Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis: a randomised, placebo-controlled, double-blind clinical trial (complete-psa)

BackgroundConventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) are the cornerstone first-line treatment in psoriatic arthritis (PsA), although there is a paucity of evidence for the effectiveness of csDMARDs and especially their combination. Assessing the efficacy and safety of combinations of csDMARDs compared with csDMARD monotherapy has been prioritized on the EULAR research agenda. We hypothesized that combining csDMARDs might be more effective than csDMARD monotherapy.ObjectivesWe aimed to investigate whether a combination of methotrexate (MTX) and leflunomide (LEF) is superior to MTX monotherapy on improvement in disease activity in patients with PsA.MethodsPatients with a clinical diagnosis of PsA and active disease (≥2 swollen joints) were included in this randomised, placebo-controlled, double-blind trial. Patients were randomised (1:1) to MTX plus LEF or MTX plus placebo. Patients received MTX 15 mg/week for four weeks and thereafter 25 mg/week, combined with two LEF 10 mg tablets or two placebo tablets daily. The primary outcome was the difference between the MTX plus LEF group and the MTX plus placebo group on the psoriatic arthritis disease activity score (PASDAS) at week 16 adjusted for baseline PASDAS. Key secondary outcomes included safety and the achievement of minimal disease activity (MDA) criteria and PASDAS low disease activity (LDA) (≤3.2).ResultsA total of 78 PsA patients (MTX + LEF n=39; MTX + placebo n=39) were included. The mean age was 53.1 (SD=12.8) years and 36% (n=28) of the patients were female. The mean PASDAS at baseline was 4.9 (SD=1) in both treatment groups. Table 1 shows that MTX plus LEF was superior to MTX plus placebo at week 16 (PASDAS 3.1, SD=1.4 vs 3.7, SD=1.3; treatment difference= -0.6, 90% CI -1.0 to -0.1, one-sided P-value=0.025). Similar and significant results were found for achievement of MDA criteria (59% vs 33%, one-sided P-value=0.013) and PASDAS LDA (59% vs 35%, one-sided P-value=0.019) (Figure 1 and Table 1). Other favorable and significant outcomes for the MTX plus LEF group included -among others- the improvement in swollen joint count (SJC) (median [IQR] = -3 [-5, -2] vs -2 [-4, 0], one-sided P-value=0.039) and the proportion of patients with active psoriasis (i.e. body surface area score >0) at week 16 (44% vs 68%, one-sided P-value=0.014). Generally mild adverse events and treatment discontinuation (MTX+LEF n/N=10/39; MTX + placebo n/N=3/39) occurred more frequently in the MTX plus LEF group.Table 1.Primary and secondary outcomes at week 16MTX + LEF(N=39)MTX + placebo (N=38)*Absolute difference [90% CI]P-valueOne-sidedPrimary endpointPASDAS at week 163.1 (1.4)3.7 (1.3)-0.6 [-1.0, -0.1]0.025Selected secondary endpointsFulfilling PASDAS LDA, N (%)23 (59)13 (35)24% [6, 42]0.019Fulfilling MDA criteria, N (%)23 (59)12 (33)26% [7, 44]0.013SJC66, change from baseline, median (Q1, Q3)-3 (-5, -2)-2 (-4, 0)..0.039TJC68, change from baseline, median (Q1, Q3)-2 (-4, 0)-2 (-5, 0)..0.457VAS physician global, change from baseline, mean (SD)-22.0 (21.9)-12.2 (19.7)-9.8 [-17.7, -1.9]0.021VAS patient global, change from baseline, mean (SD)-20.9 (24.4)-13.9 (28.3)-7.0 [-17.0, 3.0]0.124Active psoriasis, N (%)17 (44)26 (68)-25% [-43, -7]0.014* One patient in the MTX + LEF group was excluded from the efficacy analysis due to change of diagnosis.Figure 1.Proportion of patients meeting different PsA responder criteria for low disease activity at week 16* = one-sided P-value <0.05DAPSA = Disease Activity in Psoriatic ArthritisConclusionMTX plus LEF combination therapy resulted in a significantly greater improvement in disease activity according to PASDAS and MDA than treatment with MTX monotherapy in patients with PsA after 16 weeks. In addition, a greater improvement in psoriasis was found for the combination group. However, there are indications that MTX plus LEF combination is less well tolerated than MTX monotherapy.AcknowledgementsWe would like to thank all the patients that participated in this study; all rheumatologists from the Sint Maartenskliniek that helped with the patient inclusion; our patient partners and especially R. van den Griend; Dr. E. Mahler for her suggestions and advice with regard to the study design; Dr. C. Popa and Dr. D. Telgt for being members of our data safety monitoring board and the rheumatology nurses of our center for their assistance with collecting the data.Disclosure of InterestsMichelle L.M. Mulder: None declared, Johanna E. Vriezekolk Speakers bureau: Eli Lilly Netherlands BV and Galapagos Biopharma Netherlands BV, Tamara van Hal Speakers bureau: Eli Lilly and Novartis, Grant/research support from: support for attending meetings from UCB (personal funding), Lieke Nieboer: None declared, Nathan den Broeder: None declared, E.M.G.J. de Jong Speakers bureau: AbbVie, Almirall, Janssen Pharmaceutica, Novartis, Lily, Celgene, Leo Pharma, Sanofi, UCB and Galapagos (all funding is not personal but goes to the independent research fund of the department of dermatology of Radboud university medical centre Nijmegen, the Netherlands), Consultant of: AbbVie, Almirall, Janssen Pharmaceutica, Novartis, Lily, Celgene, Leo Pharma, Sanofi, UCB and Galapagos (all funding is not personal but goes to the independent research fund of the department of dermatology of Radboud university medical centre Nijmegen, the Netherlands), Grant/research support from: AbbVie, Novartis, Janssen Pharmaceutica, Leo Pharma and UCB for research on psoriasis, Alfons den Broeder: None declared, Frank van den Hoogen: None declared, Philip Helliwell Speakers bureau: Pfizer, Abbvie, Novartis and Janssen, Consultant of: Eli Lilly, Mark Wenink: None declared