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Objective: To develop initial American College of Rheumatology (ACR) guidelines on the use of exercise, rehabilitation, diet, and additional interventions in conjunction with disease-modifying antirheumatic drugs (DMARDs) as part of an integrative management approach for people with rheumatoid arthritis (RA)., Methods: An interprofessional guideline development group constructed clinically relevant Population, Intervention, Comparator, and Outcome (PICO) questions. A literature review team then completed a systematic literature review and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence. An interprofessional Voting Panel (n = 20 participants) that included 3 individuals with RA achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations., Results: The Voting Panel achieved consensus on 28 recommendations for the use of integrative interventions in conjunction with DMARDs for the management of RA. Consistent engagement in exercise received a strong recommendation. Of 27 conditional recommendations, 4 pertained to exercise, 13 to rehabilitation, 3 to diet, and 7 to additional integrative interventions. These recommendations are specific to RA management, recognizing that other medical indications and general health benefits may exist for many of these interventions., Conclusion: This guideline provides initial ACR recommendations on integrative interventions for the management of RA to accompany DMARD treatments. The broad range of interventions included in these recommendations illustrates the importance of an interprofessional, team-based approach to RA management. The conditional nature of most recommendations requires clinicians to engage persons with RA in shared decision-making when applying these recommendations., (© 2023 American College of Rheumatology.)

With the arrival of biologics and the shift toward treat-to-target therapy, the possibility of a sustained clinical response has become an achievable goal for many patients with rheumatoid arthritis (RA). Although biologics have revolutionized the treatment of RA, they are costly, potentially inconvenient, and carry risks of side effects. Whether they can or should be tapered in patients with tight disease control is a matter of clinical uncertainty. The major international rheumatology professional societies have all issued guidelines on this question, but across recommendations, consensus is lacking on how and when to consider therapy de-escalation. Recent evidence suggests that sustained remission or low disease activity is more attainable with dose reduction as opposed to outright discontinuation of biologic therapy, and certain predictors of successful taper have begun to be described. This article will (1) summarize the current evidence base for biologic tapering in RA, (2) outline real-world outcomes findings, (3) review important contextual factors relevant to therapy de-escalation, such as cost-effectiveness considerations and patient perspectives, and (4) conclude by summarizing current guidelines., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial., Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m 2 ) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse., Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections., Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies., Competing Interests: Competing interests: RMS reports grants from Roche during the conduct of the study. RBJ reports grants from GlaxoSmithKline, personal fees from ChemoCentryx outside the submitted work. US reports grants from Genentech, during the conduct of the study, grants from ChemoCentryx, grants from BMS, grants from GSK, personal fees from Astra Zeneca, outside the submitted work. AB reports grants and personal fees from Astra Zeneca, personal fees from ChemoCentryx, personal fees from Merck/MSD, personal fees from Abbvie outside the submitted work. CKC reports grants from GlaxoSmithKline, grants and consultancy fees from Retrophin outside the submitted work. CL reports grants from Genentech during the conduct of the study. NK reports personal fees and non-financial support from Roche, non-financial support from Bristol Meyers Squibb outside the submitted work. CK reports other from Genentech, other from Roche outside the submitted work. RAL reports grants from Arthritis Research UK, grants from GlaxoSmithKline, grants from MRC, grants from University of Oxford Innovation Fund, grants from Canadian Institutes of Health Research, grants from The Vasculitis Foundation, grants from Celgene, grants from Vifor, personal fees from Grunenthal, personal fees from GSK, personal fees from InflaRx, personal fees from Medpace, personal fees from MedImmune, personal fees from Roche, outside the submitted work. HM reports personal fees from AbbVie, personal fees from Boehringer-Ingelheim, personal fees from Teijin, outside the submitted work. PM reports personal fees from Kiniksa, personal fees from ChemoCentryx, personal fees from Celgene, personal fees from Insmed, outside the submitted work. PN reports other from Chemocentryx, other from InflaRx, other from Omeros, other from Aurinia outside the submitted work. CP reports grants and personal fees from Roche, personal fees from ChemoCentryx, grants and personal fees from GlaxoSmithKline, personal fees from Sanofi, personal fees from InflaRx outside the submitted work. FP reports grants from Vifor pharma outside the submitted work. RS reports grants from GlaxoSmithKline, grants from chemocentryx, grants from Roche/Genentech, grants from BIPI, personal fees from GlaxoSmithKline, personal fees from chemocentryx. RS reports personal fees from Bristol-Myers Squibb, other from Alexion outside the submitted work. VT reports other from Abbvie, other from Amgen, other from Boehringer-Ingelheim, other from Calliditas, other from Chemocentryx, other from FMC, other from Retrophin outside the submitted work. PM reports personal fees from AbbVie, grants and personal fees from AstraZeneca, personal fees from Biogen, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Boeringher-Ingelheim, grants and personal fees from Celgene, grants and personal fees from ChemoCentryx, CSL Behring, grants and personal fees from Genentech/Roche, grants and personal fees from Genzyme/Sanofi, grants and personal fees from GlaxoSmithKline, grants and personal fees from InflaRx, personal fees from Insmed, personal fees from Jannsen, personal fees from Kiniksa, grants from Kypha, personal fees from Sparrow, grants from TerumoBCT outside the submitted work. DJ reports grants from Roche/Genentech, during the conduct of the study; grants from Sanofi-Genzyme, grants and personal fees from Chemocentryx, grants and personal fees from GSK, grants from Roche/Genentech, personal fees from Takeda, personal fees from Insmed, personal fees from Astra-Zeneca, personal fees from Infla-RX, personal fees from Chugai, personal fees from Boehringer-Ingelheim outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing., Methods: Participants in an ongoing multisite, observational study completed the Pain Catastrophizing Scale (PCS) before and 12 weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models., Results: Among the 165 rheumatoid arthritis patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (p < 0.0001) after 12 weeks. Pain intensity decreased from a median of 5 to 3 on a 10-point numeric rating scale (p < 0.0001), and catastrophizing decreased, from 16.0 to 12.0 on the 52-point PCS (p = 0.0005). Among the 163 with complete data for the regression analysis, changes in CDAI were positively correlated with changes in catastrophizing (standardized β = 0.19, p = 0.01). Of the components of the CDAI, change in assessor global score was most strongly associated with changes in catastrophizing (standardized β = 0.24, p = 0.003)., Conclusions: Pain catastrophizing decreases, in conjunction with disease activity, after initiation of a new DMARD. These findings provide support for catastrophizing as a dynamic construct that can be altered with treatment directed at decreasing inflammatory disease activity and pain.

