Seminars in Arthritis and Rheumatism 44 (2015) 542–550

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Tumour necrosis factor alpha inhibitor therapy and rehabilitation for the treatment of ankylosing spondylitis: A systematic review Ennio Lubrano, MD, PhDa,n, Antonio Spadaro, MDb, Giorgio Amato, MDc, Maurizio Benucci, MDd, Ilaria Cavazzana, MDe, Maria Sole Chimenti, MDf, Giovanni Ciancio, MDg, Giuseppe D'Alessandro, MDh, Rossella De Angelis, MDi, Salvatore Lupoli, MDj, Alfredo Maria Lurati, MDk, Caterina Naclerio, MDl, Romualdo Russo, MDm, Angelo Semeraro, MDn, Paola Tomietto, MDo, Carmelo Zuccaro, MDp, Gabriele De Marco, MDq a

Department of Medicine and Health Sciences, School of Medicine, University of Molise, via F. De Sanctis, Campobasso 86100, Italy Rheumatology Unit, Department of Internal Medicine and Medicine Specialties, Sapienza University of Rome, Rome, Italy c U.O. of Rheumatology, A.O.U. Polyclinic-Vittorio Emanuele, Catania, Italy d Rheumatology Unit, Hospital S.Giovanni di Dio, Florence, Italy e Rheumatology and Clinical Immunology Unit, Spedali Civili Hospital, Brescia, Italy f Rheumatology, Allergology and Clinical Immunology Unit, Medicina dei Sistemi Department, University of Rome Tor Vergata, Rome, Italy g Section of Rheumatology, Department of Clinical and Experimental Medicine, Sant'Anna University Hospital, Ferrara, Italy h Department of General Medicine, Ospedali Riuniti—University of Foggia, Foggia, Italy i Rheumatology Clinic, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy j Rheumatology Unit, Sant'Anna e San Sebastiano Hospital, Caserta, Italy k Rheumatology Unit, Fornaroli Hospital, Magenta, Italy l Rheumatology Unit, Internal Medicine Department, Mauro Scarlato Hospital, Scafati, Italy m Rheumatology Unit, Department of General Medicine and Medical Specialties, Cardarelli Hospital, Naples, Italy n Internal Medicine Unit, Outpatient Clinic of Rheumatology, ASL Taranto “Valle d'Itria” Hospital, Martina Franca (TA), Italy o Outpatient Unit of Rheumatology, Internal Medicine Clinic, Trieste, Italy p Geriatrics Unit, Outpatient Clinic of Rheumatology, Ospedale “Di Summa—Perrino”, Brindisi, Italy q Geriatric Rheumatology Unit, “Sant'Antonio” Hospital, Padua, Italy b

a r t i c l e in f o

abstract

Keywords: Ankylosing spondylitis Biologic Exercise Rehabilitation Systematic review

Objectives: To systematically review the evidence for a synergistic effect of combining rehabilitation with biological anti-tumour necrosis factor (TNF) therapy in patients with ankylosing spondylitis (AS). Methods: Data were analysed to identify the most effective rehabilitation programmes, the best endpoints for effectiveness, and patient subgroups most likely to benefit from combination therapy. Systematic MEDLINE and Embase searches were performed to identify studies evaluating rehabilitation programmes and biological therapy in patients with AS. Evidence was categorised by study type, and efficacy, adverse effects and other outcomes were summarised.

