Ankylosing spondylitis (AS) is the most prototypic of a group of arthritides collectively known as spondyloarthritis (SpA) that are associated with the human leukocyte antigen B27 (HLA B27). The hallmarks of disease include sacroiliitis, spinal inflammatory lesions around intervertebral discs, costovertebral joints, facet joints and entheses, extraspinal inflammation in large joints as well as entheses, and extra articular manifestations such as psoriasis, inflammatory bowel disease (IBD) and acute anterior uveitis (AAU). A defining feature of disease is the development of ankylosis in the sacroiliac joints, across intervertebral discs, and in the facet joints. Disease onset is typically in the third and fourth decades of life, although it may present in children either with asymmetric involvement of large joints in the lower limbs or a syndrome of enthesopathy and involvement of the tarsal joints. Males are affected twice as frequently as females, and there is marked geographic diversity in prevalence and phenotypic manifestations. By far, the commonest presentation is lower back or buttock pain that may be difficult to distinguish from other causes of spinal pain, particularly in primary care practice. This may be the primary reason why diagnostic delay averages 8 to 9 years from onset of symptoms, even in countries with advanced health care systems. This chapter provides an integrated case-focused and evidence-based overview of the treatment of AS from its earliest manifestations to the most recalcitrant disease likely to be encountered in the clinic. A dominant theme, regardless of clinical presentation, is that this is a disease that requires decades of management for most patients and a comprehensive treatment plan that may include educational, physical, medical, and even surgical treatment modalities.
UNCOMPLICATED EARLY AKYLOSING SPONDYLITIS
A 25-year-old woman presents with a 2-year history of lower back and right buttock pain radiating into the posterior thigh associated with stiffness that is most prominent in the mornings, lasting 2 to 4 hours, and recurring after sitting for prolonged periods at her secretarial desk. Getting out of her chair and moving for 10 to 15 minutes alleviates her stiffness, as will exercise at her local gym. She is fatigued and often wakes up in the second half of the night with pain and stiffness alleviated by getting out of bed and walking around the house for 5 minutes. Her symptoms are interfering with her work. She is otherwise in good health. In the family history, she recalled that her grandmother had back trouble throughout her life. She has tried several over-the-counter analgesics and is now taking ibuprofen 200 mg 4 times a day on a regular basis for the past month. Physical examination shows no abnormalities. Laboratory analysis shows that she is HLA-B27 positive and her C-reactive protein (CRP) is slightly elevated at 12 mg/dL. Pelvic x-ray study indicates abnormal right sacroiliac joint with indistinct iliac subchondral bone and widening of the joint space in the lower one third of the joint.
This case highlights characteristic features of early disease, namely a typical history of inflammatory back pain, unremarkable physical examination, acute phase reactants that may be normal or only slightly elevated, positive screening test for HLA-B27, and minimal plain radiographic features so that more sensitive imaging modalities such as magnetic resonance imaging (MRI) may be warranted. Self-medication for spinal symptoms even before the primary care physician visit is typical, and patients often prefer analgesics with anti-inflammatory properties rather than acetaminophen alone. This patient continues to have significant symptoms of pain and stiffness despite having taken maximum recommended doses of ibuprofen for over-the-counter use and further therapy is warranted.
What are the key principles of management for patients with newly diagnosed AS?
At this stage of disease, the primary objectives are to reduce symptoms of pain, stiffness, and fatigue, and to maintain function and mobility, thereby preventing disability and improving work productivity and the quality of life. A comprehensive treatment plan for this patient should be recommended under the following headings.
Patient Education
Most patients are typically unaware of this disease and require counseling on several themes related to prognosis, impact on work and family life, an approach to regular exercise, and appropriate use of nonpharmacologic pain management techniques, relaxation, and cognitive distraction. Moreover, young patients are particularly distraught to learn that this is a genetic condition and often express anxieties regarding transmission of disease to offspring. In addition to the reassurance provided by the physician, patients should be encouraged to attend group educational programs where available specifically for patients with AS. These have been shown to improve depression, self-efficacy, psychological well-being, and self-efficacy for exercise. There are limited data on the effectiveness of these programs. No comparisons between studies are possible owing to the heterogeneous nature of these programs. However, there appears to be general agreement that they promote coping with the emotional consequences of disease diagnosis and participating in decisions concerning treatment. Increasingly patients seek help through the electronic media and patient support groups such as The Spondylitis Association of America ( www.spondylitis.org ) provide extensive resources that help patients manage their disease.
