Abstract
This manuscript focuses on the pharmacologic treatment of psoriatic arthritis and axial spondyloarthritis – including ankylosing spondylitis – using traditional biologic and non-biologic disease-modifying antirheumatic drugs. Early treatment of psoriatic arthritis and axial spondyloarthritis/ankylosing spondylitis as well as the treat-to-target concept receive particular attention. This review also surveys recent national and international guidelines for the treatment of both psoriatic arthritis and couches practice recommendations for axial spondyloarthritis/ankylosing spondylitis within the context of various international guidelines.
Pharmacologic treatment of psoriatic arthritis
Traditional non-biologic disease-modifying antirheumatic drugs in PsA
In spite of the fact that several reviews and meta-analyses demonstrate a lack of efficacy for traditional non-biologic disease-modifying antirheumatic drugs (nb-DMARDs) in psoriatic arthritis (PsA), this class is the most commonly prescribed class of drugs used in the treatment of PsA around the world. This is particularly true of methotrexate (MTX) . The most recent randomized clinical trial (RCT) involving a traditional nb-DMARD as the main treatment relied upon methotrexate (MTX) as the agent of choice (the Methotrexate In Psoriatic Arthritis trial, MIPA) . This study randomized 221 patients to MTX or placebo and tracked outcomes for 6 months with the PsA response criteria (PsARC) serving as the primary outcome. At 6 months, there were no significant differences in any of the individual outcomes except for patient global and physician global assessments between placebo and MTX groups. The investigators concluded that MTX should be defined as a “symptom modifying agent” and not a true nb-DMARD . The MIPA trial, however, contained some features that may dissuade rheumatologists from definitively discarding MTX as a potential treatment for PsA. For example, in spite of the study’s short duration, only 65% and 69% of patients in the active and placebo groups, respectively, completed the trial, which would be anticipated to bias results towards a null effect. Furthermore, patient recruitment lasted 5 years, which might reflect some selection bias. In addition, around 35% of the patients included had oligoarticular disease and the maximum dose of MTX was capped at only 15 mg/week and achieved by only 78% of patients.
Virtually all published guidelines recommend traditional nb-DMARDs (methotrexate, leflunomide, or sulfasalazine) for 3–6 months, as the first step for the treatment of peripheral arthritis in PsA ( Table 1 ). The rationale for this recommendation and the extended period of exposure to nb-DMARDs may derive from the positive experience for many rheumatologists with use of these drugs, evidence from observational studies, and the lack of evidence that relatively brief delay in the initiation of drugs with more proven efficacy produces a substantial negative impact on long-term disease progression, disability, or quality of life .
| Guideline and Year of Publication [Reference] | Targeted disease(s) | Number of NSAIDs recommended and NSAID therapy duration | Traditional nb-DMARD therapy | Time to nb-DMARD failure (months) | Number of nb-DMARDs before TNFi | TNFi without previous nb-DMARD | Time for TNFi failure |
|---|---|---|---|---|---|---|---|
| Canadian Rheumatology Association 2003, 2007 | Spondyloarthritis | Three NSAIDs, 2 weeks each at maximum dose | Methotrexate, sulfasalazine | 3 | 1 | Yes, in predominant axial disease | 16 weeks |
| French Society for Rheumatology 2007 | Ankylosing Spondylitis and Psoriatic arthritis | Three NSAIDs, optimal tolerated dosages for at least 3 months | Methotrexate, sulfasalazine, leflunomide, | 4 | ≥1 | Yes, In predominant axial disease | 6–12 weeks |
| American Academy of Dermatology 2008 | Psoriatic Arthritis | Not stated | Methotrexate, sulfasalazine, leflunomide | Not stated | 0–1 | Yes, in severe disease | Not stated |
| GRAPPA 2009 | Psoriatic Arthritis | Not stated | Methotrexate, sulfasalazine, leflunomide, cyclosporine | 3 | 1 | Yes, in predominant axial or severe disease | Not stated |
| Italian Society for Rheumatology 2011 | Psoriatic arthritis | Two NSAIDs, for at least 3 months | Methotrexate, cyclosporine, sulfasalazine, leflunomide | 3 | 1 | Yes, In predominant axial disease | 3 months |
