麻豆传媒

Patients with psoriatic arthritis whose disease manifestations are primarily articular may benefit from treatment with the interleukin (IL)-6 blocker clazakizumab, a phase IIb study suggested.

Among patients who had not previously received biologic treatment for psoriatic arthritis, 52.4% of those who received 100 mg clazakizumab subcutaneously every 4 weeks showed a 20% improvement in the response criteria of the American College of Rheumatology (ACR20) at week 16 compared with 29.3% of those given placebo (P=0.039), according to , of the University of Washington in Seattle, and colleagues.

Numerically greater responses also were seen for patients randomized to 25 mg and 200 mg every 4 weeks, at 46.3% and 39%, respectively, although those were not statistically significant differences compared with placebo, the researchers reported in

The pleiotropic cytokine IL-6 has been implicated in the pathogenesis of psoriatic arthritis, and levels of IL-6 have been found to correlate with the degree of joint involvement in the disease.

Therefore, to explore the possibility that targeting the IL-6 pathway could be beneficial in psoriatic arthritis, Mease and colleagues enrolled 165 patients from January 2012 to June 2013 from 44 sites in 13 countries.

During the 24-week double-blind phase of the study, patients could be on concomitant methotrexate and prednisone in doses of 10 mg or less per day. After week 16, patients who had less than 20% improvement could receive rescue therapy with glucocorticoids, disease-modifying anti-rheumatic drugs (DMARDs), or open-label clazakizumab.

Participants' mean age was 48, mean disease duration was 7.1 years, and slightly more than half were women. About 70% were on background methotrexate.

At baseline, tender and swollen joint counts averaged 20 and 12, respectively. Mean disease Activity Score in 28 joints (DAS28) was 5.1, and mean Psoriasis Area and Severity Index (PASI) was 8.8.

At week 24, ACR20 responses were seen in 34.1%, 56.1%, 57.1%, and 39% of the placebo, 25-mg, 100-mg, and 200-mg groups, respectively. There was no evidence of dose response, the researchers pointed out.

Also at week 24, ACR50 responses were seen in 14.6%, 34.1%, 35.7%, and 24.4% of the placebo, 25-mg, 100-mg, and 200-mg groups, respectively, while ACR70 responses were seen in 4.9%, 19.5%, 23.8%, and 12.2%.

The proportion of patients who were in DAS28 remission at week 24 were 14.6%, 41.5%, 40.5%, and 29.3% of the placebo, 25-mg, 100-mg, and 200-mg groups, respectively.

In patients with enthesitis, conflicting results were seen depending on the assessment tool used. On the Spondyloarthritis Research Consortium of Canada enthesitis index, which includes 18 entheses, scores were lower for all the active treatment groups compared with placebo, but no meaningful differences were seen between clazakizumab and placebo on the Leeds Enthesitis Index, which includes only six entheses.

Skin responses were "minimal," Mease and colleagues noted, with 75% improvement on PASI being seen at week 24 in 12.2%, 19.5%, 28.6%, and 12.2% of the placebo, 25-mg, 100-mg, and 200-mg groups.

A possible explanation for the limited effect on skin manifestations is that the inflammatory effects of IL-6 are more prominent in the joint, suggesting that there may be different mechanisms at work in the cutaneous and articular aspects of the disease, the researchers suggested.

"We don't have prior evidence of effectiveness of IL-6 blockade in psoriatic arthritis, so this could reflect another possible mechanism for us to exploit in the management of psoriatic arthritis," said director of the Rheumatology Faculty Practice Plan at the Hospital for Special Surgery in New York City, who was not involved in the study.

"Thus, clazakizumab may be particularly suited for patients with psoriatic arthritis in whom skin disease is well controlled with topical agents, ultraviolet therapy, and/or oral systemic therapy such as methotrexate, but whose musculoskeletal manifestations, such as joint signs and symptoms, enthesitis, and dactylitis, require more potent systemic therapy," Mease and colleagues wrote.

"This agent is given subcutaneously at 4-week intervals, so its convenience level is high and patients tended to respond early," Fields told 麻豆传媒. Improvements on ACR20 were seen as early as week 1 in the study.

A minimally important difference in the Health Assessment Questionnaire Disability Index of at least 0.35 units was seen in 26.8%, 51.2%, 47.6%, and 36.6% of the placebo, 25-mg, 100-mg, and 200-mg groups, respectively.

Serious adverse events were reported in two patients each in the placebo, 25-mg, and 100-mg groups, and in four patients in the 200-mg group, including a case of muscle weakness of the left arm that was considered treatment-related in a patient in the 200-mg group.

Discontinuations because of adverse events were reported in three patients in the placebo group, one in the 25-mg group, two in the 100-mg group, but seven patients in the 200-mg group.

Clazakizumab was associated with several laboratory abnormalities, including transaminase elevations, increases in lipids, and decreases in platelets and polymorphonuclear neutrophils, but clinical interventions were considered unnecessary. These findings "are consistent with the pharmacology of IL-6 blockade," the researchers noted.

There were no serious infections, opportunistic infections, malignancies, or autoimmune disorders.

There was no apparent dose response in the study, with the 200-mg group showing less efficacy, particularly on patient-reported outcomes, which may reflect less tolerability with the highest dose.

"Further data on optimal dosing are needed," Fields said.

A limitation of the study was the inconsistent use of methotrexate.

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