Arthur Kavanaugh

La Jolla Institute for Allergy & Immunology, La Jolla, California, United States

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Publications (296)1482.86 Total impact

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    ABSTRACT: Our 24-week study (NCT01197755; OSKIRA-3) compared the efficacy and safety of fostamatinib versus placebo in patients taking background methotrexate treatment with active rheumatoid arthritis (RA) and an inadequate response to a single tumor necrosis factor-α antagonist.
    The Journal of rheumatology. 09/2014;
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    ABSTRACT: This study assessed the impact of simultaneous achievement of clinical, functional and structural efficacy, herein referred to as comprehensive disease control (CDC), on short-term and long-term work-related outcomes, health-related quality of life (HRQoL), pain and fatigue.
    Annals of the rheumatic diseases. 08/2014;
  • DoQuyen Huynh, Arthur Kavanaugh
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    ABSTRACT: PsA is a systemic inflammatory condition that affects 20-30% of patients with psoriasis. It is characterized by potential involvement of diverse tissues, including peripheral and axial joints, enthesitis, dactylitis and skin and nail disease. The degree of involvement in each domain can vary over time in individual patients and can differ substantially between PsA patients. The clinical heterogeneity along with the varying extent of severity and activity can pose significant challenges to treatment. Although some studies had suggested immunopathophysiological similarities between PsA and RA, more recently important distinctions have been defined. Similarly, although some immunomodulatory therapies have proved effective for both PsA and RA, recent data suggest distinct responses to certain targeted therapies. Herein, current DMARDs and biologic agents as well as the potential role of emerging therapeutics will be reviewed.
    Rheumatology (Oxford, England) 08/2014; · 4.24 Impact Factor
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    ABSTRACT: Investigator-initiated trials, some of which have been referred to as comparative effectiveness trials, pragmatic trials, or strategy trials, are sometimes considered to be of greater clinical importance than industry-driven trials, because they address important but unresolved clinical questions that differ from the questions asked in industry-driven trials. Regulatory authorities have provided methodological guidance for industry-driven trials for the approval of new treatments, but such guidance is less clear for investigator-initiated trials. The European League Against Rheumatism (EULAR) task force for the update of the recommendations for the management of rheumatoid arthritis has critically looked at the methodological quality and conduct of many investigator-initiated trials, and has identified a number of concerns. In this Viewpoint paper, we highlight commonly encountered issues that are discussed using examples of well-known investigator-initiated trials. These issues cover three themes: (1) design choice (superiority vs non-inferiority designs); (2) statistical power and (3) convenience reporting. Since we acknowledge the importance of investigator-initiated research, we also propose a shortlist of points-to-consider when designing, performing and reporting investigator-initiated trials.
    Annals of the rheumatic diseases. 08/2014;
  • Minyoung Her, Arthur Kavanaugh
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    ABSTRACT: The measuring tools for disease activity of rheumatoid arthritis have long been adapted for assessing the disease activity of psoriatic arthritis (PsA), particularly as regards peripheral arthritis. However, because of the multifactorial aspects and multiple domains of PsA, such as axial and peripheral joints, skin and nails, enthesitis and dactylitis, must also be considered when measuring activity. After the introduction of biologic agents, it became clear that more objective measuring tools were needed to assess the varied aspects of disease activity, as well as the effect of treatment. Collaborations among international groups of rheumatologists and dermatologists have helped define key or core domains of PsA that were recommended for inclusion in clinical trials and potentially clinical practice. Groups such as the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have tried to develop and validate new outcome measures in PsA. Several new composite measures for specific PsA have been recently developed. The domains, instruments and traditional and new composite measures for PsA are reviewed herein.
