S41 Methotrexate in Psoriatic Arthritis Philip Mease, M.D. Abstract Psoriatic arthritis (PsA) is a form of inflammatory arthritis that occurs in patients with psoriasis and is distinct from rheumatoid arthritis (RA). Methotrexate (MTX) is one of the most commonly used drugs for the treatment of PsA, yet there is scant controlled trial data to document its efficacy. Controlled trials have not demonstrated significant separation from placebo, but the studies have significant limitations which inhibit our ability to draw firm conclusions about the efficacy of MTX. A number of observational studies have described benefit for joint and skin disease. As yet unstudied, are the effects on enthesitis, dactylitis, and spondylitis of PsA. Psoriasis studies have shown modest benefit for psoriatic skin lesions. It is not yet known if MTX contributes an additive or synergistic benefit when used in combination with TNF inhibitors in PsA. The potential value of low dose MTX to suppress antibody formation against biologic therapies should be considered in a patient failing benefit from such therapy. Although adverse effects are similar to those seen in RA treatment with MTX, awareness of the tendency for PsA and psoriasis patients to be obese and have non-alcoholic steato-hepatosis, which may amplify transaminitis potential, should be borne in mind. Psoriatic arthritis (PsA) is a form of inflammatory arthritis, which most typically occurs in patients with psoriasis. Psoriasis is estimated to occur in 2% to 3% of the USA population. PsA is estimated to occur in 6% to 40% of patients with psoriasis, depending on ascertainment Philip Mease, M.D., is the Director of Rheumatology Research, Swedish Medical Center; Clinical Professor University of Washington School of Medicine, Seattle, Washington. Correspondence: Philip Mease, M.D., Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, Washington 98122; pmease@philipmease.com. method, 1 with more recent studies honing in on 30% as a reasonable estimate. 2 Interestingly, up to 40% of PsA patients may not be aware of their diagnosis or be misdiagnosed. 2 Isolated case reports of a unique form of arthritis occurring in patients with psoriasis have been published since the early 1800s, but it was not until Wright s seminal publication in 1959 that PsA was more fully accepted as a form of arthritis distinct from rheumatoid arthritis (RA). 3 More recent studies have characterized the distinct genetic, pathophysiologic, clinical, and treatment response characteristics of PsA which clearly distinguish it from RA and place it more akin to the spondyloarthritides. 4-6 The clinical phenotype may be quite heterogeneous, including either oligoarticular (< 5) or polyarticular joint inflammation (often asymmetric), spondylitis, enthesitis (especially involving lower extremity tendon and ligament insertions), dactylitis, uveitis, and inflammatory bowel changes, in addition to psoriasis and nail disease. Cw6 is one of several distinctive genetic markers. Synovial pathology is different from that in RA, with less prominent cellular infiltrate and a greater preponderance of CD68 plus macrophages and neutrophils and a prominent tortuous vascularity. 4,5 Cellular pathological changes of enthesitis, dactylitis, and spondylitis are less well characterized but presumable are equally distinct from RA as these clinical features are not seen in RA. Although historic treatment patterns for PsA have typically mirrored those of RA, based on pathologic and clinical features that are distinct, it does not necessarily follow that treatment results will be the same. Thus, there is a need to evaluate controlled trial data to understand the effectiveness of individual drugs such as methotrexate (MTX), the subject of this compilation of articles. After non-steroidal anti-inflammatory drugs (NSAIDs), MTX is one of the most commonly used drugs for PsA. In the study which established the CASPAR criteria for classification of PsA, MTX was the most commonly utilized Mease P. Methotrexate in psoriatic arthritis. Bull Hosp Jt Dis. 2013;71(Suppl 1):S41-5.