Abbreviations: anti-TNFα, tumour necrosis factor alpha inhibitor; AS, ankylosing spondylitis; ASAS, Assessments of SpondyloArthritis International Society; ASQOL, Ankylosing Spondylitis Quality of Life questionnaire; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; COPM, Canadian Occupational Performance Measure; DMARDs, disease-modifying antirheumatic drugs; EQ-5Dvas, visual analogue scale of EuroQol; EULAR, European League Against Rheumatism; GPR, Global Postural Re-education; HEM, home exercise model; IRM, in-patient rehabilitation model; NHP, Nottingham Health Profile; NSAIDs, non-steroidal anti-inflammatory drugs; QoL, quality of life; SF-36, Medical Outcome Study Short Form-36 Health Survey; TNF, tumour necrosis factor; VAS, visual analogue scale. Unrestricted grant for editorial assistance was provided by Pfizer, Italy. Pfizer has not been involved in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article. Dr Spadaro reported personal fees from Abbvie, Bristol Myers-Squibb, MSD, Pfizer, Roche and UCB, outside the submitted work. Dr De Angelis received fees from Wolters Kluwer Health Italy Srl and Springer Healthcare Italia Srl outside the submitted work. Dr Zuccaro reports personal fees from Bristol Myers-Squibb, MSD, Pfizer and Roche, outside the submitted work. Drs Benucci and Tomietto received fees from Wolters Kluwer Health Italy Srl during the conduct of the study; Dr De Marco reports grant from Pfizer during the conduct of the study. Drs Amato, Cavazzana and Ciancio received fees from Pfizer during the conduct of the study. Dr D'Alessandro reports grants from Pfizer during the conduct of the study and outside the submitted work. Drs Lubrano, Lurati, Naclerio, Russo, Semeraro, Lupoli and Chimenti declare no potential conflicts of interest. n Corresponding author. E-mail address: [email protected] (E. Lubrano). http://dx.doi.org/10.1016/j.semarthrit.2014.09.012 0049-0172/& 2014 Elsevier Inc. All rights reserved.

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Results: Of the 75 studies identified, 13 investigated the combination of a rehabilitation programme with TNF inhibitor therapy, while the remainder studied rehabilitation with standard therapy (often not specified). Data from these few studies suggest that combined rehabilitation plus anti-TNF therapy is more effective in terms of symptom severity, disease activity, disability and quality-of-life indices versus biologic alone or rehabilitation with standard medical therapy, or, in non-comparative studies, compared with baseline. The most effective rehabilitation appears to be supervised or in-patient programmes with an educational component. Available data do not provide guidance on most appropriate endpoints or identify patients most likely to benefit from combination therapy. Combined, TNF inhibitor and rehabilitation therapy appear to have a synergistic effect, possibly due to increased adherence to exercise. Exercise regimes are more effective if supervised and include an education component. Conclusions: Further randomized, controlled trials comparing endpoints and investigating longer-term benefits of combining TNF inhibitors with rehabilitation in different AS subgroups are needed. & 2014 Elsevier Inc. All rights reserved.

Introduction Ankylosing spondylitis (AS) is a chronic inflammatory disease that affects the joints of the spine and the sacroiliac joint in the pelvis predominantly, leading eventually to complete fusion of the spine [1]. The disease course is highly variable; symptoms of AS can vary from mild to progressively debilitating, and patients can experience alternating periods of active inflammation and remission, while others experience only acute inflammation and pain. Approximately one-third of patients will progress to severe disability [2]. The prevalence of AS, which ranges from less than 0.01% in Japan to 1.8% in Norwegian Samis (Lapps), tends to correlate with the prevalence of the HLA-B27 tissue type [3–5], but it varies substantially in epidemiologic reports from around the world [6]. The goal of AS treatment is to control symptoms and inflammation in order to prevent deformity and disability caused by new bone formation, and to halt or slow the decline in function and social participation, thus preserving patient quality of life (QoL) [7]. In 2011, the Assessments of SpondyloArthritis international Society (ASAS) and the European League Against Rheumatism (EULAR) published an update of the existing EULAR management recommendations for AS [7]. A multidisciplinary approach, coordinated by the rheumatologist, tailored to the individual patient profile, and including a combination of non-pharmacological and pharmacological treatment modalities is recommended [7]. In this update, unlike previous versions, the perspective of patients, as well as other health care professions such as physiotherapists, was considered and incorporated [7]. Even if the modality of combination treatment is not yet clear, the concept of combination treatment as the way towards achieving better management for this disease has been strengthened [8]. ASAS/EULAR describe regular exercise and patient education as the cornerstone of non-pharmacological treatment in patients with AS [7]. The positive effects of physical therapy have been proven in many studies as shown in comprehensive reviews [9,10] and, although a wide range of exercise programs are used in AS, there is still no clear indication of the relative effectiveness of the different types of exercise regimes. However, the updated guidelines now state that while home exercises are effective, in general, supervised individual or group exercises are shown to be more effective than home exercises due to adherence, and are, therefore, preferred [7,9]. ASAS/EULAR guidelines also recommend pharmacological treatments including non-steroidal anti-inflammatory drugs (NSAIDs) as first-line therapy, and a tumour necrosis factor (TNF) alpha inhibitor (anti-TNFα) as second-line medication in patients with persistently high disease activity despite conventional pharmacological treatment [7]. The primary aim of this review was to systematically investigate the evidence for a synergistic effect of combining rehabilitation with anti-TNF therapy, e.g., etanercept, infliximab, adalimumab, golimumab and certolizumab, in patients with AS.