    Expert Review of Clinical Immunology 08/2014; · 2.89 Impact Factor
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    ABSTRACT: Objective. This phase III, 52-week study (NCT01197521; OSKIRA-1) compared fostamatinib and placebo (for 24 weeks) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX) therapy.Methods. Patients taking MTX were randomized (1:1:1) to fostamatinib 100 mg bid for 52 weeks (Group A), 100 mg bid for 4 weeks then 150 mg qd (Group B), or placebo for 24 weeks then fostamatinib 100 mg bid (Group C). At Week 24, the co-primary end points were change from baseline in American College of Rheumatology 20% response rates (ACR20) and change in modified total Sharp van der Heijde score (mTSS).Results. 918 patients were randomized and received ≥1 dose of study drug (placebo/fostamatinib); demographic/baseline characteristics were well balanced. Both fostamatinib regimens achieved a statistically significant difference in ACR20 at Week 24 versus placebo (49.0%, P < 0.001; 44.4%, P = 0.006 versus 34.2%), but failed to show a statistically significant difference in mTSS (P = 0.25; P = 0.17).The most common adverse events in patients in Groups A, B, and C were hypertension (15.8%, 15.1%, 3.9%) and diarrhea (13.9%, 15.1%, 3.9%). Elevated blood pressure (≥140/90 mmHg) occurred in 44.2%, 41.6%, and 19.3% of patients at ≥1 visit.Conclusion. Both fostamatinib regimens achieved statistically but not clinically significant improvements in ACR20 over placebo at 24 weeks and did not show a significant difference in mTSS. The overall level of response with fostamatinib was lower than observed in the phase ll program, but similar adverse events were reported. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 08/2014;
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    Arthritis Care & Research. 07/2014;
  • Laura C Coates, Christopher T Ritchlin, Arthur F Kavanaugh
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    ABSTRACT: Psoriatic arthritis (PsA) is a chronic systemic inflammatory disorder characterized by the association of arthritis and periarticular inflammation in patients with psoriasis. In addition to a heterogeneous and variable clinical course, PsA is complex and multifaceted and may include prominent involvement in the peripheral and axial diarthrodial joints, the skin and nails, and in periarticular structures such as entheses. A central mission of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) is to develop guidelines, based upon the best scientific evidence, for the optimal treatment of patients with PsA. Guidelines were previously published in 2009 based on an evidence-based systematic review. Given important recent developments and robust ongoing research into the treatment of PsA, GRAPPA undertook to update the guidelines. Herein we outline the specific methods and procedures used both in the initial and the current evidence-based, systematic reviews of treatments for PsA. We also review the numerous discussions regarding how best to finalize and publish these new guidelines in 2014.
    The Journal of rheumatology. 06/2014; 41(6):1237-9.
  • John J Cush, Arthur Kavanaugh
    Current opinion in rheumatology 05/2014; 26(3):299-301. · 4.60 Impact Factor
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    ABSTRACT: Introduction Rheumatoid arthritis (RA) is a complex and clinically heterogeneous autoimmune disease. Currently, the relationship between pathogenic molecular drivers of disease in RA and therapeutic response is poorly understood. Methods We analyzed synovial tissue samples from two RA cohorts of 49 and 20 patients using a combination of global gene expression, histologic and cellular analyses, and analysis of gene expression data from two further publicly available RA cohorts. To identify candidate serum biomarkers that correspond to differential synovial biology and clinical response to targeted therapies, we performed pre-treatment biomarker analysis compared with therapeutic outcome at week 24 in serum samples from 198 patients from the ADACTA (ADalimumab ACTemrA) phase 4 trial of tocilizumab (anti-IL-6R) monotherapy versus adalimumab (anti-TNFα) monotherapy. Results We documented evidence for four major phenotypes of RA synovium – lymphoid, myeloid, low inflammatory, and fibroid - each with distinct underlying gene expression signatures. We observed that baseline synovial myeloid, but not lymphoid, gene signature expression was higher in patients with good compared with poor European league against rheumatism (EULAR) clinical response to anti-TNFα therapy at week 16 (P =0.011). We observed that high baseline serum soluble intercellular adhesion molecule 1 (sICAM1), associated with the myeloid phenotype, and high serum C-X-C motif chemokine 13 (CXCL13), associated with the lymphoid phenotype, had differential relationships with clinical response to anti-TNFα compared with anti-IL6R treatment. sICAM1-high/CXCL13-low patients showed the highest week 24 American College of Rheumatology (ACR) 50 response rate to anti-TNFα treatment as compared with sICAM1-low/CXCL13-high patients (42% versus 13%, respectively, P =0.05) while anti-IL-6R patients showed the opposite relationship with these biomarker subgroups (ACR50 20% versus 69%, P =0.004). Conclusions These data demonstrate that underlying molecular and cellular heterogeneity in RA impacts clinical outcome to therapies targeting different biological pathways, with patients with the myeloid phenotype exhibiting the most robust response to anti-TNFα. These data suggest a path to identify and validate serum biomarkers that predict response to targeted therapies in rheumatoid arthritis and possibly other autoimmune diseases.