S42 Bulletin of the Hospital for Joint Diseases 2013;71(Suppl 1):S41-5 disease-modifying drug (DMARD) (39% of PsA patients) in monotherapy format or in combination with other DMARDs or biologics. 7,8 Numerous disease registries in Europe and the USA also show MTX to be commonly used in PsA. To justify such common use, clinicians presumably judge the drug to have efficacy in their patients. What is the evidence base that supports this judgment? The biologic rationale for use of MTX, which is postulated to exert immunomodulatory effect via inhibition of purine metabolism in rapidly turning over cells, such as lymphocytes, is supported by a synovial biopsy study performed in Dublin. Kane assessed knee synovial biopsies pre and 6 to12 months post MTX administration in 10 subjects with PsA. Reduction in synovial infiltrate and specific reduction of CD3+, CD4+, CD8+, and CD68+ cells, adhesion molecules, MMP-3, and IL-8 was noted. 9 There is limited clinical trial evidence for MTX efficacy in PsA. In a 1964 report, Black used high dose intravenous (IV) and intramuscular (IM) MTX (1 to 3 mg/kg) 3 times at 10 day intervals in 21 patients treated in a placebo-controlled crossover design. 10 Significant improvement in skin surface area involvement, a graded joint index, and ESR were noted. Adverse effects, especially gastrointestinal, were significant, and one patient who developed pancytopenia, gastrointestinal bleeding, and a pulmonary embolus had a fatal outcome. In 1984, Willkens was the first to report a trial of what is now the conventional dose MTX administered orally. 11 Thirty-seven subjects were randomized to either 7.5 or 15 mg MTX versus placebo. Statistically significant improvement of patient global evaluation and body surface area involvement with psoriasis was noted but not significant improvement of tender and swollen joint score or physician global evaluation. The study limitations included being underpowered in terms of number of subjects, and the dose of MTX used was low compared to today s standards. The most substantial controlled trial effort to date with MTX in PsA has been the Methotrexate in Psoriatic Arthritis (MIPA) study conducted largely in the UK as well as other parts of Europe. 12 Two hundred twenty-one patients were enrolled over a 5 year period. Subjects were naïve to MTX and randomized to receive either MTX or placebo for a controlled period of 6 months. MTX was initiated at a dose of 7.5 mg/wk, increased to 10 mg/wk at week 4, and then to target dose of 15 mg by week 8. If patients had persistently active disease, MTX could be dose adjusted to 20 mg at month 4 and 25 mg at month 5. Concomitant NSAIDs, but not glucocorticoids or other immunomodulatory medicines, were allowed. Of 109 subjects treated with MTX, 67 completed; of 112 in the placebo arm, 61 completed. The primary endpoint, achievement of Psoriatic Arthritis Response Criteria (PsARC) response, did not statistically separate between the MTX and placebo arms, nor did key secondary outcomes, including ACR20, DAS28, tender or swollen joint count, PASI75, ESR, CRP, pain, or HAQ score. Statistical separation was seen in patient and physician global assessment and mean PASI score. Although a trend of improvement was seen in the composite measures, logistic regression analysis (adjusted for age, sex, and disease duration) did not show a separation between the MTX and placebo arms. The investigators concluded that MTX does not improve synovitis and is therefore not disease modifying in PsA and had borderline symptom modifying properties. Thus, there was insufficient evidence to support the use of MTX as a standard treatment for PsA. Notable limitations of this study included the high dropout rate, the point that the study s power calculations were based on potential PsARC response, an instrument which gives greater weight to subjective global measures than the ACR20 or DAS28, the prolonged time taken to titrate up the MTX dose, the goal dose of 15 mg of MTX rather than 20 or 25 mg, and the potential that there was a channeling bias of enrolling subjects with milder disease than typical for a PsA study. Thus, we are left with uncertainty as to whether we can rely on the outcomes achieved to truly make a judgment about MTX effectiveness. Results of studies that are not placebo-controlled may shed light on the potential effectiveness of MTX. Baranauskaite conducted an open label study comparing MTX (15 mg/wk) alone versus MTX (15 mg/wk) plus infliximab (5 mg/kg at weeks 0, 2, 6, and 14) in 115 PsA patients with mean disease duration of 2.8 to 3.7 years, primarily residing in Russia. 13 At 16 weeks, ACR20 response was achieved by 86.3% in the infliximab plus MTX arm and 66.7% in the MTX arm (p = 0.021). ACR 50/70 response was achieved by 72.5% and 49% in infliximab plus MTX patients and 39.6% and 18.8% in the MTX-treated patients. In those patients evaluated for PASI score, i.e., with PASI greater than 2.5, PASI75 was achieved by 97.1% and 54.3% of infliximab plus MTX and MTX subjects, respectively (p < 0.0001). Whereas it is not surprising to see such a good result with the combination therapy, especially in a group of patients with relatively short disease duration, the key point for this discussion is to focus on the MTX results, which are quite respectable. Of course, one has to take the results with a grain of salt due to the open label study design, but nonetheless the suggestion is that there is some effect of MTX on ACR response in this group of patients with relatively early disease. No serious adverse events were reported in the MTX group, whereas there were two in the combination group. Ceponis has reviewed use of MTX in PsA including a summary of the results of eight non-randomized observational studies of it use in this disease. 