|Year : 2020 | Volume
| Issue : 3 | Page : 107-113
Management of ankylosing spondylitis; present concepts and guidelines
Ramaswamy Subramanian1, Shiva Prasad2
1 Department of Rheumatology and Immunology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
2 Department of Rheumatology and Immunology, Apollo BGS Hospital, Mysore, Karnataka, India
|Date of Submission||19-Oct-2019|
|Date of Acceptance||10-Nov-2019|
|Date of Web Publication||15-Jul-2020|
Dr. Shiva Prasad
Consultant Rheumatologist, Apollo BGS Hospital, Mysore, Karnataka
Source of Support: None, Conflict of Interest: None
Ankylosing spondylitis (AS) belongs to spondyloarthritis (SpA) group of inflammatory arthritis, which has common genetic, clinical, and radiological features. The management aims at improving the quality of life, long-term control of inflammation so as to prevent structural damage, preserve functional abilities, and maintain the social life of patients. Treatment strategies and modalities in inflammatory arthritis have tremendously improved in recent times. With the discovery of molecular mechanisms, a new series of targets involving the cytokines, cells, and intracellular signaling pathways have been explored. The introduction of tumor necrosis factor inhibitor drugs heralded a new era of therapeutics for SpA, especially AS. Recently, the licensing of secukinumab, an interleukin 17A inhibitor for the treatment of AS, has given a new pathway to look at. These new targets give us an opportunity to achieve disease remission in both AS and nonradiologic axial SpA. They have also opened up new horizon to look for different research strategies in achieving disease remission using biological drugs in early disease and in stratified manner. International societies have been regularly providing and updating the guidelines for the management of AS. In this review, we discuss the treatment of AS and future trends in the management.
Keywords: Ankylosing spondylitis, antitumor necrosis factor agents, spondyloarthropathy
|How to cite this article:|
Subramanian R, Prasad S. Management of ankylosing spondylitis; present concepts and guidelines. APIK J Int Med 2020;8:107-13
|How to cite this URL:|
Subramanian R, Prasad S. Management of ankylosing spondylitis; present concepts and guidelines. APIK J Int Med [serial online] 2020 [cited 2020 Aug 14];8:107-13. Available from: http://www.ajim.in/text.asp?2020/8/3/107/289800
| Introduction|| |
Spondyloarthritis (SpA) is an inflammatory musculoskeletal disease comprising different phenotypic subsets with common genetic (HLA B27), radiologic, and clinical features [Figure 1]. As per the earliest classification by Moll et al., it consists of ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, arthritis related to inflammatory bowel disease (IBD), and a subgroup of juvenile idiopathic arthritis called Juvenile AS (recently classified as Juvenile idiopathic arthritis – enthesitis-related arthritis). Recently, the Assessment of SpA International Society (ASAS) established their classification criteria that identify two large SpA subtypes, axial and peripheral SpA, with AS and psoriatic arthritis as clinical prototypes, respectively., Axial SpA (axSpA) has diverse clinical presentations. Chronic back pain is the leading symptom of the disease, and often, it is inflammatory with pronounced stiffness, which improves with exercise. Other musculoskeletal manifestations of axSpA are peripheral arthritis, enthesitis, and dactylitis. Extra-articular manifestations such as anterior uveitis, psoriasis, and IBD (in order of decreasing prevalence) are also characteristic of axSpA., Historically, end-stage patients were recognized by a characteristic stooped posture and by the presence of syndesmophytes on radiographs of the spine. Subsequently, radiographic sacroiliitis became an important finding in the diagnosis and classification of patients as per the modified New York Criteria for AS. Only recently, it has been recognized that radiographic sacroiliitis is a late finding. Magnetic resonance imaging (MRI) may show signs of inflammation much earlier than radiographs showing structural damage. These patients can be diagnosed based on a typical clinical pattern even with normal X-ray of sacroiliac (SI) joints and elevated inflammatory markers. We can now classify axSpA patients with visible radiographic damage of the SI joints on X-ray as AS, whereas patients without X-ray sacroiliitis but MRI showing sacroiliitis features are classified as nonradiographic axSpA (nr-axSpA). There is still some debate as to whether AS and nr-axSpA should be considered as two different entities or as extremes of disease spectrum. The prevailing consensus is that axSpA encompasses one disease spectrum in which patients with nonradiographic axSpA may develop radiographic changes over time.