| Spanish Society of Rheumatology 2011 | Psoriatic Arthritis | Two NSAIDs, for at least 4 weeks each | Methotrexate, leflunomide, sulfasalazine, cyclosporine A | 3 | 1 | Yes, in axial disease | 3-4 months |
| Portuguese society of Rheumatology 2011 | Psoriatic Arthritis | Two NSAIDs, 2 weeks each | Methotrexate, sulfasalazine, leflunomide, cyclosporine | 3 | 1 | Yes, in predominant axial disease | Not stated |
| British Society of Rheumatology 2012 | Psoriatic arthritis | Not stated | Methotrexate, sulfasalazine cyclosporine, leflunomide | 6 | 1–2 1 (>5 SJC + elevated CRP or structural joint damage) | No (axial disease not included) | 3 months |
| EULAR 2012 | Psoriatic arthritis | Not stated | Methotrexate, leflunomide, sulfasalazine or cyclosporine | 3–6 | 1 | Yes, in predominant axial disease | 3–6 months |
| NICE Technology Appraisal 2008 | Ankylosing spondylitis | Two NSAIDs, for at least 4 weeks each | Methotrexate, sulfasalazine, others not specified | Not stated | Not stated | Yes | 12 weeks |
| 3E Initiative in Rheumatology 2008 | Ankylosing spondylitis | Not stated | Methotrexate, sulfasalazine, others not specified | Not stated | Not stated | Not stated | Not stated |
| ASAS/EULAR 2010 | Axial Spondyloarthritis/Ankylosing spondylitis | Two NSAIDs for at least 3 months | Sulfasalazine (in peripheral arthritis) | 4 | No | Yes | 6–12 weeks |
| Spanish Society of Rheumatology 2011 | Spondyloarthritis/Ankylosing spondylitis | Two NSAIDs, optimal tolerated dosages for at least 4 months | Sulfasalazine (peripheral disease) | 3 | 1 in early arthritis with peripheral disease | Yes, in predominant axial disease | 3–4 months |
Tumor necrosis factor inhibitors in PsA
Characteristics describing the initial five tumor necrosis factor inhibitors (TNFi) approved for PsA and their dates of approval appear in Table 2 . All of the first five TNFi (infliximab, etanercept, adalimumab, golimumab, and certolizumab-pegol (CZP)) have strong evidence of efficacy in the treatment of PsA . There is also good evidence that all TNFi improve dactylitis, enthesitis, skin, and nail involvement . The evidence for benefit with regard to axial involvement is scarce, but experts and guidelines extrapolate from the efficacy seen in management of axial spondyloarthritis (ax-SpA).
| TNFi agent | Administration method | Loading dose | Most Common Maintenance Dosage/Ankylosing Spondylitis-approved dosage | Prevalence of anti-TNFi antibodies a | Year of US FDA Approval for Psoriatic Arthritis | Year of US FDA Approval for Ankylosing Spondylitis |
|---|---|---|---|---|---|---|
| Adalimumab | SQ | None; (160 mg × 1 only in IBD) | 40 mg Q2 Weeks | 30% | 2005 | 2006 |
| Certolizumab-Pegol | SQ | 400 mg at 0, 2 & 4 weeks | 400 mg Q1 Month or 200 mg Q2 Weeks | Not Reported | 2013 | 2013 |
| Etanercept | SQ | None | 50 mg Q1 Week b or 25 mg Twice a Week | 1% c | 2002 | 2003 |
| Golimumab | SQ | None; (200 mg at week 0, then 100 mg at week 2 for UC) | 50 mg Q1 Month (100 mg Q4 Weeks for UC) | 1–4% | 2009 | 2009 |
| Infliximab | IV | Infusion at 0, 2 & 6 weeks | 5 mg/kg Q6 weeks | 20–29% | 2006 | 2004 |
a i.e., anti-drug antibodies. Data derived from , .
b Approved at 50 mg twice a week only for cutaneous disease (psoriasis).
c Approximately 1% of patients develop anti-drug antibodies, but these are generally described as “non-neutralizing”.
One of the main differences between use of TNFi in the care of patients with PsA versus its use in patients with rheumatoid arthritis is that TNFi may be used as monotherapy in PsA. All post-hoc analyses of RCTs comparing TNFi as monotherapy to combination therapy with MTX have shown no differences in efficacy . There are, however, observational data from registries showing that patients on combination therapy have longer drug survival than patients on TNFi monotherapy and that the development of antibodies might be less common in patients with the combination .
As mentioned previously, TNFi are recommended by all national guidelines in PsA ( Table 1 ) after inadequate response to 3–6 months of one nb-DMARD (most of the guidelines) or two nb-DMARDs. Most of the guidelines classify TNFi failures as patients who fail to achieve remission or low disease activity after 12–16 weeks of treatment.
