DANIEL O. CLEGG
| ABSTRACT. Ankylosing spondylitis (AS) is a condition characterized by inflammatory back pain and associated with considerable disability and diminished quality of life in affected individuals. The condition is undertreated in part due to a delay in diagnosis and limited therapeutic interventions. Although traditional treatment approaches (physical therapy, exercise, patient education, nonsteroidal antiinflammatory drugs) remain important components of the management of AS, the demonstrated efficacy of tumor necrosis factor-a (TNF-a) antagonists such as etanercept and infliximab have allowed clinicians to more effectively manage this condition. These targeted therapies have demonstrated rapid and consistent effectiveness in reducing the axial and peripheral symptoms of AS, slowing disease progression, and improving patient function and quality of life. Appropriate and timely use of TNF-a antagonists offers additional options for patients with active AS who are inadequately controlled with conventional treatment. (J Rheumatol 2006;33 Suppl 78:24-31) Key Indexing Terms: ANKYLOSING SPONDYLITIS TREATMENT DISEASE MODIFYING ANTIRHEUMATIC DRUGS BIOLOGIC PRODUCTS From the Rheumatology Section, Salt Lake City Veterans Health Care System, University of Utah School of Medicine, Salt Lake City, Utah, USA. Funding for this supplement series was provided by Amgen, Inc. and Wyeth Research. D.O. Clegg, MD. Address reprint requests to Dr. D.O. Clegg, Rheumatology Section, Salt Lake City Veterans Health Care System, University of Utah School of Medicine, 50 North Medical Drive, Room 4B181, Salt Lake City, UT. E-mail: daniel.clegg@hsc.utah.edu INTRODUCTION Ankylosing spondylitis (AS) is an inflammatory condition whose main clinical feature is inflammatory back pain caused by sacroiliitis and spondylitis1. Patients with AS may also have peripheral arthritis, enthesitis, and acute anterior uveitis1. AS is associated with considerable disability, reduced quality of life, and high costs in terms of direct medical expenses and indirect costs due to lost wages and productivity2-7. Patients with AS report similar pain and functional disability as those with rheumatoid arthritis2, and leave the labor force at a 3-fold higher rate than the general population8. Until recently, the options available to clinicians for the treatment of AS have been limited, with patient education, physical therapy, and nonsteroidal antiinflammatory drugs (NSAID) being the mainstay of effective therapy. The advent of tumor necrosis factor-a (TNF-a) antagonists represents a breakthrough in the treatment of AS. Nonetheless, despite the development of these more effective treatments that can slow AS disease progression, there is still an unmet need in the management of this condition due to the suboptimal use of these therapies. This article will review the treatment of AS. UNDERTREATMENT/SUBOPTIMAL TREATMENT As discussed elsewhere in this supplement series, the diagnosis of AS is frequently missed or substantially delayed, particularly in the primary care setting9. Disease onset is insidious, making diagnosis difficult before the occurrence of irreversible damage10. A mean delay of 10 years from time of first symptoms to a definitive diagnosis has been reported11,12. This delay also means a delay in treatment, allowing significant disease progression to occur. In patients with AS, severe spinal restriction (< 3 cm of lumbar movement and < 20° of cervical thoracic movement) occurs in up to 41% of patients, and the majority (81%) of these patients are severely restricted within 10 years of onset13. It has also been shown that spinal progression is a function of disease duration14. Therefore, management of the early stages of AS is critical for slowing disease progression. TRADITIONAL APPROACHES TO TREATMENT Both nonpharmacologic and pharmacologic interventions are important in the management of AS. Important nonpharmacologic components of AS management include physical therapy, exercise (including muscle conditioning along with instruction), and encouragement of appropriate posture15. Exercise/physical therapy programs have been shown to improve measures of pain, spinal mobility, patient function, and well-being, with supervised programs being more effective than individual at-home programs16-22. For example, in a randomized trial in 144 patients with AS, supervised group physiotherapy (hydrotherapy, exercises, and sporting activities) was more effective at improving spinal mobility, fitness, and patient reported global health than an individualized program20. In addition, patient education/support programs have been shown to improve patient perception of well-being23,24. For example, a short intensive course (12 hours of education over 2 consecutive days) with sessions on