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Paul Emery - One of the best experts on this subject based on the ideXlab platform.

  • a head to head comparison of the efficacy and safety of ixekizumab and adalimumab in biological naive patients with active psoriatic arthritis 24 week results of a randomised open label blinded assessor trial
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Philip J. Mease, Josef S Smolen, F Behrens, Peter Nash, Soyi Liu Leage, Hasan Tahir, Melinda Gooderham, Eswar Krishnan, Hong Liuseifert, Paul Emery
    Abstract:

    Objectives To compare efficacy and safety of ixekizumab (IXE) to adalimumab (ADA) in biological Disease-Modifying Antirheumatic Drug-naive patients with both active psoriatic arthritis (PsA) and skin disease and inadequate response to conventional synthetic Disease-Modifying Antirheumatic Drug (csDMARDs). Methods Patients with active PsA were randomised (1:1) to approved dosing of IXE or ADA in an open-label, head-to-head, blinded assessor clinical trial. The primary objective was to evaluate whether IXE was superior to ADA at week 24 for simultaneous achievement of a ≥50% improvement from baseline in the American College of Rheumatology criteria (ACR50) and a 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI100). Major secondary objectives, also at week 24, were to evaluate whether IXE was: (1) non-inferior to ADA for achievement of ACR50 and (2) superior to ADA for PASI100 response. Additional PsA, skin, treat-to-target and quality-of-life outcome measures were assessed at week 24. Results The primary efficacy endpoint was met (IXE: 36%, ADA: 28%; p=0.036). IXE was non-inferior for ACR50 response (IXE: 51%, ADA: 47%; treatment difference: 3.9%) and superior for PASI100 response (IXE: 60%, ADA: 47%; p=0.001). IXE had greater response versus ADA in additional PsA, skin, nail, treat-to-target and quality-of-life outcomes. Serious adverse events were reported in 8.5% (ADA) and 3.5% (IXE) of patients. Conclusions IXE was superior to ADA in achievement of simultaneous improvement of joint and skin disease (ACR50 and PASI100) in patients with PsA and inadequate response to csDMARDs. Safety and tolerability for both biologicals were aligned with established safety profiles.

  • Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis.
    RMD Open, 2019
    Co-Authors: Désirée Van Der Heijde, Yoshiya Tanaka, Michael Schiff, R Ortmann, L. Xie, Gabriella Meszaros, Taeko Ishii, Marta Casillas, Paul Emery
    Abstract:

    Objectives To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were Disease-Modifying Antirheumatic Drug (DMARD)–naive or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Methods Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same baricitinib dose as at originating study completion. At 52 weeks, DMARD-naive patients receiving methotrexate (MTX) or combination therapy (baricitinib 4 mg+MTX) were switched to baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to baricitinib 4 mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo were switched to baricitinib 4 mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified Total Sharp Score. Linear extrapolation was used for missing data. Results Of 2573 randomised patients, 2125 (82.6%) entered the LTE, of whom 1893 (89.1%) entered this analysis. At year 2, progression was significantly lower with initial baricitinib (monotherapy or combination therapy) versus initial MTX in DMARD-naive patients (proportion with non-progression defined by ≤smallest detectable change (SDC): 87.3% baricitinib 4 mg+MTX; 70.6% MTX; p≤ 0.001). In MTX-IR patients, progression with initial baricitinib was significantly lower than with initial placebo and similar to initial adalimumab (≤SDC: 82.7% baricitinib 4 mg; 83.5% adalimumab; 70.6% placebo; p≤0.001). In csDMARD-IR patients, significant benefit was seen with baricitinib 4 mg (≤SDC: 87.2% vs 73.2% placebo; p≤0.01). Conclusions Treatment with once-daily baricitinib resulted in low rates of radiographic progression for up to 2 years.