Physical Modalities
Physiotherapy aimed at improving mobility of the spine and peripheral joints, and strengthening the axial and proximal musculature, and improvement in general fitness is an essential component of the management of all stages of disease. A vital role for the physiotherapist is also to promote an overall understanding of the necessity and appropriateness of regular exercise. Several exercise regimens have been described in the literature that include unsupervised individual exercise prescribed by a physiotherapist according to a predefined protocol of instruction, supervised individual exercises performed either at home or at a physiotherapy center, supervised group physical therapy, and in-patient physiotherapy typically consisting of a 2- to 4-week program of more intensive exercise aimed at correcting posture, improving flexibility, and motivating patients to pursue regular exercise when they leave the program.
It is difficult to recommend any particular approach due to their heterogeneous nature and their limited evaluation in controlled studies where interventions are poorly described. There is also a lack of consistency in outcomes assessed and use of independent blinded assessors. A Cochrane Review and a subsequent modification considered 43 studies of which only six trials met the criteria for inclusion in the review. These included a total of 561 participants enrolled in two trials that compared individualized home exercise programs with no intervention, three trials that compared weekly supervised group physiotherapy with an individualized home exercise program, and a single spa therapy clinical trial that assessed a program of physical exercises, walking, postural correction, hydrotherapy, sports, bathing in thermal water or sauna received at a spa compared with a home-based program of weekly group therapy. It was concluded that there was some benefit for group physiotherapy with small improvements in spinal mobility and patient global assessment, which could be due to mutual motivation and exchange of experience with similarly affected participants. Spa therapy was also beneficial for pain, although most studies were generally consistent in demonstrating that no approach is of benefit for treating symptoms, especially pain. Longitudinal study has shown that exercise intervention should be regularly reinforced and consistently applied by the patient to prevent functional disability and is most useful among those who have had AS for 15 years or less.
Disease-Modifying Antirheumatic Drugs
These agents are primarily used to improve pain, stiffness, function, mobility, and overall patient wellbeing. Two categories of drugs are available; nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant therapies such as analgesics and antidepressants.
NSAIDs have been the cornerstone of pharmacologic intervention for AS since their introduction in the 1950s. Their ability to suppress the production of proinflammatory prostaglandins through inhibition of cyclo-oxygenase is well known, although additional properties have been described, including suppression of neutrophil functions, which may lead to reduction of free oxygen radicals, reduced adhesion to endothelium, and decreased chemotaxis. These agents also inhibit both constitutively expressed cyclo-oxygenase-1 (COX-1), which is responsible for the physiologic production of cytoprotective prostaglandins in the gastric mucosa, as well as the highly regulated cyclo-oxygenase-2 (COX-2), which is increased in inflammatory tissues. Although these agents express varying degrees of inhibition of the cellular and enzymatic pathways leading to inflammation, this appears to have relatively little relevance with respect to their efficacy in AS. However, it is likely that the minimal efficacy of aspirin and salicylates for AS is due to their low potency in inhibiting COX-2. A total of six randomized placebo-controlled trials have shown that NSAIDs are effective for alleviating pain and stiffness and improving function and mobility. These studies evaluated two agents that are not commonly used in clinical practice, namely piroxicam and ximoprofen, and were generally of only 2 to 6 weeks in duration. One study compared piroxicam with meloxicam over 52 weeks after a 6 week placebo-controlled phase. Two more recent studies examined COX-2–selective agents, celecoxib and etoricoxib, and suggested that these agents might be more effective than nonselective NSAIDs. What all studies have shown is that maximal efficacy is attained by 2 weeks, which constitutes an appropriate trial of therapy. The clinical benefit of attempting second and third trials of treatment with alternative NSAIDs cannot be determined from the controlled studies performed to date which have typically enrolled patients experiencing a flare following withdrawal of NSAID and have therefore preselected for NSAID responsive patients. Nevertheless, several treatment recommendations support the use of at least two to three courses of different NSAIDs over 2 to 4 weeks before patients are considered NSAID refractory.