AS disease information, exercises, posture, and home checks for monitoring mobility produced improvements in depression and self-efficacy (daily ability to manage pain, fatigue, and physical functioning) at 3 weeks, with a trend toward continued improvement at 6 months23. The frequency and range of types of exercise both significantly decreased over time, underscoring the importance of continued followup and reinforcement of exercise programs in the AS population. NSAID are the foundation of management of AS, and are currently the first-line drugs for initial management of pain and stiffness. In mostly short-term studies (up to 3 months), conventional NSAID produced significant improvements in symptoms in patients with AS, including spinal pain, duration of morning stiffness, night pain, immobility, stiffness, and peripheral pain25-37. More recently, selective cyclooxygenase-2 (COX-2) inhibitors have been evaluated in patients with AS38,39. Although etoricoxib is no longer available, a 6-week study in 387 patients with AS treated with etoricoxib 90 mg/day or 120 mg/day showed similar efficacy (spine pain, functionality, and patient global assessment of disease activity) to naproxen 1000 mg/day, and both agents had significantly greater efficacy than placebo38. These improvements were maintained over a 52-week double-blind continuation of the 6-week study38. Similarly, 6 weeks of treatment with celecoxib 100 mg twice daily showed similar efficacy to ketoprofen 100 mg twice daily and significantly greater efficacy than placebo in terms of global pain intensity and functional impairment in 246 patients with AS39. After 6 weeks of therapy, patients were randomly assigned either continuous or as-needed treatment with celecoxib 100 mg twice daily for 2 years (allowed to increase to 200 mg twice daily at patient's discretion)40. Despite a similar effect on measures of pain, inflammation, and spinal mobility, continuous use of celecoxib (or other NSAID taken continuously) slowed radiographic progression to a significantly greater degree than intermittent use after 2 years40. Disease modifying antirheumatic drugs (DMARD) are a potential second-line therapy but their efficacy in AS is unproven. There has been a lack of consistent results in clinical trials with DMARD41-47. Sulfasalazine has generally demonstrated efficacy at improving AS-associated peripheral arthritis, but not back pain42,48,49. For example, a 36-week study of 264 patients with chronic long-standing AS (mean duration 18.5 years) reported no significant differences between sulfasalazine 2000 mg/day and placebo recipients for any clinical measures of efficacy, including physician and patient global assessment, morning stiffness, back pain, night pain, duration of morning stiffness, spondylitis functional index, and joint pain/tenderness49. Another study showed some improvement in clinical symptoms (morning stiffness and chest expansion) relative to placebo following 26 weeks of treatment with sulfasalazine ≤ 3000 mg/day50. However, a subgroup analysis in patients with AS reported no significant difference in axial response rates between sulfasalazine and placebo in patients with axial disease only or in patients with combined axial/peripheral disease, but did show a peripheral response in patients with axial/peripheral disease49. In a combined analysis of patients with seronegative spondyloarthropathies (264 AS, 221 psoriatic arthritis, and 134 reactive arthritis), sulfasalazine produced better treatment response rates (composite index of 4 outcome measures) in patients with peripheral arthritis than in those with exclusively axial disease48. Methotrexate (MTX) also has not demonstrated consistent efficacy for AS-associated back pain, and has shown inconsistent efficacy for peripheral disease41,47,51. In a small study (n = 51), there were no significant differences in efficacy observed between naproxen and MTX plus naproxen after 1 year47. Another small study (n = 35) showed some benefit with MTX therapy over placebo after 24 weeks for a composite index of improvement [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Health Assessment Questionnaire for Spondyloarthropathies, severity of morning stiffness, physical well-being, and physician and patient global assessment of disease activity], with a statistical difference between the 2 groups observed only at Week 2451. Both of these studies used relatively low dosages of MTX (7.5 mg/wk). Leflunomide was not effective for axial manifestations of AS, but may provide some benefit for peripheral arthritis. In a 6-month open-label study in 20 patients with AS, treatment with leflunomide (100 mg/day for 3 days, then 20 mg/day for 6 months) did not produce significant improvement in a number of measures, including BASDAI, BASFI, patient