Treatment outcomes in patients with seropositive versus seronegative rheumatoid arthritis in Phase III randomised clinical trials of tofacitinib.
ABSTRACT: Objectives:Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA. Methods:Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). 'Serotype' subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared. Results:Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups. Conclusion:Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients.
Project description:OBJECTIVE:Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post hoc analysis explored the relationship between early disease activity changes and the achievement of low disease activity (LDA) and remission targets with tofacitinib. METHODS:Data were from 2 randomized, double-blind, phase III studies. In the ORAL Start trial, methotrexate (MTX)-naive patients received tofacitinib 5 or 10 mg twice daily, or MTX, for 24 months. In the placebo-controlled ORAL Standard trial, MTX inadequate responder patients received tofacitinib 5 or 10 mg twice daily or adalimumab 40 mg every 2 weeks, with MTX, for 12 months. Probabilities of achieving LDA (using a Clinical Disease Activity Index [CDAI] score ?10 or the 4-component Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] ?3.2) at months 6 and 12 were calculated, given failure to achieve threshold improvement from baseline (change in CDAI ?6 or DAS28-ESR ?1.2) at month 1 or 3. RESULTS:In ORAL Start, 7.2% and 5.4% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to show improvement in the CDAI ?6 at month 3; of those who failed, 3.8% and 28.6%, respectively, achieved month 6 CDAI-defined LDA. In ORAL Standard, 18.8% and 17.5% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to improve CDAI ?6 at month 3; of those who failed, 0% and 2.9%, respectively, achieved month 6 CDAI-defined LDA. Findings were similar when considering improvements at month 1 or DAS28-ESR thresholds. CONCLUSION:In patients with an inadequate response to MTX, lack of response to tofacitinib after 1 or 3 months predicted a low probability of achieving LDA at month 6. Lack of an early response may be considered when deciding whether to continue treatment with tofacitinib.
Project description:This 28-week, phase IIIb study assessed safety and maintenance of response to certolizumab pegol (CZP) in a diverse population of rheumatoid arthritis (RA) patients, stratified by prior anti-TNF exposure, concomitant methotrexate (MTX) use and disease duration. The ability to predict achievement of low disease activity (LDA) at week 28 from improvements in Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), swollen joint count (SJC) and Clinical Disease Activity Index (CDAI) up to week 12 was assessed.The 28-week study population included all patients who completed the double-blind (DB) phase and entered the open-label (OL) phase, receiving 200 mg CZP every 2 weeks (Q2W) ?16 weeks. In the 12-week DB period, patients with active RA and an inadequate response to ?1 disease-modifying antirheumatic drug (DMARD) were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4 then 200 mg Q2W) or placebo (Q2W), stratified by prior anti-TNF use, concomitant use of MTX and disease duration (<2 years vs. ?2 years).A total of 955 patients entered the OL phase. At week 28, similar clinical improvements were seen in those receiving CZP throughout (CZP???CZP; n?=?771) and those receiving placebo during the DB phase and switching to CZP in the OL phase (placebo???CZP; n?=?184) (ACR20 response rate?=?59.7% vs. 53.3%; ACR50/ACR70 response rates were also similar). Effect of CZP treatment was similar regardless of prior anti-TNF use, disease duration and concomitant DMARDs, based on ACR20 response rates. The percentage of patients achieving DAS28(ESR) LDA at week 28 was calculated for DAS28(ESR), SJC or CDAI responders at earlier time points. Reductions from baseline (?) of DAS28(ESR) <1.2, ?SJC <25% or ?CDAI <10 by week 12 were associated with <9% chance of achieving LDA at week 28 regardless of prior anti-TNF exposure. Adverse event rates were similar for placebo???CZP and CZP???CZP patients, with no new safety signals identified.A diverse population of RA patients with varying disease duration showed rapid and sustained clinical improvements on CZP treatment, regardless of prior anti-TNF or concomitant DMARD use. Failure to achieve improvements in DAS28(ESR), SJC or CDAI within the first 12 weeks of CZP therapy was associated with a low chance of achieving LDA at week 28. No new safety signals were observed.ClinicalTrials.gov, NCT00717236 , 15 July 2008.
