the sometimes uneasy connections that exist between medical practice and science.

Introduction: Biologic therapies are used to treat several inflammatory diseases, including rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Data from a commercial claims database were used to evaluate utilization and cost of biologic treatment for these conditions., Methods: Data were obtained from the Optum Research Database. Patients were aged 18-63 years with diagnosis of moderate to severe RA, PsO, PsA, and/or AS and first (index) claim for biologics abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, or ustekinumab or non-biologic tofacitinib between March 1, 2011 and February 28, 2013. One-year treatment costs were based on observed paid amounts and used to impute dosing. Treatment patterns (persistence, switching, discontinuing, restarting) were evaluated., Results: Data from 20,159 patients were analyzed for index medications abatacept (n = 583), adalimumab (n = 6521), certolizumab pegol (n = 415), etanercept (n = 9116), golimumab (n = 231), infliximab (n = 1906), rituximab (n = 295), tocilizumab (n = 165), ustekinumab (n = 922), and tofacitinib (n = 5). For patients with RA only, costs were lowest for tofacitinib ($18,769), rituximab ($19,569), or abatacept ($21,877), and ranged from $23,682 to $30,269 for all other medications. For patients with PsO only, costs were lowest for adalimumab ($29,186), etanercept ($31,212), and infliximab ($32,409) compared with ustekinumab ($53,746). For patients with PsA only, costs were lowest for etanercept ($26,916), followed by golimumab ($27,987), adalimumab ($28,749), and infliximab ($31,974). Costs were lowest with etanercept for RA plus PsA ($25,477) and for PsO plus PsA ($29,376), and with golimumab for AS only ($24,225). Across indications, annual costs were $29,521, $27,488, and $28,672 for adalimumab, etanercept, and infliximab, respectively; persistence was greatest with infliximab (range 66-79%) compared with 11-59% for all other biologics., Conclusion: One-year treatment costs varied considerably between medications and indications. Some newly approved agents had lower costs but further research is needed to confirm these estimates as more patients are treated., Funding: Immunex (a wholly owned subsidiary of Amgen Inc.) and Wyeth (acquired by Pfizer).

Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected, and includes corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate or tumor necrosis factor-alpha and interleukin-1 blockers. We present a case series of four refractory BD patients successfully treated with intravenous immunoglobulins (IVIG). All patients fulfilled International Study Group criteria. The patients' mean age was 38.75 ± 12.09 years and mean disease duration 10.25 ± 8.5 years. Human leukocyte antigen B51 was positive in two of four patients. In addition to oral aphthosis, all patients suffered from genital ulcers and cutaneous BD-related manifestations; central nervous system involvement and arthralgia were found in two patients. Peripheral nervous system, gastrointestinal and eye involvement occurred in 25% of cases. In all patients, previously treated according to EULAR recommendations without reaching satisfactory results, IVIG induced immediate and sustained response over time without incurring any side effects. We propose IVIG administration as an additional effective and safe treatment option in patients with severe and resistant BD.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous disorders of chronic arthritis in childhood and remains the commonest pediatric rheumatic disease associated with significant long-term morbidity. Advances in understanding of the pathogenesis, better definition of disease control/remission measures, and the arrival of biological agents have improved the outcomes remarkably. Methotrexate (Mtx) remains the first-line disease modifying (DMARD) therapy for most children with JIA due to its proven efficacy and safety. Sulphosalazine (SSz) (especially for enthesitis) and leflunomide may also have a secondary role. Tumor necrosis factor inhibitors (TNF-I), alone or in combination with Mtx have shown tremendous benefit in children with polyarticular JIA, enthesitis related arthritis (ERA) and psoriatic arthritis. Tocilizumab appears very efficacious in systemic arthritis and abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear, though clearly beneficial in adult RA. TNF-I with Mtx is also effective in uveitis associated with JIA. Biologicals have demonstrated an impressive safety record in children with JIA, although close monitoring for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of cancers is warranted.