Data were also analysed with respect to whether there is a particular subgroup of patients who are most likely to benefit from combination therapy.

Methods Search strategy A systematic search of MEDLINE and Embase was performed including clinical studies, conference abstracts, case reports and review articles. The following search terms were used and combined as follows: Ankylosing spondylitis AND (rehabilitation or physical therapy or exercise therapy or exercise protocol or home-based exercise or physiotherapy) AND (tumour necrosis factor or monoclonal antibodies or drug therapy); ankylosing spondylitis AND (rehabilitation or physical therapy or exercise therapy or exercise protocol or home-based exercise or physiotherapy) AND (education or anthropometry or anthropometric measurements or functional index or activities of daily living or metrology index or severity or illness or QoL). Publications from January 1996 to October 2013 were included; only English articles plus foreign-language articles with English abstracts and human studies were included.

Study selection The resulting articles were then subjected to manual searching of the bibliographies of identified papers, plus ad hoc searching was also performed. Clinical studies of physical rehabilitation in patients with AS receiving TNF inhibitors were selected manually from the search results and included in this review. Other clinical studies of physical rehabilitation in AS were also selected, e.g., in patients receiving other pharmacological interventions such as NSAIDs. Case reports and preclinical studies were excluded. Metaanalyses and systematic reviews were discussed separately. Narrative review articles, editorials and commentaries were not included in the review but were used for additional material for discussion. Articles not in the field of interest of this review, studies without clinical outcomes for AS and studies where the majority of the population had other spondyloarthropathies or AS patient data were not reported separately, were not included.

Data summaries For each included study, information concerning the study (authors, citation, year of publication, type of study, patient characteristics, treatment, details of rehabilitation regime used, endpoints and outcomes) was tabulated and the main findings were discussed.

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A comparison of study designs showed that the studies were mostly randomized, controlled trials (n ¼ 21), or prospective observational studies (n ¼ 18) (Fig. 2). Regarding pharmacological therapy, of the 75 publications, 45 publications did not mention the drug taken or did not provide details. In 12 of the studies, patients were already stabilized on TNF inhibitors at baseline or were randomized to TNF inhibitor treatment or rehabilitation or both, an anti-TNF agent or NSAID therapy was used in one study, NSAID 7 analgesics in eight, NSAIDs and/or disease-modifying antirheumatic drugs (DMARDs) were used in seven and DMARDs alone in two studies (Fig. 3). An analysis of the type of rehabilitation programmes used showed that exercise regimes were used in over 90%, over a quarter included any patient education and less than 10% included an occupational therapy component. Over two-thirds of studies used exercise regimes only, a fifth used a combination of exercise and patient education, and 4% used all three (Fig. 4). Data discussion

Fig. 1. Results of literature searching and results filtering.

