Best Practice & Research Clinical Rheumatology 28 (2014) 793e806

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10

Pharmacologic treatment of psoriatic arthritis and axial spondyloarthritis with traditional biologic and non-biologic DMARDs Enrique Roberto Soriano a, 1, Maria Laura Acosta-Felquer a, 1, Phat Luong b, 2, Liron Caplan b, * a

Rheumatology Unit, Internal Medical Services, Hospital Italiano de Buenos Aires, Argentina and Instituto Universitario, Peron 4190 (C1199ABB), CABA, Argentina b Section of Rheumatology, Denver Veterans Affairs Hospital and University of Colorado School of Medicine, 1775 Aurora Court, B115, Aurora, CO 80045, USA

a b s t r a c t Keywords: NLM MeSH terms Arthritis Psoriatic Spondylitis Ankylosing Therapeutics Biological therapies

This manuscript focuses on the pharmacologic treatment of psoriatic arthritis and axial spondyloarthritis e including ankylosing spondylitis e using traditional biologic and non-biologic diseasemodifying 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. Published by Elsevier Ltd.

* Corresponding author. Tel.: þ54 11 49590200x5443. E-mail addresses: [email protected] (E.R. Soriano), [email protected] (M.L. AcostaFelquer), [email protected] (P. Luong), [email protected] (L. Caplan). 1 Tel.: þ54 11 49590200x5443. 2 Tel.: þ1 303 724 7606.

http://dx.doi.org/10.1016/j.berh.2014.10.011 1521-6942/Published by Elsevier Ltd.

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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) [1e5]. 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) [6]. 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 [6]. 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 3e6 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 [7]. 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 [1,8,5,3]. There is also good evidence that all TNFi improve dactylitis, enthesitis, skin, and nail involvement [8,5,3]. 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). 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 [9e11]. There are, however, observational data from registries showing that patients on combination therapy have longer drug survival than patients on TNFi monotherapy [12] and that the development of antibodies might be less common in patients with the combination [10]. As mentioned previously, TNFi are recommended by all national guidelines in PsA (Table 1) after inadequate response to 3e6 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 12e16 weeks of treatment. Treatment after TNFi failure in PsA Until very recently e at which time new biologics and oral nb-DMARDs were approved for the treatment of PsA e 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 [13]. Interestingly, improvements in ACR (American

Table 1 A selection of guidelines published since 2007 related to non-steroidal anti-inflammatory drugs, non-biologic disease modifying anti-rheumatic drugs, and tumor necrosis inhibitors for patients with psoriatic arthritis and ankylosing spondylitis/axial spondyloarthritis Targeted disease(s)

Number of NSAIDs recommended and NSAID therapy duration

Traditional nbDMARD therapy

Time to nb-DMARD failure (months)

Number of nb-DMARDs before TNFi

TNFi without previous nbDMARD

Time for TNFi failure

Canadian Rheumatology Association 2003, 2007 [74,75] French Society for Rheumatology 2007 [76]

Spondyloarthritis

Methotrexate, sulfasalazine

3

1

16 weeks

Methotrexate, sulfasalazine, leflunomide,

4

1

Yes, in predominant axial disease Yes, In predominant axial disease

Methotrexate, sulfasalazine, leflunomide Methotrexate, sulfasalazine, leflunomide, cyclosporine Methotrexate, cyclosporine, sulfasalazine, leflunomide Methotrexate, leflunomide, sulfasalazine, cyclosporine A Methotrexate, sulfasalazine, leflunomide, cyclosporine Methotrexate, sulfasalazine cyclosporine, leflunomide Methotrexate, leflunomide, sulfasalazine or cyclosporine

Not stated

0e1

Yes, in severe disease

Not stated

3

1

Not stated

3

1

Yes, in predominant axial or severe disease Yes, In predominant axial disease

3

1

Yes, in axial disease

3-4 months

3

1

Yes, in predominant axial disease

Not stated

6

1e2 1 (>5 SJC þ elevated CRP or structural joint damage)

No (axial disease not included)

3 months

3e6

1

Yes, in predominant axial disease

3e6 months

American Academy of Dermatology 2008 [77]

Psoriatic Arthritis

Three NSAIDs, 2 weeks each at maximum dose Three NSAIDs, optimal tolerated dosages for at least 3 months Not stated