Objective: The Patient-Reported Outcomes Measurement Information System (PROMIS) is a calibrated item bank used to assess patient-reported outcomes across multiple domains. The purpose of this study was to describe the performance of selected PROMIS measures in patients with rheumatoid arthritis (RA) with active disease who were initiating a disease-modifying antirheumatic drug (DMARD)., Methods: Participants in an ongoing prospective observational study completed 8 PROMIS measures before and after DMARD initiation. Linear regression models were performed to identify cross-sectional associations between baseline PROMIS measures and disease activity, measured using the Clinical Disease Activity Index (CDAI). Paired t-tests were performed to evaluate responsiveness after 12 weeks of DMARD treatment. Associations between changes in PROMIS measures and changes in the CDAI score were assessed using linear regression., Results: Among the 156 participants who completed the first study visit, the mean ± SD baseline CDAI score was 25.5 ± 14.0. Baseline scores for PROMIS measures of physical health, pain, and sleep were associated with the baseline CDAI score (P ≤ 0.05). Among the 106 participants with 12-week data, all PROMIS scores improved after DMARD initiation (P ≤ 0.05). With the exception of depression, changes in all assessed PROMIS measures were correlated with changes in the CDAI score (standardized βs from |0.23| to |0.38|)., Conclusion: These data provide support for the utility of PROMIS measures for the assessment of physical and mental health in individuals with active RA. All PROMIS measures improved significantly after DMARD initiation, with the magnitudes of association between changes in PROMIS measures and changes in the CDAI score in the low-to-moderate range., (© 2018, American College of Rheumatology.)

Objective: The Outcome Measures in Rheumatology (OMERACT) 3×3 method analyzes the occurrence of benefit and harm simultaneously at the individual patient level. We applied this method to 2 recent rheumatoid arthritis (RA) trial data sets., Methods: The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) and the Rheumatoid Arthritis Comparison of Active Therapies (RACAT) randomized trial outcomes for safety were defined according to OMERACT as having no adverse events (AEs), non-serious AEs, and serious AEs. Treatment efficacy was defined as good, moderate, or no response. A good treatment response without any AEs was labeled an unqualified success, and no treatment response but at least 1 AE was considered an unmitigated failure. The association between benefit and harm was assessed by chi-square or exact tests, as appropriate., Results: In TEAR, 612 of 755 patients had response data at 48 weeks: 14% of patients experienced unqualified success and 9% had unmitigated failure, with no difference between the treatment arms. Treatment response and AE rates were not correlated. In RACAT, 309 of 353 patients had response data at 48 weeks: 6% of patients experienced unqualified success and 11% had unmitigated failure, with no differences between the treatment arms. Response and AE rates were negatively correlated. The frequency of AEs and serious AEs increased as response decreased (P = 0.008)., Conclusion: We found some evidence that clinical response may be reduced by the co-occurrence of AEs., (© 2018 American College of Rheumatology.)

Objective: Abnormal function of high-density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL-associated proteins over 2 years of follow-up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial., Methods: The antioxidant capacity of HDL, paraoxonase 1 (PON-1) activity, and levels of HDL-associated haptoglobin (Hp), HDL-associated apolipoprotein A-I (Apo A-I), and myeloperoxidase (MPO) were measured in 550 TEAR participants at 4 time points (time 0 [pretreatment] and at 24, 48, and 102 weeks of treatment). Repeated-measures analysis using mixed-effects linear models with an autoregressive covariate structure was performed to model the within-subject covariance over time., Results: Mixed-effects models, which were controlled for traditional CV risk factors, treatment regimen, prednisone use, and statin use, demonstrated significant associations between RA disease activity, measured using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate, or C-reactive protein level, and the profile of HDL function over time. Specifically, decreases in RA disease activity over time were associated with increases in PON-1 activity and levels of HDL-associated Apo A-I, and decreases in the HDL inflammatory index and levels of MPO and HDL-associated Hp., Conclusion: Reduced disease activity in patients with early RA treated with MTX monotherapy, MTX + ETN combination therapy, or MTX + SSZ + HCQ triple therapy in the TEAR trial was associated with improvements in the HDL function profile. Additional studies are warranted to evaluate abnormal HDL function as a potential mechanism and therapeutic target for CV risk in patients with RA., (© 2016, American College of Rheumatology.)