14 In general, these studies reported clinical improvement in joint and skin assessments, pain, morning stiffness, and acute phase reactants, buttressing our clinical impression that a subset of patients clearly can respond to MTX. Data from two clinical registries deserves highlighting. Lie reported on effectiveness and retention rates of PsA patients initiating MTX compared to RA in a Norwegian registry known as NOR-DMARD. 15 The analysis was of 430 MTX-naïve PsA patients and 1,218
S43 patients with RA. At baseline, key differences were that in PsA, patients were younger, equigender, and had lower measures of disease activity. When adjustments for age, sex, and disease activity were made, after 6 months of therapy with MTX, improvements in swollen joint count, physician global assessment, ESR, and CRP were similar between PsA and RA patients, whereas tender joint count and DAS28 change was greater in RA than in PsA. The key point is that improvement occurred and was not too dissimilar from RA. In the first 6 months of MTX therapy, 17% of both PsA and RA patients discontinued therapy, primarily because of adverse events but also lack of efficacy. At 2 years, 65% of patients retained MTX monotherapy. Liver function test abnormalities were greater in PsA than RA patients. In the long-standing University of Toronto PsA registry, Chandran reappraised the effectiveness of MTX, especially regarding impact on progressive joint damage as assessed radiographically. 16 A prior study from this cohort comparing matched patients who were either treated or not with MTX, analyzing subjects treated between 1978 and 1993, found no advantage regarding clinical response or progressive radiographic damage in those treated with MTX. 17 Thirteen years later, treating patients more aggressively earlier and with higher doses of MTX, Chandran wondered if outcomes would be different. Fifty-nine patients were treated for at least 2 years between January 1994 and December 2004. The average dose of MTX was 16.2 mg/wk as compared to 10.8 mg/wk in the earlier cohort. Two thirds of patients had a greater than or equal to 40% reduction in tender and swollen joint count, and 57% had a PASI50 response of the skin. The radiographic progression score was 1.5 as opposed to 2.3 in the previous study. The investigators concluded that MTX did have a beneficial clinical effect, and although there was progression of radiographic damage, it was less than that seen in the prior cohort. 16 No study has yet assessed whether MTX contributes an additive or synergistic effect when used in combination with biologic therapy, for example, anti-tnfs. Trials with anti- TNF agents have shown substantial benefit in all clinical domains of PsA, including arthritis, enthesitis, dactylitis, psoriasis, nail disease, and patient reported domains, such as pain, fatigue, function, and quality of life. 5,18 Most of these trials allowed the subject to remain on background MTX therapy if already being used. Typically between 40% and 50% of subjects were on MTX and were stratified equally to receive study medication or placebo. In all of these trials, the presence or absence of background MTX did not have an impact on clinical or radiographic treatment outcomes. 5,18 However, note that these patients came into the trials as MTX inadequate responders, thus not an appropriate population to assess the potential value of combination therapy. It is anticipated that in the near future, this question will be assessed in a formal clinical trial in which PsA patients with relatively short disease duration, MTX-naïve, will be randomized to one of four arms: MTX alone, biologic alone, MTX plus biologic, and placebo. Such a trial will allow us to more accurately analyze the effect of each of these approaches on clinical and radiographic outcomes. In RA, the combination has generally been shown to be more effective than either MTX or biologic monotherapy, either because of the additive efficacy of MTX or because of its ability to inhibit the formation of neutralizing antibodies to the biologic agent or both. Whether the same paradigm will hold true in PsA remains to be determined. The issue of prevention of antibody formation against the biologic agent is particularly important but elusive to determine due to the lack of standard laboratory assays which can be used in clinical practice to determine their presence. If a patient with PsA on an anti-tnf monotherapy is losing efficacy, we cannot know whether this is due to simple loss of efficacy or due to antibody neutralization of effect which could be corrected by abrogation of antibody formation. Although it is common to simply switch to a different anti-tnf agent, one could also try adding in MTX to empirically attempt to deter antibody formation or provide additional efficacy from the MTX itself. In a more recent study with adalimumab in RA, a minimum dose of 10 mg MTX has been recommended for this purpose. 