GRAPPA 2009 [8]

Psoriatic Arthritis

Not stated

Italian Society for Rheumatology 2011 [78]

Psoriatic arthritis

Two NSAIDs, for at least 3 months

Spanish Society of Rheumatology 2011 [79]

Psoriatic Arthritis

Two NSAIDs, for at least 4 weeks each

Portuguese society of Rheumatology 2011 [80]

Psoriatic Arthritis

Two NSAIDs, 2 weeks each

British Society of Rheumatology 2012 [81]

Psoriatic arthritis

Not stated

EULAR 2012 [82]

Psoriatic arthritis

Not stated

Ankylosing Spondylitis and Psoriatic arthritis

6e12 weeks

3 months

795

(continued on next page)

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Guideline and Year of Publication [Reference]

796

Table 1 (continued ) Targeted disease(s)

Number of NSAIDs recommended and NSAID therapy duration

Traditional nbDMARD therapy

Time to nb-DMARD failure (months)

Number of nb-DMARDs before TNFi

TNFi without previous nbDMARD

Time for TNFi failure

NICE Technology Appraisal 2008 [83]

Ankylosing spondylitis

Two NSAIDs, for at least 4 weeks each

Not stated

Not stated

Yes

12 weeks

3E Initiative in Rheumatology 2008 [84,85]

Ankylosing spondylitis

Not stated

Not stated

Not stated

Not stated

Not stated

ASAS/EULAR 2010 [44]

Axial Spondyloarthritis/ Ankylosing spondylitis

Two NSAIDs for at least 3 months

4

No

Yes

6e12 weeks

Spanish Society of Rheumatology 2011 [86]

Spondyloarthritis/ Ankylosing spondylitis

Two NSAIDs, optimal tolerated dosages for at least 4 months

Methotrexate, sulfasalazine, others not specified Methotrexate, sulfasalazine, others not specified Sulfasalazine (in peripheral arthritis) Sulfasalazine (peripheral disease)

3

1 in early arthritis with peripheral disease

Yes, in predominant axial disease

3e4 months

Modified from International Journal of Clinical Rheumatology, 2009;4:329-42, with permission of Future Medicine Ltd. NSAID ¼ non-steroidal anti-inflammatory drugs. nb-DMARD ¼ non-biologic disease modifying anti-rheumatic drugs. TNFi ¼ tumor necrosis factor inhibitors. ASAS ¼ Assessment in SpondyloArthritis international Society. EULAR ¼ European League Against Rheumatism. GRAPPA ¼ Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. NICE ¼ National Institute for Health and Care Excellence. SJC ¼ swollen joint count. CRP ¼ C reactive protein.

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Guideline and Year of Publication [Reference]

TNFi agent

Administration method

Loading dose

Most Common Maintenance Dosage/Ankylosing Spondylitis-approved dosage

Prevalence of anti-TNFi antibodiesa

Year of US FDA Approval for Psoriatic Arthritis

Year of US FDA Approval for Ankylosing Spondylitis

Adalimumab

SQ

40 mg Q2 Weeks

30%

2005

2006

Certolizumab-Pegol

SQ

2013

2013

SQ

1%c

2002

2003

Golimumab

SQ

400 mg Q1 Month or 200 mg Q2 Weeks 50 mg Q1 Weekb or 25 mg Twice a Week 50 mg Q1 Month (100 mg Q4 Weeks for UC)

Not Reported

Etanercept

None; (160 mg  1 only in IBD) 400 mg at 0, 2 & 4 weeks None

1e4%

2009

2009

Infliximab

IV

20e29%

2006

2004

None; (200 mg at week 0, then 100 mg at week 2 for UC) Infusion at 0, 2 & 6 weeks

5 mg/kg Q6 weeks

SQ ¼ subcutaneous. IV ¼ intravenous. UC ¼ ulcerative colitis. Q ¼ (latin) quaque, meaning “every”. US FDA ¼ United States Food and Drug Administration. a i.e., anti-drug antibodies. Data derived from [87e90], [60]. 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”.

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Table 2 Characteristics of various tumor necrosis factor inhibitors (TNFi).

