The role of etanercept in ankylosing spondylitis

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1 The role of etanercept in ankylosing spondylitis J.C. Davis Jr. John C. Davis Jr., MD, MPH, MS, Assistant Professor of Medicine, Division of Rheumatology, University of California, San Francisco, Parnassus Avenue, San Francisco, CA Clin Exp Rheumatol 2002; 20 (Suppl. 28): S-S. Copyright CLINICAL AND EXPERIMEN- TAL RHEUMATOLOGY Key words: Ankylosing spondylitis, TNF, human, controlled trial, treatment. ABSTRACT A n kylosing spondylitis is a ch ro n i c inflammatory disease that leads to sig - nificant loss of function and disability in patients. Current conventional ther - apies ha ve not demonstrated improve - ment in axial symptoms and progres - sive ankylosis of the spine. The use of n ew biologic agents that bl o ck the actions of tumor necrosis factor-alpha have, for the first time, reported signif - icant improvement in axial symptoms and reduction in spinal inflammation in short - t e rm studies. F u t u re studies with larger numbers of patients over long periods of time will eve n t u a l ly determine the long-term success and safety of these agents. Introduction Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine implicated in playing a central role in the pathogenesis of a number of inflammat o ry processes. Recent observat i o n s from animal models also suggest that T N F -α m ay play a role in mu l t i p l e autoimmune diseases. Transgenic mice ex p ressing modified human T N F -α develop a clinical picture resembling human rheumatoid arthritis (RA), and mice expressing a truncated form of the TNF-α gene from the white-footed mouse develop a syndrome closely resembling human ankylosing spondylitis (AS), with axial involvement and subsequent ve rt eb ral end plate destruction and fusion (, 2). These observations suggest that TNF-α may play a causative role in the spondyloarthropathies. Results from human studies also support the involvement of TNF-α in AS and the other seronegative spondyloarthropathies. Levels of serum TNF-α have been reported to be significantly higher in patients with AS than in patients with non-infl a m m at o ry back pain (), and a trend toward higher serum TNF-α in AS patients as compared with healthy controls has been noted (4). High levels of TNF-α mrna have been found in the peripheral and axial joint synovia of patients with RA, spondyloarthritis (SpA), juvenile SpA, and AS (-7). Etanercept (TNFR:Fc; ENBREL ) is a soluble fusion protein comprising an epitope derived from the p7 tumor necrosis factor receptor fused to the Fc p o rtion of IgG (Fi g. ). It has been shown to bind TNF with high affinity and to block the effects of TNF-α in model systems. In seve ral mu l t i c e n t e r, d o u bl e - bl i n d, placebo-controlled studies, etanercept has been shown to improve the signs and symptoms of RA and to be effec- Fig.. Schematic diagram of etanercept. Reproduced from Franklin CM: Clinical experience with soluble TNF p7 receptor in RA, Semin Arthritis Rheum 999; 29: 72-82, with permission from W.B. Saunders Co. S-