and physician global assessment, Medical Outcome Study Short Form-36 General Health Survey (SF-36) mental component, and C-reactive protein52. Significant improvement in peripheral arthritis, as assessed by the mean number of inflamed joints, was noted in this study. NEW APPROACHES TO TREATMENT With the advent of biologic agents, it is now possible to slow disease progression in AS rather than simply allay symptoms. TNF-a is a proinflammatory cytokine involved in the pathogenesis of AS and other spondyloarthropathies53,54. Etanercept and infliximab are TNF-a antagonists approved by the US Food and Drug Administration for the treatment of AS55,56, and both drugs have demonstrated rapid and sustained efficacy in the treatment of this condition. Adalimumab57 is another TNF-a antagonist in development for the treatment of AS, with preliminary evidence of similar efficacy58-62. Etanercept. Etanercept 25 mg twice weekly has demonstrated consistent efficacy in a number of clinical trials in patients with AS (Table 1). In a 4-month study, the percentage of responders (composite index of outcome measures) was significantly higher in etanercept than placebo recipients (80% vs 30%; p = 0.004)63. In a 6-month extension of this trial in which all patients received etanercept, these results were maintained in the original etanercept group and patients who had originally received placebo achieved an 80% response rate within 1 month of initiating etanercept treatment63. Similar results were observed in a 24-week study, which had a 6-week placebo-controlled portion followed by 6 weeks of continued treatment in the etanercept group and 12 weeks' treatment with etanercept in the placebo group (all patients received 12 weeks' total therapy with etanercept)64. Patient function, spine mobility, and quality of life improved with treatment, and one-third of patients experienced a partial remission [Assessments in Ankylosing Spondylitis (ASAS) criteria] after 12 weeks of etanercept treatment. After drug cessation, 75% of patients experienced relapse of symptoms within 3 months64. A 54-week open-label extension of this study was conducted in 26 patients who had discontinued etanercept per study protocol (for a mean 26.8 weeks) and who had developed high disease activity65. Eighty-eight percent of patients were still receiving etanercept at the end of the extension period, 58% had a ≥ 50% improvement in BASDAI, and 31% were in partial remission65. These results are consistent with the results obtained in the initial 12-week study64.
Infliximab. Infliximab 5 mg/kg at Weeks 0, 2, and 6 (and then every 6 weeks thereafter in studies with a duration > 12 weeks) demonstrated consistent efficacy in patients with AS for a number of different primary efficacy measures (Table 1)70-72. In the study presented by Braun, et al, partial remission was observed in about 20% of infliximab-treated patients compared with about 3% of patients in the placebo group70. The longterm efficacy of infliximab for AS has been evaluated in an open-label extension of the Braun, et al70 study. Patients continued to receive infliximab 5 mg/kg every 6 weeks after the induction dosing phase; data for 54 weeks73, 102 weeks74, and 156 weeks75 are available. Of the 69 patients who entered the open-label extension, 54 continued to receive infliximab at 54 weeks73. Forty-seven percent of patients who had received continuous infliximab and 51% of patients who received placebo for 12 weeks followed by infliximab were BASDAI50 responders at Week 54, and partial remission was reported in 18% and 17% of patients, respectively73. These results were maintained in the 49 patients who completed 102 weeks of the study (41% and 49%, respectively)74, and in the 46 patients who completed 156 weeks (47% and 43%, respectively)76. An assessment of 41 patients from the 2-year analysis74 showed a slowing of radiographic damage in infliximab-treated patients relative to an untreated cohort77. In the large Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) study (n = 279), 24 weeks of treatment with infliximab produced a significantly higher percentage of ASAS20 responders than placebo (61.2% vs 19.2%; p < 0.001), and demonstrated significant improvement in a number of other measures, including BASDAI, BASFI, chest expansion, and the physical component score of the SF-3672. Recent 30-week data indicated that infliximab in combination with MTX produced significantly greater reductions in BASDAI scores than MTX alone in 42 patients with AS, and significantly greater regression in enthesitis/osteitis as assessed by MRI78. The addition of MTX did not appear to extend the dosing interval for infliximab, however, as evidenced by the occurrence of disease flares 8 weeks after the last infliximab infusion78. Adalimumab. Adalimumab, another