797

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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 [13]. Data from several registries have evaluated drug survival (persistence on medication) and the clinical effectiveness of switching TNFi in PsA [14e17]. 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) e an antibody against the common p40 unit of IL12 and IL23 e 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 [18]. Sustained ustekinumab efficacy was also observed among patients previously treated with at least one TNFi [18]. Of note, ustekinumab 45 and 90 mg treatments showed significant inhibition of radiographic progression of joint damage in patients with active PsA [19]. 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 [20e22]. PALACE 4 evaluated apremilast in nb-DMARDs-naïve PsA patients [23]. 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 [24]. 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 [25]. 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 [25]. 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 [26]. 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 [27]. 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 ¼ 0.001) and worse (OR 2.2, p ¼ 0.004) HAQ [28]. 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 followup [29]. 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.

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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 [30]. 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 [31]. 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 [31]. 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 [31,32]. Data have shown that MDA criteria accurately represent the concept of MDA, have an ability to predict outcomes, and are feasible in clinical practice [33e35] e all prerequisites necessary to implement a treateto-target approach. The percentage of patients achieving MDA and other remission criteria vary considerably, further arguing for the need for such strategies [36]. More recently, results from the TICOPA (Tight COntrol in Psoriatic Arthritis) study have been presented at various meetings [34]. TICOPA is a UK multicenter, open-label, randomized, controlled, parallel group trial of 206 patients with early PsA [34]. 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 [37,34]. 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. Pharmacologic treatment of axial spondyloarthritis/ankylosing spondylitis Non-steroidal anti-inflammatory drugs in AS Meta-analysis-level evidence supports the use of NSAIDs in ankylosing spondylitis (AS) to improve self-reported clinical outcomes such as pain, physical function, and patient's global assessment of their condition [38]. In addition, preliminary evidence derived from a few prospective and retrospective observational studies suggest a possible role for NSAIDs in curtailing the progression of bony change of the spine [39]. However, some studies have been unable to identify an association of NSAID exposure and radiographic progression [40]. The most common NSAIDs studied in RCT include indomethacin, phenylbutazone (which is unavailable in North America), naproxen, and celecoxib. Weak evidence favors the efficacy of continuous use of NSAIDs over intermittent or “on-demand” use [41]; however, this putative advantage in efficacy must be carefully weighed against the potential for adverse events with long-term NSAID administration. Guidelines published by various nations vary on the approach to NSAID use, but most generally follow the recommendations of the Assessment in SpondyloArthritis international Society (ASAS), which require the initial use of NSAIDS, mandating a failure of two to three agents over 4 weeks before augmenting pharmacologic therapy [42e44]. Traditional nb-DMARDs in AS In contrast to NSAIDs, the literature does not generally support the use of traditional nb-DMARDs in patients with AS, making the term “disease-modifying” in fact a misnomer with regard to AS e

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mirroring the situation with regard to PsA. The most commonly examined nb-DMARDs include sulfasalazine, which has been studied in at least 11 RCT [45], and methotrexate, which has been studied in three RCTs [46]. Only one trial demonstrated consistent benefit for sulfasalazine in axial disease [47] and none of the studies consistently favored outcomes for patients randomized to methotrexate compared to placebo [46]. These findings were echoed in a formal meta-analysis which concluded that sulfasalazine produced no effect on axial pain scores compared with placebo [48]. The benefit of sulfasalazine for peripheral arthritis associated with AS is likely quite modest, given the lack of clear improvements in tender and swollen joint counts; the favorable effect on peripheral disease has been distinguished only by composite indices [49]. A single uncontrolled study of leflunomide failed to reveal any benefit for this agent in AS [50]. On the other hand, an unblinded RCT of thalidomide in AS patients recently discontinued from etanercept suggested lower rates of flares compared to NSAIDs [51]. However, these positive results e also reported in a few case series [52e54] e are tempered by the frequent occurrence of adverse drug reactions and narrow therapeutic window for this drug. For this reason, regular use of thalidomide in AS is discouraged. Little evidence exists in support of intravenous bisphosphonates for treatment of AS. One doubleblind RCT comparing high- and low-dose pamidronate found improvements across a variety of patient reported outcomes in the subjects treated with higher doses [55], mirroring the purported benefit described in a few uncontrolled studies [56,57]. Other uncontrolled studies, however, did not reveal a beneficial effect [58]. Interestingly, a contemporary report from an unblinded RCT has suggested that a high-dose intravenous amino-bisphosphonate (neridronate) may rival infliximab in clinical efficacy [59]. Despite this early optimism, national guidelines do not yet endorse bisphosphonate use for diminishing disease activity in AS patients. About half of existing national guidelines promote or require a trial of one or more traditional nbDMARDs prior to initiation of biologic agents [42], in spite of the weak evidence supporting this tactic. TNFi in AS The initial five TNFi approved for AS e all of which were also approved for PsA e appear in Table 2, which also includes characteristics relevant to AS. Four of the agents include formulations deliverable