2 tive in treating the joint and skin manifestations of psoriatic arthritis (PsA), a s e ro n egat ive spondy l o a rt h o p at hy (8- ). Pre l i m i n a ry rep o rts from open l abel and placeb o - c o n t rolled studies suggest that TNF blockers may be effective in other seronegative spondyloarthropathies, such as reactive arthritis, resistant spondy l o a rt h ro p at hy, u n d i f- fe re n t i ated spondy l o a rt h ro p at hy, re f ra c- t o ry juvenile ankylosing spondy l i t i s, and ankylosing spondylitis (2-6). A recent study using Etanerc ept in patients with spondylitis demonstrated significant clinical efficacy (). This study also reported a decrease in inflammation of the peripheral arthritis, the spine, and the sacroiliac joint after several months of therapy by MRI. At the end of the study 86% of the patients tre ated had resolution or improvement in MRI sites of inflammation (). These encouraging preliminary reports suggest that TNF-α blockade could be associated with regression of inflammation and have potential implications for the progression of long-term structural damage associated with the disease. Based on () the animal models, (2) elevated levels of the cytokine in pat i e n t s, () encouraging results of reduced radiographic inflammation, and (4) the success in related autoimmune diseases, we undertook a randomized double-blind, placebo-controlled study to evaluate the safety and efficacy of Etanercept in patients with AS (6). In a recent study, we enrolled 40 patients with AS in a 4-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of Etanercept, 2 mg, delivered SC twice weekly. Inclusion criteria were: () a diagnosis of AS as defined by the m o d i fied New Yo rk Clinical Cri t e ri a for definite AS, and (2) active disease; defined as morning stiffness of 4 minutes or more, inflammatory back pain, and patient and physician global assessments of disease of moderate or higher. Patients continued stable doses of non-steroidal anti-infl a m m at o ry d rugs (NSAIDS), c o rt i c o s t e ro i d s, o r disease modifying anti-rheumatic dru g s (DMARDs) during the trial. Patients were excluded if they had other forms Table I. Baseline demographics of subjects. of spondylitis other than AS or complete spinal fusion. The primary endpoint of the study was the proportion of patients who responded to tre atment in the etanerc ept gro u p vs. the placebo group. To be considered responders, patients had to demo n s t rate at least 20% improve m e n t from baseline in at least of the foll owing outcome measures re c o m- mended by the Assessments in Ankylosing Spondylitis Working Group (7): m o rning stiff n e s s, spinal pain, f u n c- tion, patient global assessment of disease, and swollen joint score, with one being morning stiffness or spinal pain, and without worsening in any of these symptoms. Multiple secondary measures of efficacy were also evaluated. [The study analysis used intention-totreat principles with the last available assessment for each patient carried forward.] Baseline demographic and cl i n i c a l characteristics of the patients are summarized in Table I. Groups were similar in terms of race, proportion of patients who we re HLA-B27 positive, age, duration of disease, and concomitant medicines. Several measures suggest that the Etanerc ept group may have had more severe disease at the start of the trial: physical function was s i g n i fi c a n t ly poorer in the Etanerc ep t group (judged by responses on Medical Outcomes Study Short - Fo rm Health S u rvey [SF-6], m o re Etanerc ept patients we re re c e iving second-line therapies (steroids and/or DMARDs), a n d e ry t h ro cyte sediment ation rate (ESR) was higher. Over the course of the study, patients w i t h d rew : from the Etanerc ept gro u p, for reasons unrelated to the study, and 2 from the placebo groups for lack of efficacy. The primary endpoint of this study, the p ro p o rtion of patients ach i eving a response at Day 2, was significantly higher in the group of patients treated with Etanercept (7%) than in those treated with placebo (40%). (Table II, Fig. 2) The response to etanercept occurred as quickly as one month and did not diminish over the course of the study. In addition, improvements were seen in a number of secondary outcome Etanercept Placebo Characteristic n=20 n=20 Male sex (%) 6 90 Caucasian (%) 7 70 HLA-B27+ (%) 9 90 Mean age (yr) 8 ± 0 9 ± 0 Mean duration of AS (yr) ± 0 2 ± 9 Concomittant medications NSAIDs (%) Steroids (%) 2 0 DMARDs (%) 40 Multiple medications for AS (%) 4 Clinical features Duration of morning stiffness (min) 90.0 ± ± 70.7 Modified Schober s test (cm) 2. ±.. ±. Patient global assessment 4.0 ± ± 0.7 Physician global assessment 4. ± ± 6.4 Erythrocyte sedimentation rate (mm/hr) 4. ± ± 6. Plus-minus values are median values ± SD; differences between groups were all not statistically significant. 2 NSAIDs denotes nonsteroidal antiinflammatory drugs DMARDs denotes disease-modifying antirheumatic drugs. 4 Scores can range from 0 (no disease) to (most severe). Scores can range from 0 to 00 mm on a visual analogue scale with 00 mm indicating most severe disease. S-2

Fig. 2. Percent of patients considered responders at month 4 (p < 0.0). Table II. Primary outcomes month 4. 7 Etanercept Placebo P 2 n=20 n=20 Number (%) of responders (7) 8 (40) 0.

000 BASFI Baseline 4. ± 2..2 ± 2. 0.06 Day 2 2.2 ± 2.. ±.0 < 0.000 Patient global assessment 6 Baseline.0 ± 0.7.0 ± 0.7 0. Day 2 2.0 ± 0.6.0 ± 0.9 < 0.00 Swollen joint score 7 (mean) Baseline.7 ± 8.

