Tofacitinib Shows Promise in Psoriatic Arthritis

Nicola M. Parry, DVM

October 18, 2017

Data from two clinical trials have shown that the orally administered Janus kinase inhibitor tofacitinib is more effective than placebo for treating patients with active psoriatic arthritis (PsA) and inadequate response to treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor (TNF) inhibitors.

Philip J. Mease, MD, from Seattle Rheumatology Associates in Washington, and colleagues, and Dafna Gladman, MD, from the University of Toronto in Ontario, Canada, and colleagues published the results of the two phase 3 studies in the October 19 issue of the New England Journal of Medicine.

The results from these two company-funded randomized trials show that tofacitinib "also has a place in the arsenal of drugs for the treatment of PsA," write Robert A. Colbert, MD, PhD, and Michael M. Ward, MD, both from the National Institutes of Health, Bethesda, Maryland, in an accompanying editorial.

PsA is a chronic inflammatory arthritis that develops in about 30% of patients with psoriasis and can significantly affect quality of life and activities of daily living.

For patients with active PsA that does not respond adequately to conventional synthetic DMARDs, current treatment guidelines recommend that clinicians use TNF inhibitors. However, TNF inhibitor therapy is limited in patients who experience a poor response because of loss of efficacy or adverse events.

Research has shown that Janus kinase inhibitors may target inflammatory pathways in both articular and extra-articular locations in patients with psoriasis.

Tofacitinib After DMARDs

"Although tofacitinib does not directly control the response to TNF and interleukin-17, two cytokines important in psoriatic arthritis, it indirectly reduces their production by blocking upstream cytokines such as interleukin-6 and interleukin-23," Dr Colbert and Dr Ward explain.

The OPAL Broaden trial, led by Dr Mease, evaluated the efficacy and safety of tofacitinib in patients with PsA who had an inadequate response to conventional synthetic DMARDs. Eligible patients were randomly assigned to receive 5 mg tofacitinib taken orally twice daily (n = 107), 10 mg tofacitinib taken orally twice daily (n = 104), 40 mg adalimumab administered subcutaneously once every 2 weeks (n = 106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (n = 52), or placebo with a blinded switch to receiving the 10-mg tofacitinib dose at 3 months (n = 53). The adalimumab group served as an active control group in the trial, as this TNF inhibitor is known to benefit patients with PsA.

"[T]ofacitinib at a dose of 5 mg or 10 mg showed superior efficacy to placebo in several clinical domains of psoriatic arthritis at 3 months," Dr Mease and colleagues write.

Tofacitinib led to greater improvement than placebo in the two primary endpoints, assessed at month 3: the rate of American College of Rheumatology 20 (ACR20) response, and patients' ability to perform certain activities of daily living as measured by change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ-DI).

At 3 months, ACR20 response rates were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group compared with just 33% in the placebo group (P = .01 and P < .001 for comparison of 5- and 10-mg tofacitinib, respectively, with placebo) and 52% in the adalimumab group.

Patients receiving 5 or 10 mg tofacitinib also showed significant baseline to month 3 improvements in HAQ-DI vs those receiving placebo (mean change, −0.35 vs −0.40 vs −0.18; P = .006 and P < .001 for comparison of 5- and 10-mg tofacitinib, respectively, with placebo). Patients receiving adalimumab experienced a mean score change of −0.38.

During the 3-month placebo-controlled period, the researchers also found a higher rate of adverse events in patients who received 5 mg tofacitinib (39%), 10 mg tofacitinib (45%), and adalimumab (46%) than in those who received placebo (35%).

During the 12-month trial, there were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib. However, none of these serious adverse events occurred in patients who received placebo or adalimumab. One patient who switched from placebo to 5 mg tofacitinib died of cardiac arrest during month 4.

Tofacitinib After TNF inhibitors

"Further studies are required in order to determine the long-term efficacy and safety of tofacitinib in patients with psoriatic arthritis," Dr Mease and colleagues conclude.

The OPAL Beyond trial, led by Dr Gladman, went a step further and evaluated tofacitinib in patients with active PsA who had an inadequate response to one or more TNF inhibitors.

Eligible patients were randomly assigned to receive 5 mg tofacitinib taken orally twice daily for 6 months (n = 132), 10 mg tofacitinib taken orally twice daily for 6 months (n = 132), placebo with a switch to 5 mg tofacitinib twice daily at 3 months (n = 66), or placebo with a switch to 10 mg tofacitinib twice daily at 3 months (n = 65).

Similar to the findings in OPAL Broaden, Dr Gladman and colleagues also found that "tofacitinib was more effective than placebo over 3 months in reducing disease activity" in this trial, also published in the October 19 issue of the journal.

At 3 months, ACR20 response rates were 50% in the 5 mg tofacitinib group and 47% in the 10 mg tofacitinib group compared with just 24% in the placebo group (P < .001 for both comparisons).

Patients receiving 5 or 10 mg tofacitinib also showed significant improvements from baseline to month 3 in HAQ-DI compared with those receiving placebo (mean change, −0.39 and −0.35 vs −0.14; P < .001 for both comparisons).

During the 3-month placebo-controlled period, the researchers also found a higher rate of adverse events in patients who received 5 mg tofacitinib (55%) and 10 mg tofacitinib (53%) than in those who received placebo (44%).

During the 6-month period of the trial, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke in patients who received tofacitinib continuously. Patients in this group also experienced "[e]levations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range," Dr Gladman and colleagues write.

They also describe early elevations in low-density lipoprotein and high-density lipoprotein cholesterol levels in patients who received tofacitinib, but note that these levels did not increase further after month 3 through month 6, except in patients who received placebo during the first 3 months.

In their editorial, Dr Colbert and Dr Ward say the results of these two trials may open the door to tofacitinib playing a key role alongside TNF inhibitors and phosphodiesterase-4 inhibitors in managing PsA.

"Comparisons of tofacitinib with other biologic DMARDs will inform its place in the treatment algorithm of psoriatic arthritis," they write, stressing that differences in safety will also guide treatment selection.

"Although more head-to-head comparisons will be useful, other factors, such as cost, convenience, safety, and the extent of skin disease, will be considerations in treating patients and improving outcomes," the editorialists conclude.

These studies were supported by grants from Pfizer. One or more authors has reported receiving grants, personal fees, and/or nonfinancial support from one or more of the following: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, Merck & Co, Merck Serono, Novartis, Pfizer, Roche, Sanofi, and UCB. One editorialist has reported being the Principal Investigator on a Cooperative Research and Development Agreement between his institute (National Institute of Arthritis and Musculoskeletal and Skin Diseases) and Eli Lilly and Company. The second editorialist has disclosed no relevant financial relationships.

New Engl J Med. 2017;377:1525-1550, 1582-1584. Mease abstract, Editorial extract, Gladman abstract

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