Objective: To evaluate the cost-effectiveness of all 4 interventions in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) clinical trial: immediate triple (IT), immediate etanercept (IE), step-up triple (ST), and step-up etanercept (SE). Step-up interventions started with methotrexate and added either etanercept or sulfasalazine plus hydroxychloroquine to patients with persistent disease activity., Methods: We built a Markov cohort model that uses individual-level data from the TEAR trial, published literature, and supplemental clinical data. Costs were in US dollars, benefits in quality-adjusted life years (QALYs), perspective was societal, and the time horizon was 5 years., Results: The immediate strategies were more efficacious than step-up strategies. SE and IE were more costly than ST and IT, primarily due to treatment cost differences. In addition, IT was the least expensive and most effective strategy when the time horizon was 1 and 2 years. When the time horizon was 5 years, IE was marginally more effective than IT (3.483 versus 3.476 QALYs), but IE was substantially more expensive than IT ($148,800 versus $52,600), producing an incremental cost-effectiveness ratio of $12.5 million per QALY. These results were robust to both one-way deterministic and joint probabilistic sensitivity analyses., Conclusion: IT was highly cost-effective in the majority of scenarios. Although IE was more effective in 5 years, a substantial reduction in the cost of biologic agents was required in order for IE to become cost-effective in early aggressive RA under willingness-to-pay thresholds that most health care settings may find acceptable., (© 2016, American College of Rheumatology.)

Objective: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement., Methods: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay., Results: In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005)., Conclusions: Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: The aim was to compare the effect of etanercept (ETN) and conventional synthetic disease-modifying anti-rheumatic drug (DMARD) therapy on serum amyloid A (SAA) levels and to determine whether SAA reflects rheumatoid arthritis (RA) disease activity better than C-reactive protein (CRP)., Methods: We measured SAA and CRP at baseline, 24, 48, and 102 week follow-up visits in 594 patients participating in the Treatment of early RA (TEAR) study. We used Spearman correlation coefficients (rho) to evaluate the relationship between SAA and CRP and mixed effects models to determine whether ETN and methotrexate (MTX) treatment compared to triple DMARD therapy differentially lowered SAA. Akaike information criteria (AIC) were used to determine model fits., Results: SAA levels were only moderately correlated with CRP levels (rho = 0.58, p < 0.0001). There were significant differences in SAA by both visit (p = 0.0197) and treatment arm (p = 0.0130). RA patients treated with ETN plus MTX had a larger reduction in SAA than patients treated with traditional DMARD therapy. Similar results were found for serum CRP by visit (p = 0.0254) and by treatment (p < 0.0001), with a more pronounced difference than for SAA. Across all patients and time points, models of the disease activity score of 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) using SAA levels were better than models using CRP; the ΔAIC between the SAA and CRP models was 305., Conclusions: SAA may be a better biomarker of RA disease activity than CRP, especially during treatment with tumor necrosis factor (TNF) antagonists. This warrants additional studies in other cohorts of patients on treatment for RA., Trial Registration: (ClinicalTrials.gov identifier: NCT00259610 , Date of registration: 28 November 2005).

With the introduction of more objective disease activity measures and the development of biological therapies, there were dramatic changes in the treatment of rheumatoid arthritis (RA). The combination therapy with tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) has unprecedentedly improved prognosis and outcomes, and very low disease activity or remission has been achievable goal in RA. Although the concept of remission induction and maintenance was first discussed in longstanding RA patients, several clinical trials have demonstrated that there is a therapeutic window of opportunity, and early effective control of inflammation in early RA could lead to less joint damage and better long-term outcomes. Emerging evidence suggests that early combination therapy with TNF inhibitor and MTX leads to rapid clinical remission and thereby improved quality of life. Furthermore, remission status may be sustained in some patients even if a TNF inhibitor is discontinued after sustained remission in early RA patients. While there are many potential benefits of early remission induction therapy with the combination of a TNF inhibitor and MTX, the best therapeutic regimen and strategy for remission induction and maintenance in early RA remain controversial. There are no data to decide a priori when and in whom TNF blocker drugs are indicated in early disease-modifying anti-rheumatic drug (DMARD)-naïve RA.

Second-generation assays for anti-cyclic citrullinated peptide (anti-CCP), a highly sensitive and specific marker for rheumatoid arthritis (RA), have redefined the epidemiology of RA. In the Women's Health Initiative (WHI) RA study (2009-2011), we evaluated the prevalence of anti-CCP positivity among 15,691 (10.2% of 161,808) WHI participants aged 50-79 years who reported RA. Using stored baseline specimens, we measured serum anti-CCP, rheumatoid factor (RF), and antinuclear antibody in a defined sample of 9,988 of black, white, and Hispanic women. In a subset of women, we measured plasma cytokine levels and number of copies of the human leukocyte antigen (HLA)-DRB1 (HLA-DRB1) shared epitope in DNA by means of Luminex polymerase chain reaction typing (Luminex Corporation, Austin, Texas). We validated classification of probable clinical RA in 2 clinics as anti-CCP positivity or self-reported validated use of disease-modifying antirheumatic drugs (DMARDs). The prevalence of anti-CCP positivity was 8.1%, and the prevalence of RF positivity was approximately 16.0%. DMARD use including prednisone was reported by 1,140 (11.4%) participants (841 excluding prednisone) but by 57.5% of anti-CCP-positive women. The prevalence of 2 shared epitopes was also much higher for anti-CCP-positive women (18.2%, as opposed to only 5.5% for women with anti-CCP-negative DMARD-positive RA and 6.6% for anti-CCP-negative, RF-negative DMARD nonusers). Median cytokine levels were much higher for anti-CCP-positive/RF-positive women. Women with anti-CCP-positive RA and anti-CCP-negative RA had different characteristics with regard to HLA shared epitope, cigarette smoking, and inflammation (cytokines).