Background: The use of biologic agents has revolutionized the treatment of rheumatoid arthritis (RA). However, there is much uncertainty about whether any agent may be preferable., Purpose: The aim of the study was to evaluate the comparative efficacy of biologic agents with a disease-modifying antirheumatic drug (DMARD) in RA patients without prior exposure to a DMARD, that is, DMARD naive., Methods: MEDLINE, Cochrane, and Clinicaltrials.gov were searched from 1990 to August 2013 for randomized controlled trials comparing biologic agents in conjunction with a DMARD and DMARDs alone in DMARD (methotrexate [MTX])-naive RA patients. Information on patient characteristics, disease duration, and the American College of Rheumatology (ACR) 20/50/70/90 response rates after 52 weeks was extracted., Results: Six randomized controlled trials totaling 9 study arms fulfilled the inclusion criteria. Data were analyzed by direct and indirect pairwise comparisons of 2 drugs against a common comparator. In the direct comparison, all 6 biologic therapies were associated with significantly higher likelihood of achieving an ACR20 compared with MTX alone (mean ORs, 1.43-2.99). For ACR50 and ACR70, all biologic agents except golimumab showed statistically significant mean ORs of 1.31 to 2.52 (ACR20) and 1.79 to 2.59 (ACR50). At ACR90, abatacept 10 mg/kg, adalimumab 40 mg, and rituximab 500 and 1000 mg were significantly better compared with MTX (mean ORs 1.92-2.89). The indirect comparison for ACR20 showed etanercept 50 mg significantly favored against adalimumab 40 mg (OR, 1.05-3.34), golimumab 50 mg (OR, 1.16-4.07), infliximab 3 mg/kg (OR, 1.21-3.61), and infliximab 6 mg/kg (OR, 1.02-3.06). At ACR50, etanercept 50 mg and rituximab 1000 mg showed significantly higher ORs compared with golimumab 100 mg at ORs 1.06 to 3.42 and ORs 1.07 to 3.42, respectively. No significant differences were observed in the biologic agents for indirect pairwise comparisons at ACR70 and ACR90.Lack of head-to-head clinical trial data directly comparing biologic agents makes indirect meta-analysis the only substitute. Safety and cost of these agents were not evaluated. Only a small number of trials could be evaluated because of the strict inclusion criteria required for an indirect meta-analysis. Unmeasured confounders could contribute to trial heterogeneity. The data on golimumab were difficult to reconcile with the other trials because of methodological differences., Conclusions: Overall, biological agents in conjunction with a DMARD performed similarly in the settings evaluated. However, there were some statistically significant differences. Etanercept 50 mg appears superior to adalimumab 40 mg, golimumab 50 mg, and infliximab 3 and 6 mg/kg at ACR20. Rituximab 1000 mg and etanercept 50 mg appeared superior to golimumab 100 mg at ACR50 in DMARD-naive patients. No agent was superior to all others at each ACR level.

Objectives: New evidence has lightened the linkage between psoriatic arthritis (PsA) and the development of atherosclerosis and cardiovascular disease (CVD). We aimed to describe the prevalence of cardiovascular events and associated risk factors among patients with PsA., Methods: Retrospective evaluation of medical records from consecutive PsA patients who fulfilled the CASPAR criteria for PsA attending a specialised spondyloarthritis clinic at a single referral centre. CVD was defined based on the occurrence of coronary artery disease (CAD) or cerebrovascular ischaemic disease events., Results: We evaluated 158 PsA patients, 48.7% females and 51.3% males, aged 53.7±13.9 yrs. Mean PsA duration was 13.7±8.9 yrs and polyarticular subtype affected 66 (42%) patients. According to drug therapy, 85 (54%) were using NSAIDs and 21 (13%) low-dose prednisone; 32 (20%) were on anti-TNF agents, 94 (60%) metothrexate, 18 (11%) leflunomide, 13 (8%) sulfasalazine, 5 (3%) other immunossupressors and 4 (2.5%) were on chloroquine. Over half patients (87, 55%) had arterial hypertension (AH); 51 (32%) had dyslipidaemia (DLP), 38 (29%) hypertriglyceridemia and 36 (23%) diabetes mellitus (DM). Lipid profile was similar for both genders with mean total cholesterol= 186.5±38.6mg/dl, LDL=112.3±30.6 mg/dl, HDL= 47.89±14.6 and triglycerides= 127.4± 65.6 mg/dl. Of note, 14% PsA patients have had CVD, namely cerebrovascular or coronary heart disease. Sex, age, disease duration, joint involvement subtype, disease activity, CRP and lipid levels were similar among patients with and without CVD. The prevalence of AH (95% vs. 45%, p<0.001), DLP (75% vs. 27.7%, p<0.001) and DM (60% vs. 19%, p<0.001) were significantly greater in PsA patients who have had CVD compared to those without CVD, conferring an odds ratio of 21.0 for AH and of 5.4 for DM., Conclusions: The high prevalence of CVD in PsA patients is influenced by increased AH and DM. Hence early recognition and specific treatment is mandatory in order to reduce the risk for CVD, avoiding early morbidity and mortality.

