Abstract
Axial involvement in patients with psoriatic arthritis (PsA) remains common and can be defined in terms of spinal disease alone or in combination with peripheral manifestations. Diagnosis is based upon inflammatory spinal symptoms or the presence of radiological sacroiliitis and other radiographic signs of spondylitis, or by criteria for axial spondyloarthritis (SpA) defined by ASAS (Assessment of SpondyloArthritis International Society). Although recent data are scarce for efficacy of traditional therapies for axial disease (e.g., nonsteroidal antiinflammatory drugs, methotrexate, etc.), limited data are available for targeted biologics and novel agents. We identify and evaluate the efficacy of therapeutic interventions for treatment of axial disease in PsA. This review is an update of the axial PsA section of the treatment recommendations project by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).
Despite shared features with ankylosing spondylitis (AS), important distinctions in patients with axial psoriatic arthritis (axPsA) include reduced male preponderance; less overall spinal disease severity; asymmetric and less severe sacroiliitis; “spotty” asymmetric distribution of marginal and paramarginal syndesmophytes with random progression, better preservation of spinal mobility; relative sparing of apophyseal joints; frequent involvement of cervical spine; and reduced association with the HLA-B*27 allele1,2,3. However, although recent data confirm these observations, no differences were found in the effect of axPsA on functional capacity, disease activity, and quality of life, compared to AS4.
Treatments for axial disease in PsA have not been specifically studied, because no formal effort has been undertaken to identify this patient subset. Small numbers of patients in PsA trials have defined “spondylitis,” and equally small numbers of patients in AS trials have psoriasis. In the absence of adequate studies in patients with axPsA, criteria and outcome measures developed for AS have been accepted by consensus for use in axPsA, and response to therapy assumed to be equivalent between AS and axPsA. This view is supported by 2 recent studies comparing axPsA and AS that confirmed no differences as far as effect on functional capacity, disease activity, and quality of life5. However, in a prospective cohort study of 201 patients with axPsA, the Bath AS Disease Activity Index (BASDAI) showed only good to moderate ability to discriminate between high and low disease activity, and no significant superiority over the AS Disease Activity Score (ASDAS). Moreover, sensitivity to change and minimal clinically significant differences have not been demonstrated6.
This systematic review is an update of one published with GRAPPA collaboration in 20065. We set out to answer the following questions: What published graded evidence is available to guide therapy for axPsA? Given the paucity of clinical trial data for axPsA, what evidence base exists for therapy in AS?
The literature of Medline, Embase, CINAHL, and the Cochrane Library from 2006 to March 2014 was searched using the key words [MeSH (US National Library of Medicine Medical Subject Headings)] “Ankylosing Spondylitis (AS),” “Psoriatic Arthritis (PsA),” “AS and PsA,” “PsA and axial disease,” “spondylarthropathy (SpA) and psoriasis,” “spondylitis and psoriasis,” “anti-rheumatic therapy,” as well as combinations of the following key words with PsA: spondylarthropathy or spondylitis: salazopyrine, methotrexate (MTX), physiotherapy, pamidronate, gold oral and intramuscular, azathioprine, cyclosporine, hydroxychloroquine, infliximab, etanercept, adalimumab, and tumor necrosis factor (TNF), apremilast, ustekinumab, tocilizumab, secukinumab, brodalumab, rituximab, and abatacept.
Articles were selected that specifically addressed axial disease and its therapy in psoriasis, PsA, AS, or SpA. In addition, abstracts were extracted from annual meetings of the American College of Rheumatology and the European League Against Rheumatism from 2006 to 2014. Abstracts were admitted only if sufficient detail was available to determine level of evidence.
Evidence extracted from the published literature and/or from expert opinion was graded according to the recommendations of AHCPR 1994 as defined in previous articles5.
Satisfactory treatment for axPsA should aim to relieve signs and symptoms (i.e., pain, stiffness, and restriction in spinal mobility); improve physical functioning and quality of life; inhibit progression of structural damage; and prevent disability. Although outcome measures in axPsA are under active assessment and require formal validation, the ASAS Working Group has developed response criteria for improvement in AS; by consensus these were used in this review7. ASAS-validated composite measures assess disease activity (BASDAI), function (Bath AS Functional Index), patient global (Bath AS Global Index), and spinal mobility (Bath AS Metrology Index). Structural damage is evaluated using validated radiographic instruments [Bath AS Radiology Index/modified Stoke AS Spine Score (BASRI/mSASSS)]. The recently defined Psoriatic Arthritis Spondylitis Radiology Index needs further validation8,9.
