Editorial

Methotrexate Therapy for Psoriatic Arthritis: Reappraisal of an Old Remedy

LESLEY ANN SAKETKOO, MD, MPH;

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RAQUEL CUCHACOVICH, MD;
LUIS R. ESPINOZA, MD,
Section of Rheumatology,
LSU Health Sciences Center,
2020 Gravier Street,
New Orleans, Louisiana 70112-2822, USA

Address reprint requests to Dr. Espinoza. E-mail: luisrolan@msn.com

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Contrary to previously accepted thought, psoriatic arthritis (PsA) is a progressive disabling disease carrying a burden and severity comparable to that of rheumatoid arthritis (RA). PsA requires rigorous attention to quell skin disease activity and stave off peripheral and axial joint destruction, cardiovascular morbidity, and emotional, social and functional disability contributing to loss of work productivity and social isolation¹. However, existent randomized controlled clinical trials involving disease modifying antirheumatic drugs (DMARD) in the treatment of PsA are dismally and astoundingly poor^2,3. Lack of prior investigational interest lies in the clinical complexity of the disease, with manifold components: skin, nail, peripheral and axial joint involvement, equivocal correlation of inflammatory markers, and psychosocial burden. Over the past 4 years groups like GRAPPA (Group for Research and Assessment in Psoriasis and Psoriatic Arthritis) and OMERACT 8 (Outcome Measures in Rheumatology) have shown exquisite dedication and made persistent efforts in compiling evidence to establish assessment and clinical response criteria^4,5.

Another logistical issue is the low numbers of patients studied in DMARD efficacy analyses. To be sure, there is no shortage of patients with PsA; patients are simply not finding their way to rheumatologic care, where they are more apt to receive appropriate treatment^6-8, and as a consequence, power in non-industry funded PsA studies is lost. In recognition of this lack, a growing number of dedicated rheumatologists are maintaining their own registries of PsA patients to supply data for future evaluation. Part of improving PsA health outcomes requires strengthening communication with local dermatology colleagues. Sharing rheumatologic expertise via specialist education or, more simply and conveniently, encouraging initial referral of all psoriasis patients to rheumatology, with followup within one year or sooner regarding patients' perceived rheumatic symptoms.

The study by Chandran, et al published in this issue is the first to examine moderate to high-dose methotrexate (MTX) in a sustained longitudinal trial with a credible sample size; it suggests that a second look is warranted at a once commonly used and poorly investigated therapy⁹. More recently, in an unintentional prelude to Chandran, et al, Scarpa, et al demonstrated the efficacy of low-dose MTX on the clinical manifestations of early PsA¹⁰. Radiographic improvement has been noted with the use of anti-tumor necrosis factor-a (TNF-a), but until the Chandran report this was not clearly substantiated with early, aggressive DMARD treatment¹¹. Given the worldwide escalation of healthcare costs and the high expense of biologics, the Chandran "reappraisal" warrants close scrutiny of biologics in fair comparison to more affordable medications administered as single agents or in combination. At a 10-year horizon, the incremental cost-effectiveness ratio (ICER) for etanercept compared with so-called "palliative care" was 26,361 pounds sterling per quality-adjusted life-year (QALY) gained for the best-case rebound scenario, which increased to £30,628 for the worst-case. The ICER for infliximab versus etanercept was £165,363 for best case and £205,345 for worst case for QALY. The QALY of the average patient for palliative care, etanercept, and infliximab, respectively, were 3.26, 4.36, and 4.46¹². With cost considerations of anti-TNF treatment far exceeding those of traditional DMARD, investigation of early, aggressive DMARD treatment may be the key to curtailing severity of disease, excessive costs related to disease burden and disability, while avoiding costly biologics save for refractory cases.

Lack of early aggressive optimal systemic treatment is linked to worsening psoriasis and progression to PsA. Currently, 40% of psoriasis patients receive no treatment at all and 73% with moderate disease (3%–10% of body surface area, BSA) and 57% of patients with severe psoriasis (> 10% BSA) are being treated with topical therapy only and may not have had rheumatologic evaluation⁶. Given that at least 30% of patients with psoriasis develop joint disease within 5–10 years and a high percentage of dermatologists admit suspicion of joint disease on the first visit but do not investigate further, clearly the opportunity of early treatment is missed⁷. Informal discussions with dermatologists have identified the difficulty competing with persuasive pharmaceutical voices representing topical preparations and "educating" dermatology colleagues on coincident "osteoarthritis" in their psoriasis patients.

