Arthur Kavanaugh

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

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Publications (304)1490.44 Total impact

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    ABSTRACT: There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit. We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan-Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit. We identified 717 eligible patients with RA from 35 656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit. Discontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases. 12/2014;
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    ABSTRACT: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.
    Annals of the rheumatic diseases. 11/2014;
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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. Simultaneous inflammation in the skin and musculoskeletal structures in a single patient, a relatively common scenario, often leads to marked decrease in function and quality of life. Thus, it is essential for the clinician to document the extent of disease involvement and craft a therapeutic plan that addresses the different domains of disease. In an effort to update previous treatment recommendations developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), several evidence-based, systemic reviews of therapies for PsA were completed, analyzed, and circulated for consensus.
    The Journal of rheumatology. 11/2014; 41(11):2273-2276.
  • Arthritis Care & Research. 11/2014;
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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;
  • Renata Baronaite Hansen, Arthur Kavanaugh
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    ABSTRACT: Current treatment options for patients with active psoriatic arthritis (PsA) include synthetic disease-modifying antirheumatic drugs and biologic agents. Propelled by increased understanding of immunopathogenesis of PsA, new therapeutic agents targeting different biologic pathways have been evaluated. This article discusses novel small-molecule, orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA. This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase (JAK) inhibitors. Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA. Tofacitinib, an oral inhibitor of JAK3, JAK1, and, to a lesser degree, JAK2, approved for the treatment of rheumatoid arthritis in several countries, has demonstrated positive results in psoriasis in phase II studies. Studies in PsA are ongoing. With these new developments, treatment options will continue to improve in the future.
    Current Rheumatology Reports 09/2014; 16(9):443.
  • Clinical and experimental rheumatology 09/2014; 32 Suppl 85(5):1. · 2.66 Impact Factor
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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.
  • Renata Baronaite Hansen, Arthur Kavanaugh
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    ABSTRACT: Introduction: Recent years have witnessed tremendous development in the treatment of patients with psoriatic arthritis (PsA). Driven by greater understanding of the immunopathogenesis of disease, a number of novel treatment approaches have been developed and brought to the clinic. Additional therapies and treatment strategies are being explored. Areas covered: This paper discusses conventional and novel therapeutic options for treatment of PsA including agents under development. Novel treatment paradigms are also considered. Expert opinion: With newer therapies, in particular TNF inhibitors, treatment outcomes for patients with PsA have substantially improved. This has driven in advances in the approach to assessment of PsA, including composite measures of disease activity. Furthermore, novel treatment paradigms such as treat to target, early diagnosis and treatment, and consideration of tapering therapy among patients achieving low levels of disease activity are being actively explored. With these exciting developments, it is likely that outcomes for patients with PsA will continue to be improved in the foreseeable future.
    Expert Opinion on Orphan Drugs. 05/2014;
  • 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
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    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

Publication Stats

9k Citations
1,490.44 Total Impact Points

Institutions

  • 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
  • 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
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
    • Janssen Research & Development, LLC
      Raritan, New Jersey, 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
    • State University of New York Downstate Medical Center
      • Department of Dermatology
      Brooklyn, NY, United States
    • 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
  • 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