| Guiding Principles In The Management Of Ankylosing Spondylitis|| |
The primary goal of treating the patient with axSpA is to maximize long-term health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, and preservation/normalization of functional and social participation. The optimal management of axSpA requires the combination of both nonpharmacological and pharmacological treatment modalities., axSpA is a potentially severe disease with diverse manifestations, thereby requiring multidisciplinary management coordinated by the rheumatologist. Approximately 40% of the patients experience at least one extra-articular manifestation during the disease. These extra-articular manifestations require immediate consultation from other experts such as ophthalmologists and gastroenterologist. Treatment of axSpA should aim at the best care, and this must be based on a shared decision between the patient and the rheumatologist., High disease activity may lead to loss of work and later to depression due to functional inability. Treatment of axSpA incurs high individual, medical, and societal costs, all of which should be considered in its management. Information and education of patients about the disease represent key factors for improving SpA outcome, as well as rehabilitation represented by home exercises.
| Treatment Strategies in Spondyloarthritis|| |
Similar to the evolutions in the treatment of rheumatoid arthritis (RA) in the last decade, it becomes more relevant to define not only treatment strategies but also drugs or treatment options in AS. In RA, it has already been shown that early aggressive treatment has not only resulted in prevention of structural damage but also resulted in increased clinical response rate, with regard to low disease activity and remission.,, Both aspects are important to achieve a more favorable long-term outcome as it prevents structural damage. It is not still clear that treatment strategies such as early intervention, combination treatment, treat-to-target, and tight control are relevant or how much useful in SpA? Similarly, the type of evidence that needs to be generated to validate these strategies and the possible hurdles that to implement these strategies in clinical practice are yet to be established. This concept has not yet been clinically established in SpA as compared to RA. This may be because early diagnosis remains still a challenge (as there is no serological marker for SpA as in RA, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies). And also, nonsteroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are still considered the cornerstones due to financial constraints in our country and a gradual step-up treatment paradigm, leading to loss of precious time and structural damage. The concept of treatment strategies is yet to evolve in the field of SpA.
| Treatment Modalities for Axial Spondyloarthritis|| |
Patients of AS suffering from pain and stiffness should use an NSAID as the first-line drug treatment up to the maximum dose, taking risks and benefits into account., For patients who respond well to NSAIDs, continuous use is preferred. Other analgesics, paracetamol and opioid-(like) drugs, might be considered for residual pain after previously recommended treatments have failed, or contraindicated and/or poorly tolerated. Glucocorticoid injections to the local site of musculoskeletal inflammation such as joints, enthesitis, or dactylitis may be considered., Patients with axial disease should not receive long-term treatment with systemic glucocorticoids; usually, pulsing with high dose for acute control of disease activity is considered rather than using it continuously at low doses. Patients with purely axial disease should normally not be treated with csDMARDs as it has been observed that they are not going to decrease the pain or stiffness; sulfasalazine may be considered in patients with peripheral arthritis., Biologic DMARDs (bDMARDs) should be considered in patients with persistently high disease activity despite conventional treatments [Figure 2]., Two classes of bDMARDs showed efficacy and are recommended for the treatment of axSpA: tumor necrosis factor-alpha (TNFα) inhibitors (TNFi) and the interleukin (IL) 17 inhibitor secukinumab. Current practice is to start with TNFi therapy. Efficacy response should be assessed following 3–6 months of therapy and responders should then be reassessed every 6 months. If a patient is in sustained remission, tapering off a bDMARD can be considered. In the event of anti-TNF failure due to inefficacy or adverse events, an alternative TNFi agent or an anti-IL-17 therapy should be offered if clinically appropriate., The safety of TNFi agents in axSpA is similar to other inflammatory joint diseases such as RA.
