JAK Inhibitor Succeeds as Monotherapy in Rheumatoid Arthritis Save

The oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq) given as monotherapy was more effective than methotrexate alone in methotrexate-naive patients with active rheumatoid arthritis (RA) in a multinational phase III trial.

At week 12, 50% improvements on the criteria of the American College of Rheumatology (ACR50) were seen in 52% of patients randomized to 15 mg/day of upadacitinib and 56% of those given 30 mg/day compared with 28% of those receiving methotrexate in weekly doses up to 20 mg, which were significant differences, reported Ronald van Vollenhoven, MD, of Amsterdam University in the Netherlands, and colleagues.

And at week 24, a Disease Activity Score in 28 joints (DAS28) below 2.6, indicating remission, was achieved by 48% and 50% of the 15 mg and 30 mg upadacitinib groups, respectively, compared with 19% of those in the methotrexate group, which again was a significant difference, according to the team's study online in Arthritis & Rheumatology.

Guidelines and treatment recommendations from the ACR and the European League Against Rheumatism (EULAR) favor methotrexate as the initial therapy for RA, but the majority of patients are unable to reach remission with this drug and some are unable to tolerate it. Adverse events include nausea, oral ulcers, alopecia, and general malaise, and some patients have had serious events including hepatotoxicity, myelosuppression, and interstitial pneumonitis.

"Thus, methotrexate is not always the ideal treatment for all patients and the search for alternative therapies is legitimate," van Vollenhoven and colleagues wrote.

Current options for those patients include biologics and targeted molecules such as JAK inhibitors, as monotherapy or in combination with conventional disease-modifying antirheumatic drugs.

Upadacitinib was found to be effective in the pivotal clinical trials, given both alone or in combination in patients with previous methotrexate experience and established RA. The drug received FDA approval in August 2019 for treating RA.

The current study, known as SELECT-EARLY, evaluated upadacitinib as monotherapy in methotrexate-naive patients (or those with minimal exposure to methotrexate) with moderately to severely active RA and poor prognostic factors such as seropositivity for rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA) and radiographic damage present at baseline. The trial, which was sponsored by AbbVie, took place at 236 centers in 43 countries, enrolling 945 patients.

The use of nonsteroidal anti-inflammatory drugs, acetaminophen, and low-dose prednisone was permitted.

Participants' mean age was 54, and three-quarters were women. Median time since diagnosis was 0.5 years.

Mean baseline DAS28 was 5.9, and in 78% the DAS28 was above 5.1, indicating high disease activity. Erosions were already present in more than half of the patients, and 69% were positive for RF and ACPA. Tender and swollen joint counts were 25 and 17, respectively, and mean pain score was 66 on a 100-point visual analog scale.

Efficacy

At week 12, the differences in ACR50 responses between upadacitinib and methotrexate were 24% (95% CI 16-31, P<0.001) for the 15 mg dose and 28% (95% CI 21-35, P<0.001) for the 30 mg dose.

At week 24, the differences in the proportions of patients achieving a DAS28 below 2.6 were 30% (95% CI 23-37, P<0.001) for those on the 15 mg dose and 32% (95% CI 25-39, P<0.001) for those on the 30 mg dose.

Upadacitinib monotherapy also was superior to methotrexate on various secondary endpoints. At week 12, significantly more patients on upadacitinib 15 mg or 30 mg had ACR20 responses compared with methotrexate (76% and 79% vs 54%). In addition, ACR70 responses at week 12 were 33% and 45%, compared with 14%, respectively.

Significantly greater improvements also were seen with both doses on the Health Assessment Questionnaire-Disability Index throughout the 24-week period of the study as well as on other patient-reported outcomes such as morning stiffness and fatigue.

Finally, the proportion of patients who had no radiographic progression was significantly higher for both upadacitinib dose groups, at 88% and 89%, compared with 78% for methotrexate, the researchers reported.

Safety

Overall adverse events were noted in 64% and 71% of the 15 mg and 30 mg groups and in 65% of the methotrexate group.

Serious adverse events included acute myocardial infarction in two patients on methotrexate and one on the 30 mg dose of upadacitinib; pneumonia in two patients on methotrexate, in one in the 15 mg group, and three in the 30 mg group; and osteoarthritis in two patients in the 30 mg group.

Treatment-emergent adverse events that led to study discontinuation were reported in 4.4% of the 15 mg group, 3.8% of the 30 mg group, and 5.1% of the methotrexate group.

Serious infections were reported in 1.6% and 2.5% of the 15 mg and 30 mg groups and 1.3% of the methotrexate group. Cases of herpes zoster occurred in 2.2% of both upadacitinib groups and 0.3% of the methotrexate group.

More patients in the 30 mg group had decreases in hemoglobin, neutrophils, and platelets, while more in the methotrexate group had elevated liver enzymes.

Six deaths occurred: one due to myocardial infarction in a patient on methotrexate; a case of hypoxic-ischemic encephalopathy and a case of metastatic malignant melanoma in a patient who had a history of the malignancy in the 15 mg group; and one case each of sudden cardiovascular death, pneumonia/sepsis, and peritonitis in a patient with a history of gastrointestinal bleeding in the 30 mg group.

A limitation of the study, the researchers said, was its inclusion of only patients with risk factors for radiographic progression.

JAK Inhibitors in Perspective

Asked for his perspective, Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas, pointed to the superiority of upadacitinib compared with methotrexate as shown on clinical, functional, and radiographic measures.

"These results are similar to what was shown in the ORAL-START study with tofacitinib [Xeljanz] and the RA-BEGIN study with baricitinib [Olumiant] -- although the result with baricitinib was with the 4 mg dose and was not statistically superior to methotrexate for radiographic progression," explained Fleischmann, who was not involved in the current research but was an investigator for the other two studies.

"When these three studies are viewed together, it gives credibility to the observation that the JAK inhibitor class of molecules is uniformly quite effective in the methotrexate-naive population," he told MedPage Today. "Realistically," however, for reasons including cost, both the ACR and EULAR continue to recommend methotrexate first-line for active RA, he added.

"What SELECT-EARLY does not show -- as neither did ORAL-START or RA-BEGIN -- is whether it is preferable to use upadacitinib as monotherapy preferentially over a combination of upadacitinib plus methotrexate. As shown in ORAL-STRATEGY with tofacitinib and a post-hoc analysis from RA-BEGIN, although monotherapy with these agents is very effective in many patients, the combination of the JAK inhibitor plus methotrexate is efficacious in more patients than the monotherapy," Fleischmann continued.

Van Vollenhoven and colleagues concluded: "These head-to-head data provide consistent evidence of the efficacy of this JAK inhibitor versus the gold standard of initial RA therapy, supporting the potential of upadacitinib as a new therapeutic option for patients with RA."

Disclosures

The study was sponsored by AbbVie. Van Vollenhoven reported financial relationships with Bristol Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, UCB, AbbVie, AstraZeneca, Biogen, Biotest, Celgene, Janssen, Novartis, and Servier; co-authors also reported financial relationships with multiple companies.

Source Reference: van Vollenhoven R, et al "Efficacy and safety of upadacitinib monotherapy in methotrexate-naive patients with moderately to severely active rheumatoid arthritis (SELECT-EARLY): a randomized, double-blind, active-comparator, multicenter, multi-country trial" Arthritis Rheum 2020; DOI: 10.1002/art.41384.