Results Literature search The results of literature search and results filtering are shown in Figure 1. Supplementary Table S1 summarises the 75 clinical study publications identified and included in this review. The publications identified include 68 published as full articles and seven as abstracts (two of the same study).

Outcomes with or without pharmacological therapy Of the 13 studies in which some or all of patients received a TNF inhibitor, 12 investigated the combination of TNF inhibitor and a rehabilitation programme (two abstracts describing the same study) [11–23]. Of these, the patient populations were comparable among the studies, with similar inclusion criteria; most of the studies used the New York criteria (or modified version) to classify AS (Supplementary Table S1). In these 12 studies, the combination therapy of anti-TNF therapy plus rehabilitation was more effective in terms of symptom severity, functional and QoL indices, activities of daily living, exercise parameters and anthropometric measurements, versus biologic alone, baseline, and/or control, and, in single-arm non-comparative studies, compared with previous regimen or baseline (Supplementary Table S1). In most of the studies (12 of 13) involving TNF inhibitor therapy, the patients were stabilised on their TNFα inhibitor before the start of the rehabilitation programme [11–14,17–24]. In two studies [15,16], patients were initiated on to etanercept for the purposes of the study, either after they had undergone several months of intensive rehabilitation [16] or at the same time

Fig. 2. Breakdown of studies by type.

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Fig. 3. Breakdown of studies by pharmacological therapy.

as starting exercise therapy [15]. In both studies, combination therapy with etanercept and exercise-based rehabilitation programme improved function, disability, and QoL in patients with active AS compared to either rehabilitation without etanercept [16] or with etanercept alone [15]. Two studies evaluated outcomes with exercise before and after the start of TNF inhibitor therapy [12,14]. A cross-sectional survey of 32 AS patients showed that levels of home-based patient exercise (walking and swimming) increased with anti-TNF compared with prior to anti-TNFα treatment. In addition, patients perceived mild to moderate benefits in stiffness, function, fitness and overall outcome from physical therapy and anti-TNF, and motivation levels for exercise improved significantly with antiTNFα treatment [14]. A second study in which patients started a rehabilitation programme before anti-TNFα therapy showed that

although patients achieved improved metrology (spine mobility/ stiffness), pain and disease activity on rehabilitation alone, further significant improvements in mobility, pain and disease activity were seen when patients started anti-TNFα therapy, together with improvements in function and fitness [12]. Several studies showed the benefit of combination rehabilitation plus TNFα inhibitor versus TNFα inhibitor alone. In a study comparing etanercept alone or with spa-rehabilitation therapy in 60 AS patients, improvements in terms of function, disability and QoL were greater in the combination treatment group versus etanercept alone [11]. In an open, randomized, controlled trial in 60 AS patients receiving etanercept with or without a 12-week exercise programme, both groups achieved significant improvement (P o 0.05) in clinical outcomes, but the group receiving combination etanercept plus exercise achieved significantly

Fig. 4. Breakdown of rehabilitation programmes used in the studies.

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greater improvements in motor ability, functional capacity and QoL [15]. Similar results were seen in another study evaluating etanercept with and without rehabilitation; combination treatment improved function, disability and QoL versus etanercept alone [16]. In another trial of 62 AS patients stabilized on TNF inhibitor therapy, a combination of intensive group exercise with an educational–behavioural programme was more effective than an educational–behavioural programme alone and both provided in functional improvements and reduction in pain severity versus a control group that received only pharmacological treatment [17]. One study investigated the long-term impact of a 4-month exercise programme plus TNF inhibitor. In an evaluation of benefits with an aerobic exercise programme in patient stabilized on infliximab, the exercise was shown to provide short-term improvement in disease activity and disability, but this was not maintained long term. The authors speculated on the need for regular follow-up to ensure correct performance of exercises and improve compliance [13,21]. In most of the studies (60%) investigating impact of exercise/ lifestyle on outcome, pharmacological therapy was either not given or not mentioned and/or adjusted for in the analyses (Supplementary Table S1).