On the heels of their previous analysis that demonstrated decreased mortality associated with early aggressive MTX treatment in PsA¹³, Chandran, et al have now reinforced the potential that lies untapped within MTX and DMARD in general. Associated side effects of anti-TNF treatment in PsA patients require closer examination, as these patients carry higher risk and mortality of malignancy and cardiovascular disease versus the general population¹³. Comorbid disease burden and mortality of PsA is significant and may even surpass that of RA, for which the addition of one DMARD such as hydroxychloroquine positively affects cardiovascular risk in RA and associated cardiovascular burden^8,13. Chloroquine has also been shown to be effective without skin worsening in the treatment of PsA¹⁴. However, its use in combination with other DMARD including MTX has not been explored. Prolongation of survival as seen in patients with systemic lupus erythematosus may benefit patients with PsA, who carry a high mortality compared to the general population. These are a few of the many questions about use of DMARD in PsA that merit examination.

Introduction of anti-TNF therapy a decade ago conferred relief to progressive, crippling autoimmune diseases refractory to conventional treatments. Among these were RA and inflammatory bowel disorders, which, even prior to the advent of anti-TNF therapy, had undergone painstaking investigation for validated assessment and therapeutic response tools as well as measurements of efficacy and safety of available agents. As a result of efficacy in these diseases, numerous anti-TNF trials initiated over a handful of years demonstrated efficacy and subsequently established indication for treatment in diseases such as PsA, which historically had received incomplete investigative attention. These anti-TNF trials outnumber by several-fold all the DMARD trials ever conducted for PsA; and prior to Scarpa, et al¹⁰, there had been only 2 randomized controlled trials of MTX, both reporting efficacy in skin and joint manifestations: one 23 years ago with pulsed low-dose¹⁵ and the other 43 years ago with parenteral ultra-high-dose (radiographic progression was not assessed)¹⁶. Such paucity of DMARD literature makes anti-TNF therapy highly visible and perhaps unwittingly gives it prominence in clinicians' minds as the "default" therapy. There is no debate regarding the efficacy of anti-TNF therapy in the therapy of refractory PsA, but questions remain whether anti-TNF therapies should be the agents of choice in patients with early PsA or in those PsA patients with higher risk and mortality of malignancy and cardiovascular disease.

The marked response of psoriasis and PsA to anti-TNF therapy demands reevaluation of current hypotheses, looking beyond widely accepted theories that psoriasis and PsA are a predominantly T-helper (Th)-1 cell-mediated disease¹⁷. There is likely an important role for other T cell populations, i.e., Th-17, through the production of interleukin 17 (IL-17), has been implicated in PsA^18,19; and that of T regulatory cells as well as for dendritic cells, fibroblasts, macrophages, and IL-22, IL-23 and IL-20^18-20.

Nevertheless, as a distinct entity PsA carries different complexities versus RA and therefore deserves dedicated therapeutic approaches rather than extrapolation. In regard to treatment options, do patients with psoriasis have a "different," more susceptible liver, a "psoriatic liver" per se, that should prevent the use of high-dose MTX? Or do associated comorbid conditions such as obesity exert a culprit effect? These are questions that are open to investigation and may be answered by future MTX or DMARD trials evaluating parallel variables such as body mass index, hypertension, dyslipidemia, alcohol consumption, and other comorbidities linked to psoriasis patients⁸.

In order to intelligently justify the use of biologics in PsA, more studies are needed on the efficacy of DMARD, both alone and in combination; these will hopefully give rise to step-wise approaches in treatment, reserving biologics for refractory disease. Collaborative efforts with the dermatology community to identify patients and institute early referral, or combined clinics, should be a priority. With the close of the 2007 American College of Rheumatology conference, confidence is inspired that ground gained through the acquisition of assessment tools will be duly applied to proper investigation of the less glamorous therapeutic options.

REFERENCES

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