Project description:Antibodies to citrullinated proteins have been described in patients with rheumatoid arthritis (RA) and these appear to be the most specific markers of the disease. Our objective was to determine the frequency of antibodies to cyclic citrullinated peptides (CCPs) in patients with RA and the association of anti-CCP antibodies with disease activity, radiological erosions and HLA DR genotype. Forty patients with RA and 38 patients with fibromyalgia were included in this study. Serum samples were collected from both patient groups with RA and fibromyalgia. Anti-CCP was measured by the corresponding enzyme-linked immunosorbent assay. Additionally, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score (DAS), visual analog scala (VAS), HLA genotype and radiographic information were determined in patients with RA. The rate of sensitivity and specificity of anti-CCP reactivity for the diagnosis RA were measured (sensitivity 50%, specificity 100%). There is no significant difference between anti-CCP (+) and anti-CCP (-) RA patients for DAS28, VAS, ESR, CRP, disease duration, HLA genotype, and radiological assessment of hand. However, there was a significant difference between anti-CCP (+) and anti-CCP (-) RA patients for RF and the radiological assessment of left and right wrists (respectively, P < 0.05, P = 0.04, P = 0.01). There was no significant correlation between anti-CCP antibody and ESR, CRP, VAS, DAS 28 or radiological assessment. A small but significant correlation was found between RF and anti-CCP antibody (P = 0.02, r = 0.35).
Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (?12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (?17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.
Project description:Background:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods:ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ?1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results:ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions:Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier:NCT00856544 and NCT00413699.
Project description:OBJECTIVES: This meta-analysis was conducted to investigate whether the status of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody are associated with the clinical response to anti-tumor necrosis factor (TNF) alpha treatment in rheumatoid arthritis (RA). METHODS: A systemic literature review was performed using the MEDLINE, SCOPUS, Cochrane Library, ISI Web of Knowledge, and Clinical Trials Register databases, and Hayden's criteria of quality assessment for prognostic studies were used to evaluate all of the studies. The correlation between the RF and anti-CCP antibody status with the treatment effect of anti-TNF? agents was analyzed separately using the Mantel Haenszel method. A fixed-effects model was used when there was no significant heterogeneity; otherwise, a random-effects model was applied. Publication bias was assessed using Egger's linear regression and a funnel plot. RESULTS: A total of 14 studies involving 5561 RA patients meeting the inclusion criteria were included. The overall analysis showed that the pooled relative risk for the predictive effects of the RF and anti-CCP antibody status on patient response to anti-TNF? agents was 0.98 (95% CI: 0.91-1.05, p=0.54) and 0.88 (95% CI: 0.76-1.03, p=0.11), respectively, with I(2) values of 43% (p=0.05) and 67% (p<0.01), respectively. Subgroup analyses of different anti-TNF? treatments (infliximab vs. etanercept vs. adalimumab vs. golimumab), response criteria (DAS28 vs. ACR20 vs. EULAR response), follow-up period (? 6 vs. <6 months), and ethnic group did not reveal a significant association for the status of RF and anti-CCP. CONCLUSIONS: Neither the RF nor anti-CCP antibody status in RA patients is associated with a clinical response to anti-TNF? treatment.
Project description:Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes.UMIN CTR UMIN000012200.
Project description:OBJECTIVE:To explore relationships between immunological status, clinical features, radiographic damage, disease activity, and functional disability in Tunisian patients with rheumatoid arthritis (RA). MATERIALS AND METHODS:The study was carried out in 112 patients with RA. Demographic characteristics, disease duration, disease activity score 28 (DAS28), the Health Assessment Questionnaire (HAQ), and the Sharp/van der Heijde score were collected. Anticyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) were performed. RESULTS:We found that anti-CCP positivity was associated with longer disease duration (P = 0.001), presence of RF (P = 4.89 × 10(-8) ), and night pain positivity (P = 0.025). Patients with positive RF had more night pain and higher anti-CCP positivity (for all P ? 0.05). Anti-CCP titer was correlated with disease duration (P = 0.034) and Sharp total score (P = 1.2 × 10(-4) ). Moreover, there was a significant correlation between RF and anti-CCP antibodies titers (P = 0.011). Indeed, DAS28 correlated with HAQ (P = 1.8 × 10(-7) ) and morning stiffness duration (P = 0.045). In multivariate regression analysis, the main factors associated with anti-CCP titers were radiographic damage (P = 1.625 × 10(-4) ) and RF (P = 0.013). For DAS28, only HAQ (P = 2.9 × 10(-4) ) was associated. CONCLUSION:These findings suggest that anti-CCP antibodies are associated with RF and more severe joint damage. Moreover, disease activity is associated with functional disability.
