Roughly 20% of cases of psoriasis are complicated by a seronegative arthritis (psoriatic arthritis). This condition has been neglected for many years relative to rheumatoid arthritis, and treatment algorithms based on robust evidence specifically from clinical trials of psoriatic arthritis are few in number. Conventional treatment usually begins with DMARDs and NSAIDs, followed by tumour necrosis factor α (TNFα) inhibitors. It has been postulated that T-helper-17 (Th17) cells have a major role in psoriatic inflammation, and thus various biological drugs directed against interleukins 17 and 23 are being investigated. Ustekinumab is a fully human IgG 1κ monoclonal antibody that binds to the common p40 subunit shared by interleukins 12 and 23. Phase II data showed that ustekinumab was efficacious in treatment of psoriatic arthritis. In The Lancet, researchers present 52 week data from the phase III, randomised, double-blind, placebo controlled PSUMMIT 1 trial of ustekinumab in 615 patients with active psoriatic arthritis (≥5 tender and ≥5 swollen joints, C-reactive protein ≥3.0 mg/L) despite ≥3 months of DMARDs or ≥4 weeks of NSAIDs, or both.
Patients were randomised to 45mg ustekinumab (n= 205), 90mg ustekinumab (n= 204), or placebo (n= 206) at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with <5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45mg ustekinumab (if on placebo) or 90mg ustekinumab (if on 45mg group). At week 24, all remaining patients in placebo group received ustekinumab 45mg, which they continued at week 28 and every 12 weeks thereafter. The primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24.
More ustekinumab-treated (87 of 205 [42.4%] in the 45mg group and 101 of 204 [49.5%] in the 90mg group) than placebo-treated (47 of 206 [22.8%]) patients achieved ACR20 at week 24 (p<0.0001 for both comparisons); responses were maintained at week 52.
There were also differences at week 24 for ACR50 (108 of 409 [26.4%] patients in the combined ustekinumab group, 51 of 205 [24.9%] in the 45mg group, and 57 of 204 [27.9%] in the 90mg group vs. 18 of 206 [8.7%] in the placebo group achieved an ACR50 response; p<0.0001 for all placebo comparisons) and ACR70 (54 of 409 [13.2%], 25 of 205 [12.2%], and 29 of 204 [14.2%] vs. 5 of 206 [2.4%]; p<0.0001, p=0.0001, and p<0.0001, respectively).
At weeks 12 and 24, a higher proportion of patients in the ustekinumab groups than in the placebo group achieved DAS28-CRP (EULAR) responses (p<0.0001). Compared with placebo, treatment with ustekinumab (both doses) resulted in a higher proportion of patients with DAS28-CRP scores <2.6 at week 24 (p=0.0002). By week 52, 118 of 383 (30.8%) combined ustekinumab patients and 54 of 184 (29.3%) of patients in the placebo→45 mg group had a DAS28- CRP score <2.6.
Ustekinumab was reported to be generally well tolerated (at week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups: 171 of 409 [41.8%] vs. 86 of 205 [42.0%]), although three major adverse cardiovascular events—specifically, myocardial infarction at 8 weeks and 22 weeks, and stroke at 29 weeks after initiation of ustekinumab— were noted. A possible link between major adverse cardiovascular events and interleukin 12/23 blockers, especially in the first 12 weeks of treatment, is much debated in the dermatology world. The researchers note that the safety of ustekinumab merits close long-term follow up in the context of registries, especially to fully assess cardiovascular risks. They add that interpretation of their data is restricted because rules for handling of early-escape data were not applied after week 24, and because of the shortness of the placebo controlled period. In addition, radiographic data have been collected but not reported as yet. Findings related to ustekinumab treated patients with psoriatic arthritis who were anti-TNFα-experienced will also be reported in a forthcoming paper which will be specific to the efficacy and safety findings of the PSUMMIT 2 trial.
According to an accompanying comment article, algorithms of care for patients with severe psoriasis in whom traditional systemic treatments are unsuccessful advocate use of TNFα inhibitors in patients with coexisting psoriatic arthritis. It suggests that these current trial data indicate ustekinumab might have a role in treatment of both psoriasis and psoriatic arthritis in the future. However ustekinumab has a slower onset of action compared to anti-TNFα drugs though there might be equivalent response rates after 52 weeks- the authors acknowledge the dangers of making cross-study, post-placebo interpretations of the data and a head to head study of ustekinumab and an anti-TNFα drug is needed.
Currently in the UK, ustekinumab is only licensed for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA.
NICE guidance supports the use of etanercept, infliximab, adalimumab and golimumab for the treatment of active and progressive psoriatic arthritis, when the following criteria are met: the person has peripheral arthritis with ≥3 tender joints and ≥3 swollen joints, and the psoriatic arthritis has not responded to adequate trials of at least two DMARDs, administered either individually or in combination. Treatment choice should be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). The guidance recommends that treatment should be discontinued if a person's disease does not show an adequate response on the Psoriatic Arthritis Response Criteria at 12 weeks. An adequate response is defined as an improvement in at least two of the four PsARC criteria, (one of which has to be joint tenderness or swelling score) with no worsening in any of the four criteria.