Apart from drug therapy, these patients require nonpharmacological treatment as regular physiotherapy for the preservation of the range of movements of the spine and other joints. Recent studies confirm the beneficial effects of physical therapy and self-rehabilitation programs on disease activity and functional status (Bath AS Disease Activity Index [BASDAI] and BASFI).,, Total hip or knee arthroplasty or corrective osteotomy should be considered in patients with refractory pain or disability and radiographic evidence of structural damage, independent of age; in specialized centers, it may be considered in patients with severe disabling deformity., In a given clinical situation, causes other than inflammation, such as a spinal fracture, should be considered with appropriate evaluation, including imaging, should be performed.,
| When to Start Tumor Necrosis Factor Alpha Inhibitor Drugs in Spondyloarthritis|| |
Data from several clinical trials have demonstrated good efficacy and safety profiles from those TNFi drugs.,,,,,,, According to the current ASAS-European League Against Rheumatism (ASAS-EULAR) recommendations for patients with axSpA (both radiographic and nonradiographic), patients whose disease activity remains high despite the adequate therapeutic trial of at least two different NSAIDs, in maximal doses for at least 4 weeks in total, may be candidates for biological DMARDs., High disease activity is defined by the ASAS group as the AS Disease Activity Score ~2.1 and BASDAI ~4., Patients with nr-axSpA are additionally required to have either an elevated level C-reactive protein (CRP) or presence of active inflammation on MRI) of the SI joints, and they have also not responded to conventional treatment with NSAIDs.,
| Tumor Necrosis Factor Alpha Inhibitor Agents|| |
Since the beginning of 2000, TNFis are used for the management of SpA. There are five TNFi agents available for the treatment of AS: adalimumab, golimumab (both are completely humanized monoclonal antibodies), infliximab (chimeric monoclonal antibodies against TNFα), certolizumab pegol (a PEGylated Fab fragment of a monoclonal antibody against TNFα), and etanercept (a soluble TNF-receptor construct). Only infliximab is administered intravenously and has an induction regimen at 0, 2, and 6 weeks followed by a maintenance regimen for every 6–8 weeks. The other TNFis are administered subcutaneously. The evidence for these drugs comes from phase III randomized double-blind placebo-controlled clinical trials that included patients with confirmed AS that were treated with TNFi and compared with placebo. Evaluation of treatment responses in these studies was demonstrated by the ASAS response criteria. All the bDMARD therapies display efficacy against placebo, but no direct comparison on efficacy between biologics can be made as there are no head-to-head trials.,,,,,,,
| Action on Articular Symptoms|| |
All TNFis have demonstrated good efficacy clinically and in radiological responses. TNFi demonstrated strong and similar efficacy in clinical trials in active AS with substantial improvement of the symptoms (ASAS 40 response in 40%–50% of the patients; 50% improvement of the BASDAI achieved by 50%–60% of patients) and also reduction of active inflammation on MRI.,,,,,,, TNFi therapy is effective at reducing disease activity and spinal pain in axSpA, while short-term MRI data support the efficacy of TNFi therapy in treating inflammatory SI joint and spinal lesions in axSpA. However, the evidence for TNFi therapy on long-term radiographic progression is limited. Trials have been conducted with etanercept, one of which demonstrated a response rate of 57% among 138 individuals with AS., Infliximab trial in patients with AS showed an ASAS 20 response rate of 61.2% among 201 individuals with AS. In a study, both clinical and MRI assessments were conducted to explore the efficacy of infliximab compared with placebo in 40 HLA-B27-positive patients with MRI determined early sacroiliitis and symptoms of <3 years' duration. The mean reduction in total MRI score was significantly greater with infliximab than placebo, suggesting that infliximab is effective in treating early sacroiliitis. Notably, 55.6% of patients achieved partial