Comparison of rehabilitation components Comparison of the various types of physical exercise regime, patient education and/or occupational therapy used in each study (Supplementary Tables S1 and S2) showed that physical exercise regimes alone produced improved outcomes regardless of patient education or occupational therapy. Very few of the studies compared programmes with exercise with or without patient education or occupational therapy. Masiero et al. [17] demonstrated that a combination of intensive group exercise plus an educational– behavioural programme was significantly more effective than an educational–behavioural programme alone in patients stabilized with anti-TNF therapy, particularly in terms of improvements in Bath Ankylosing Spondylitis Metrology Index (BASMI) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), in chest expansion, and in most spinal active range of motion measurements [17], but the study did not contain an exercise-only arm, which would have been interesting. In another trial, supervised training and home-based rehabilitation (n ¼ 22) was compared with educational–behavioural therapy (n ¼ 24) or neither (n ¼ 24) in patients with stabilized AS receiving anti-TNFα therapy; significantly greater improvements in long-term outcome were seen in the rehabilitation group compared with the other two groups [23]. Two other studies have also demonstrated that home-based exercise or standard care can be enhanced by using an educational intervention package comprising exercise/information video or DVD, progress chart, patient education booklet, AS exercise reminder stickers and reminder follow-up calls [24,25]. In one of these, self-efficacy for exercise and self-reported levels of exercise were significantly improved and there was also a trend towards improved function in patients who had received the intervention package compared with those who had not [25]. In the other study, patients receiving education took more regular exercise, and physical function and QoL were higher as a result compared with those not receiving the educational intervention [24]. Another study demonstrated the benefits of a 1-day exercise coaching course in helping to change attitudes towards exercise and increasing confidence and motivation to exercise [26]. The possibility of added clinical benefits due to including an occupational health component as part of the rehabilitation programme was not investigated in any of the studies using it [12,18,27–29]; however, one controlled study showed that

occupational therapy was beneficial for patients with stable AS treated with anti-TNF agents, with synergistic effects on pain, function and disability [18]. Only three studies included all three components [18,27,28]. In one study, an in-patient rehabilitation model (IRM) was compared with a home exercise model (HEM) in 120 patients with RA and AS [27]. Benefits with IRM versus HEM were minimal in patients with AS [27]. In a short-term study of rehabilitation including a home exercise programme, individualised educational information on AS and individualised occupational therapy, and TNF inhibitor therapy, combination therapy provided synergistic benefits on pain, disability and function and these were greater than TNF inhibition alone [18]. In the study by Kjeken et al. [28], a 3-week multidisciplinary in-patient rehabilitation programme was individualised for the patient and included a physiotherapist-designed weekly exercise programme (a combination of gym and hot water pool exercises, and outdoor physical activities to develop cardiorespiratory fitness), individual physiotherapy including manual techniques, occupational therapy, education on energy conservation, alternative working methods, use of assistive technology, home and workplace modification, and fatigue management and sleep hygiene. The study found that the rehabilitation programme had a positive overall effect on disease activity, pain, function and well-being in patients with AS [28].