Tumor necrosis factor inhibitors in PsA
Characteristics describing the initial five tumor necrosis factor inhibitors (TNFi) approved for PsA and their dates of approval appear in Table 2 . All of the first five TNFi (infliximab, etanercept, adalimumab, golimumab, and certolizumab-pegol (CZP)) have strong evidence of efficacy in the treatment of PsA . There is also good evidence that all TNFi improve dactylitis, enthesitis, skin, and nail involvement . The evidence for benefit with regard to axial involvement is scarce, but experts and guidelines extrapolate from the efficacy seen in management of axial spondyloarthritis (ax-SpA).
| TNFi agent | Administration method | Loading dose | Most Common Maintenance Dosage/Ankylosing Spondylitis-approved dosage | Prevalence of anti-TNFi antibodies a | Year of US FDA Approval for Psoriatic Arthritis | Year of US FDA Approval for Ankylosing Spondylitis |
|---|---|---|---|---|---|---|
| Adalimumab | SQ | None; (160 mg × 1 only in IBD) | 40 mg Q2 Weeks | 30% | 2005 | 2006 |
| Certolizumab-Pegol | SQ | 400 mg at 0, 2 & 4 weeks | 400 mg Q1 Month or 200 mg Q2 Weeks | Not Reported | 2013 | 2013 |
| Etanercept | SQ | None | 50 mg Q1 Week b or 25 mg Twice a Week | 1% c | 2002 | 2003 |
| Golimumab | SQ | None; (200 mg at week 0, then 100 mg at week 2 for UC) | 50 mg Q1 Month (100 mg Q4 Weeks for UC) | 1–4% | 2009 | 2009 |
| Infliximab | IV | Infusion at 0, 2 & 6 weeks | 5 mg/kg Q6 weeks | 20–29% | 2006 | 2004 |
a i.e., anti-drug antibodies. Data derived from , .
b Approved at 50 mg twice a week only for cutaneous disease (psoriasis).
c Approximately 1% of patients develop anti-drug antibodies, but these are generally described as “non-neutralizing”.
One of the main differences between use of TNFi in the care of patients with PsA versus its use in patients with rheumatoid arthritis is that TNFi may be used as monotherapy in PsA. All post-hoc analyses of RCTs comparing TNFi as monotherapy to combination therapy with MTX have shown no differences in efficacy . There are, however, observational data from registries showing that patients on combination therapy have longer drug survival than patients on TNFi monotherapy and that the development of antibodies might be less common in patients with the combination .
As mentioned previously, TNFi are recommended by all national guidelines in PsA ( Table 1 ) after inadequate response to 3–6 months of one nb-DMARD (most of the guidelines) or two nb-DMARDs. Most of the guidelines classify TNFi failures as patients who fail to achieve remission or low disease activity after 12–16 weeks of treatment.
Treatment after TNFi failure in PsA
Until very recently – at which time new biologics and oral nb-DMARDs were approved for the treatment of PsA – a patient failing TNFi had little recourse but to switch to another TNFi. Unfortunately, the evidence for the effectiveness of this strategy is scarce. In the CZP RCT (Rapid-PsA), approximately 20% of patients failed one prior TNFi . Interestingly, improvements in ACR (American College of Rheumatology) responses at week 12 and week 24 in CZP patients compared with placebo patients were observed irrespective of prior TNFi exposure. ACR20 response difference from placebo was seen by week 1 in patients with prior TNF inhibitor experience ( p < 0.05) and those without . Data from several registries have evaluated drug survival (persistence on medication) and the clinical effectiveness of switching TNFi in PsA . In general, they show that survival on the second TNFi is shorter than the first TNFi and that clinical response is in general less robust than with the first TNFi. Adequate response could be expected in between 20% and 60% of TNFi switchers.
Ustekinumab (anti-IL12/23) – an antibody against the common p40 unit of IL12 and IL23 – has been recently approved for use in PsA in several countries. In the PSUMMIT2 RCT at 24 weeks, significantly more patients randomized to ustekinumab achieved ACR20 response (44% vs. 20%), improved Health Assessment Questionnaire (HAQ) score, and obtained PASI75 response, compared to placebo . Sustained ustekinumab efficacy was also observed among patients previously treated with at least one TNFi . Of note, ustekinumab 45 and 90 mg treatments showed significant inhibition of radiographic progression of joint damage in patients with active PsA .
Lastly, apremilast is an oral phosphodiesterase 4 inhibitor that induces elevated intracellular cyclic adenosine monophosphate (AMP) levels within immune cells, leading to their immunomodulation. The PALACE 1, 2, 3, phase III RCTs, compared the efficacy and safety of apremilast with placebo in PsA patients previously treated with nb-DMARDs and/or biologic therapy . PALACE 4 evaluated apremilast in nb-DMARDs-naïve PsA patients . In all studies, apremilast showed significantly better results than placebo for virtually all outcomes assessed (ACR20/50/70, enthesitis, dactylitis, HAQ, and PASI). As a result of these recent trials, ustekinumab and apremilast represent useful alternatives for patients with TNFi failure, or even as first-line therapy in selected cases, assuming patients have access to these medications.
