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

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Abstract

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.

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.

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], [4], [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.

Section snippets

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

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).

A comparison of study designs showed that the studies were mostly randomized, controlled trials (n = 21), or prospective observational studies (n = 18) (Fig. 2).

Regarding pharmacological therapy, of

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], [12], [13], [14], [15], [16], [17], [18], [21], [22]. Postulated reasons for this appear to be multifactorial, encompassing improvements in pain, inflammation, functionality, mobility, stiffness and fatigue achieved with

Conclusions

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

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.

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    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.

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