Between 10% and 60% of patients receiving NSAIDs experience minor gastrointestinal symptoms such as nausea, dyspepsia, epigastric pain, and diarrhea, whereas more serious effects such as ulcers, upper gastrointestinal bleeding, and perforation occur in 2% to 4% of patients using NSAIDs for 12 months. Increasing age, use of NSAID combinations, and comorbidity increase the risk for such adverse events. Although COX-2–selective agents are associated with significantly decreased risk of major gastrointestinal side effects, the risk of less serious and more common gastrointestinal symptoms (dyspepsia, abdominal pain, nausea, flatulence, diarrhea) are not significantly reduced. An increased risk for significant cardiovascular events is now well established for COX-2–selective agents. One study of etorocoxib that recruited 387 patients who received treatment for up to a year recorded five serious cardiovascular thrombotic events in patients receiving this agent. Additional concerns include hypertension, peripheral edema and congestive heart failure, and compromise of renal function in patients with pre-existing renal dysfunction.
Summary of Management Recommendations for Prototypic Case of Early Uncomplicated Ankylosing Spondylitis
This patient was reassured that satisfactory disease control could be achieved in up to two thirds of patients with a conservative regime of regular daily exercise aimed at maintaining spinal flexibility and core muscle strength, together with the use of NSAIDs such as naproxen taken in doses up to 500 mg twice daily as required for the relief of symptoms of pain and stiffness ( Table 5-1 ). Review of the patient’s background medical history verified no propensity to gastrointestinal side effects. The patient was referred to group physiotherapy and an educational program aimed at patients with AS and provided with the website address for The Spondylitis Association of America ( www.spondylitis.org ).
| Principal Clinical Features | Objectives of Treatment | Management Considerations | Key References |
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ESTABLISHED AS UNRESPONSIVE TO CONSERVATIVE THERAPIES
A 45-year-old man presents with a 16-year history of AS that has until the past 6 months been symptomatically well controlled with diclofenac 75 mg twice daily. He has morning stiffness of 2 hours’ duration that is alleviated when he works as a construction laborer. He sleeps poorly due to frequent nocturnal awakening with pain and stiffness and is fatigued throughout the day. He is increasingly taking days off work due to sick leave. In his past medical history, he had a prolapsed lumbar disc associated with heavy lifting at work. Physical examination showed restricted lumbar flexion, with Schober’s test being 2.5 cm, chest expansion being 3 cm, and cervical rotation measured with a goniometer being 50 degrees to left and right. Laboratory evaluation showed that he is HLA-B27 positive and has normal acute phase reactants but elevated serum metalloproteinase 3. Radiography showed sacroiliitis and several syndesmophytes in the thoracic and lumbar spine with fusion of several of the facet joints. The attending physician discontinued diclofenac and instituted naproxen 500 mg bd. One month later, the patient reported no significant benefit.
This patient has ongoing symptoms of pain and stiffness despite an adequate trial of 2 NSAIDs at maximum recommended dosage, has impaired spinal mobility, and x-rays indicate progression of disease from the sacroiliac joints to the spine. It would be appropriate to monitor this patient’s progress in a systematic manner using validated outcome instruments such as the Bath AS Disease Activity Index (BASDAI) and the Bath AS Function Index (BASFI). Both are self-reported questionnaires, the former having 6 items and the latter having 10 items. Each has a scoring range from 0 to 100, using a 0 to 100 Visual Analogue Scale for each item. Treatment recommendations call for the re-evaluation of treatment in AS patients who have active symptoms as recorded by a BASDAI score of at least 40 despite the use of at least 2 different NSAIDS. Additional evidence of disease activity is desirable such as an elevated CRP, which may be normal in up to a half of all patients, or active inflammation on MRI of the spine and/or sacroiliac joints.
What should be the approach to the management of established AS when patients have active disease and are refractory to NSAIDs?
Only anti-tumor necrosis factor-α (anti-TNF-α)–directed therapies are of proven efficacy in this category of patient.