Comparing differences in exercise programmes Several studies compared exercise programmes or investigated the effect of exercise over time. From these, the more effective programmes were those that were group based or supervised [23,30–33] or included one-to-one physiotherapy sessions, or were residential or in-patient programmes [27,28] compared with home-based or conventional exercise [34–36]. One 6-year observational study showed that all AS patients had deteriorating mobility over time and this was not related to disease duration or to the frequency of unsupervised exercise [37]. Two studies have reported data showing that in-patient rehabilitation programmes were more effective than home-based exercises [27,28]. However, a study showed that the effectiveness of an in-patient rehabilitation programme declined over time, with clinical outcomes better at 6 weeks than at 12 weeks [38], and another showed that in-patient programmes were more effective in rheumatoid arthritis patients than for AS patients [27]. Another randomised study comparing intensive in-patient physiotherapy versus outpatient hydrotherapy plus home exercises or home exercises alone showed that although there were some shortterm benefits (2–4 months) for patients undergoing in-patient and hydrotherapy-based regimes, there was no difference in outcomes among the three groups at 6 months [33]. Several other studies have investigated the effect of spa treatments or balneotherapy for improvements of clinical AS outcomes [11,20,39–45]. In all studies, balneotherapy resulted in improved outcomes versus conventional exercise or pharmacotherapy alone. Findings from one prospective study suggest that balneotherapy alone can produce “sufficient” clinical improvement [45]. Another study investigating water-based exercise showed that swimming or aerobic exercise was beneficial in terms of improved QoL, pulmonary function and functional capacity compared with conventional exercise [46]. Four studies showed that Global Postural Re-education (GPR)based exercise, in which specific strengthening and flexibility exercises are sued to stretch and strengthen shortened muscle chains, resulted in better clinical outcomes than conventional stretching and breathing exercises [47–50]. So et al. [22] showed greater improvements in outcomes with combination incentive spirometer exercise (ISE)—a device that

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achieves and sustains maximal inspiration—plus conventional exercise versus conventional exercise alone, in 46 AS patients stabilized on TNF inhibitor therapy. Climate may also have an impact. This was suggested in a study comparing in-patient rehabilitation programmes in a Mediterranean country or in Norway [51]. While patients in both settings had similar improvements in physical function, both spinal mobility and ASAS improvement criteria were greater and more sustained in the Mediterranean setting.

Studies supporting the use of rehabilitation to improve pulmonary function Findings from a small pilot study investigating correlation between respiratory muscle performance and exercise capacity in AS suggest that respiratory pressure and respiratory muscle endurance may determine exercise capacity in AS [52]. Another small study showed that exercise training improves spinal flexibility and respiratory function in AS [53]. These data were supported by findings from a more recent study investigating links between pulmonary function and exercise tolerance in AS and healthy controls showing that exercise intolerance in AS patients was due mainly to impaired pulmonary function (resulting from restriction of chest expansion) and not musculoskeletalrelated disability [54], indicating that cardiopulmonary fitness should be an additional key treatment outcome in AS. Another recent study also showed that restrictive pulmonary function is associated with impaired spinal mobility AS, further emphasising the importance of maintaining spinal flexibility in AS [55]. Study endpoints A wide range of endpoints were used (Supplementary Table S1), although most focused on clinical outcomes and many were patient-reported outcomes, e.g., function [Bath Ankylosing Spondylitis Functional Index (BASFI)], spine mobility (BASMI) and disease activity (BASDAI), spinal pain VAS, etc. One study compared subjective and objective endpoints to measure rehabilitation effectiveness [56]. In this study, van Weely et al. [56] compared the BASFI scores—a subjective measure—with objective performance-based tests based on the BASFI items. They concluded that in the BASFI questionnaire, patients incorporate exertion and pain into their assessment of perceived physical function, whereas performancebased tests provide more objective measurement of physical function. Some studies included endpoints that assessed motivation and adherence to exercise/rehabilitation programmes [18,26,57–61]. Several studies reported QoL endpoints including Ankylosing Spondylitis Quality Of Life (ASQOL) questionnaire [15,62–64], the Nottingham Health Profile (NHP) total and social isolation scores [30,39,46], Medical Outcome Study Short Form-36 Health Survey (SF-36) [19,28,36,40,41,49,65,66] and the visual analogue scale of EuroQol (EQ-5Dvas) [11,16]. Two studies investigated the impact of educational programme on QoL [49,65]. One showed significant improvements in sleep disturbances, social functioning, and SF-26 role limitations due to emotional problems score with implementation of a swimming programme [65]. The other showed that a GPR-based exercise programme improved the SF-36 physical component score compared with conventional self-stretching and breathing exercises [49].