  • biologic and oral disease modifying Antirheumatic Drug monotherapy in rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2013
    Co-Authors: Paul Emery, Anthony Sebba, Tom W J Huizinga
    Abstract:

    Clinical evidence demonstrates coadministration of tumour necrosis factor inhibitor (TNFi) agents and methotrexate (MTX) is more efficacious than administration of TNFi agents alone in patients with rheumatoid arthritis, leading to the perception that coadministration of MTX with all biologic agents or oral Disease-Modifying Antirheumatic Drugs is necessary for maximum efficacy. Real-life registry data reveal approximately one-third of patients taking biologic agents use them as monotherapy. Additionally, an analysis of healthcare claims data showed that when MTX was prescribed in conjunction with a biologic agent, as many as 58% of patients did not collect the MTX prescription. Given this discrepancy between perception and real life, we conducted a review of the peer-reviewed literature and rheumatology medical congress abstracts to determine whether data support biologic monotherapy as a treatment option for patients with rheumatoid arthritis. Our analysis suggests only for tocilizumab is there evidence that the efficacy of biologic monotherapy is comparable with combination therapy with MTX.

  • relationship between early bone mineral density changes and long term function and radiographic progression in rheumatoid arthritis
    Arthritis Care and Research, 2012
    Co-Authors: Victoria Bejarano, Paul Emery, Andrew K Brown, Elizabeth M A Hensor, Maya H Buch, Michael J Green, Glenn Haugeberg, Philip G Conaghan
    Abstract:

    Objective To ascertain whether bone mineral density loss during the first year of treatment for early rheumatoid arthritis (RA) as assessed by dual x-ray absorptiometry (DXA) is associated with long-term function, quality of life, and radiographic progression. Methods Early RA patients, prior to commencing Disease-Modifying Antirheumatic Drug therapy, underwent evaluation with DXA scans of both hands, femoral neck, and lumbar spine at the time of diagnosis, then at 1 year and final followup at >6 years. Clinical and laboratory data and hands and feet radiographs were obtained at baseline and final followup. Results Sixty-four patients were assessed. At baseline, median disease duration was 6 months, mean 28-joint Disease Activity Score was 5.85, and median Health Assessment Questionnaire score was 1.38. Median followup was 6.4 years (range 5.1–7.2 years). For erosion scores, 86% of patients with hand bone density loss above the smallest detectable change after 1 year progressed versus 55% of those with no hand bone density loss (P = 0.006). However, baseline radiographs showed a similar strength of association. Eighty-four percent of patients with erosions at baseline had erosion progression versus 57% of those with no baseline erosions (P = 0.021). Additionally, first-year bone density loss was not associated with function and quality of life status at followup. Conclusion Hand bone loss during the first year of treatment in early RA, as assessed with DXA, was associated with a high likelihood of radiographic progression; however, in the current study this was not superior to baseline radiographs. Furthermore, it was not associated with patient-reported outcomes.

  • presence of significant synovitis in rheumatoid arthritis patients with disease modifying Antirheumatic Drug induced clinical remission evidence from an imaging study may explain structural progression
    Arthritis & Rheumatism, 2006
    Co-Authors: Andrew K Brown, Mark A Quinn, Zunaid Karim, Philip G Conaghan, Charles Peterfy, Elizabeth M A Hensor, Richard J Wakefield, Philip Oconnor, Paul Emery
    Abstract:

    Objective More timely and effective therapy for rheumatoid arthritis (RA) has contributed to increasing rates of clinical remission. However, progression of structural damage may still occur in patients who have satisfied remission criteria, which suggests that there is ongoing disease activity. This questions the validity of current methods of assessing remission in RA. The purpose of this study was to test the hypothesis that modern joint imaging improves the accuracy of remission measurement in RA. Methods We studied 107 RA patients receiving Disease-Modifying Antirheumatic Drug therapy who were judged by their consultant rheumatologist to be in remission and 17 normal control subjects. Patients underwent clinical, laboratory, functional, and quality of life assessments. The Disease Activity Score 28-joint assessment and the American College of Rheumatology remission criteria, together with strict clinical definitions of remission, were applied. Imaging of the hands and wrists using standardized acquisition and scoring techniques with conventional 1.5T magnetic resonance imaging (MRI) and ultrasonography (US) were performed. Results Irrespective of which clinical criteria were applied to determine remission, the majority of patients continued to have evidence of active inflammation, as shown by findings on the imaging assessments. Even in asymptomatic patients with clinically normal joints, MRI showed that 96% had synovitis and 46% had bone marrow edema, and US showed that 73% had gray-scale synovial hypertrophy and 43% had increased power Doppler signal. Only mild synovial thickening was seen in 3 of the control subjects (18%), but no bone marrow edema. Conclusion Most RA patients who satisfied the remission criteria with normal findings on clinical and laboratory studies had imaging-detected synovitis. This subclinical inflammation may explain the observed discrepancy between disease activity and outcome in RA. Imaging assessment may be necessary for the accurate evaluation of disease status and, in particular, for the definition of true remission.