remission, which is substantially higher than 22% who achieved partial remission in a study of the same therapy in established disease, thereby indicating the benefit of early treatment in patients with early nr-axSpA which is more reversible disease. Similarly, in a seminal trial of patients with AS involving adalimumab, the response rate for a 20% improvement in ASAS criteria (ASAS 20) was 58.2% in 208 participants in the active treatment arm. Studies have demonstrated the efficacy of TNFi therapy in nr-axSpA.,,, However, the burden of disease and the benefit derived from TNFi therapy are similar. Other TNFis, certolizumab and golimumab, have also shown similar efficacy in AS and nr-axSpA.,,
| Action on Extra-Articular Manifestations|| |
The most common extra-articular manifestations are uveitis, bowel disease, and skin involvement. TNFi (infliximab and adalimumab) decreases the rate of recurrences., A meta-analysis of studies about the use of TNFi (etanercept and infliximab) revealed that they significantly reduce the incidence of uveitis flares compared with placebo in patients with AS. Flares of anterior uveitis occurred less frequently under TNFi therapy (6.8/100 patient-years) compared with placebo (15.6/100 patient-years). TNFis (infliximab, etanercept, adalimumab, and golimumab) are effective in the treatment of skin and nail lesions of psoriasis. However, paradoxically, between 1.5% and 5% of patients may present an onset or exacerbation of psoriasis during treatment with TNFi., TNFi also decreases cardiovascular manifestations and atherosclerotic cardiovascular risk in SpA patients.,, The role of TNFi in the treatment of dactylitis and enthesitis has not been studied as the primary outcome measure in any trial. However, it has been looked as the secondary outcome. There is no consensus in the treatment modality for dactylitis. However, the current deduction from the trials basically from PsA has shown that NSAIDs and bDMARDs are efficient in resolution of dactylitis. All TNFis are similarly efficient in dactylitis and enthesitis.,,,,,,,
The best predictors of efficacy of TNFi in achieving a good response are raised CRP, short symptom duration or young age, and active inflammation on MRI. The main indicator of poor response is smoking, as shown from the German SpA Inception Cohortthat smokers suffer a dose-dependent deterioration on their structural damage over 2 years. Long-term results for biological treatment of SpA are available only for infliximab, etanercept, and adalimumab in AS. Overall, biological therapy in AS shows only partial remission or low disease activity based on the ASAS criteria.
Similar to RA, sustained drug-free remission is unlikely to be achieved following treatment with TNFi therapy. Studies in AS have demonstrated the near inevitability of disease relapse after discontinuation of treatment., The mean time to flare ranges from 6 weeks with etanercept to 17.5 weeks with infliximab. This suggests that continuous therapy with TNFi will be necessary to maintain clinical benefit in patients with AS. In a study, 97.6% of patients had relapsed by 52 weeks after discontinuation of infliximab following 3 years of continuous treatment. In the ESTHER Trial, patients with axSpA were treated with etanercept for 1 year; those in clinical and imaging remission were then discontinued and followed for a further year. Only 8% were in drug-free remission at 2 years. The impact of TNFi therapies on work participation in patients with AS has also been analyzed in a recent systematic review; 39 comparisons were reviewed, in nine studies, with most comparisons, suggesting positive work outcomes with treatment, but they were not tested for statistical significance. Overall, TNFi therapy has been shown to be an effective treatment for axSpA, but there is an unmet need because not all patients respond well to or are able to tolerate these treatments. In addition, however, no new safety signals were identified in patients with AS. TNFis are associated with an increased risk of infections and other adverse events and may not be tolerated or appropriate for all patients. Hence, there is a need for alternative treatment approaches that are safe and effective in axSpA.