TNF-a antagonist, is under investigation for the treatment of AS. In a small (n = 14) open-label 20-week study, adalimumab 40 mg every other week produced significant improvement in spinal symptoms in patients with AS79. Preliminary results of the phase 3 Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS) in 315 patients showed that a significantly higher proportion of adalimumab (40 mg every other week) than placebo recipients achieved ASAS partial remission status (21.6% vs 6.5%) and ASAS5/6 criteria (44.2% vs 13.1%) (both p ≤ 0.001)59. Safety. In the clinical trials discussed above, the TNF-a antagonists were well tolerated, with the rates of adverse events generally being similar in active drug and placebo groups. Injection site reactions, upper respiratory tract infections, and accidental injury were reported in significantly more etanercept- than placebo-treated patients66. Infliximab was generally as well tolerated in the large AS study: elevated transaminase levels were reported in more infliximab than placebo recipients72. Although the rate of infusion reactions was similar for infliximab and placebo in this AS study, clinical studies have reported a higher rate of this adverse event in infliximab-treated patients56. The adalimumab data from the ATLAS study were published in abstract form, and no specific adverse event details were provided for these AS patients (adverse events were comparable between the adalimumab and placebo groups)59. General precautions with the use of TNF-a antagonists include (1) an increased risk of opportunistic infections, possible increased risk of lymphoma, and hepatotoxicity (infliximab); and (2) avoidance of use in patients with pre-existing demyelinating disease or moderate to severe heart failure55-57,80,81. Rare cases of tuberculosis have been reported in patients receiving TNF-a antagonists, including etanercept55. Infliximab and adalimumab carry a black-box warning highlighting the risk for tuberculosis56,57. Guidelines for use of TNF-a antagonists. There are a number of published treatment guidelines for biologic therapies in AS15,82-85. Many patients with AS meet the criteria for anti-TNF-a treatment (reflecting severe disease) in established guidelines, but do not receive these agents86. Recently, a survey of AS patients indicated that nearly two-thirds of patients had poor functional status and quality of life (BASDAI score ≥ 40) and would meet the British Society of Rheumatology criteria for TNF-a antagonist use86. The results of this survey, conducted between 2001 and 2003 (just as biologics were being introduced for AS), suggested that there may be a substantial unmet need for effective treatment in AS. An overview of guidelines for the use of TNF-a antagonists, including the US modifications of European guidelines, is presented in Table 215,84.
CONCLUSIONS Ankylosing spondylitis is associated with significant pain, functional disability, and diminished quality of life. This disease represents a therapeutic challenge for clinicians because of its insidious onset that often results in delays in recognition. Radiologic damage may occur early in the course of AS, underscoring the importance of early recognition and appropriate treatment. The major goal of therapy of inflammatory conditions such as AS is to slow disease progression and improve function. Conventional approaches to the management of AS, such as physical therapy, exercise, patient education, and NSAID therapy remain important components of AS treatment. Traditional DMARD, such as sulfasalazine and MTX, have not consistently shown benefit, particularly for axial manifestations. The development of targeted anti-TNF therapies that provide disease control has heralded a new era for the treatment of AS and provided hope for many patients suboptimally controlled. Etanercept and infliximab, the 2 TNF-a antagonists currently approved for the treatment of AS, have demonstrated rapid and consistent effectiveness in reducing the axial and peripheral symptoms, and improving patient function and quality of life. Data are also available to support the longterm use of these agents. The established efficacy and safety profiles of the TNF-a antagonists makes this class of agents an important new addition to the previously limited armamentarium available to rheumatologists for the treatment of AS. ACKNOWLEDGMENT The author wishes to thank Rick Davis, MS, RPh, whose work was funded by Amgen, Inc., for providing assistance in the drafting of this report, and Scott Baumgartner, MD, of Amgen, Inc., for contributing to the concept development. REFERENCES 3. Doward LC, Spoorenberg A, Cook SA, et al. Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 2003;62:20-6. [MEDLINE] 4. 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