Project description:OBJECTIVES:To investigate the frequency and predictors of sustained 28-joint DAS (DAS28) remission and low disease activity (LDA) in patients receiving anti-TNF therapy and changes in responses over a 12 year period. METHODS:Data from the British Society for Rheumatology Biologics Registry for Rheumatoid Arthritis were used. Sustained remission and LDA were defined according to DAS28-ESR thresholds sustained for 6 months. The dataset was dichotomized into sequential chronological subgroups (2001-2010 and 2010-2013). Predictive variables were identified from a previous systematic review and modelled using multivariable logistic regression. RESULTS:Overall, 2144 (14.9%) and 3802 (26.3%) patients achieved sustained remission or LDA, respectively. Positive predictors of sustained remission/LDA included adalimumab (vs etanercept), greater patient global assessment, never- and ex-smoker status (vs current smoking), greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription (except in the 2010-2013 subgroup). Negative predictors of sustained remission and LDA included poor baseline functional status (HAQ), female gender, older age at starting anti-TNF, infliximab use (vs etanercept), increasing BMI and greater baseline ESR. Increasing tender joint count was negatively associated with sustained LDA only. The overall proportion of patients achieving sustained remission and LDA has increased significantly over time. CONCLUSION:Sustained remission/LDA on anti-TNF treatment remains uncommon. Adalimumab use, greater patient global assessment, never- and ex-smoker status, greater swollen joint count, more recent commencement of anti-TNF and MTX co-prescription are associated with achievement of sustained remission/LDA. However, co-prescription of MTX was not associated with an increased likelihood of achieving sustained remission or LDA in the analysis of more recent anti-TNF responses.
Project description:Tofacitinib is an oral JAK inhibitor that is used for the treatment of rheumatoid arthritis (RA). In previous clinical trials of tofacitinib, a Disease Activity Score in 28 joints (DAS28)-based analysis was used to assess outcomes. In this study, remission rates according to various remission criteria were evaluated across 5 phase III randomized controlled studies.In all 5 studies, tofacitinib was administered at a dosage of 5 mg twice daily or 10 mg twice daily, either as monotherapy or with background methotrexate or other conventional synthetic disease-modifying antirheumatic drugs. One of the studies included adalimumab 40 mg once every 2 weeks. In addition to the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]), a primary efficacy variable used in the phase III studies, disease activity was assessed post hoc by the 4-variable DAS28 using the C-reactive protein level (DAS28-4[CRP]), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), and Boolean-based assessment.A total of 3,306 patients were analyzed (1,213 of these patients received tofacitinib 5 mg twice daily, 1,212 received tofacitinib 10 mg twice daily, 679 received placebo, and 202 received adalimumab 40 mg every 2 weeks). Remission rates varied according to the criteria used, with higher rates in the active-treatment groups for the DAS28-4(CRP) than for other scores. At month 3, remission rates with tofacitinib 5 mg twice daily were 18-22% using the DAS28-4(CRP), 5-10% using the DAS28-4(ESR), 4-7% using the SDAI, 5-6% using the CDAI, and 2-7% using the Boolean-based method. In contrast, the remission rates with placebo varied from 0% to 7%, with small differences between the DAS28-4(ESR) and the DAS28-4(CRP).Although tofacitinib at dosages of 5 mg twice daily and 10 mg twice daily was effective compared with placebo in achieving disease remission, regardless of the disease activity measure, remission rates were substantially higher when the DAS28-4(CRP) was used. The presence or absence and type of acute-phase reactants in remission criteria were significant contributors to remission rates across treatment groups. This finding has important consequences for trial design and clinical practice.