Psoriatic Disease: Update on Traditional Disease-modifying Antirheumatic Drugs

Methotrexate

Until 2010, the efficacy of MTX in improving the symptoms of psoriatic synovitis had been evaluated by a few low-quality studies. Since 2010, 3 relevant studies on this topic have been published. In the NOR-DMARD register, 430 patients with PsA were compared with 1218 patients with rheumatoid arthritis (RA). After 6 months, both groups showed improvement in most disease activity indices; the change was more evident in patients with RA. The 2-year retention rate was similar in PsA and RA patients (65% and 66%, respectively). The authors concluded that, in a real-life setting, MTX treatment of PsA was associated with improvement in disease activity and that its 2-year retention rate was not different from that of RA³. In the Methotrexate in PsA (MIPA) trial, 109 patients taking MTX were compared with 112 patients treated with placebo. At Month 6, only the improvement in patient and assessor global score was significantly higher in MTX-treated patients. The responder rate according to the PsA Response Criteria (PsARC)⁴, which was the primary outcome, was not superior in the MTX group. The authors concluded that low-dose oral MTX was not better than placebo in improving synovitis and that there was “insufficient evidence to support the use of MTX as a standard treatment for PsA.”⁵ The MIPA trial had, however, the following limitations: long enrollment time period (> 5 yrs), dropout rates higher than anticipated (38% and 46% for the MTX and placebo arms, respectively), high number of imputed data, and relatively low dose of the drug (target dose 15 mg/weekly). In the RESPOND study, 57 patients with PsA taking infliximab (IFX) and MTX in combination were compared with 58 patients with PsA receiving MTX alone. As expected, at Week 16 the combination therapy was significantly more effective than MTX alone. However, the proportion of patients achieving the primary efficacy endpoint (American College of Rheumatology 20 response at Week 16⁶) in the MTX-only population was quite high (66.7%)⁷. Taken together, the available data seem to indicate that MTX has a moderate symptom-modifying effect on psoriatic synovitis. More specific and large randomized controlled trials (RCT) should be conducted to weigh the efficacy of MTX.

The effect of MTX on radiographic progression was recently addressed in a cohort analysis of patients followed prospectively in a PsA clinic⁸. In that study, 65 patients treated with tumor necrosis factor-α inhibitors (anti-TNF-α) were compared with 70 patients receiving MTX. The proportion of patients with progression of radiographic damage at 1–2 years and 3–4 years was significantly higher in the MTX group. Multivariate analysis showed that MTX treatment was associated with an increase in radiographic progression compared to TNF-α inhibitors. An exploratory study conducted on a small number of patients (28 taking TNF-α inhibitors and 13 MTX) using high-resolution microcomputerized tomographic imaging showed that both therapies did not stop progression of bone apposition in the metacarpophalangeal joints⁹. The available data suggest that MTX is not a disease-modifying agent in PsA; however, well-performed RCT on this topic are needed.

There are scarce data on whether MTX might be beneficial for enthesitis, dactylitis, and spondylitis in PD. The general opinion of experts is that MTX has no or little effect on these clinical manifestations.

Leflunomide

In the well-known RCT published in 2004, LEF was proven to be better than placebo but with a small effect size in psoriatic synovitis¹⁰. After 2010, other data on this drug have come from a large observational study¹¹. Of the 514 patients with PsA enrolled in this study, 74 (12.3%) discontinued treatment and 380 of the remaining 440 (86.4%) achieved a PsARC response at Week 24. Significant improvement was also observed in dactylitis. There are no data on the effect of LEF on enthesitis, spondylitis, or radiographic progression. Available data suggest that, in PsA, LEF has a moderate symptom-modifying effect on peripheral synovitis and might improve dactylitis. Its effects on the other articular manifestations of PD are unknown.

Sulfasalazine

At least 7 RCT and some open-label or case-control studies on SSZ in PsA were published before 2010. The resulting evidence indicates that this drug is effective in improving the symptoms of peripheral synovitis, although with a modest effect size. Dactylitis, enthesitis, spondylitis, and radiographic progression do not seem to be affected by this drug. However, with the exception of peripheral synovitis, the level of evidence supporting these statements is very low. Since 2010 no further relevant studies on the effect of SSZ on the articular components of PD have been published.

