Therapeutic Controversies in Spondyloarthritis




Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a first-line therapy in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis. NSAIDs reduce pain and stiffness effectively in most patients, are able to reduce systemic and local inflammation, and can inhibit progression of structural damage in the spine. However, effective control of symptoms and retardation of radiographic progression often require continuous and long-term treatment, which raises safety concerns. This article discusses controversies related to the current role of NSAIDs in axSpA treatment, risks and benefits of this treatment, and current trends for individualized treatment.








  • Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a first-line therapy in axial spondyloarthritis, including ankylosing spondylitis.



  • NSAIDs are highly effective in reduction of spondyloarthritis symptoms, including pain and stiffness.



  • NSAIDs also reduce activity of systemic inflammation and might have a (small) impact on the activity of local inflammatory lesions in the sacroiliac joints and the spine.



  • NSAIDs are able to reduce progression of structural damage in the spine if administered continuously, especially in patients who already have signs of structural damage (syndesmophytes) and elevated C-reactive protein and/or erythrocyte sedimentation rate.



  • Cardiovascular, gastrointestinal, renal, and hepatic risks should be taken into account if an NSAID is administered, especially if a long-term and continuous treatment is anticipated.



Key Points


Introduction


Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a first-line therapy in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS). Beyond NSAIDs, only tumor necrosis factor α (TNF-α) blockers are currently available and effective for treating axial signs and symptoms of patients with active axSpA. In contrast to rheumatoid arthritis, for example, disease-modifying antirheumatic drugs and corticosteroids play only a minor role in the management of axSpA, and only in the case of peripheral joint involvement. In the joint ASAS (Assessment of SpondyloArthritis international Society) and EULAR (European League Against Rheumatism) recommendations for the management of axSpA, continuous treatment with NSAIDs is preferred for patients with persistently active symptomatic disease. Continuous treatment with NSAIDs, however, raises safety issues. In a survey on the application of the ASAS/EULAR recommendations, 38% of European rheumatologists mentioned safety concerns as the main barrier for not using NSAIDs more consistently in patients with AS.


This article discusses the current role of NSAIDs in axSpA treatment, including the risks and benefits of NSAID use and current trends for more individualized treatment strategies.




Clinical efficacy of NSAIDs


So far, clinical trials with NSAIDs have only been performed in patients with established AS. However, based mainly on clinical experience, NSAIDs can be expected also to be highly effective in patients with nonradiographic axSpA (nr-axSpA), or those with axSpA who did not develop (yet) radiographic sacroiliitis. Thus, patients with nr-axSpA should be treated with NSAIDs similarly to those with AS. Furthermore, NSAIDs also play an important role in the management of patients with predominant peripheral spondyloarthritis, who show only a limited response to conventional disease-modifying antirheumatic drugs.


High clinical efficacy of NSAIDs for treating axial signs and symptoms of active axSpA/AS was shown (against placebo and an active comparator) in several clinical trials with nonselective cyclooxygenase (COX) inhibitors and selective COX-2 antagonists. All NSAIDs, independently from their COX selectivity, are nearly equally effective in their therapeutic doses for reducing pain and stiffness in axSpA/AS. Nonetheless, great individual variation exists in response to and tolerability of NSAIDs. In general, trying at least one NSAID, but frequently several others, is worthwhile in case one is found to be ineffective. This sampling is also frequently performed in clinical practice: more than 20% of 1080 patients with AS who participated in a survey on NSAID use in Germany reported that they used at least 2 different NSAIDs (5% used ≥3 NSAIDs) within the past year.


Good or very good improvement of AS symptoms is usually reported by 60% to 80% of patients treated with NSAIDs. In contrast, this level of response is only reported by approximately 15% of patients with chronic low back pain from noninflammatory causes. Furthermore, a good response to NSAID treatment is also used as a diagnostic approach to differentiate chronic back pain of inflammatory origin from other causes. Moreover, good pain control is necessary to perform physiotherapy effectively. Many clinical trials showed that reduction of pain and stiffness during NSAID therapy was associated with improvement of functional status in patients with AS measured using the Bath Ankylosing Spondylitis Functional Index. Up to 35% of active patients with AS treated with a full dose of an NSAID can fulfill even the ASAS criteria for partial remission. In a survey performed in Germany, almost 20% of the patients with AS reported complete pain control with NSAIDs, and another 60% of the patients reported a reduction in pain level from one-quarter to one-half.