Studies investigating subgroups None of the studies investigated differences in rehabilitation in patients with early or newly diagnosed AS versus longer duration AS, none analysed data according to patient age and none

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specifically evaluated outcomes with biological versus standard NSAID/DMARD therapy. Cost-effectiveness studies Two studies analysed the cost-effectiveness of rehabilitation programme in patients with AS [43,67]. Using data from a randomized, controlled trial of 120 AS patients plus diary data, the cost-effectiveness of spa treatment was compared with homebased activities plus standard therapy (control group) [43]. Although the mean total costs per patient were considerably more for the spa-treated group, combined spa–exercise therapy plus standard pharmacotherapy and weekly group physical therapy was more effective and cost effective compared with standard treatment alone [43]. In a questionnaire-based cost-effectiveness analysis of supervised group physical therapy compared with unsupervised exercises at home in 144 AS patients, considerable benefits in terms of improved mobility, fitness and global heath were seen and total medical costs were reduced with supervised group physical therapy; however, overall costs increased [67].

Discussion Synergistic effect of rehabilitation plus biologic anti-TNFα therapy Rehabilitation therapy, particularly supervised or group-exercise programmes, in combination with TNF inhibitor therapy, appears to have a synergistic effect in patients with AS, with improved efficacy compared with biological therapy alone reported in most studies [11–18,21,22]. Postulated reasons for this appear to be multifactorial, encompassing improvements in pain, inflammation, functionality, mobility, stiffness and fatigue achieved with anti-TNF therapy, which in turn improves QoL and morale, and increases patient motivation for physical exercise [14]. Improved patient motivation is required to begin and maintain an exercise regime and more motivated patients are likely to spend longer periods of time on exercise as they will have greater perceived benefits of rehabilitation and exercise regimes [14]. Clinical implications/recommendations The present review showed that, even though TNF inhibitors have changed the treatment scenario of AS patients, there is still a strong rationale for rehabilitation, as we proposed few years ago [8]. In fact, the synergistic relationship between rehabilitation and biologic agents is clearly evident in all studies published. No clear data on the optimum form of rehabilitation have been obtained from the many published studies, but data suggest that the way towards an effective rehabilitation programme should include a supervised exercise programme with an educational component. In addition, there is some evidence to suggest that cardiorespiratory exercise could be beneficial. This review reveals that the endpoints evaluated in all studies aimed to assess all domains affected by AS. These results confirmed that measurement of function, pain, QoL and perception of disease status could be the core set to be included in further studies. Moreover, the inclusion of these outcomes in real-life clinical practice could improve motivation and adherence to a rehabilitation programme for an individual patient. The measurement of rehabilitation effectiveness and its effect on patient QoL should take specific and validated tools into consideration. For instance, occupational therapy requires specific instruments to promote a patient-centred approach, such as the Canadian Occupational Performance Measure (COPM), a reliable tool in patients with AS [68].

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Another issue that has emerged from this review is the absence of data identifying particular subsets of patients most benefitting from treatment with combination rehabilitation and TNF inhibitor therapy. As a result, there is still an unmet need for definition of patients who should receive combination rehabilitation/TNF inhibitor therapy. In fact, no studies investigated the effect of combination therapy in the early stages of the disease (even in the pre-radiographic stages), and there were no subgroup analyses comparing a shorter disease duration with late-stage AS. This could be a crucial aspect for investigation in further studies. Nevertheless, data show that a rehabilitation approach is the cornerstone of AS treatment in all patients, whereas, due to the wide range of damage and disease activity seen in clinical practice, additional specific interventions may be required for optimal treatment of individual patients.

Additionally, since most studies include patients with longstanding AS or do not specifically state the duration of disease at baseline or provide details of the pharmacotherapy used, the effects of combination TNF inhibitor and physical therapy in early AS are unknown. It would be useful to ascertain whether use of biological agents and rehabilitation programmes in patients with newly diagnosed/early AS are effective so that deformity and disability can be prevented. One could hypothesise that patients with shorter duration of disease and less disability may benefit greatly in the long term from a combined TNFα inhibitor and rehabilitation regimen, but data are lacking and large controlled trials are required. Given that rehabilitation and physical therapy are often among the first interventions to be dropped under increased pressures to cut costs [78], studies to assess the cost-effectiveness in this area are also urgently required.