Cyclosporine

Before 2010, data on the efficacy of CSA had been provided by 2 small RCT and some open-label studies. These data suggest that this drug can improve peripheral synovitis but has little or no effect on spondylitis and radiographic progression. No data on enthesitis and dactylitis were available at that time. Since then, only 1 study with CSA used as a monotherapy in PsA has been published¹². In that open-label, non-randomized, controlled trial, CSA alone (57 patients) was compared with adalimumab (ADA) alone (58 patients) and with ADA and CSA in combination (55 patients). At Month 12, the primary efficacy endpoint (PsARC response) was met by 65% of CSA-treated, 85% of ADA-treated, and 95% of combination-treated patients. Although the proportion of responders in the CSA group was significantly lower than in the other groups, the number of patients who responded to CSA alone was quite high. Dactylitis and enthesitis were present in only about 7–15 patients in each therapy arm. While most of the ADA-treated patients showed an improvement in these manifestations, only 28% (dactylitis) and 15% (enthesitis) of the CSA monotherapy patients responded to the treatment. On the basis of all existing evidence, it can be affirmed that CSA can improve peripheral synovitis but has no effect on the other articular manifestations of PD. However, as for the other synthetic DMARD, the level of evidence supporting these conclusions is low.

Combination therapies

The only RCT aimed at evaluating the combination of 2 synthetic DMARD in PsA was published in 2008¹³. That trial showed that adding CSA to MTX-unresponsive patients was better than adding placebo, although the only significant difference was the reduction of inflamed joints as detected by ultrasound. The combination MTX and LEF in PsA has never been tested in an RCT. A small experiment in 11 unresponsive patients in whom LEF was added to MTX showed only modest improvement in the mean value of the disease activity score¹⁴.

As already reported in the MTX and CSA sections, 2 small open-label controlled trials on the combination of these 2 drugs with IFX and ADA, respectively, have been published^7,12. In both studies, combination therapy was superior to monotherapy in improving peripheral synovitis, dactylitis, and enthesitis. However, because in the RESPOND trial the monotherapy arm was treated with MTX only, it cannot be excluded that the superiority of the combination therapy was entirely due to IFX. In contrast, in the CSA plus ADA trial, both drugs were singularly inferior to their combination, although the difference was less pronounced for ADA.

Interesting data on the longterm usefulness of concomitant MTX in patients with PsA treated with TNF-α inhibitors come from observational studies. Data from the NOR-DMARD and the DANBIO registers showed that concomitant MTX use did not lead to a better clinical response but was associated with a higher retention rate of TNF-α inhibitor therapy^15,16. Finally, it should be mentioned that in the phase III trials of TNF-α inhibitors in PsA, concomitant MTX did not lead to better disease control. Although the existing evidence is insufficient to establish whether DMARD combination is indicated in PsA, concomitant MTX might at least increase the retention rate of TNF-α inhibitors.

Safety

Since 2010, no new safety signals in addition to those already known for the 4 synthetic DMARD have been reported. A systematic review of observational studies in patients with psoriasis has revealed that MTX is likely to increase the risk of liver fibrosis. The authors of that review suggested considering all patients taking this drug to be at risk of this adverse event, pending further research¹⁷. Another systematic review showed that liver function tests, procollagen-3 N-terminal peptide, and liver ultrasound have poor clinical utility in detecting MTX-induced liver fibrosis in patients with psoriasis, and that there are insufficient data to evaluate newer methods including Fibroscan¹⁸. In a 1-year prospective study on 225 patients with PsA, CSA alone or in combination with other immunosuppressive agents did not induce a reactivation of the viruses commonly tested in clinical practice¹⁹.

Studies published from 2010 to 2014 confirm that MTX, SSZ, LEF, and CSA have moderate symptom-modifying effect on psoriatic synovitis. They do not seem to influence radiographic progression and they are likely to be ineffective on the other articular manifestations of PD. However, the evidence supporting these statements remains poor.