Objective: To compare the effectiveness of switching to rituximab (RTX) with switching to alternative tumour necrosis factor (TNF) antagonists in patients with rheumatoid arthritis (RA) failing on TNF antagonists., Methods: A multicentre prospective 3-year observational study was performed in patients with RA treated with RTX or an alternative TNF antagonist. The baseline 28-joint disease activity score (DAS28) and Health Assessment Questionnaire (HAQ) score were compared with 6, 9 and 12 month values, adjusting for propensity score quintiles. Propensity scores were estimated for each patient using logistic regression with treatment as the dependent variable and baseline prior number of TNFs >1, years from diagnosis >5, extra-articular manifestations, previous toxicity, use of ≥2 disease-modifying antirheumatic drugs, age and sex as independent variables., Results: 1124 patients were treated with either RTX (n=591, 52.6%) or alternative TNF antagonists (n=533, 47.4%). RTX-treated patients had longer disease duration (p=0.0001), larger numbers of previous TNF antagonists (p<0.0001) and tender and swollen joints (p<0.0001). There was no significant difference in the reduction in DAS28 at 6, 9 and 12 months between RTX-treated patients and those treated with TNF antagonists. However, the reduction in DAS28 was significantly different between RTX-treated patients and adalimumab/infliximab-treated patients (p=0.001 and p=0.05, respectively). There was a marginally significant difference at any time period in the proportion of patients achieving an improvement in the HAQ score of >0.22 (p=0.06)., Conclusions: Optimal treatment for patients with RA failing on treatment with TNF antagonists may include RTX. This study suggests that the improvement in DAS28 is larger in patients treated with RTX than in those treated with monoclonal anti-TNF agents.

Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.

The treatment of rheumatoid arthritis traditionally includes symptomatic drugs, showing a prompt action on pain and inflammation, but without any influence on disease progression, and other drugs that could modify the disease course and occasionally induce clinical remission (DMARDs or disease modifying anti-rheumatic drugs). This review describes the historical steps that led to the use of the main DMARDs in rheumatoid arthritis, such as gold salts, sulphasalazine, chloroquine and hydroxychloroquine, D-penicillamine, and other immunoactive drugs, including methotrexate, azathioprine, cyclosporin and leflunomide. The historical evolution of use of these drugs is then discussed, including the strategy of progressive ("therapeutic pyramid") or of more aggressive treatment, through the simultaneous use of two or more DMARDs ("combination therapy").

Background: Data suggest that differences in patient preferences may account for racial disparities in the use of medical interventions. Racial disparities have also been noted in outcomes and the delivery of healthcare services in chronic disease. Whether treatment preferences in chronic disease differ by race is not known., Methods: We elicited treatment preferences for aggressive therapy in patients with rheumatoid arthritis who identified themselves as being black or white., Results: One hundred fifty consecutive eligible patients were invited to participate. Of these, 136 subjects completed the interview. In unadjusted analysis, 51% of white participants preferred aggressive therapy compared with 16% of blacks (P < 0.0001). Subjects who were married and reported having at least some college education had stronger preferences for aggressive therapy compared with their respective counterparts. After adjusting for covariates, race remained the strongest predictor of aggressive therapy examined in this study [adjusted odds ratio (95% confidence interval) = 11.2 (1.9-64.9)]., Conclusions: In this study, fewer black patients preferred aggressive treatment compared with white patients with similar disease severity. These results have important clinical implications because use of aggressive treatment improves both short- and long-term outcomes in rheumatoid arthritis. Efforts to improve patient education and physician communication should be made to ensure that all patients have an accurate understanding of the benefits, as well as risks, associated with the best available treatment options.