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

Objective: Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA., Methods: In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2., Results: Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar., Conclusion: These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy., (Copyright © 2013 by the American College of Rheumatology.)

Objective: To assess the overall safety, including rare events, of intravenous (IV) abatacept treatment in rheumatoid arthritis (RA)., Methods: Data from 8 clinical trials of IV abatacept in RA were pooled. Safety events were assessed during the short-term (duration ≤ 12 months) and cumulative (short-term plus longterm extensions) abatacept treatment periods. Incidence rates per 100 patient-years were calculated. Standardized incidence ratios (SIR) for hospitalized infections and malignancies were compared with external RA cohorts and, for malignancies, with the US general population., Results: There were 3173 IV abatacept-treated patients with 2331 patient-years of exposure in the short-term periods, and 4149 IV abatacept-treated patients with 12,132 patient-years of exposure in the cumulative period. Incidence rates for serious infections were low and consistent over time (3.68 for abatacept vs 2.60 for placebo during the short-term, and 2.87 for abatacept during the cumulative period). Hospitalized infections were generally similar to external RA patient cohorts and were consistent over time. Incidence rates of malignancies were similar for abatacept- and placebo-treated patients during the short-term period (0.73 vs 0.59) and remained low during the abatacept cumulative period (0.73). SIR of some tissue-specific malignancies (e.g., colorectal and breast) in the cumulative period tended to be lower, while others (lymphoma and lung) tended to be higher, compared with the general population; however, incidence rates were comparable with RA cohorts. Autoimmune events were rare and infusion reactions uncommon., Conclusion: Longterm safety of IV abatacept was consistent with the short-term, with no unexpected events and low incidence rates of serious infections, malignancies, and autoimmune events.

Objective: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy., Methods: This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks., Results: At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02)., Conclusion: Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Rapidly predicting future outcomes based on short-term clinical response would be helpful to optimize rheumatoid arthritis (RA) management in early disease. Our aim was to derive and validate a clinical prediction rule to predict low disease activity (LDA) at 1 year among patients participating in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial escalating RA therapy by adding either etanercept or sulfasalazine + hydroxychloroquine [triple therapy (TT)] after 6 months of methotrexate (MTX) therapy., Methods: Eligible subjects included in the derivation cohort (used for model building, n = 186) were participants with moderate or higher disease activity [Disease Activity Score 28-erythrocyte sedimentation rate (DAS-ESR) > 3.2] despite 24 weeks of MTX monotherapy who added either etanercept or sulfasalazine + hydroxychloroquine. Clinical characteristics measured within the next 12 weeks were used to predict LDA 1 year later using multivariable logistic regression. Validation was performed in the cohort of TEAR patients randomized to initially receive either MTX + etanercept or TT., Results: The derivation cohort yielded 3 prediction models of varying complexity that included age, DAS28 at various timepoints, body mass index, and ESR (area under the receiver-operator characteristic curve up to 0.83). Accuracy of the prediction models ranged between 80% and 95% in both derivation and validation cohorts, depending on the complexity of the model and the cutpoints chosen for response and nonresponse. About 80% of patients could be predicted to be responders or nonresponders at Week 12., Conclusion: Clinical data collected early after starting or escalating disease-modifying antirheumatic drug/biologic treatment could accurately predict LDA at 1 year in patients with early RA. For patients predicted to be nonresponders, treatment could be changed at 12 weeks to optimize outcomes.

Objective: Cigarette smoking has emerged as a risk factor for the development of rheumatoid arthritis (RA). Recent studies have suggested that cigarette smoking may lead to lower treatment response rates with methotrexate (MTX) and some biologic agents in RA. Knowledge of whether tobacco exposure reduces treatment efficacy is important, since smoking could represent a modifiable factor in optimizing RA treatment., Methods: The study participants included patients with early RA (<3 years in duration) enrolled in the Treatment of Early Aggressive Rheumatoid Arthritis study, a randomized, blinded, placebo-controlled clinical trial comparing early intensive therapy (MTX + etanercept or MTX + hydroxychloroquine + sulfasalazine triple therapy) versus initial treatment with MTX with step-up to MTX + etanercept or to triple therapy if the disease was still active at 24 weeks. Serum cotinine was measured using a commercially available enzyme-linked immunosorbent assay at baseline and at 48 weeks, with detectable concentrations at both visits serving as an indicator of smoking status. The mean Disease Activity Score in 28 joints (DAS28) was compared by smoking status, adjusting for baseline disease activity., Results: Of the 412 subjects included in the analysis, 293 (71%) were categorized as nonsmokers and 119 (29%) as current smokers. There were no differences in the mean DAS28 score between 48 and 102 weeks based on smoking status for the overall group (P = 0.881) or by specific treatment assignment., Conclusion: Among patients enrolled in a large randomized controlled trial of early RA with poor prognostic factors, smoking status did not impact treatment responses for those receiving early combination or initial MTX with step-up therapy at 24 weeks if the disease was still active., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of ≥ 3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine., Methods: The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was ≥ 3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102., Results: At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047)., Conclusion: There were no differences in the mean DAS28-ESR during weeks 48-102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy., (Copyright © 2012 by the American College of Rheumatology.)

The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia(®), UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn's disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.