19 A major deficit in our understanding of MTX effect in PsA is the lack of data about its impact on important clinical domains such as enthesitis, dactylitis, and spondylitis. The principle reason for this is the overall paucity of controlled trial data on its use in PsA, and the fact that in the few studies that have been done, enthesitis, dactylitis, and spondylitis response has not been measured. Because the pathobiology of these domains may differ from synovitis, we are unable to extrapolate about the potential effect from response in joints. In practice, there are anecdotal observations suggesting that enthesitis and dactylitis may improve, perhaps to a lesser degree and slower than joints, but this has not been systematically studied with the newer outcome measures available for assessing these domains. MTX has been studied in ankylosing spondylitis and found not to be helpful for the spine. 20 These results are often used as a surrogate to surmise that MTX will not be effective for the spondylitis component of PsA. In pure psoriasis studies, MTX has demonstrated efficacy in treating psoriasis skin lesions. Several recent trials show consistent results. In a comparison of the TNF inhibitor adalimumab (40 mg every other week) versus MTX (up to 25 mg per week), 35.5% achieved a PASI75 response at week 16 as compared to 79.6% treated with adalimumab. 21 In a comparison of an IL12-23 inhibitor, briakinumab (100 mg monthly after a loading dose) against MTX (up to 25 mg weekly), PASI75 was achieved by 39.9% of the MTXtreated group compared to 81.8% of the briakinumab-treated group. 22 In a study of infliximab (5 mg/kg at weeks 0, 2, 6, and 14) versus MTX (up to 20 mg weekly), PASI75 response was demonstrated in 42% of MTX-treated and 78% of infliximab-treated patients. 23 Thus, although these
S44 Bulletin of the Hospital for Joint Diseases 2013;71(Suppl 1):S41-5 results are modest for MTX, it does demonstrate the potential magnitude of response achievable in the skin. It is common for dermatologists to use MTX for limited periods of time in order to minimize the potential for adverse effects from MTX, especially liver toxicity. Historically, dermatologist s MTX treatment guidelines have called for periodic liver biopsy, in addition to regular assessments of liver transaminases, to assess for liver toxicity in the form of fibrosis. However, more recent guidelines are less stringent, and the frequency of monitoring liver biopsies has diminished. The same overall safety and tolerability issues of MTX are present in PsA as in RA, such as nausea, oral sores, hair loss, infection, rare pulmonary toxicity, transaminitis, cytopenias, and rare lymphoma risk, which are reviewed elsewhere in this supplement. A number of studies have suggested that liver toxicity may be more of an issue in PsA and psoriasis than RA. An older meta-analysis of serial liver biopsy studies suggest higher rates of fibrosis occurring in psoriasis patients than in RA, partly related to alcohol use. 24 Another key factor may be the known proclivity of psoriasis and PsA patients to develop metabolic syndrome, including obesity, with resultant increased frequency of non-alcoholic steato-hepatosis (NASH), which may work in concert with MTX to increase frequency of liver toxicity. In registries wherein some comparison can be made between PsA and RA cohorts, such as NOR-DMARD or CORRONA, it does appear that transaminitis is more frequently observed in PsA. 15,25 Fortunately, the frequency of 2 or 3 times upper limit of normal is rare, for example 2.3% and 0.7%, respectively, in the CORRONA cohort. 26 Note that in all of the studies discussed in this manuscript, MTX was administered orally rather than parenterally, with the exception of the original Black study. 10 Whether more common use of parenteral MTX, discussed elsewhere in this compendium, would make a difference in efficacy, safety, or tolerability in PsA is unknown at this time. Summary Although controlled trials of MTX in PsA have not yielded convincing data about its effectiveness in the treatment of joint disease, observational and registry studies have suggested benefit which mirrors our experience in clinical practice. Modest benefit for psoriatic skin lesions has been demonstrated in PsA and psoriasis clinical trials. Although benefit can be noted, many patients will have inadequate response and require additional therapy. The effects of MTX on PsA-specific manifestations, such as enthesitis, dactylitis, and spondylitis, have not been studied. MTX is commonly used in combination with TNF inhibitors. It is not known whether potential benefit in this situation is due to direct effect of MTX or indirect effect of the ability of MTX to inhibit antibody formation directed against the therapeutic protein. The safety profile of MTX in PsA is similar to that of RA; however, it must be borne in mind that PsA patients, similar to psoriasis, have a proclivity to obesity and the metabolic syndrome. In such patients, non-alcoholic steato-hepatosis ( fatty liver ) is common and may contribute to an increased risk for transaminitis when MTX is used. 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