Joel M Kremer - One of the best experts on this subject based on the ideXlab platform.

  • immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis
    PLOS ONE, 2019
    Co-Authors: Siri Lillegraven, Joel M Kremer, Jeffrey D Greenberg, Jeffrey R Curtis, Marc C Hochberg, George W Reed, Katherine C Saunders, Leslie R Harrold, Dimitrios A Pappas, Daniel H Solomon
    Abstract:

    Objective Inflammation and anti-inflammatory treatments might influence the risk of diabetes. The objective of this study was to assess factors associated with incident diabetes in rheumatoid arthritis (RA). Methods The study population consisted of RA patients from a multi-center cohort study, Corrona. To assess risk associated with disease modifying Antirheumatic Drug (DMARD) exposure, we assessed five mutually exclusive DMARD groups. Additionally, we assessed the risk associated with body mass index (BMI, 30 kg/m2) and glucocorticoid usage. Incident cases of diabetes were confirmed through adjudication, and Cox regression models were fit to estimate the risk of incident diabetes. Results We identified 21,775 DMARD treatment regimens, the mean (SD) age at the index visit was 58 (13) years, disease duration 10 (10) years, and 30% used oral glucocorticoids at the time. Eighty-four incident cases of diabetes were confirmed within the treatment exposure periods. The hazard ratio (HR, 95% confidence interval) for diabetes was significantly reduced in patients receiving TNF inhibitors, HR 0.35 (0.13, 0.91), compared to patients treated with non-biologic DMARDs other than hydroxychloroquine and methotrexate. Hydroxychloroquine, methotrexate and use of other biologic DMARDs had a numerically reduced risk compared to the same group. Patients prescribed ≥7.5 mg of glucocorticoids had a HR of 2.33 (1.68, 3.22) of incident diabetes compared with patients not prescribed oral glucocorticoids. RA patients with a BMI >30 had a HR of 6.27 (2.97, 13.25) compared to patients with BMI ≤25. Conclusion DMARDs, glucocorticoids and obesity influenced the risk of incident diabetes in a large cohort of RA patients. Monitoring for the occurrence of diabetes should be part of routine RA management with a focus on specific subgroups.

  • a randomised phase iib study of mavrilimumab a novel gm csf receptor alpha monoclonal antibody in the treatment of rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Gerd R Burmester, Joel M Kremer, Iain B Mcinnes, Pedro Miranda, Mariusz Korkosz, Jiri Vencovsky, Andrea Rubbertroth, Eduardo Mysler, Matthew A Sleeman, A Godwood
    Abstract:

    Objectives Despite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte–macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA. Methods In a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic Disease-Modifying Antirheumatic Drug(s), Disease Activity Score 28 (DAS28)−C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28−CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24). Results 326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012–June 2013). Mavrilimumab treatment significantly reduced DAS28−CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: −1.90 (0.14), 100 mg: −1.64 (0.13), 30 mg: −1.37 (0.14), placebo: −0.68 (0.14); p Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p Conclusions Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential. Trial registration number NCT01706926; results.

  • tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis
    Annals of the Rheumatic Diseases, 2011
    Co-Authors: Jeffrey D Greenberg, Joel M Kremer, Jeffrey R Curtis, Marc C Hochberg, George W Reed, Peter Tsao, Adeel Nasir, Soko Setoguchi
    Abstract:

    Objective To examine the association of cardiovascular events with tumour necrosis factor (TNF) α antagonist use compared with non-biological Disease-Modifying Antirheumatic Drug (DMARD) utilisation in patients with rheumatoid arthritis (RA). Methods The study population included 10 156 patients enrolled in the Consortium of Rheumatology Researchers of North America RA registry. Three study cohorts were defi ned based on three mutually exclusive Drug use categories, including TNF antagonists, methotrexate and other non-biological DMARDs. HR were calculated adjusting for cardiovascular risk factors, RA disease characteristics and prednisone use. The primary study outcome was a composite of non-fatal myocardial infarction (MI), transient ischaemic attack (TIA) or stroke and cardiovascular-related death. Results There were 88 cardiovascular events, including 26 MI, 45 TIA/strokes and 17 cardiovascular-related deaths. After adjusting for age, gender, cardiovascular risk factors and RA disease characteristics, patients using a TNF antagonist experienced a reduced risk of the primary composite cardiovascular endpoint (HR 0.39, 95% CI 0.19 to 0.82) compared with users of nonbiological DMARDs. Methotrexate was not associated with a reduced risk (HR 0.94, 95% CI 0.49 to 1.80). Prednisone use was associated with a dose-dependent increased risk (p=0.04). The risk reduction associated with TNF antagonists was also observed for non-fatal cardiovascular events (HR 0.35, 95% CI 0.16 to 0.74). Conclusion TNF antagonist use was associated with a reduced risk of cardiovascular events in patients with RA.

  • etanercept treatment in adults with established rheumatoid arthritis 7 years of clinical experience
    The Journal of Rheumatology, 2006
    Co-Authors: Linley W Moreland, Joel M Kremer, Michael E Weinblatt, Edward C. Keystone, Michael Schiff, James Boyd Whitmore, Richard W Martin, Barbara White
    Abstract:

    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.

  • starting a disease modifying Antirheumatic Drug or a biologic agent in rheumatoid arthritis standards of practice for ra treatment
    The Journal of Rheumatology, 2001
    Co-Authors: Frederick Wolfe, Qaiser Rehman, Nancy E Lane, Joel M Kremer
    Abstract:

    Our aim was to investigate the practices and standards by which disease modifying Antirheumatic Drugs (DMARD) and biologics are and have been prescribed. We reviewed the literature and examined data from patients with rheumatoid arthritis (RA) participating in a national cohort: the National Data Bank for Rheumatic Diseases (NDB). Four pathways for DMARD prescription were identified: (1) A time-based pyramidal approach (the RA pyramid); (2) a severity-based pyramid in which the most effective treatment is given to those with more active disease; (3) a cost-based pathway in which the primary goal is cost containment--this pathway intertwines with the severity-based pathway; and (4) a patient preference pathway where treatment is geared to patient needs and wishes regardless of severity. Data show that the time-based and severity-based pathways are not generally used in contemporary expert practice, and that patients with all degrees of severity and disease duration are receiving DMARD and biologic treatment. With the abandonment of the pyramid and the development of effective therapy, rheumatic disease care has swung away from the imperative of time and severity-based treatment to the imperative of care based on patient preference. It is the standard of practice to treat patients with mild and early disease with aggressive therapy, with the goal of limiting subsequent damage and retarding progression, and with the realistic purpose of relieving symptoms. The standard may at times be in conflict with the goals of insurers, but there is no legitimate medical reason for such limitations.

Deborah P M Symmons - One of the best experts on this subject based on the ideXlab platform.

  • risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti tnf therapy results from the british society for rheumatology biologics register
    Annals of the Rheumatic Diseases, 2011
    Co-Authors: James Galloway, Kimme L Hyrich, Kath D Watson, Mark Lunt, Louise K Mercer, William G Dixon, Andrew Ustianowski, M Helbert, Deborah P M Symmons
    Abstract:

    OBJECTIVES: To evaluate the risk of septic arthritis (SA) in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. METHODS: Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, the authors compared the risk of SA between 11 881 anti-TNF-treated and 3673 non-biological Disease-Modifying Antirheumatic Drug (nbDMARD)-treated patients. RESULTS: 199 patients had at least one episode of SA (anti-TNF: 179, nbDMARD: 20). Incidence rates were: anti-TNF 4.2/1000 patient years (pyrs) follow-up (95% CI 3.6 to 4.8), nbDMARD 1.8/1000 pyrs (95% CI 1.1 to 2.7). The adjusted HR for SA in the anti-TNF cohort was 2.3 (95% CI 1.2 to 4.4). The risk did not differ significantly between the three agents: adalimumab, etanercept and infliximab. The risk was highest in the early months of therapy. The patterns of reported organisms differed in the anti-TNF cohort. Prior joint replacement surgery was a risk factor for SA in all patients. The rate of postoperative joint infection (within 90 days of surgery) was 0.7%. This risk was not significantly influenced by anti-TNF therapy. CONCLUSIONS: Anti-TNF therapy use in RA is associated with a doubling in the risk of SA. Physicians and surgeons assessing the RA patient should be aware of this potentially life-threatening complication.

  • early treatment with and time receiving first disease modifying Antirheumatic Drug predicts long term function in patients with inflammatory polyarthritis
    Annals of the Rheumatic Diseases, 2010
    Co-Authors: Tracey M Farragher, Mark Lunt, Diane Bunn, Deborah P M Symmons
    Abstract:

    Objectives To investigate the infl uence of early diseasemodifying Antirheumatic Drug (DMARD) treatment on long-term functional outcome in patients with recentonset infl ammatory polyarthritis (IP), and the impact of the duration of fiand subsequent DMARD treatment. Methods 642 subjects from a primary care registry of patients with new-onset IP, recruited 1990–4, were followed up for 10 years. Mean change in Health Assessment Questionnaire (HAQ) scores between baseline and 10 years were compared by time to, and time receiving, fi rst DMARD treatment and total time receiving treatment, using linear regression. Adjustment for time-dependent confounders and censoring was performed using marginal structural weights. Results When adjusted for baseline and subsequent disease severity, those treated early ( 3 years experienced an improvement (adj_MDIC in HAQ –0.37; 95% CI –0.77 to 0.04). Conclusions The importance of time to, and response to, fi rst DMARD treatment and total duration of DMARD treatment in modifying the 10-year function in patients with IP has been demonstrated.

  • comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease modifying Antirheumatic Drug in patients with rheumatoid arthritis results from the british society for rheumatolog
    Arthritis & Rheumatism, 2006
    Co-Authors: Kimme L Hyrich, Deborah P M Symmons, Kath D Watson, A J Silman
    Abstract:

    OBJECTIVE: To compare outcome at 6 months in unselected "real-world" patients with rheumatoid arthritis treated with etanercept or infliximab as either monotherapy, cotherapy with methotrexate (MTX), or cotherapy with another Disease-Modifying Antirheumatic Drug (DMARD). METHODS: A total of 2,711 subjects starting treatment with their first biologic agent (1,453 infliximab and 1,258 etanercept) were followed up for 6 months. Outcome was assessed using the European League Against Rheumatism (EULAR) response criteria. Ordinal regression was used to model the response in the MTX and other DMARD cotherapy groups relative to the monotherapy group separately for the 2 anti-tumor necrosis factor alpha agents, after adjusting for baseline differences. RESULTS: Etanercept-treated patients had an increased likelihood of achieving a higher EULAR response category with cotherapy with MTX (odds ratio [OR] 2.0, 95% confidence interval [95% CI] 1.5-2.7) and with another DMARD (OR 1.2, 95% CI 0.9-1.6) as compared with monotherapy. For infliximab-treated patients, the likelihoods were 1.4 (95% CI 0.9-2.0) for MTX and 1.3 (95% CI 0.8-2.1) for other DMARDs versus monotherapy. Cotherapy with MTX or another DMARD produced significantly higher rates of remission with etanercept (12% and 11%, respectively) as compared with etanercept monotherapy (5%). Infliximab-treated patients showed similar remission rates in the MTX and other DMARD cotherapy groups (8% and 5%, respectively) as in the monotherapy group (7%). CONCLUSION: In this study of real-world patients, the use of MTX and, to a lesser extent, other DMARDs as cotherapy with etanercept was associated with a higher likelihood of response. Although the infliximab guidelines suggest that MTX be used as cotherapy, in clinical practice, both monotherapy and cotherapy with DMARDs other than MTX are used. These data suggest that either of the latter strategies may be useful in patients who are intolerant to MTX.

