COMBINATION TREATMENT WITH ETANERCEPT AND AN INTENSIVE SPA REHABILITATION PROGRAM IN ACTIVE ANKYLOSING SPONDYLITIS

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1 INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY Vol. 22, no. 4, (2009) COMBINATION TREATMENT WITH ETANERCEPT AND AN INTENSIVE SPA REHABILITATION PROGRAM IN ACTIVE ANKYLOSING SPONDYLITIS M. COLINA, G. CIANCIO, R. GARAVINP, M. CONTP, F. TROTTAandM. GOVONI Rheumatology Section, Department ofclinical andexperimental Medicine, University offerrara; 1Presidio di Medicina Fisica e Riabilitazione delle Terme di Castrocaro, Italy Received May 8, AcceptedSeptember 24, 2009 The aim of this study is to determine the effects of a combination treatment with etanercept and spa rehabilitation versus etanercept alone on function, disability and quality of life in a group of patients with active ankylosing spondylitis (AS). Sixty patients with AS underwent etanercept as suggested by ASAS/EULAR recommendations. As the clinical and laboratory conditions improved, 30 patients accepted the proposal of coupling the medical therapy with a 7-day rehabilitation program in a thermal baths centre; the remaining 30 subjects continued to take the biologic agent alone. The comparisons between the 2 groups were made after 3 and 6 months. The primary outcome was an improvement in BASFI. The secondary outcome was an improvement in the visual analogic scale of EuroQol (EQ 5Dvas). After 6 months a statistically significant improvement in BASFI (p < 0.05) and EQ-5D vas (p < 0.05) scores was observed in both groups. The mean change in EQ-5D vas value showed a statistically significant difference in favour of the combination therapy group versus the monotherapy group (22 vs 32, P < 0.05). A therapeutic regimen combining etanercept with an intensive rehabilitation program contributes to disability reduction and ameliorates quality of life for AS patients. Ankylosing spondylitis (AS) is a chronic, inflammatory disease predominantly affecting young men. It is found worldwide, but more often in Caucasians, and the prevalence is reported to be about 0.1 to 0.2% (1-2). A typical target of the disease is the axial skeleton, and in particular the sacroiliac joints. Some patients may also experience peripheral arthritis and/or extra-articular manifestations such as acute anterior uveitis (3). The disease is mainly characterized by reduced spinal mobility with stiffness and pain, leading to severe functional impairment, disability and poor quality of life (4). As required pharmacological and nonpharmacological therapy and advice from different health professionals is suggested. Pharmacological therapy has been based for many years on nonsteroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine and methotrexate, which have only shown some beneficial effect on peripheral arthritis (5-7). Anti-tumor necrosis factor-a (TNF-a) agents have changed the approach to treatment of AS patients (8-10). Among them, etanercept has proved effective in controlling painful symptoms, reducing disability and improving the quality of life (10). Despite this, physiotherapy is still important in the treatment ofthe disease and it is more effective when carried out in a supervised spa group setting (11). It Key words: ankylosing spondylitis, rehabilitation, etanercept, BASFL quality oflife Mailing address: Matteo Colina, MD Sezione di Reumatologia, Dipartimento di Medicina Clinica e Sperimentale Universita degli Studi di Ferrara, Azienda S. Anna, Corso della Giovecca, Ferrara, Italy Fax: teocolina@libero.it (2009) Copyright by BIOLIFE, s.a.s, This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties

2 1126 M. COLINA ET AL. is well accepted that the strong effect of anti-tnfa agents in relieving pain and stiffness could play a crucial role in warranting a favourable background for an effective rehabilitation program in AS patients (12). The aim ofthis study is to compare and evaluate the effects of anti-tnfa agent etanercept and spa rehabilitation vs etanercept alone on function, disability and quality of life in a group of patients with active AS. MATERIALS AND METHODS We enrolled 60 patients consecutively referred to our Clinic between September 2006 and August 2007 with active AS, who underwent etanercept therapy. All patients satisfied the modified New York classification criteria for AS (13). Inclusion criteria to start anti- TNFa therapywere the following: previous NSAIDs therapy failure (given for at least 3 months), a Bath AS Functional Index (BASFI) 2': 4, persistently high markers ofinflammation and a global health visual analogic scale (VAS) score or a pain VAS score 2': 40 (on a scale of 100 mm), Etanercept was selfadministered by patients as a 25 mg dose subcutaneously twice weekly. When etanercept treatment began, the majority ofpatients initially refused the physical program due to discomfort and pain. However, after 2 months, as the clinical conditions improved, 30 patients accepted the proposal to couple the medical therapy with a 7-day intensive rehabilitation program in a thermal baths center, while the remaining 30 subjects continued the therapy with the biologic agent alone. This proportion was completely random and was not dependent on prior decision. The intensive rehabilitation program was conducted in a thermal baths center by expert physiotherapists under the supervision of a physiatrist and included: hydro-kinesitherapy sessions, respiratory fitness sessions, massotherapy, muscular strengthening exercises with active and passive kinesitherapy, postural education and education on home self-treatment (Table I). The evaluation of efficacy and comparison between the 2 groups was made after 3 and 6 months. The primary outcome measure was an improvement ofbasfi, while the secondary outcome measure was an improvement in the self-rating VAS scale (0-100) of the European quality of life (EuroQol) questionnaire (EQ-5Dvas). The BASFI and the EQ-5D vas score were administered at the beginning of etanercept therapy, at the beginning of the intensive spa therapy and after 3 and 6 months following the 7-day rehabilitation program. Peripheral joint involvement, as well as ocular and skin manifestations were also tabulated, and HLA-B27 was assessed. Descriptive data were expressed as mean ± standard deviation. Statistical analysis was carried out using the t-test for paired and unpaired data. RESULTS As far as demographic characteristics and disease activity indices at the baseline are concerned, Table II shows that the two groups were homogeneous. Notably, we were dealing with long-standing diseases (with a mean duration of more than 8 years in both groups). Before starting etanercept, considering the two groups as a whole, mean BASDAI value was 7.3 ± 1.9 and mean BASFI value was 6.9 ± 1.6; mean EQ-5D vas value was 16 ± 4.8. After 2 months.of etanercepttherapy, the mean BASFI value had decreased to 5.6 ± 2.2 in the group who decided to couple the pharmacological therapy with the spa rehabilitation program and to 5.3 ± 2.5 in the group who continued the biologic agent alone. Quality of life also improved in all patients. The primary and secondary outcome measures at3 and 6 months are shown in Fig. 1. Three months after.,the intensive spa rehabilitation program a statistically significant improvement in BASFI scores was observed in both groups, without significant statistical differences between the 2 groups for the mean change in BASFI score. These results were confirmed after 6 months. After 3 and 6 months a statistically significant improvement in EQ-5Dvas scores was observed in both groups. In addition, the mean change in EQ-5Dvas value showed a statistically significant difference in favour of the combination therapy group both at 3 and 6 months. No patient experienced major adverse events due to etanercept. DISCUSSION Before the development of TNF-u antagonists, the treatment of AS was disappointing, leading to debilitating pain, spinal fusion and progressive disability. Because of the few pharmacological options, physical therapy has remained a mainstay for the treatment ofas in order to reduce pain, preserve spinal flexibility, prevent postural deformities and improve muscle strength. Although the TNF-a antagonism has dramatically changed the therapeutic scenario for patients with AS by providing symptom relief, retarding spinal inflammation and improving

3 Int. J. ImmunopatboI. Pbarmacol MONTHS FROM BA SELINE 5 MONTHS FROM II BASEUNE 8 MONTHS FROM BASEUNE _ ---'= = "-"-- BASEUNE I T w 80 P.tIe",. a BASFI : 2 69 m. G R EQ-5Dva s: ETA a 16 u p s $! I I BASI"I: BathAnkyJosingSpondJllilis l"unctionallndex; EQ-5Dvas: visualamjogicscale oferoqoi; mls: mol'llhs Fig. 1. Disposition ofthe patients in the study. Table I. Daily spa rehabilitation program. Morning Activities Description Session -Flex/extension ofthe trunk and lower limbs Individual Balneokinesitherapy -Trunk torsion and twist shoulderjoints Individual program ofexercise in thermal water -Controlled relaxing ofthe spine 30' Respiratory Kinesiterapy -Thoraco-pulrnonary mobilization Active - assisted exercises and respiratory -Chest and upper arms mobilization 30' exercises -Thoraco-pulmonary push and pull Functional Rehabilitation (passive and active mobilization: stretching and massage) -Cervical spine and upper trunk mobility -Exercises for lumbar and dorsal spine strength 40' Postural rehabilitation (exercises and advice on body balance) Afternoon -Postural correction therapy -Stategy for good body mechanics 40' -Education on selfcare Health meeting groups -Specific information from specialists in psychology, rheumatology and rehabilitation 60' quality of life, the role of physical therapy should not be considered obsolete. The importance of exercise in AS was also highlighted by the Authors of the Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism (EULAR) recommendations for the management of AS, who included exercise therapy among their 10 recommendations (14). The

1128 M. COLINA ET AL. Table II. Demographics characteristics at the baseline. Monotherapy Combination therapy Number of patients 30 30 Mean age (SD) 41.6 ± 6.9 40.7 ± 7.