    Arthritis Research & Therapy 04/2014; 16(2):R90. · 4.30 Impact Factor
  • Arthur Kavanaugh, Alvin F Wells
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    ABSTRACT: Glucocorticosteroids (GCs) have been employed extensively for the treatment of rheumatoid arthritis (RA) and other autoimmune and systemic inflammatory disorders. Their use is supported by extensive literature and their utility is reflected in their incorporation into current treatment guidelines for RA and other conditions. Nevertheless, there is still some concern regarding the long-term use of GCs because of their potential for clinically important adverse events, particularly with an extended duration of treatment and the use of high doses. This article systematically reviews the efficacy for radiological and clinical outcomes for low-dose GCs (defined as ≤10 mg/day prednisone equivalent) in the treatment of RA. Results reviewed indicated that low-dose GCs, usually administered in combination with synthetic DMARDs, most often MTX, significantly improve structural outcomes and decrease symptom severity in patients with RA. Safety data indicate that GC-associated adverse events are dose related, but still occur in patients receiving low doses of these agents. Concerns about side effects associated with GCs have prompted the development of new strategies aimed at improving safety without compromising efficacy. These include altering the structure of existing GCs and the development of delayed-release GC formulations so that drug delivery is timed to match greatest symptom severity. Optimal use of low-dose GCs has the potential to improve long-term outcomes for patients with RA.
    Rheumatology (Oxford, England) 04/2014; · 4.24 Impact Factor
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    ABSTRACT: The efficacy of pegloticase, a polyethylene glycol (PEG)-conjugated mammalian recombinant uricase, approved for chronic refractory gout, can be limited by the development of antibodies (Ab). Analyses from 2 replicate, 6-month, randomized controlled trials were performed to characterize Ab responses to pegloticase. Anti-pegloticase, anti-PEG, and anti-uricase Ab were determined by validated enzyme-linked immunosorbent assays. Ab titers were analyzed for possible relationships with serum pegloticase concentrations, serum uric acid (sUA) lowering, and risk of infusion reactions (IRs). Sixty-nine (41 %) of 169 patients receiving pegloticase developed high titer anti-pegloticase Ab (> 1:2430) and 40 % (67/169) developed anti-PEG Ab; 1 patient receiving placebo developed high titer anti-pegloticase Ab. Only 14 % (24/169) of patients developed anti-uricase Ab, usually at low titer. In responders, patients showing sustained UA lowering, mean anti-pegloticase titers at week 25 (1:837 +/- 1687 with biweekly and 1:2025 +/- 4506 with monthly dosing) were markedly lower than in nonresponders (1:34,528 +/- 42,228 and 1:89,658 +/- 297,797, respectively). Nonresponder status was associated with reduced serum pegloticase concentrations. Baseline anti-pegloticase Ab, evident in 15 % (31/212) of patients, did not predict subsequent loss of urate-lowering response. Loss of sUA response preceded IRs in 44 of 56 (79 %) pegloticase-treated patients. Loss of responsiveness to pegloticase is associated with the development of high titer anti-pegloticase Ab that increase clearance of pegloticase and are associated with a loss of the sUA lowering effect and increased IR risk. Pre-infusion sUA can be used as a surrogate for the presence of deleterious anti-pegloticase Ab.Trial registration: NCT00325195, NCT01356498.
    Arthritis research & therapy 03/2014; 16(2):R60. · 4.27 Impact Factor
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    ABSTRACT: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. NCT01172938.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: Available psoriasis surveys offer valuable information about psoriasis and psoriatic arthritis (PsA), but are limited by methodology or enrollment requirements. To further the understanding of the unmet needs of psoriasis and PsA patients. This was a large, multinational, population-based survey of psoriasis and/or PsA patients in North America and Europe. Patients were selected by list-assisted random digit dialing and did not have to currently be under the care of a health care provider, a patient organization member, or receiving treatment; 139,948 households were screened and 3426 patients completed the survey. The prevalence of psoriasis/PsA ranged from 1.4% to 3.3%; 79% had psoriasis alone and 21% had PsA. When rating disease severity at its worst, 27% (psoriasis) and 53% (PsA ± psoriasis) of patients rated it as severe. Psoriasis patients indicated that their most bothersome signs or symptoms were itching (43%), scales (23%), and flaking (20%). Of psoriasis patients, 45% had not seen a physician in a year; >80% of psoriasis patients with ≥4 palms body surface area and 59% of PsA patients were receiving no treatment or topical treatment only. Of patients who had received oral or biologic therapy, 57% and 45%, respectively, discontinued therapy, most often for safety/tolerability reasons and a lack/loss of efficacy. The survey lacked a control group, did not account for ethnic and health care system differences across countries, and was limited by factors associated with any patient survey, including accurate recall and interpretation of questions. Several identified unmet needs warrant additional attention and action, including improved severity assessment, PsA screening, patient awareness, and treatment options.