The dawn of the biologic era has been an exciting period for clinical research and patient care in rheumatoid arthritis (RA). Targeted biologic therapies have changed the outcome of this disease and made remission a realistic outcome for many patients. Tocilizumab (TCZ, Actemra(®)), is a humanized monoclonal antibody against the interleukin 6 receptor and has been approved in many countries for the treatment of moderate to severe RA. There have been a number of important clinical trials demonstrating the efficacy of TCZ in active rheumatoid arthritis. This review summarizes the data on efficacy, patient-reported outcomes, adverse events, and safety from some of these trials. Current trends in clinical practice will be discussed. It is difficult to place TCZ and many new medications in the algorithm of treatment at present. However, the next few years will hopefully reveal their role as we better define abnormal immune processes in individuals with RA.

Objective: Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy., Methods: A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (triangle upDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models., Results: Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the triangle upDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99)., Conclusion: Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.

We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-alpha) inhibitors for rheumatologic disorders. Although TNF-alpha inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti-TNF-alpha drugs and herpes simplex virus encephalitis has not been previously described.

Objective: To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA)., Methods: MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1)., Results: An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively., Conclusion: Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.

Objective: To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis., Methods: Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years., Results: Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20=77.1% vs 82.7%; ACR50=53.0% vs 65.4%; ACR70=28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State=48.2% vs 58.5%; Disease Activity Score-28-defined remission=25.3% vs 45.3% at Years 1 and 5, respectively)., Conclusion: Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation., Clinical Trial Registry: ClinicalTrials.gov; clinical trial registration number: NCT00254293.

Objective: To evaluate the efficacy, radiographic changes, and safety of abatacept and methotrexate therapy through 2 years in a long-term extension of a previously published 1-year study., Methods: Patients who received placebo during year 1 were switched to abatacept. Patients taking abatacept continued to take it. Efficacy and safety were assessed through 2 years., Results: Of 539 patients enrolled in the initial 1-year study, 488 completed 1 year of the long-term extension (2% discontinued for lack of efficacy). At 2 years, patients taking abatacept had maintained their responses on the American College of Rheumatology (ACR) improvement criteria and the Disease Activity Score in 28 joints (DAS28; using the C-reactive protein [CRP] level), as well as their physical function (according to the Health Assessment Questionnaire [HAQ] disability index [DI]) and health-related quality of life (HRQOL; assessed with the Short Form 36 [SF-36] health survey), that were observed at the end of the double-blind period (year 1 versus year 2 values were 81.9% versus 80.3% for ACR 20% improvement, 25.4% versus 30.9% for a DAS28 [CRP] of <2.6, 71.8% versus 66.8% for the HAQ DI, and 9.7 versus 10.6 and 7.3 versus 7.2, respectively, for the mean change in the physical and mental components summary scores of the SF-36). In the abatacept group, post hoc analysis demonstrated further inhibition of radiographic progression during year 2 (57% reduction in mean change of total score in year 2 versus year 1; P<0.0001), and minimal radiographic progression was observed (mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2, respectively). Rates of adverse events (AEs) and severe AEs were consistent throughout the cumulative period., Conclusion: The improvements in signs and symptoms, physical function, and HRQOL observed after 1 year of abatacept treatment were maintained through 2 years of treatment. This durability was accompanied by a safety profile consistent with that in the double-blind portion of the study. Radiographic progression was further inhibited in year 2 compared with year 1, suggesting an increasing effect of abatacept on the inhibition of structural damage in year 2.

Background: The anti-folate drug methotrexate (MTX) is commonly used to treat rheumatoid arthritis., Objective: To determine the allele frequencies of five common coding single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene in African-Americans and Caucasians with rheumatoid arthritis and controls to assess whether there are differences in allele frequencies among these ethnic or racial groups and whether these SNPs differentially affect the efficacy or toxicity of MTX., Methods: Allele frequencies in the 677, 1298 and 3 additional SNPs in the MTHFR coding region in 223 (193 Caucasians and 30 African-Americans) patients with rheumatoid arthritis who previously participated in one of two prospective clinical trials were characterised, and genotypes were correlated with the efficacy and toxicity of MTX. Another 308 subjects with rheumatoid arthritis who participated in observational studies, one group predominantly Caucasian and the other African-American, as well as 103 normal controls (53 African-Americans and 50 Caucasians) were used to characterise allele frequencies of these SNPs and their associated haplotypes., Results: Significantly different allele frequencies were seen in three of the five SNPs and haplotype frequencies between Caucasians and African-Americans. Allele frequencies were similar between patients with rheumatoid arthritis and controls of the same racial or ethnic group. Frequencies of the rs4846051C, 677T and 1298C alleles were 0.33, 0.11 and 0.13, respectively, among African-Americans with rheumatoid arthritis. Among Caucasians with rheumatoid arthritis, these allele frequencies were 0.08 (p<0.001 compared with African-Americans with rheumatoid arthritis), 0.30 (p = 0.002) and 0.34 (p<0.001), respectively. There was no association between SNP alleles or haplotypes and response to MTX as measured by the mean change in the 28-joint Disease Activity Score from baseline values. In Caucasians, the 1298 A (major) allele was associated with a significant increase in MTX-related adverse events characteristic of a recessive genetic effect (odds ratio 15.86, 95% confidence interval 1.51 to 167.01; p = 0.021), confirming previous reports. There was an association between scores of MTX toxicity and the rs4846051 C allele, and haplotypes containing this allele, in African-Americans, but not in Caucasians., Conclusions: : These results, although preliminary, highlight racial or ethnic differences in frequencies of common MTHFR SNPs. The MTHFR 1298 A and the rs4846051 C alleles were associated with MTX-related adverse events in Caucasians and African-Americans, respectively, but these findings should be replicated in larger studies. The rs4846051 SNP, which is far more common in African-Americans than in Caucasians, can also be proved to be a useful ancestry informative marker in future studies on genetic admixture.