4 1128 M. COLINA ET AL. Table II. Demographics characteristics at the baseline. Monotherapy Combination therapy Number of patients Mean age (SD) 41.6 ± ± 7.2 Mean duration of disease (SD) 8.8 ± ±3.2 Peripheral arthritis (%) 6 (20%) 7 (22%) Skin involvement 1 1 Ocular involvement 1 0 HLAB27+(%) 24 (80%) 23 (78%) Mean age and mean duration ofdisease are expressedin years. SD: standard deviation strong effect of etanercept on inflammation and fatigue, in fact, surely plays a role in enhancing the physical performance ofas patients. It has also been demonstrated as important in increasing their motivational levels for physical therapy (15). To the best of our knowledge, this is the first study reporting the comparison between combination therapy with etanercept and an intensive spa rehabilitation program and etanercept therapy alone. In our studywe couldnot demonstrate an improvement of the functional index probably because we treated long-standing diseases and the functionality is strictly dependant on anatomical changes that had already occurred in the majority of our patients. For this reason it would be of huge interest to evaluate the efficacy of the combination therapy in patients with "early" axial spondyloarthropathies, in whom a greater improvement of the functionality index would be expected. For this reason, we believe that the "old" spa therapy is regaining credit in the midst of this "new", exciting, biologic era. It is worthy ofnote that we observed a significant beneficial effect of the combination therapy on quality of life, lasting up to 6 months after the intensive 7 day rehabilitation program. As we have shown, the association of etanercept and a spa rehabilitation program can induce a better quality of life in AS patients even in the short term. Unfortunately, the short observation period does not permit us to deduce the real effect that this therapeutic strategy can yield over the very long natural history of this disease and further studies with longer follow-up are needed. Our study did not.consider socio-economic aspects, since bothetanercept and spa rehabilitation are expensive for the national health system in Italy. This might represent a limitation requiring a cost! benefit evaluation. It is also worth underlining that the spa rehabilitation program did not begin at the same time as the therapy with etanercept because the majority of the patients refused the physical activity due to pain and stiffness. Consequently, we preferred to wait until a significant number ofpatients agreed to participate in the thermal rehabilitation program. In conclusion, our study confirms that combination treatment with etanercept and an intensive spa rehabilitation program contributes to disability reduction and ameliorates quality of life for AS patients. Combination treatment should be considered the best choice for the treatment ofas. ACKNOWLEDGEMENTS This work was supported by a grant of CARIFE in as part of the University of Ferrara sponsorship collaboration

Int. J. Immunopathol. Pharmacol. 1129 REFERENCES 1. Gran JT, Husby G. The epidemiology of ankylosing spondylitis. Semin Arthritis Rheum 1993; 22:319 34. 2. Will R, Edmunds L, Elswood J, et al.

5 Int. J. Immunopathol. Pharmacol REFERENCES 1. Gran JT, Husby G. The epidemiology of ankylosing spondylitis. Semin Arthritis Rheum 1993; 22: Will R, Edmunds L, Elswood J, et al. Is there sexual inequality in ankylosing spondylitis? A study of 498 women and 1,202 men. J Rheumatol1990; 17: Khan MA. Clinical features ofankylosing spondylitis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology, 3rd edn. Mosby, London 2003, Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis: an overview. Ann Rheum Dis 2002; 61(S): Clegg DO, Reda DJ, Weisman MH, et al. Comparison of sulfasalazine and placebo in treatment of ankylosing spondylitis: a Depatments of Veteran Affairs cooperative study. Arthritis Rheum 1996; 39: Dougados M, van der Linden S, Leirisalo Repo M, et al. Sulfasalazine in the treatment of spondyloarthropathy: a randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 1995; 38: Roychowdhury B, Bintley-Bagot S, Bulgen DY, et al. Is methotrexate effective in ankylosing spondylitis? Rheumatology 2002; 41: Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor a. N Engl J Med 2002; 346: Braun J, Brandt J, Listing J, et al. Treatment ofactive ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: Ca1inA, Dijkmans BA, Emery P, et al. Outcome ofa multi centre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2004; 63: Dagfinrud H, Kvien TK, Hagen KB. The Cochrane review ofphysiotherapy interventions for ankylosing spondylitis. J Rheumato12005; 32: Lubrano E, D' Angelo S, Parson WJ, et al. Effects ofa combination treatment of an intensive rehabilitation program and etanercept in patients with ankylosing spondylitis: a pilot study. J Rheumatol 2006; 33: Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modifications ofthe New York criteria. Arthritis Rheum 1984; 27: Zochling J, van der Heijde D, Burgos-Vargas R, et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 2006; 65: Dubey SG, Leeder J, Gaffney K. Physical therapy in anti- TNF treated patients with ankylosing spondylitis. Rheumatology 2008; 47:

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