    Journal of the American Academy of Dermatology 02/2014; · 4.91 Impact Factor
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    ABSTRACT: Evaluate ustekinumab, an anti-interleukin (IL)-12 and IL-23 antibody, effects on radiographic progression in psoriatic arthritis (PsA). We conducted preplanned integrated analyses of combined radiographic data from PSUMMIT-1 and PSUMMIT-2 phase 3, randomised, controlled trials. Patients had active PsA despite prior conventional and/or biologic disease-modifying antirheumatic drugs (≥5/66 swollen, ≥5/68 tender joints, C-reactive protein ≥3.0 mg/L, documented plaque psoriasis). Patients (PSUMMIT-1, n=615; PSUMMIT-2, n=312) were randomised to ustekinumab 45 mg, 90 mg, or placebo, at weeks (wk) 0, 4 and every (q) 12 wks. At wk 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape. All other placebo patients received ustekinumab 45 mg at wk 24 and wk 28, then q 12 wks. Radiographs of hands/feet at wks 0/24/52 were assessed using PsA-modified van der Heijde-Sharp (vdH-S) scores; combined PSUMMIT-1 and PSUMMIT-2 changes in total vdH-S scores from wk 0 to wk 24 comprised the prespecified primary radiographic analysis. Treatment effects were assessed using analysis of variance on van der Waerden normal scores (factors=treatment, baseline methotrexate usage, and study). Integrated data analysis results indicated that ustekinumab-treated patients (regardless of dose) demonstrated significantly less radiographic progression at wk 24 than did placebo recipients (wk 0-24 total vdH-S score mean changes: 0.4-combined/individual ustekinumab dose groups, 1.0-placebo; all p<0.02). From wk 24 to wk 52, inhibition of radiographic progression was maintained for ustekinumab-treated patients, and progression was substantially reduced among initial placebo recipients who started ustekinumab at wk 16 or wk 24 (wk 24 - wk 52, total vdH-S score mean change: 0.08). Ustekinumab 45 and 90 mg treatments significantly inhibited radiographic progression of joint damage in patients with active PsA.
    Annals of the rheumatic diseases 02/2014; · 8.11 Impact Factor
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    ABSTRACT: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60. The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.
    Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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    ABSTRACT: To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials. Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naïve, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naïve), with early escape at wk 16 (wk 28, methotrexate-naïve); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial. Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for ≥156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma. SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.
    Annals of the rheumatic diseases 12/2013; · 8.11 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) treatment recommendations suggest target attainment within the first 3 months of therapy, yet delayed clinical responses can occur. This analysis assessed the longterm clinical, functional, and radiographic outcomes associated with delayed responses to methotrexate (MTX) monotherapy or to the combination of adalimumab (ADA) + MTX. In this posthoc analysis, patients with early RA who received MTX monotherapy or ADA + MTX in the PREMIER study were categorized based on clinical responses at 3 and 6 months [American College of Rheumatology response, 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) improvement and targets]. "Month 3" responders met the clinical measure at both months 3 and 6, and "Month 6" responders met the clinical measure only at Month 6. The odds of achieving longterm outcomes [remission (DAS28-CRP < 2.6), normal function (Health Assessment Questionnaire-Disability Index < 0.5), or rapid radiographic progression (Δ modified total Sharp score > 3 U/yr)] were modeled using logistic regression, including treatment, response, and interaction. A delayed or low-level response was associated with poorer longterm outcomes. Generally, MTX Month 6 responders demonstrated worse clinical, functional, and radiographic outcomes than Month 3 MTX and Month 3 or 6 ADA + MTX responders. Although similar longterm benefit was observed for ADA + MTX responders, delayed (Month 6) responders exhibited downward trends in clinical, functional, and radiographic outcomes that were comparable with those experienced by Month 3 MTX responders. Response speed and magnitude predict longterm outcomes in patients with early RA treated with MTX or ADA + MTX. MTX-treated patients failing to demonstrate a Month 3 clinical response have less-favorable outcomes than other groups, while outcomes in ADA + MTX Month 3 and Month 6 responders tended to be comparable.