3 Fig. 2. Percent of patients considered responders at month 4 (p < 0.0). Table II. Primary outcomes month 4. 7 Etanercept Placebo P 2 n=20 n=20 Number (%) of responders (7) 8 (40) 0.0 Duration of morning stiffness (min) Baseline 90.0 ± ± Day ± ± 6.0 < Nocturnal spinal pain 4 Baseline 6.0 ± ± Day 2.0 ± ± 27.8 < BASFI Baseline 4. ± 2..2 ± Day ± 2.. ±.0 < Patient global assessment 6 Baseline.0 ± ± Day ± ± 0.9 < 0.00 Swollen joint score 7 (mean) Baseline.7 ± 8..2 ±. 0. Day 2.6 ±.8.7 ± Plus-minus values are median values ± SD; 2 p values calculated by Mann-Whitney t-tests; p value calculated by Fisher s exact test; 4 Pain (00 mm VAS): 0, none; 00, most severe; Functional limitations (0-0): 0, none; 0, completely limited; 6 Disease activity (0-): 0, no disease activity;, very severe; 7 Peripheral joint count of 66 joints on 4 point swelling scale (0, none;, mild; 2, moderate;, severe). Fig.. Percent of patients achieving ASAS 20, 0 and measures (Table III; measures in bold were components of the definition of response used to evaluate the primary endpoint). Function, stiffness, global assessments of disease, and signs of p e ri p h e ral disease had all improve d significantly by the 4th month of the trial, and benefit continued through the end of the study. Measures of spinal mobility showed a less dra m atic response than other measures at 4 months, but both chest expansion and occiputt o - wall measurements continued to i m p rove with longer drug tre at m e n t, s u ggesting that the spinal re s p o n s e takes longer to develop. Quality of life, assessed using the SF-6, also improved in patients treated with etanercept (data not shown). Although the ASAS response criteria were not published at the time of the study, post-hoc analysis demonstrated significant improvement of the ASAS 20, ASAS 0 and ASAS 70 response measures (Fig. ) (8). There were no serious adverse events or withdrawals due to adverse events and there were no statistically significant differences in the adverse events o b s e rved between the tre atment gro u p s. The most common adverse events in the blinded trial consisted of self-limited injection-site reactions ( patients in the etanercept group; one patient in the placebo group) and minor uncomplic ated infections (0 patients in the e t a n e rc ept group; 2 patients in the placebo group) that occurred at comparable rates between the two treatment groups. Two neurologic events were reported in a single patient treated with etanercept. The patient experienced tinnitus, which lasted for days and resolved spontaneously, and later, an increased frequency of pre-existing muscle fascic u l ation. Neuro l ogic and lab o rat o ry examinations were normal. Study med i c ation was held pending complete n e u ro l ogic consultation and eva l u a- tion. No abnormality was noted on any of the evaluations, and the patient was diagnosed with benign fasciculations. The frequency of the patient s symptoms returned to baseline and remained at this level with the re-initiation of study medication. S-

4 Table III. Secondary outcomes at month 4. Conclusions The encouraging results from this trial (and others reviewed in this volume) s u ggest that TNF bl o cking therap i e s may be effective and safe treatments for AS, and may offer distinct advantages over commonly used therapies. NSAIDs only treat the pain of the dise a s e, and few doubl e - bl i n d, p l a c eb o - controlled studies of other DMARDs have been done in patients with AS. No Etanercept Placebo P 2 n=20 n=20 Spinal pain Baseline 62.0 ± ± Day 2 2. ± ± Physician global assessment 4 Baseline 4. ± ± Day ± 0.6. ± 22.7 < Dougados Functional Index Baseline 8.0 ± ± Day ± ± Modified Newcastle Enthesis Index 6 Baseline 4. ± ± Day ±.0. ± Swollen joint count 7 (mean) Baseline. ± ± Day 2. ± ± Tender joint count 7 Baseline.0 ± ± Day 2.0 ± ± Tender joint score 7 Baseline. ± ± Day 2.0 ± ± ESR (mm/hr) Baseline 4. ± ± Day 2 8. ± ± 8.7 < Fatigue Severity Scale 8 Baseline 4.6 ±.6 4. ±. 0.2 Day ± ± Chest expansion (cm) Baseline 2.6 ±.6. ±.7.00 Day 2. ± ± Modified Schober s test (cm) Baseline 2. ±.. ±. 0. Day 2.4 ±.6.4 ± Occiput-to-wall measurement (mean cm) Baseline.7 ± ± Day ± ± Plus-minus values are median values ± SD. 2 p values calculated by Mann-Whitney t-tests. Pain without time restrictions (00 mm VAS): 0, none; 00, severe. 4 Disease activity (00 mm VAS): 0, none; 00, severe. Functional limitations (0-40): 0, none; 40, completely limited. 6 Seventeen entheses on a 4 point scale (0, none;, mild; 2, moderate;, severe). 7 Peripheral joint count of 66 joints on 4 point pain scale (0, none;, mild; 2, moderate;, severe). 8 Fatigue Severity Scale (0-7) currently used therapy has been shown to improve axial symptoms of AS. The c u rrent trial supplies evidence that e t a n e rc ept can be of benefit even to patients with long duration of disease (mean disease duration years in patients initially ra n d o m i zed to re c e ive etanercept) and with moderate to severe disease. Patients treated with etane rc ept demonstrated evidence of improvement in not only the pain associated with A S, but also showed increased function and quality of life, and had improvement in the axial symptoms of the disease. Etanerc ept wa s also safe in conjunction with other AS medications. This study was designed to determine the short-term efficacy of etanercept in A S. Although benefit was sustained throughout the trial, the long-term effects of etanerc ept tre atment in A S have not yet been studied. Etanercept has been shown to slow the radiographic progression of RA, and ev i d e n c e from MRI scans collected as part of a 6-month open-label descri p t ive study () suggests that etanercept may indeed help control entheseal lesions in patients with AS. Further research will evaluate the long-term safety and efficacy of etanercept (and other TNF inhibitors) in AS and the effects of these drugs on the peripheral and axial radiographic progression of the disease. References KEFFER J, PROBERT L, CAZLARIS H et al.: Transgenic mice expressing human tumour necrosis factor:a predictive genetic model of arthritis. Embo J 99; 0: CREW MD, EFFROS RB, WALFORD RL, ZEL- L E R E, C H E RO U T R E H, BRAHN E: Tra n s- genic mice expressing a truncated Peromy - scus leucopus TNF-alpha gene manifest an arthritis resembling ankylosing spondylitis. J Interferon Cytokine Res 998; 8: GR ATAC O S J, C O L L A D O A, FILELLA X e t al.: Serum cytokines (IL-6, TNF-alpha, IL- beta and IFN-gamma) in ankylosing spondylitis: A close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol 994; : TOUSSIROT E, LAFFORGUE P, BOUCRAUT J et al. : S e rum levels of interleukin -beta, tumor necrosis fa c t o r- a l p h a, s o l u ble interleukin 2 receptor and soluble CD8 in seronegative spondylarthropathies. Rheumatol Int 994; : CANETE JD, L L E NA J, COLLADO A et al. : Comparative cytokine gene expression in synovial tissue of early rheumatoid arthritis and s e ro n egat ive spondy l o a rt h ro p athies. Br J Rheumatol 997; 6: GROM AA, MURRAY KJ, LUYRINK L et al.: Patterns of expression of tumor necrosis factor alpha, tumor necrosis factor beta, a n d their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondy l a rt h ro p at hy. A rt h ritis Rheum 996; 9: BRAUN J, BOLLOW M, NEURE L et al.: Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with a n kylosing spondy l i t i s. A rt h ritis Rheum 99; 8: S-4