Background: The selective co-stimulation modulator abatacept demonstrated efficacy for treating rheumatoid arthritis in early clinical studies., Objective: To evaluate the effects of abatacept in patients with persistent, active rheumatoid arthritis despite methotrexate treatment., Design: One-year, multicenter, randomized, double-blind, placebo-controlled trial (November 2002 to October 2004)., Setting: 116 centers worldwide., Patients: 652 patients with active rheumatoid arthritis despite methotrexate treatment., Intervention: Once-monthly infusion of a fixed dose of abatacept, approximately 10 mg/kg of body weight, or placebo., Measurements: Co-primary end points were a 20% improvement in American College of Rheumatology (ACR) response criteria (ACR 20) at 6 months, clinically meaningful improvements in physical function, and change from baseline in joint erosion score at 1 year., Results: Four hundred thirty-three and 219 patients were randomly assigned to abatacept or placebo, respectively, and 385 (89%) and 162 (74%), respectively, completed 1 year of treatment. In a modified intention-to-treat analysis, 6-month ACR 20, ACR 50, and ACR 70 responses were 67.9% for abatacept versus 39.7% for placebo (difference, 28.2 percentage points [95% CI, 19.8 to 36.7 percentage points]), 39.9% for abatacept versus 16.8% for placebo (difference, 23.0 percentage points [CI, 15.0 to 31.1 percentage points]), and 19.8% for abatacept versus 6.5% for placebo (difference, 13.3 percentage points [CI, 7.0 to 19.5 percentage points]), respectively. At 1 year, the responses increased to 73.1% for abatacept versus 39.7% for placebo (difference, 33.4 percentage points [CI, 25.1 to 41.7 percentage points]), 48.3% for abatacept versus 18.2% for placebo (difference, 30.1 percentage points [CI, 21.8 to 38.5 percentage points]), and 28.8% for abatacept versus 6.1% for placebo (difference, 22.7 percentage points [CI, 15.6 to 29.8 percentage points]), respectively (P < 0.001 for all). Physical function significantly improved in 63.7% versus 39.3% of patients (P < 0.001). At 1 year, abatacept statistically significantly slowed the progression of structural joint damage compared with placebo. Abatacept-treated patients had a similar incidence of adverse events (87.3% vs. 84.0%; difference, 3.3 percentage points [CI, -2.5 to 9.1 percentage points]) and a higher incidence of prespecified serious infections (2.5% vs. 0.9%; difference, 1.6 percentage points [CI, -0.3 to 3.6 percentage points]) and infusion reactions (acute, 8.8% vs. 4.1%; difference, 4.7 percentage points [CI, 0.9 to 8.4 percentage points]; peri-infusional, 24.5% vs. 16.9%; difference, 7.6 percentage points [CI, 1.2 to 14.0 percentage points]) compared with placebo recipients., Limitations: The study involved only 1 group of patients over 1 year., Conclusions: Abatacept statistically significantly reduced disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate. Longer treatment in different patient populations is needed to establish its appropriate role in rheumatoid arthritis.

Objective: To evaluate safety and efficacy of longterm etanercept treatment in patients with disease modifying antirheumatic drug (DMARD) refractory rheumatoid arthritis (RA)., Methods: Safety results are reported for 714 patients who received etanercept in one of 7 initial trials or a longterm extension. Efficacy results are reported for 581 patients who enrolled in the extension., Results: Of the 714 patients enrolled in the initial trials, 581 (81%) enrolled in the extension, and 388 (54%) patients are continuing to receive etanercept therapy. The longest individual treatment was 8.2 years, with 3139 total patient-years of etanercept exposure. Rates of serious adverse events (overall rate=14.8 events/100 patient-yrs), serious infections (overall rate=4.2 events/100 patient-yrs), cancer (overall rate=1.0 events/100 patient-yrs), and deaths (overall rate=0.7 events/100 patient-yrs) were stable each year, through 8 years of etanercept exposure. For 356 patients who completed 6 years of etanercept treatment, response rates were ACR20=73%, ACR50=52%, ACR70=27%, DAS28 CRP good response=52%, and DAS28 CRP remission=37% of patients. Similar responses occurred in 167 patients who completed Year 7. Doses of concomitant methotrexate or corticosteroids were reduced in many patients who maintained clinical responses., Conclusion: The safety profile of etanercept was consistent over time, with rates of adverse events similar to those reported for patients with RA in general. Durable clinical responses were observed in some patients for 7 years or more. The benefit-to-risk ratio for longterm etanercept treatment remains highly favorable.

Objective: To assess the long-term impact of etanercept on fatigue in patients with recent-onset (mean duration 11 months) or established (mean duration 12 years) rheumatoid arthritis (RA)., Methods: Patients participating in either of 2 multicenter, randomized, double-blind clinical trials were included. In one trial, patients with recent-onset RA received either etanercept 25 mg twice weekly or methotrexate in a double-blind fashion for 12 months, then open label for 12 months. All patients then received open-label etanercept. In the second trial, patients with established RA received etanercept 25 mg or placebo twice weekly for 6 months in a double-blinded fashion, then open-label etanercept. Up to 46 months of followup data were included. Fatigue was measured regularly using the Health Assessment Questionnaire vitality domain., Results: Patients with recent-onset RA who received etanercept had a significantly faster improvement in fatigue than those receiving methotrexate in the first 2 months. Subsequently, patients receiving etanercept and methotrexate had 23-29% and 17-24% reductions in fatigue scores, respectively. In the group with established RA, patients who received etanercept had significantly greater reductions in fatigue than those receiving placebo during the blinded period. Patients initially receiving etanercept sustained a mean fatigue reduction of 25-36% for the entire followup. Patients achieving clinically meaningful improvement in fatigue were more likely to meet the American College of Rheumatology improvement criteria., Conclusion: Etanercept therapy reduces fatigue in patients with recent-onset or established RA. Improvement in fatigue was sustained for up to 46 months, and correlated with other RA-relevant outcomes.