    The Journal of Rheumatology 12/2013; · 3.26 Impact Factor
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    ABSTRACT: To evaluate the longterm safety of adalimumab administered with or without methotrexate (MTX) and compare the efficacy of combination therapy initialization to adalimumab or MTX monotherapy initialization during the open-label extension (OLE) of the PREMIER trial ( Identifier:NCT00195663). Patients with early rheumatoid arthritis (RA) were randomized to receive blinded adalimumab + MTX, adalimumab alone, or MTX alone for 2 years. Following the double-blinded period, patients enrolling in the OLE were given adalimumab for up to 8 additional years, beginning as monotherapy; investigators could add MTX at their discretion. Results for clinical, functional, and radiographic progression were collected for up to 10 years of treatment. During the PREMIER OLE, 250/497 patients (50.3%) completed the trial without new safety signals arising. Similar proportions of patients discontinued the trial early, although lack of efficacy was reported less often for patients initially randomized to the adalimumab + MTX arm (9.3%; 21.2%, and 23.7% for adalimumab and MTX monotherapies, respectively). Clinical and functional disease control was maintained throughout the trial. Patients initially randomized to adalimumab + MTX displayed better outcomes, particularly in prevention of radiographic progression (modified total Sharp score change = 4.0, 8.8, 11.0 at Year 10 for the initial adalimumab + MTX, adalimumab, and MTX arms, respectively). Intensive therapy with adalimumab + MTX combination in patients with early RA has longterm benefits compared to patients initiating with 2-year adalimumab or MTX monotherapy that persists up to 10 years following adalimumab OLE. No new safety findings were observed following longterm adalimumab treatment.
    The Journal of Rheumatology 11/2013; · 3.26 Impact Factor
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    ABSTRACT: Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7·5 mg/week, increased by 2·5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with, number NCT00420927. The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate. AbbVie.
    The Lancet 10/2013; · 39.06 Impact Factor

Publication Stats

9k Citations
1,482.86 Total Impact Points


  • 2006–2014
    • La Jolla Institute for Allergy & Immunology
      • Division of Cell Biology
      La Jolla, California, United States
    • University of San Diego
      San Diego, California, United States
  • 2000–2014
    • University of California, San Diego
      • • Division of Rheumatology, Allergy and Immunology
      • • Department of Medicine (1)
      San Diego, California, United States
    • University of Texas at Arlington
      Arlington, Texas, United States
  • 2013
    • University of Geneva
      Genève, Geneva, Switzerland
    • University of Leeds
      • Section of Clinical Musculoskeletal Disease
      Leeds, England, United Kingdom
  • 2012–2013
    • Inje University
      Kŭmhae, South Gyeongsang, South Korea
    • Janssen Research & Development, LLC
      Raritan, New Jersey, United States
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2010–2013
    • Brigham and Women's Hospital
      • • Division of Rheumatology, Immunology, and Allergy
      • • Center for Brain Mind Medicine
      • • Department of Medicine
      Boston, MA, United States
    • Imperial College London
      • Faculty of Medicine
      London, ENG, United Kingdom
    • Mount Sinai Hospital
      New York City, New York, United States
  • 2008–2013
    • Medical University of Vienna
      • Universitätsklinik für Innere Medizin II
      Wien, Vienna, Austria
    • Goethe-Universität Frankfurt am Main
      • Klinik für Dermatologie, Venerologie und Allergologie
      Frankfurt am Main, Hesse, Germany
    • CSU Mentor
      Long Beach, California, United States
  • 2005–2013
    • Leiden University Medical Centre
      • Department of Rheumatology
      Leyden, South Holland, Netherlands
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 2004–2013
    • Stanford University
      • • Division of Rheumatology
      • • Division of Immunology
      Palo Alto, California, United States
  • 2010–2012
    • University of California, Los Angeles
      • Division of Rheumatology
      Los Angeles, CA, United States
  • 2011
    • St. Olavs Hospital
      • Department of Rheumatology
      Nidaros, Sør-Trøndelag, Norway
  • 2009
    • National University (California)
      San Diego, California, United States
    • University of the Pacific (California - USA)
      Stockton, California, United States
    • Tufts Medical Center
      Boston, Massachusetts, United States
    • State University of New York Downstate Medical Center
      • Department of Dermatology
      Brooklyn, NY, United States
  • 2007–2008
    • Johnson & Johnson
      New Brunswick, New Jersey, United States
  • 2002
    • Tufts University
      • Department of Medicine
      Boston, GA, United States
  • 2001
    • Virginia Mason Medical Center
      Seattle, Washington, United States
  • 1991–2001
    • University of Texas Southwestern Medical Center
      • • Department of Internal Medicine
      • • Division of Rheumatic Diseases
      Dallas, TX, United States
  • 1999–2000
    • University of Texas at Dallas
      Richardson, Texas, United States