5 8. WEINBLATT ME, KREMER JM, BANKHURST AD et al.:a trial of etanercept,a recombinant tumor necrosis factor receptor:fc fusion prot e i n, in patients with rheumatoid art h ri t i s receiving methotrexate. N Engl J Med 999; 40: MORELAND LW, BAU M G A RTNER SW, SCHIFF MH et al.: Treatment of rheumatoid a rt h ritis with a recombinant human tumor necrosis factor receptor (p7)-fc fusion protein. N Engl J Med 997; 7: MORELAND LW, SCHIFF MH, BAU M G A RT- NER SW et al.: Etanercept therapy in rheum atoid art h ritis. A ra n d o m i ze d, c o n t ro l l e d trial. Ann Intern Med 999; 0: MEASE P, KIVITZ A, BURCH F, SIEGEL E, COHEN S, BU R G E D: I m p rovement in disease activity in patients with psoriatic arthritis receiving etanercept (ENBREL): results of a phase multicenter trial. A rt h ri t i s Rheum 200; 44: S MEADOR RJ HSIA EC, KITUMNUAYPONG T, SCHUMACHER HR: Is etanercept (Enbrel) effective in the treatment of reactive and undifferentiated arthritis? Arthritis Rheum 200; 44: S48.. MARZO-ORTEGAH, MCGONAGLE D, O CON- NOR P, EMERY P: Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: A clinical and magnetic resonance imaging study. Arthritis Rheum 200; 44: BRANDT J, HAIBEL H, REDDIG J, SIEPER J, BRAUN J: Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis fa c t o r- a l p h a monoclonal antibody infliximab. J Rheuma - tol 2002; 29: RE I F F A, H E N R I C K S O N M: P ro l o n ged efficacy of etanercept in refractory juvenile ankylosing spondylitis (JAS). Arthritis Rheum 200; 44: S GORMAN JD, SACK KE, DAVIS JC JR: Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor α. N Engl J M e d 2002; 46: VAN DER HEIJDE D, CALIN A, DOUGADOS M, K H A N M A, VAN DER L I N D E N S, B E L L A M Y N: Selection of instruments in the core set for D C - A RT, S M A R D, p hysical therapy, a n d clinical record keeping in ankylosing spondylitis. Progress report of the ASAS Working Group. Assessments in Ankylosing Spondylitis. J Rheumatol 999; 26: ANDERSON JJ, BARON G, VAN DER HEIJDE D, FELSON DT, DOUGADOS M: Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum 200; 44: S-

Scottish Medicines Consortium

Scottish Medicines Consortium etanercept 25mg vial of powder for subcutaneous injection (Enbrel ) (No. 212/05) Wyeth New indication: severe active ankylosing spondylitis inadequately controlled by conventional