In most cases, NSAIDs reduce pain and stiffness rapidly, and a full effect can normally be observed after 48 to 72 hours. In some cases, a longer treatment period (up to 2 weeks) is necessary to achieve the complete anti-inflammatory and analgesic effect of an NSAID. However, if a response is not experienced within 2 weeks, it is unlikely to occur with continued treatment.


To judge the therapeutic effect of an NSAID in a patient with axSpA/AS, a full therapeutic (inflammatory) dose is usually required. The dose and the intake frequency could be, however, adjusted based on the patient’s symptom intensity. In some patients with AS, a moderate dose might be sufficient for long-term treatment, whereas in others the highest tolerated dose might be necessary to achieve an optimal effect. On the group level, a higher efficacy could be demonstrated in patients treated with a higher dose of celecoxib (400 vs 200 mg/d), etoricoxib (120 vs 90 mg/d), or meloxicam (22.5 vs 15 mg/d) compared with a lower dose.


Recently, the ASAS developed a recommendation for collecting, analyzing, and reporting NSAID intake in clinical trials and/or epidemiologic studies in axSpA. An index of NSAID intake was proposed, taking both dose and duration into account ( Box 1 ). This index includes an NSAID equivalent score, which represents a standardized dose of an NSAID taken. Daily diclofenac dose of 150 mg (maximal recommended dose for treatment of arthritis) was accepted by consensus as a reference value, with the equivalent score of 100. Equivalent doses of other widely used NSAIDs are presented in Table 1 . Daily doses of NSAIDs presented in table can be considered as full therapeutic doses for treatment of axSpA/AS.



Box 1



Index of NSAID intake = NSAID equivalent score × Days of intake during period of interest × Days per week Period of interest in days


Example: patient took diclofenac, 75 mg every day over the last 4 weeks that was also a period of interest. Index of NSAID intake = 50 (equivalent score for 75 mg of diclofenac every day) × 28 (4 weeks of intake) × 7/7 (the NSAID was taken daily)/28 (period of interest) = 50.


Formula for calculating the ASAS index of NSAID intake

Data from Dougados M, Simon P, Braun J, et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. Ann Rheum Dis 2011;70(2):249–51.


Table 1

Daily doses of NSAIDs equivalent to diclofenac 150 mg/d (NSAID equivalent score = 100)

















































NSAID Dose Therapeutically Equivalent to 150 mg of Diclofenac (Full Therapeutic Dose) in AS
(mg)
Aceclofenac a 200
Celecoxib 400
Etodolac 600
Etoricoxib a 90
Flurbiprofen 200
Ibuprofen 2400
Indomethacin 150
Ketoprofen 200
Meloxicam 15
Naproxen 1000
Nimesulide b 200
Phenylbutazone c 400
Piroxicam 20
Tenoxicam a 20

Data from Dougados M, Simon P, Braun J, et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiologic studies in axial spondyloarthritis. Ann Rheum Dis 2011;70(2):249–51.

a Currently not available in the United States.


b Not available in the United States, limited available in the European Union for short-term (up to 2 weeks) treatment of acute pain and primary dysmenorrhoea.


c Not available in the United States, limited available in the European Union for short-term (up to 1 week) treatment.





Clinical efficacy of NSAIDs


So far, clinical trials with NSAIDs have only been performed in patients with established AS. However, based mainly on clinical experience, NSAIDs can be expected also to be highly effective in patients with nonradiographic axSpA (nr-axSpA), or those with axSpA who did not develop (yet) radiographic sacroiliitis. Thus, patients with nr-axSpA should be treated with NSAIDs similarly to those with AS. Furthermore, NSAIDs also play an important role in the management of patients with predominant peripheral spondyloarthritis, who show only a limited response to conventional disease-modifying antirheumatic drugs.