| Precautions Before Prescribing Tumor Necrosis Factor Alpha Inhibitor|| |
It is recommended that before treatment with bDMARDs, patients should undergo relevant screening to identify potential contraindications, comorbidities, and risks. This is similar to axSpA as it is for other rheumatic diseases. It includes looking for prior history of demyelinating disease, malignancy, moderate-to-severe congestive heart failure using the New York Heart Association Grade III or IV, and case history risk assessment for tuberculosis (TB). Before starting TNFi therapy, screening for latent TB and hepatic viral infections is suggested to identify people at high risk of reactivating the disease. It is recommended that latent TB should be evaluated with either Mantoux or interferon gamma-related assays (Quantiferon gold TB test).
| Anti-Interleukin-17 Therapy in Axial Spondyloarthritis|| |
Antagonism of the IL-17 pathway represents an alternative approach in disrupting inflammation by targeting the predominant cytokine made by Th17 cells as well as a number of other cells. Secukinumab is a fully human monoclonal antibody (mAb) that selectively binds to IL-17A and is currently licensed for use in adult patients with active AS who have responded inadequately to conventional therapy; secukinumab is not licensed for use in nr-axSpA. In a double-blind, placebo-controlled study of 30 patients with active AS, 59% of patients who received secukinumab achieved an ASAS 20 response at week 6 compared with 24% of those on placebo, which sits favorably alongside response rates from TNFi therapies. Secukinumab has also been shown on MRI to reduce spinal inflammation as early as week 6 in patients with AS. Further evidence from two larger phase 3 studies (MEASURE 1 and MEASURE 2) showed significant reductions in disease activity in patients with AS, leading to the current license for secukinumab.,, Longer-term controlled studies are needed before definite. Conclusions can be made as to whether anti-IL-17 therapy is effective in inhibiting radiographic progression. It has also been effective in resolution of dactylitis and enthesitis. These come from the trials in PsA.
| Guidelines Review|| |
The guidelines given by international societies (ASAS-EULAR, ACR/SPARTAN) recommends the use of NSAIDs as the initial treatment for AS., This should be added with physiotherapy and patient education about the disease. If the patient responds to NSAIDs, it should be continued with regular monitoring. If the patient does not respond to two different NSAIDs given for a total duration of at least 4 weeks, then should be considered for biologic treatment. Since the evidence and experience of TNFi are higher, it is the first bDMARD to be started. If the patient does not respond or has side effects with it, then to be shifted to another TNFi or can be started on secukinumab., The tapering of bDMARDs is still speculated. Ideally, if response is present, it has to be continued. However, due to financial reasons, Tapering of the biological drugs should be attempted with gradual increase in the time interval in between the doses. For example, If a patient is on Etanercept 50 mg weekly, gradually increased the time interval between the doses to 10 days once, then two weekly once and three weekly once like that and stop afterwards if sustained remission is present. If there is any relapse of disease, it has to considered as described before.
| New Biologic Treatment Paradigms in Spondyloarthritis|| |
Despite the profound clinical efficacy of TNFi in SpA, a significant proportion of patients have either no response, a partial response with residual disease activity, or a loss of response over time. Ustekinumab, a mAb toward the p40 subunit of IL-23 and IL-12 was the first approved non-TNFi biologic in PsA. Two pivotal phase 3 studies demonstrated the efficacy of ustekinumab on peripheral arthritis, enthesitis, dactylitis, and skin disease in PsA., Efficacy was maintained over time, was inhibited radiographic progression, and was present albeit lower in patients previously exposed to TNFi. No specific safety signals emerged. In the absence of head-to-head trials with TNFi in PsA, the trend toward lower and slower response with ustekinumab on the joint but its good efficacy on skin may favor the use of this drug in TNFi-incomplete responders and in PsA patients with extensive skin disease. This includes the anti-IL-17RA antibody brodalumab (which reported phase 2 data, but the clinical program was interrupted because of a signal for suicidal ideation), the monoclonal anti-IL17A/F antibody bimekizumab, several antibodies toward the p19 (subunit of IL-23, guselkumab, tildrakizumab, and risankizumab), and several Janus kinase inhibitor (tofacitinib and baricitinib). If and when these treatments will be approved and will become available in clinical practice, it remains to be determined.
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[Figure 1], [Figure 2]