Objective: To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha (TNF-alpha) blocker-naäve active rheumatoid arthritis (RA)., Methods: Seventy-seven patients with RA were randomized in an unequal allocation (2:1) in a blinded fashion to receive either 50 mg (51 patients) or 25 mg (26 patients) of etanercept twice a week for 24 weeks., Results: The primary outcome measure, the ACR-N AUC at 24 weeks, showed no difference between the 2 dose groups. In addition, there was no difference in ACR 20, 50, and 70 responses or in EULAR response criteria by Week 24. There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event. The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg (26% vs 4%, p = 0.027)., Conclusion: Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the standard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients.

Background: The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA)., Methods: This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0., Results: Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials., Conclusion: Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.

Purpose: Following its licensure, tuberculosis (TB) was reported as a potential adverse effect of infliximab. Subsequently, the product circular was changed to recommend tuberculin skin testing before patients received infliximab, which was reinforced by several risk communication efforts. The aim of this study was to evaluate patterns and predictors of documented tuberculin skin testing in patients before and after manufacturer, federal, and academic risk communications., Methods: Patients administered infliximab were identified from 11 health plans located throughout the United States, and claims data were examined to determine whether the patients had received a tuberculin skin test. Patients were divided into three cohorts depending on the timing of their first infliximab treatment in relation to the risk communication efforts., Results: The overall tuberculin skin testing rate doubled from 15.4% in the first cohort to 30.9% in the last cohort, while the rate of pre-infliximab treatment testing increased from 0 to 27.7% (Chi-squared test for trend, p < 0.0001 for both). Tuberculin skin testing rates were significantly higher in women, those with a diagnosis of rheumatoid or psoriatic arthritis, and those with a rheumatologist as prescriber. After multivariable analysis, only rheumatologist remained significantly associated with tuberculin skin testing., Conclusions: Although the tuberculin skin testing rate was relatively low overall, tuberculin skin testing doubled over 30 months of ongoing risk communication efforts and under ascertainment likely occurred. We also found variation in the tuberculin skin testing rate associated with physician specialty. This study demonstrates a significant change in patient care following risk communication efforts., ((c) 2005 John Wiley & Sons, Ltd.)

T cell costimulation is believed to be crucial in orchestrating immune responses that lead to inflammation and destruction in rheumatoid arthritis (RA). Abatacept is a novel recombinant CTLA4Ig fusion protein that selectively modulates costimulation via interrupting the CD28:CD80/86 pathway, resulting in downregulation of T cell activation and multiple ensuing effector mechanisms. Abatacept has been shown to be efficacious, either when given alone or in combination with methotrexate, in patients with active RA, including anti-TNF failures. Improvements in clinical signs and symptoms, slowing of radiological progression, and enhancement in patient function and pain have been reported in clinical trials. Infusions were well-tolerated with a favourable safety profile similar to placebo and no appreciable immunogenicity. Abatacept is the first in a new class of biological response modifiers called costimulatory blockers.

Objective: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered., Methods: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure., Results: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54., Conclusion: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.

Objective: To evaluate safety, efficacy, and radiographic progression in patients with early rheumatoid arthritis (RA) undergoing longterm treatment with etanercept., Methods: Patients with early RA (disease duration of 3 years or less) who had completed a 2-year efficacy study comparing etanercept and methotrexate (MTX) were followed in an extension where they received 25 mg etanercept twice weekly. Safety was summarized descriptively and compared with data from the efficacy study. Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria, disease activity scores, and Total Sharp Score (TSS)., Results: Rates of serious adverse events and serious infections did not increase with longterm exposure to etanercept, and were similar to rates reported for the blinded portion of the efficacy study. Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report (N = 201), even in those who decreased or discontinued use of MTX or corticosteroids. No radiographic progression (change in TSS < or = 0) was seen in 55% of patients with 5-year radiographs; negative change (TSS < 0) was seen in 11%., Conclusion: Etanercept treatment in patients with early RA was generally well tolerated for up to 5 years. The results indicate sustained efficacy and decreased rate of radiographic progression. The rate of radiographic progression was low compared with other studies, emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept.

Objective: To describe the methods by which remarkable levels of subject retention and adherence were achieved in a 30-month multicenter randomized placebo-controlled trial (RCT) of a disease-modifying osteoarthritis drug (DMOAD)., Methods: Subjects were obese 45-64-year-old women with unilateral knee osteoarthritis. Before randomization, each volunteer completed a 4-week "faintness-of-heart" (FOH) test, during which she was required to demonstrate reliable appointment keeping and > or =80% adherence to the dosing regimen. Subjects who passed the FOH test were randomized to treatment with doxycycline or placebo for 30 months. The double-blind phase entailed 15 bimonthly followup visits; intervisit adherence data were downloaded from the dosing monitor and used to estimate therapeutic coverage and to identify correctable patterns of nonadherence. Subjects received token incentives and a small cash payment at each followup visit. Measures to prevent or treat side effects of doxycycline were dispensed free of charge. Study coordinators monitored safety and reinforced participation through between-visit telephone calls., Results: Of 463 eligible volunteers, 32 (7%) failed the FOH test and were excluded from the double-blind phase. Among the 431 subjects randomized to treatment groups, 307 (71%) completed the 30-month RCT and 124 discontinued the study drug prematurely. Nearly half of the dropouts returned for their 16- and 30-month radiographs, resulting in loss to followup of 14.8% of randomized subjects. The 2 treatment groups did not differ significantly with respect to rates of discontinuation or retention. Therapeutic coverage over 30 months was very high in both groups., Conclusion: The rate of discontinuation in this 30-month RCT (29%) was lower than that of any DMOAD trial of > or =2 years duration published to date. The proportion of subjects for whom 30-month radiographs were available (85%) and adherence to the dosing regimen (mean >80%) also were remarkably high.