Table 3 Randomized controlled trials reporting tumor necrosis factor inhibitors' effect on c-reactive protein among patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Name

AS Braun 2011 [91] Davis 2003 [92] Dougados 2011 [93] Gorman 2002 [94] Hu 2012 [95] Huang 2013 [96] Inman 2010 [97] van der Heijde 2006 [98] Both nr-axSpA + AS Song 2011 [99] nr-axSpA Dougados 2014 [100] ALL STUDIES

TNFi-treated Mean (mg/L)

SD

10.6 13.0 18.5 13.0 17.3 17.8 6.7 13.0

5.6 18.8 14.0 21.1 27.7 23.8 16.3 14.4

7.7

4.1

3.0

1.1

Controls n 1076 379 138 39 20 24 229 39 208 20 20 106 106 1202

Mean (mg/L)

SD

1.6 1.0 1.4 5.0 13.1 4.2 2.2 1.0

5.9 21.7 14.0 30.5 23.8 21.2 14.9 10.3

2.1

5.2

0.1

1.0

n 668 187 139 43 20 20 115 37 107 36 36 109 109 813

Effect estimate

¡11.99 9.02 12.00 19.90 18.00 4.20 13.60 8.85 12.00 ¡5.60 5.60 ¡3.10 3.10 ¡10.09

SE

0.52 2.44 3.10 8.29 7.77 2.53 3.58 1.41 1.26 0.14

CI start

CI end

Weight

¡14.69 10.04 16.78 25.97 34.24 19.43 18.55 15.86 14.76 ¡8.06 8.06 ¡3.38 3.38 ¡13.45

¡9.29 8.00 7.22 13.83 1.76 11.03 8.65 1.84 9.24 ¡3.14 3.14 ¡2.82 2.82 ¡6.74

73.13 13.75 10.86 9.57 3.27 3.60 10.69 8.66 12.73 12.96 12.96 13.92 13.92 100.00

Test for overall effect of TNFi on CRP: Z ¼ 5.89 (P < 0.00001). Test for differences among subgroups (AS vs. nr-axSpA þ AS vs. nr-axSpA): Chi [2] ¼ 44.86, df ¼ 2 (P < 0.00001). Studies are divided according to whether they enrolled AS, nr-axSpA, or both. SD ¼ standard deviation; SE ¼ standard error; CI ¼ 95% confidence interval; TNFi ¼ reporting tumor necrosis factor inhibitor; CRP ¼ c-reactive protein; AS ¼ ankylosing spondylitis . nr-axSpA ¼ non-radiographic axial spondyloarthritis