High clinical efficacy of NSAIDs for treating axial signs and symptoms of active axSpA/AS was shown (against placebo and an active comparator) in several clinical trials with nonselective cyclooxygenase (COX) inhibitors and selective COX-2 antagonists. All NSAIDs, independently from their COX selectivity, are nearly equally effective in their therapeutic doses for reducing pain and stiffness in axSpA/AS. Nonetheless, great individual variation exists in response to and tolerability of NSAIDs. In general, trying at least one NSAID, but frequently several others, is worthwhile in case one is found to be ineffective. This sampling is also frequently performed in clinical practice: more than 20% of 1080 patients with AS who participated in a survey on NSAID use in Germany reported that they used at least 2 different NSAIDs (5% used ≥3 NSAIDs) within the past year.


Good or very good improvement of AS symptoms is usually reported by 60% to 80% of patients treated with NSAIDs. In contrast, this level of response is only reported by approximately 15% of patients with chronic low back pain from noninflammatory causes. Furthermore, a good response to NSAID treatment is also used as a diagnostic approach to differentiate chronic back pain of inflammatory origin from other causes. Moreover, good pain control is necessary to perform physiotherapy effectively. Many clinical trials showed that reduction of pain and stiffness during NSAID therapy was associated with improvement of functional status in patients with AS measured using the Bath Ankylosing Spondylitis Functional Index. Up to 35% of active patients with AS treated with a full dose of an NSAID can fulfill even the ASAS criteria for partial remission. In a survey performed in Germany, almost 20% of the patients with AS reported complete pain control with NSAIDs, and another 60% of the patients reported a reduction in pain level from one-quarter to one-half.


In most cases, NSAIDs reduce pain and stiffness rapidly, and a full effect can normally be observed after 48 to 72 hours. In some cases, a longer treatment period (up to 2 weeks) is necessary to achieve the complete anti-inflammatory and analgesic effect of an NSAID. However, if a response is not experienced within 2 weeks, it is unlikely to occur with continued treatment.


To judge the therapeutic effect of an NSAID in a patient with axSpA/AS, a full therapeutic (inflammatory) dose is usually required. The dose and the intake frequency could be, however, adjusted based on the patient’s symptom intensity. In some patients with AS, a moderate dose might be sufficient for long-term treatment, whereas in others the highest tolerated dose might be necessary to achieve an optimal effect. On the group level, a higher efficacy could be demonstrated in patients treated with a higher dose of celecoxib (400 vs 200 mg/d), etoricoxib (120 vs 90 mg/d), or meloxicam (22.5 vs 15 mg/d) compared with a lower dose.


Recently, the ASAS developed a recommendation for collecting, analyzing, and reporting NSAID intake in clinical trials and/or epidemiologic studies in axSpA. An index of NSAID intake was proposed, taking both dose and duration into account ( Box 1 ). This index includes an NSAID equivalent score, which represents a standardized dose of an NSAID taken. Daily diclofenac dose of 150 mg (maximal recommended dose for treatment of arthritis) was accepted by consensus as a reference value, with the equivalent score of 100. Equivalent doses of other widely used NSAIDs are presented in Table 1 . Daily doses of NSAIDs presented in table can be considered as full therapeutic doses for treatment of axSpA/AS.



Box 1



Index of NSAID intake = NSAID equivalent score × Days of intake during period of interest × Days per week Period of interest in days


Example: patient took diclofenac, 75 mg every day over the last 4 weeks that was also a period of interest. Index of NSAID intake = 50 (equivalent score for 75 mg of diclofenac every day) × 28 (4 weeks of intake) × 7/7 (the NSAID was taken daily)/28 (period of interest) = 50.


Formula for calculating the ASAS index of NSAID intake

Data from Dougados M, Simon P, Braun J, et al. ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. Ann Rheum Dis 2011;70(2):249–51.


Table 1

Daily doses of NSAIDs equivalent to diclofenac 150 mg/d (NSAID equivalent score = 100)

















































NSAID Dose Therapeutically Equivalent to 150 mg of Diclofenac (Full Therapeutic Dose) in AS
(mg)
Aceclofenac a 200
Celecoxib 400
Etodolac 600
Etoricoxib a 90
Flurbiprofen 200
Ibuprofen 2400
Indomethacin 150
Ketoprofen 200
Meloxicam 15
Naproxen 1000
Nimesulide b 200
Phenylbutazone c 400
Piroxicam 20
Tenoxicam a 20

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Therapeutic Controversies in Spondyloarthritis
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