Anti-Tumor Necrosis Factor-α–Directed Therapies
The introduction of anti-TNF-α–directed therapies for the treatment of AS constitutes a significant advance in the treatment of this disease, particularly for patients who are refractory to NSAIDs. TNF-α is a pivotal cytokine associated with inflammation and has been demonstrated in mononuclear cells invading cartilage in both sacroiliac joints and entheses, whereas over-expression in mice is associated with the development of sacroiliitis. Inhibition of TNF-α has been achieved by the development of either monoclonal antibodies that bind both circulating and cell membrane bound forms of TNF-α or by soluble receptor proteins that primarily bind circulating TNF-α. Currently available monoclonal antibodies include infliximab, a chimeric monoclonal IgG1 that has a variable portion that is murine in origin while the remainder is of human origin, and adalimumab which is completely human in origin. Etanercept is a complex recombinant protein whereby two 75-kDa TNF receptor moieties are bound by an IgG1 Fc portion, which prolongs the half life of the receptor portion from a few minutes to about 16 hours. Infliximab is administered as an intravenous infusion over 2 hours at baseline, and 2 weeks, 6 weeks and every 6 to 8 weeks thereafter. Clinical trials primarily evaluated a dose of 5 mg/kg, although a lower dose of 3 mg/kg may also be effective and considered at the start of treatment with dose escalation for suboptimal responses. Etanercept is administered as a dose of 50 mg by once-weekly subcutaneous injection. Adalimumab is also given by subcutaneous injection at a dose of 40 mg on alternate weeks.
A total of nine randomized placebo-controlled trials have demonstrated substantial symptomatic benefit in NSAID refractory patients with reduction in pain, stiffness, function, and fatigue, which may be seen as soon as 2 weeks after the start of therapy while improvement in spinal mobility is also evident from 12 weeks onward. Maximal benefit is seen by 12 weeks and is sustained over prolonged periods of several years. Other benefits include improved quality of life, reduced sick leave, improvement in work productivity, reduced acute phase reactants, improvement in synovial histopathology and reduction in MRI features of inflammation that are sustained over several years. These agents appear to be of similar clinical efficacy for axial and peripheral joint inflammation with clinically evident responses being observed in about 60% of patients. All categories and subgroups of patients appear to respond, although younger patients with shorter disease duration, minimal impairment of function, elevated CRP, and MRI features of inflammation appear to respond best. However, even patients with complete spinal ankylosis report significant symptomatic improvement.
Despite the circumstantial data cited above suggesting that these agents might have a beneficial impact on the progression of radiographic changes, recent studies do not support such an effect in the spine. Radiographic change in the spine is measured using the modified Stoke AS Spinal Score (mSASSS), which records sclerosis, squaring, erosion, syndesmophytes, and ankylosis in the anterior vertebral corners of the cervical and lumbar spine. Changes in the thoracic spine are not recorded owing to lack of adequate visibility caused by overlapping soft tissues. The rate of progression in patients on standard therapy is slow and requires 2 years before change can be reliably detected, which is problematic for clinical trials where ethical considerations require that patients receiving only background NSAID treatment switch to open label anti-TNF therapy after 12 to 24 weeks. Consequently, patients in the long term open label extensions of placebo-controlled randomized trials of anti-TNF agents have been compared with a historical cohort of patients on standard therapy. No differences in rates of radiographic progression have been observed with any of the three available anti-TNF agents. It should be noted that the same comparator cohort was evaluated in all three studies, and AS patients had long-established disease so that potential for reversibility may have been limited.
Potential adverse events of anti-TNF agents are similar to those that have been reported in patients with rheumatoid arthritis (RA). Tuberculosis and other forms of sepsis may be less common in AS patients in view of the younger demographic and lack of concomitant immunosuppressive therapy. There is little information on malignancies, and the reported higher frequency of lymphoma in RA patients receiving these therapies may not necessarily be observed in AS, which has not been associated with increased rates of lymphoma. Infusion reactions have been noted in patients with AS receiving infliximab, although less commonly than anticipated, considering the lack of use of concomitant methotrexate therapy. Nevertheless higher rates of infusion reactions and loss of efficacy are related to the development of antichimeric antibodies.
Summary of Management Recommendations for Prototypic Case of Established Ankylosing Spondylitis Unresponsive to Conservative Therapies
In view of this patient’s occupation and prior history of disc prolapse, an MRI was ordered and showed active inflammation in the spine and sacroiliac joints. A BASDAI was completed, and the patient scored 7.8, indicating highly symptomatic AS. The use of any one of the three available anti-TNF agents is appropriate, the choice of specific agent being dictated largely by patient preference with respect to mode of administration. The patient was sent for another course of group physiotherapy. NSAID therapy should be continued on a regular basis because one 2-year study has shown that continuous therapy was associated with less radiographic progression than on demand treatment. This patient has already developed syndesmophytes on x-ray study, and this is a risk factor for further progression, together with elevated serum metalloproteinase-3. This recommendation has to be weighed against individual patient risk for gastrointestinal and cardiovascular adverse events ( Table 5-2 ).
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