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by subcutaneous injection while intravenous formulations are available for only two of the agents (the IV formulation of golimumab is approved for rheumatoid arthritis). Loading doses are recommended for two of the agents (certolizumab and infliximab) and rates of anti-drug antibody development in AS vary between 0% and 30% for each of the agents. The clinical implications of different prevalences in anti-drug antibodies remain ill-defined at present for patients with AS, nor is it clear that combination treatment with traditional nb-DMARDs alters outcomes [60]. At least four independent meta-analyses have systematically reviewed the 20 þ RCTs evaluating the efficacy of TNFi in AS and non-radiographic axial spondyloarthritis (nr-axSpA) e that is, patients with clinical and/or laboratory findings compatible with AS, but without features meeting formal classification criteria for AS on plain radiographs. These meta-analyses overwhelmingly vouch for the efficacy of TNFi in mitigating disease activity scores and improving functional status and physical function scores [61,62]. The studies found no differences between results for individual TNFi agents suggesting that structural differences between various TNFi do not translate into major divergences in clinical efficacy for treatment of AS. Selection of TNFi should therefore reflect patient preference for method of administration, cost, and the need to treat extra-articular manifestations. Practically speaking, this means that providers should favor monoclonal antibodies over the fusion protein etanercept when treating AS patients with concomitant inflammatory bowel disease (IBD) [63]. Similarly, patients who develop recalcitrant anterior uveitis on etanercept should be switched to monoclonal antibodies. Controversy surrounds the question of whether TNFi's retard radiographic progression in AS. The short length of RCTs in AS e now typically 6 months in length prior to unblinding e precludes demonstration of a decrease in ankylosis of sacroiliac joints or syndesmophyte formation. However, at least two recent observational cohort studies lend credence to the notion that TNFi slow the rate of damage visible on radiographs when administered early in the course of and over multiple years [64,65]. Heretofore, national recommendations guiding the use of TNFi for AS and nr-axSpA have been largely based on ASAS consensus statements and guidelines issued since 2003 and revised most recently in 2010e2011 [44,66,67,43]. A joint initiative sponsored by the ACR, Spondyloarthritis Research and Treatment Network (SPARTAN), and Spondylitis Association of America (SAA) is underway to issue guidelines for a North American audience. Early treatment in AS The ambiguity and complexities around confidently defining early AS, manifest as a considerable diagnostic delay in past decades [68], make treatment of early AS difficult. The degree to which nraxSpA represents a milder form of AS versus an earlier form of AS remains to be clarified [69,70]. For the time being, the 2010 update of ASAS guidelines suggest treatment of nr-axSpa in a manner identical to that of AS [44]. Given the observed clinical differences [69], less robust response to TNFi among nraxSpA [61], and genetic inconsistencies between these two entities, however, providers should consider individual patient factors when selecting therapies for patients with nr-axSpA. Specifically, the risk of interventions, potential for progressive untreated or under-treated disease (e.g., preexisting syndesmophytes increasing the risk of subsequent bony proliferation), and likelihood of response to therapy (e.g., C reactive protein (CRP) predicting response to TNFi) [71], as well as comorbidities should all contribute to the decision-making process. For example, summary data from RCTs suggest that in nraxSpA patients treated with TNFi show more modest declines than patients with AS (Table 3). It is also worth noting that the US Food and Drug Administration has declined, at least initially, to extend the indication for use of TNFi to nr-axSpA [72] and that the European Medicine Agency has only approved etanercept, CZP, and adalimumab for severe nr-axSpA when adults present with elevated CRP and/or signs of inflammation on magnetic resonance imaging, rather than nr-axSpA, in general. Treat to target in AS As implied above, the “treat-to-target” concept fundamentally espouses a view whereby quantifiable surrogates of disease severity and/or activity measured in individual patients warrant a proportionally aggressive approach to management; that is, biomarkers (e.g., CRP), physical exam findings

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(e.g., swollen joint counts), or patient-report indices (e.g., Bath Ankylosing Spondylitis Disease Activity Index) inform the intensity of management decisions, such as the choice of therapy or dose of a chosen therapy. This view should be predicated on: (1) evidence confirming that the quantifiable measuring guiding management decision closely reflects the severity/activity of the disease process; (2) a broad armamentarium available to providers so that treatment can be adjusted for mild to severe disease; (3) evidence that more aggressive approaches produce better outcomes; and (4) knowledge of the optimal goal, or at least the minimum target sufficient to affect a more favorable outcome. In AS, unfortunately, while disease activity measures may reasonably reflect the health of a patient cohort and may be associated with risk of radiographic progression [73], it is not clear that available instruments sufficiently depict an individual patient's health precisely enough to guide therapy. Second, the pharmacologic armamentarium remains limited, without rigorous evidence to guide a graduated approach to management or clear sequence of interventions. Third, more intensive treatments have not proven more efficacious. Use of combination therapy with traditional nb-DMARDs, for example, has not resulted in better outcomes [48]. Fourth, investigators have yet to define the preferred measurement instruments or threshold/target values necessary to achieve better outcomes in the context of an RCT that examines these various components in comparison with usual care. Notwithstanding these deficits and a systematic literature review that found virtually no relevant literature [32], guidelines have been issued with strong recommendations that advocate for a target of clinical remission/inactive disease based on clinical and laboratory results and the regular assessment of composite measures of disease activity [31]. A systematic approach to examination of patients may provide advantages in terms of consistency and efficiency of practice. However, until such an approach is based on more substantive data and a more compelling rationale, the implementation of these suggestions should be tempered. Illustrations Not applicable

Practice points  The evidence for use of nb-DMARDs in the management of PsA is weak, but may be a viable approach if exposure is limited to 3e6 months.  The early use of TNFi should be strongly encouraged.  Preliminary evidence supports the role of treat-to-target strategies in PsA.  nb-DMARDs have no efficacy benefit in treatment of axial disease in AS.  Treat-to-target strategies are currently not well justified in AS.  Patients with AS benefit greatly from the use of NSAIDs and TNFi.