Comparison with previous systematic reviews and treatment guidelines Conclusions These findings support those found in previous reviews or meta-analyses of non-pharmacological therapy in AS in that evidence suggests that any exercise is better than no exercise, group or supervised exercise is better than home exercise, home exercise can be improved by regular follow-up, all exercise regimes can be improved by the addition of patient education to the rehabilitation programmes, use of TNF inhibitors can increase the adherence to exercise programmes compared with standard pharmacotherapy, and the addition of a spa-based or residential exercise programme improves overall outcomes [9,10,57,69–76]. These findings are in agreement with the 2011 ASAS/EULAR recommendations and other guidelines for AS management, which recommend a multidisciplinary approach including a combination of pharmacological treatment and rehabilitation [7,72,77]. There is little evidence to show the benefit of one type of exercise or physical therapy over another; the important factor is that patients adhere to a regular and frequent regime to improve and/or preserve mobility and, thus, maintain QoL [10]. Limitations of this review Possible limitations of this systematic review are the small number of patients and the lack of controls in many of the studies, and the small number of studies investigating TNF inhibitor therapy in combination with a rehabilitation programme, all of which could influence the conclusions drawn. Future research needs Generally, there is a lack of data on the optimum physical therapy for patients with AS [75] and this has been confirmed in this systematic review. Although many studies have been published, most are small observational studies and there is a clear need for larger randomized, controlled studies, particularly those investigating the use of patient education and occupational therapy as an integral part of physical rehabilitation programs. A review of the literature on the effectiveness of non-pharmacological treatment modalities in AS supports the use of exercise and educational interventions with a cognitive behavioural component [69]. Another review highlighted the importance of patient educational and occupational therapy components in a comprehensive rehabilitation programme, in order to stabilise the course of the disease [78]. This systematic review showed that there are very limited longterm data on the effectiveness of combination TNF inhibitor treatment and physical therapy or rehabilitation programmes in AS and, therefore, the long-term benefits are unclear.

The combination of a TNF inhibitor with rehabilitation therapy appears to have a synergistic effect, providing improved efficacy in patients with AS. Although the data are not clear, studies suggest that an effective rehabilitation programme should include supervised exercise and patient education. Our findings also show that core assessment parameters should include measurement of function, pain, QoL and perception of disease status and should be adopted in clinical studies and in real-life clinical practice to improve motivation and adherence to a rehabilitation programme. Our recommendations should be used in conjunction with current treatment guidelines. Although our data confirm that a rehabilitation approach is the cornerstone of AS treatment, there is an unmet need regarding the identification of patients who would most benefit from combination rehabilitation/TNF inhibitor therapy, particularly regarding effects in patients with shorter disease duration compared with late-stage AS. Therefore, randomized, controlled trials investigating the short- and long-term benefits of combining TNF inhibitors with rehabilitation in early, as well as later-stage AS, are needed, as are trial-identifying patients who would be most likely to benefit from this treatment modality.

Acknowledgements This review is dedicated to the memory of Professor Antonio Spadaro, who joined, intellectually conceived and contributed to the present study. He was a scientist and a respected and beloved physician of the Sapienza University of Rome. Medical writing assistance and technical editing have been provided by Andrea Bothwell and Mary Hines of Springer Healthcare Communications.

Appendix A. Supporting Information Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.semarthrit.2014.09.012.

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Tumour necrosis factor alpha inhibitor therapy and rehabilitation for the treatment of ankylosing spondylitis: a systematic review.

To systematically review the evidence for a synergistic effect of combining rehabilitation with biological anti-tumour necrosis factor (TNF) therapy i...
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