Tsutomu Takeuchi - One of the best experts on this subject based on the ideXlab platform.

  • effects of the anti rankl antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease modifying Antirheumatic Drugs desirable study a randomised double blind placebo controlled phase
    Annals of the Rheumatic Diseases, 2019
    Co-Authors: Tsutomu Takeuchi, Yoshiya Tanaka, Satoshi Soen, Hisashi Yamanaka, Toshiyuki Yoneda, Sakae Tanaka, Takaya Nitta, Naoki Okubo, Harry K Genant, Désirée Van Der Heijde
    Abstract:

    Objective To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic Disease-Modifying Antirheumatic Drug (csDMARD) therapy in patients with rheumatoid arthritis (RA). Methods This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated. Results In total, 654 patients received the trial Drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1–L4) BMD in the placebo, Q6M and Q3M groups were −1.03%, 3.99% (p Conclusions Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

  • Patient-reported outcomes of baricitinib in patients with rheumatoid arthritis and no or limited prior Disease-Modifying Antirheumatic Drug treatment
    Arthritis Research & Therapy, 2017
    Co-Authors: Michael Schiff, Tsutomu Takeuchi, Carol L. Gaich, Roy Fleischmann, Douglas E Schlichting, Amy M. Delozier, Wen Ling Kuo, Ji Eon Won, Tara Carmack, Terence Rooney
    Abstract:

    This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic Disease-Modifying Antirheumatic Drugs (DMARDs) and naive to biological DMARDs. Patients were randomized 4:3:4 to MTX administered once weekly (N = 210), baricitinib monotherapy (4 mg once daily (QD), N = 159), or combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX, N = 215). PROs included the Patient’s Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models. Compared to MTX, patients in both baricitinib groups reported greater improvement (p ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements (p ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p ≤ 0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib + MTX at week 52. In this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures. ClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.

  • effectiveness and safety of tocilizumab in achieving clinical and functional remission and sustaining efficacy in biologics naive patients with rheumatoid arthritis the first bio study
    Modern Rheumatology, 2017
    Co-Authors: Naoki Ishiguro, Yoshiya Tanaka, Tsutomu Takeuchi, Tatsuya Atsumi, Masayoshi Harigai, Tsuneyo Mimori, Norihiro Nishimoto, Takayuki Sumida, Ayako Nakasone, Nobuhiro Takagi
    Abstract:

    AbstractObjective: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes.Methods: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to ≥1 conventional synthetic Disease-Modifying Antirheumatic Drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed.Results: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index ≤0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (M...

  • efficacy and safety of the oral janus kinase inhibitor peficitinib asp015k monotherapy in patients with moderate to severe rheumatoid arthritis in japan a 12 week randomised double blind placebo controlled phase iib study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Tsutomu Takeuchi, Satoshi Saeki, Hiroaki Ishikura, Yoshiya Tanaka, Manabu Iwasaki, Yuichiro Kaneko
    Abstract:

    Objective To evaluate the efficacy, safety and dose response of a novel oral Janus kinase inhibitor, peficitinib (ASP015K), as monotherapy in Japanese patients with moderate to severe rheumatoid arthritis (RA). Methods In a 12-week, double-blind study, 281 adult patients with RA with active disease not on concomitant Disease-Modifying Antirheumatic Drug therapy were randomised equally to once-daily placebo or peficitinib 25, 50, 100 and 150 mg. The primary endpoint was American College of Rheumatology (ACR) 20 response in the peficitinib treatment groups versus placebo at week 12. Results Mean age was 53.0 years, 81.1% were female and 25.3% had previously used antitumour necrosis factor therapy. Peficitinib 50, 100 and 150 mg each showed statistically significantly higher ACR20 response rates compared with placebo, and response rates increased up to 150 mg with a statistically significant dose response. The total incidence of treatment-emergent adverse events (TEAEs) was similar between the placebo (64.3%) and peficitinib 25, 50, 100 and 150 mg groups (70.9%, 64.9%, 52.7% and 67.2%, respectively). TEAEs occurring more frequently in the peficitinib group compared with the placebo group included nasopharyngitis, increased blood creatine phosphokinase and diarrhoea. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in peficitinib 25 and 100 mg). Conclusions Treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed acceptable safety profile. These findings support further developments of peficitinib for RA treatment. Trial registration number NCT01649999; Results.

  • Effectiveness and safety of tocilizumab in achieving clinical and functional remission, and sustaining efficacy in biologics-naive patients with rheumatoid arthritis: The FIRST Bio study
    2016
    Co-Authors: Naoki Ishiguro, Yoshiya Tanaka, Tsutomu Takeuchi, Tatsuya Atsumi, Masayoshi Harigai, Tsuneyo Mimori, Norihiro Nishimoto, Takayuki Sumida, Ayako Nakasone, Nobuhiro Takagi
    Abstract:

    Objective: To evaluate effectiveness and safety of tocilizumab (TCZ) in biologic-naive Japanese patients with rheumatoid arthritis (RA) in real-world settings, and to analyze the relationship between disease duration and clinical outcomes. Methods: The FIRST Bio study was a postmarketing surveillance study of intravenous TCZ in biologics-naive patients who had a prior inadequate response or were intolerant to ≥1 conventional synthetic Disease-Modifying Antirheumatic Drug (csDMARD). Effectiveness, safety, and concomitant csDMARD administration were assessed. Results: Of the 839 patients analyzed, 72.3% completed 52 weeks of treatment. The Clinical Disease Activity Index (CDAI) remission rate at week 52 was 36.8%. Contributing factors for CDAI remission were younger age, early disease stage, and no comorbidities. Health Assessment Questionnaire Disability Index ≤0.5 was achieved in 65.1% of patients, and was significantly associated with disease duration. Discontinuation of concomitant methotrexate (MTX) and glucocorticoids (GCs) was possible in 19.3% and 34.1% of patients, respectively, without decreasing remission rate. The incidence (events/100 patient-years) of serious adverse events was 18.09, the most common being infection. Conclusion: These data validate the importance of TCZ treatment in the early stages of RA in biologic-naive patients to achieve increased effectiveness. The safety profile of TCZ was reconfirmed. Furthermore, TCZ therapy may allow discontinuation of concomitant MTX and GCs without affecting remission.

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  • effects of the anti rankl antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease modifying Antirheumatic Drugs desirable study a randomised double blind placebo controlled phase
    Annals of the Rheumatic Diseases, 2019
    Co-Authors: Tsutomu Takeuchi, Yoshiya Tanaka, Satoshi Soen, Hisashi Yamanaka, Toshiyuki Yoneda, Sakae Tanaka, Takaya Nitta, Naoki Okubo, Harry K Genant, Désirée Van Der Heijde
    Abstract:

    Objective To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic Disease-Modifying Antirheumatic Drug (csDMARD) therapy in patients with rheumatoid arthritis (RA). Methods This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated. Results In total, 654 patients received the trial Drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1–L4) BMD in the placebo, Q6M and Q3M groups were −1.03%, 3.99% (p Conclusions Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

  • Low rates of radiographic progression of structural joint damage over 2 years of baricitinib treatment in patients with rheumatoid arthritis.
    RMD Open, 2019
    Co-Authors: Désirée Van Der Heijde, Yoshiya Tanaka, Michael Schiff, R Ortmann, L. Xie, Gabriella Meszaros, Taeko Ishii, Marta Casillas, Paul Emery
    Abstract:

    Objectives To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were Disease-Modifying Antirheumatic Drug (DMARD)–naive or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Methods Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same baricitinib dose as at originating study completion. At 52 weeks, DMARD-naive patients receiving methotrexate (MTX) or combination therapy (baricitinib 4 mg+MTX) were switched to baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to baricitinib 4 mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo were switched to baricitinib 4 mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified Total Sharp Score. Linear extrapolation was used for missing data. Results Of 2573 randomised patients, 2125 (82.6%) entered the LTE, of whom 1893 (89.1%) entered this analysis. At year 2, progression was significantly lower with initial baricitinib (monotherapy or combination therapy) versus initial MTX in DMARD-naive patients (proportion with non-progression defined by ≤smallest detectable change (SDC): 87.3% baricitinib 4 mg+MTX; 70.6% MTX; p≤ 0.001). In MTX-IR patients, progression with initial baricitinib was significantly lower than with initial placebo and similar to initial adalimumab (≤SDC: 82.7% baricitinib 4 mg; 83.5% adalimumab; 70.6% placebo; p≤0.001). In csDMARD-IR patients, significant benefit was seen with baricitinib 4 mg (≤SDC: 87.2% vs 73.2% placebo; p≤0.01). Conclusions Treatment with once-daily baricitinib resulted in low rates of radiographic progression for up to 2 years.

  • Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment
    Arthritis & Rheumatology, 2017
    Co-Authors: Roy Fleischmann, Michael Schiff, Désirée Van Der Heijde, Cesar Ramos-remus, A Spindler, Marina Stanislav, Cristiano A. F. Zerbini, Sirel Gurbuz, C. Dickson, Stephanie De Bono
    Abstract:

    Objective We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic Disease-Modifying Antirheumatic Drugs (DMARDs) and who were naive to biologic DMARDs. Methods A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24. Results The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX. Conclusion Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

  • Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Maxime Dougados, Désirée Van Der Heijde, E. Drescher, Scott D. Beattie, Ying-chou Chen, Maria Greenwald, Jiajun Liu, Sarah Witt, Inmaculada De La Torre, Carol L. Gaich
    Abstract:

    Background Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. Methods In this phase III, double-blind 24-week study, 684 biologic Disease-Modifying Antirheumatic Drug (DMARD)-naive patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. Results More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. Conclusions In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. Trial registration number NCT01721057; Results.

  • 2010 update of the international asas recommendations for the use of anti tnf agents in patients with axial spondyloarthritis
    Annals of the Rheumatic Diseases, 2011
    Co-Authors: Désirée Van Der Heijde, M Dougados, Joachim Sieper, Walter P Maksymowych, Ruben Burgosvargas, R Landewe, Martin Rudwaleit, Jurgen Braun
    Abstract:

    This paper presents the second update of the Assessment in SpondyloArthritis international Society (ASAS) consensus statement on the use of anti-tumour necrosis factor (anti-TNF) agents in patients with axial spondyloarthritis (SpA). A major change from the previous recommendations is that patients fulfilling the ASAS axial SpA criteria, which also include patients fulfilling the modified New York criteria for ankylosing spondylitis, can be treated with anti-TNF agents. This makes an earlier start in the disease process possible. A second major change is the mandatory pretreatment before anti-TNF agents can be started. All patients should have tried a minimum of two non-steroidal anti-inflammatory Drugs for a minimum of 4 weeks in total. This is significantly shorter than the previous requirement of 3 months. As previously, patients with axial symptoms require no further pretreatment. Patients with symptomatic peripheral symptoms should normally have had an adequate therapeutic trial of a Disease-Modifying Antirheumatic Drug, preferably sulfasalazine. Sulfasalazine is no longer mandatory in this group of patients. Finally, efficacy should be evaluated after at least 12 weeks. The remaining recommendations stayed largely unchanged.