Research agenda  Further investigations should determine the optimal sequence of therapeutic interventions for both PsA and axial spondyloarthritis, including AS.  Treat-to-target approaches in axial spondyloarthritis/AS will depend on the availability of additional DMARDs, and efforts to identify such agents should be vigorously expanded.  Future studies should clarify whether treatment of non-radiographic axial spondyloarthritis and AS should be identical, or whether distinct treatment regimen exists for each condition.

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Summary In summary, all national and international guidelines recommend the use of traditional nbDMARDs as first-line therapy in PsA, though the recommendations for AS do not support this approach for axial disease. After one nb-DMARD failure, TNFi have shown considerable effectiveness across a broad spectrum of clinical manifestations of psoriasis disease. The treatment goal should be remission or minimal disease activity, and these are better achieved with a tight control strategy for PsA. While similar goals seem appropriate in AS, the specific management approach appears less clear with fewer therapeutic options. Early diagnosis and treatment are important to avoid long-term damage in both PsA and AS. New options such as ustekinumab and apremilast are now available for PsA patients failing TNFi, or even after traditional nb-DMARDs failure in selected cases. Similar agents should be sought for AS. Conflict of interest statement All authors acknowledge that they have no financial and personal relationships with other people or organizations that could inappropriately influence the content of this article. This project received no specific function. Dr. Caplan is supported by the U.S. Department of Veterans Affairs (VA); however, the VA had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Acknowledgment Dr. Caplan would like to express his appreciation to Elizabeth Cheng, for her assistance in preparation of the manuscript. References *[1] Ash Z, Gaujoux-Viala C, Gossec L, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012;71:319e26. [2] Helliwell PS, Taylor WJ. Treatment of psoriatic arthritis and rheumatoid arthritis with disease modifying drugs e comparison of drugs and adverse reactions. J Rheumatol 2008;35:472e6. [3] Soriano ER, Rosa J. Update on the treatment of peripheral arthritis in psoriatic arthritis. Curr Rheumatol Rep 2009;11: 270e7. [4] Ravindran V, Scott DL, Choy EH. A systematic review and meta-analysis of efficacy and toxicity of disease modifying anti-rheumatic drugs and biological agents for psoriatic arthritis. Ann Rheum Dis 2008;67:855e9. [5] Soriano ER, McHugh NJ. Therapies for peripheral joint disease in psoriatic arthritis. A systematic review. J Rheumatol 2006;33:1422e30. [6] Kingsley GH, Kowalczyk A, Taylor H, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatol Oxf 2012;51:1368e77. [7] Soriano ER. The actual role of therapy with traditional disease-modifying antirheumatic drugs in psoriatic arthritis. J Rheumatol Suppl 2012;89:67e70. http://dx.doi.org/10.3899/jrheum.120248. *[8] Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 2009;68:1387e94. [9] Gladman DD, Mease PJ, Ritchlin CT, et al. Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum 2007;56:476e88. [10] Kavanaugh A, McInnes IB, Mease P, et al. Clinical efficacy, radiographic and safety findings through 5 years of subcutaneous golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial (the GO-REVEAL study). Ann Rheum Dis 2014;73:1689e94. [11] van der Heijde D, Kavanaugh A, Gladman DD, et al. Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: results from the induction and maintenance psoriatic arthritis clinical trial 2. Arthritis Rheum 2007;56:2698e707. [12] Fagerli KM, Lie E, van der Heijde D, et al. The role of methotrexate co-medication in TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR-DMARD study. Ann Rheum Dis 2014;73: 132e7. [13] Mease PJ, Fleischmann R, Deodhar AA, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis 2014;73:48e55. [14] Fagerli KM, Lie E, van der Heijde D, et al. Switching between TNF inhibitors in psoriatic arthritis: data from the NORDMARD study. Ann Rheum Dis 2013;72:1840e4.

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