Objectives: There is a lack of agreement on assessing disease activity in patients with RA and determining when the RA treatment should be changed or continued. A panel of rheumatologists was convened to develop guidelines to assess adequacy of disease control, focusing on the use of disease-modifying anti-rheumatic drugs., Methods: The Research and Development/University of California in Los Angeles (RAND/UCLA) Appropriateness Method was used to evaluate disease control adequacy. After a literature review, 108 scenarios were developed to simulate situations most likely to be encountered in clinical practice and rated on a 9-point scale by a 10-member expert panel., Results: Final appropriateness rankings for the scenarios were as follows: 37% 'appropriate', 48% 'inappropriate', and 16% 'neutral'. The panelists felt that patients with disease control in the 'appropriate' range have adequate control with their current therapy, whereas those in the 'inappropriate' range should be considered for a change in therapy. Those in 'neutral' areas should have their therapy reviewed carefully. The panelists recommended that the clinically active joint count should be considered the most important decision factor. In patients with no clinically active joints, regardless of other factors no change in therapy was felt to be warranted. Patients with five or more active joints should be considered inadequately treated, and in patients with one to four active joints other variables must be considered in the decision to change therapy., Conclusion: These preliminary guidelines will assist the clinician in determining when a patient's clinical situation warrants therapy escalation and when continuing the current regimen would be appropriate.

Rheumatoid arthritis is a chronic inflammatory disease, which mainly affects the peripheral joints. Nurses are integral to the care of patients with this disease. This article discusses the role of the rheumatology nurse in the management of patients with this disabling condition.

Recent years have shown considerable advances in the understanding of pathophysiology and clinical course of patients with rheumatoid arthritis. We now know that there is preclinical disease. Autoantibodies precede clinical symptoms and erosive disease can be seen in patients as early as at the beginning of the symptoms. Clinical progress has come from a better recognition of the natural history of disease. Outcome measures were developed and validated, allowing innovative trial design. Therapy must aim at achieving clinical remission, reversal from destructive to nondestructive arthritis and even healing of erosions. Such aim necessitates early diagnosis of disease and aggressive treatment. Regular assessment of the disease state should be performed. For disease assessment validated tools should be used. The search for new therapies is ongoing. Studies indicate there is a considerable window of opportunity in very early rheumatoid arthritis. If we can use this window of opportunity with an efficient therapeutic strategy we should be able to change the course of disease or even achieve long term remission.

The past few years have witnessed a major change in the approach to the treatment of rheumatoid arthritis. The present focus is on early recognition and prompt treatment with disease-modifying antirheumatic drugs of which methotrexate continues to be the drug of choice. Leflunomide is an important recent addition to the list of available drugs. The use of combinations of disease-modifying antirheumatic drugs is gaining wide acceptance. A better understanding of the pathobiology of rheumatoid arthritis has led to the development of targeted therapies such as tumour necrosis factor blockers. There are robust data to show the clinical utility of tumour necrosis factor blockers in patients with rheumatoid arthritis.

At a time when many managed care organizations increasingly shift costs to patients through tiered formularies and widening copay differentials, biologic agents represent a significant clinical and financial challenge unlikely to be managed optimally with tiered formularies and greater patient cost sharing. The information discussed in this article is intended for healthcare professionals involved with rheumatoid arthritis therapy, including but not limited to physicians in both the inpatient and outpatient setting, and for other managed care professionals, including medical directors, pharmacy directors, long-term care decision makers, nurses, pharmacists, and case managers.