Early treatment in PsA
Patients with PsA can develop erosive disease early in the course of the disease. One study including patients within 5 months of symptoms onset showed that 27% develop erosive disease within 2 years of follow-up, despite the fact that the majority had been treated with nb-DMARDs . There is limited evidence that early treatment is effective or that might prevent the progression of damage, disability, or increase survival. Scarpa et al. randomized 35 patients with early PsA oligoarthritis who were already taking non-steroidal anti-inflammatory drugs (NSAIDs) on demand, to continue with NSAIDs at full dose for the following 3 months and then add methotrexate (MTX) for another 3 months or to a combination of NSAIDs and MTX for the entire 6-month period . At 3 months, patients on the combination therapy showed a significant improvement in tender and swollen joint count compared with patients on NSAID monotherapy. However, at 6 months there were no differences in any of the variables analyzed, suggesting that in patients with early oligoarthritis, a delay of 3 months in the introduction of MTX did not make a difference on clinical efficacy or that the effect of this delay is small . Unfortunately, in this study, X-rays were not examined, and only patients with oligoarthritis were included, so the implications of this study on the broader category of PsA is not known.
In patients with more severe disease, the evidence must be culled from observational studies. Gladman et al. showed that patients followed up prospectively in a specialized clinic within 2 years of diagnosis had significantly diminished rate of damage/radiographic progression compared with those first seen after 2 years of disease diagnosis, suggesting that patients with PsA should be treated earlier . Similarly, Tillett et al. analyzed their cohort of 267 PsA patients and found that symptom duration of ≥1 year before diagnosis was significantly associated with an increase in HAQ scores . Haroon et al. published their experience with an Irish cohort and found that more than 6 months delay to the first rheumatologic visit was associated with the development of peripheral joint erosions (odds ratio (OR) 4.25, p = 0.001) and worse (OR 2.2, p = 0.004) HAQ . Recently, in a follow-up study of the Swedish Early Psoriatic Arthritis Register, a short delay between onset of symptoms and diagnosis was found to be an independent predictor of attaining minimal disease activity (MDA) at the 5-year follow-up . In summary, although there are no RCTs-level data, evidence from cohort studies support the idea that early diagnosis and treatment are beneficial in PsA patients.
Treatment to target in PsA
Treat to target has become an attractive concept in the clinical management of many rheumatic diseases. It is defined as a strategy in which the clinician treats the patient aggressively enough to reach and maintain explicitly specified and sequentially measured goals, such as remission or low disease activity . An international task force of expert physicians and patients, based on results of a systematic literature review and expert opinion, developed five overarching principles and 11 recommendations for the treat-to-target strategy in peripheral SpA and PsA . The task force defined the treatment target as remission or, alternatively, low disease activity, but recognized that the evidence base underlying this recommendation was not strong and needed to be expanded by future research . Although the systematic literature review that served the task force did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimized approach to therapy .
Data have shown that MDA criteria accurately represent the concept of MDA, have an ability to predict outcomes, and are feasible in clinical practice – all prerequisites necessary to implement a treat–to-target approach. The percentage of patients achieving MDA and other remission criteria vary considerably, further arguing for the need for such strategies .
More recently, results from the TICOPA (Tight COntrol in Psoriatic Arthritis) study have been presented at various meetings . TICOPA is a UK multicenter, open-label, randomized, controlled, parallel group trial of 206 patients with early PsA . Patients were randomized on a 1:1 basis to receive either standard care (with patient encounters every 12 weeks) or intensive management (with patient encounters every 4 weeks) for a period of 48 weeks. Patients assigned to the intensive management group followed a strict treatment protocol whereby dose continuation/escalation were determined through the objective assessment of the MDA criteria . At 48 weeks, significantly more patients in the intensive management strategy achieved ACR20 response (primary outcome), ACR50 response, and ACR70 response. No differences were found related to enthesitis, dactylitis, nail involvement, or radiographic progression. Significantly, higher numbers of patients (37%) in the tight control arm were receiving biologics at week 48 versus 7.6% of patients receiving standard care. This trial provides strong evidence that treat to target and tight control are effective in the management of PsA.
Related posts:
The concept of spondyloarthritis: Where are we now?
Genetics of psoriatic arthritis
Disease activity measurements and monitoring in psoriatic arthritis and axial spondyloarthritis
Novel imaging modalities in spondyloarthritis
Bone formation in axial spondyloarthritis
Nonpharmacologic therapies in spondyloarthritis
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