Objective: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA)., Methods: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24., Results: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%)., Conclusions: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.

Objective: To compare etanercept-induced improvement in disability of patients with recent onset of rheumatoid arthritis (RA) to that of patients with established RA., Methods: Health Assessment Questionnaire (HAQ) scores were collected over 3 years in 2 groups of patients with RA who were treated with etanercept. The first group consisted of 207 patients with recent onset RA (mean duration of 1 year) who had not previously received methotrexate, and the second group consisted of 464 patients with established RA (mean duration of 12 years) who had failed one or more disease-modifying antirheumatic drugs., Results: Baseline demographics and disease characteristics were similar in the 2 groups, except for HAQ scores and C-reactive protein levels, which were higher in the established RA group. Patients in both groups showed rapid and sustained clinical responses with etanercept therapy, but patients with recent onset RA showed significantly greater improvement in HAQ scores compared with patients with established RA. The difference in magnitude of HAQ score improvement between groups was observed as early as week 2 after initiation of etanercept and persisted throughout the 3-year time frame. At year 3, significantly more patients with recent onset RA had a HAQ score of zero (26%) versus those with established RA (14%, p = 0.0095)., Conclusion: Although etanercept therapy significantly improved disability scores in both groups, patients with recent onset of RA showed greater benefit in HAQ scores than patients with established RA. These results support prompt treatment of RA at an early stage of disease to minimize patient disability.

Three biological response modifiers that inhibit tumour necrosis factor-alpha (TNF-alpha) are approved for treating rheumatoid arthritis (RA). Etanercept is a fusion protein comprising two soluble human TNF-alpha receptors linked to the Fc fragment of human immunoglobulin G1. Infliximab is a chimeric (human/mouse) monoclonal antibody and adalimumab is a humanised monoclonal antibody. In placebo-controlled trials in established disease-modifying antirheumatic drug (DMARD)-refractory RA, the anti-TNF-alpha agents have reduced disease activity, as monotherapy or in combination with methotrexate. In long-term, open-label studies with etanercept or adalimumab, clinical response was sustained for up to 5 years. In early RA, etanercept has similar efficacy to methotrexate. However, etanercept was more effective than methotrexate in preventing radiographic progression. Preventing or delaying disease progression and disability with etanercept therapy in early RA may reduce costs associated with long-term disease outcomes. Data also suggest a benefit of infliximab plus methotrexate or adalimumab plus methotrexate in early RA. All three agents have been shown to improve functionality as assessed by health assessment questionnaire (HAQ) disability scores. Health-related quality of life is also improved in terms of physical and mental health and vitality. Furthermore, etanercept and adalimumab are associated with a reduction in fatigue. Long-term etanercept or infliximab therapy is associated with increased job employment and etanercept also reduces healthcare utilisation. Mild, transient injection-site reactions occur in about 33% of patients treated with etanercept and 20% of patients treated with adalimumab. In patients treated with infliximab, 16-20% have infusion reactions. The incidence of serious infection associated with etanercept and infliximab was low, about 2-3% in etanercept studies of up to 5 years duration, and 5% in a survey of more than 10 infliximab trials. This paper reviews the evidence for efficacy, safety and effectiveness of anti-TNF-alpha agents in RA.

Background: Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX., Objective: This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy., Methods: This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg i.v. or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg i.v. or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve., Results: Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24-73 years), and the mean body weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events., Conclusions: Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX (P < or = 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumab's long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

Objective: Approximately 3% of the US population over the age of 65 years has rheumatoid arthritis (RA). We compared the safety and efficacy of etanercept (Enbrel) in patients with RA who were > or = 65 years to those < 65 years in open-label and double-blind, randomized clinical trials., Methods: Patients from 4 double-blind, randomized controlled trials and 5 open-label trials were included in this retrospective analysis. Patients were grouped by age (< 65 or > or = 65 yrs) at time of study entry. All patients received etanercept subcutaneously twice weekly. Improvement in signs and symptoms was assessed by the proportion of patients who achieved the American College of Rheumatology definition of improvement (ACR 20). The ACR 50 and ACR 70 responses were calculated in an analogous fashion. Safety was assessed at regularly scheduled visits., Results: Of 1128 patients enrolled in etanercept trials, 197 (17%) were > or = 65 years of age. Clinical response was rapid and sustained and did not differ between age groups. At one year, 69% of patients < 65 years and 66% of patients > or = 65 years met the ACR 20. Forty percent of the patients > or = 65 years met the ACR 50 and 17% met the ACR 70. Etanercept was well tolerated. Although injection site reactions, headache, and rhinitis occurred somewhat more frequently in younger patients, the overall rates and types of other adverse events were comparable in both groups., Conclusion: Etanercept is a new treatment option for older patients with RA and has substantial benefit and comparable safety regardless of patient age.

Objective: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX., Methods: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks., Results: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events., Conclusion: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.