Results in Previous GRAPPA Review
No new studies have been published since the 2006 GRAPPA article on the following specific therapies for axPsA: physiotherapy, simple analgesia, nonsteroidal antiinflammatory drugs (NSAID), corticosteroids, sulfasalazine, thalidomide, auranofin, cyclosporine, leflunomide, MTX, anakinra, and bisphosphonates5.
Results Specific to This Review
NSAID
Two studies in AS have suggested that continuous NSAID therapy could retard radiographic progression in AS10,11. This has not been examined in axPsA.
Methotrexate
Although no new data are available, the Methotrexate in Psoriatic Arthritis (MIPA) study12 was unable to show significant superiority of MTX compared to placebo in PsA; however, no attempt was made to analyze efficacy in axPsA.
Targeted Biologic Therapies
Anti-TNF therapy
In AS, psoriasis, and PsA, Level A evidence is available for significant benefit with etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab on disease activity, range of motion, physical function, and quality of life, both as monotherapy and as add-on therapy to other disease modifying antirheumatic drugs (DMARD). Radiological progression was retarded in PsA with etanercept, adalimumab, certolizumab, golimumab, and infliximab13,14,15,16,17. Significant response was seen with certolizumab in NSAID-refractory patients with long-standing and severe disease (RAPID-axSpA trial), and benefit was maintained out to 12 months with continued therapy (level of evidence 1a Grade A)13. In an observational study of patients with PsA with axial manifestations, the effectiveness at 12 months of etanercept therapy was assessed per the ASAS response criteria; 72% of patients had improvement in the BASDAI, as well as in other outcome measures15.
In the golimumab PsA study16, enthesitis and dactylitis were scored, but no attempt was made to score axial disease or assess response to treatment, despite 10%–12% of patients having spondylitis with peripheral arthritis. In the golimumab AS study, despite 5%–11.4% of patients having psoriasis, no attempt was made to analyze this small cohort for response separate to the overall AS group18.
In the certolizumab, RAPID-axSpA trial, no psoriasis subset was defined13. In the adalimumab study of nonradiographic axSpA, psoriasis and PsA were exclusions19. Two studies with etanercept have shown some evidence that anti-TNF therapy may retard structural damage in AS20,21, but this is unknown in axPsA.
With the exception of infliximab, DMARD co-therapy (MTX) does not appear to improve anti-TNF survival/retention22.
Outstanding issues under investigation include optimal longterm maintenance dosage and schedule of administration, formal economic analysis assessing the cost-benefit of these therapies in SpA, and prognostic factors for determining response to anti-TNF treatment.
For considerations of safety, both short- and long-term, and the effect size of therapeutic interventions, physicians should refer to ASAS recommendations.
Novel Agents
In a phase 3, 12-month study, ustekinumab [monoclonal antibody directed against the p40 subunit of interleukin 12 (IL-12) and IL-23] showed significant reduction in BASDAI 20 and 70 (but not 50) at the 45-mg dose (subcutaneous; baseline, week 4, then every 12 weeks), and significant reduction at BASDAI 20/50/70 levels at the 90-mg dose, in addition to significant reductions in enthesitis and dactylitis (Level 1a)23.
A study of secukinumab (IL-17 inhibitor) excluded SpA24; however, enthesitis was not significantly improved. A placebo-controlled, phase 2, 12-week study of subcutaneous brodalumab, an IL-17A receptor antibody, showed BASDAI was significantly improved at the 280-mg dose but not 140-mg dose, nor were there improvements in enthesitis and dactylitis25.
Tocilizumab and sarilumab (IL-6 inhibitors), abatacept (T cell costimulation inhibitor), and rituximab (CD20 inhibitor) have failed to show efficacy in AS and have not been formally tested in axPsA26,27,28,29. In the PALACE studies of apremilast (phosphodiesterase type 4 inhibitor), PsA patients were analyzed for dactylitis and enthesitis but not axial disease30. JAKinase inhibitors are presently under study.
We suggest that the 2010 updated ASAS specifications and definitions for diagnosis, assessment of disease, treatment failure, treatment contraindications, and assessment of response be applied to study axPsA until more formal studies are performed in this subset and validated outcome measures are developed for this domain7.