Damian McNamara

November 08, 2017

SAN DIEGO, California ― For patients with moderate to severe rheumatoid arthritis whose condition is refractory to methotrexate, pain relief is better with the JAK inhibitor baricitinib than with the TNF inhibitor adalimumab or placebo, according to a 24-week post hoc analysis of data from the RA-BEAM trial.

The assessment of pain during treatment for rheumatoid arthritis helps inform "shared decision making between physicians and their patients," said Peter Taylor, PhD, from the University of Oxford in the United Kingdom.

Pain relief can have a positive effect on other patient-reported outcomes, he told the audience during a packed session here at the American College of Rheumatology (ACR) 2017 Annual Meeting.

"We know pain is a generic feature of inflammation, but not all pain is inflammatory in origin," Dr Taylor pointed out.

"Interestingly, the differences in pain relief between baricitinib and adalimumab could not be accounted for by differential effects of inflammation alone," he added, which suggests that baricitinib reduces pain through an unknown mechanism.

RA-BEAM Study

In the initial phase 3 RA-BEAM study, once-daily baricitinib 4 mg was associated with a significant clinical improvement in pain at 12 weeks, as previously reported by Medscape Medical News.

At 12 weeks, more patients in the baricitinib group than in the adalimumab and placebo groups achieved an improvement in rheumatoid arthritis symptoms of at least 20%; an ACR20 score was achieved in 70% vs 61% vs 40%, respectively.

In the intent-to-treat analysis of 1305 patients with moderate to severe active rheumatoid arthritis, 487 people were treated with baricitinib, 330 with adalimumab, and 488 with placebo. Mean age was 53 years.

Baseline joint pain attributable to rheumatoid arthritis was similar in the three treatment groups, at about 60 mm on a 100 mm visual analog scale, with 100 indicating the worst possible pain.

At 24 weeks, improvement in pain of at least 50% was achieved by more patients in the baricitinib group than in the adalimumab and placebo groups (61% vs 52% vs 32%).

The Need for Speed of Improvement

The time to achieve this 50% improvement was faster with baricitinib than with adalimumab or placebo (4 vs 8 vs 14 weeks). This improvement was significantly faster with the two treatments than with placebo (P < .001).

The time to achieve a 30% improvement in pain was similar in the baricitinib and adalimumab groups, and both were faster than placebo.

But the time to achieve a 70% improvement in pain was "much faster" with baricitinib than with adalimumab, Dr Taylor reported. The difference ― 12 weeks for baricitinib and 20 weeks for adalimumab ― was significant (P < .01).

"Baricitinib has a shorter median time to onset of more profound pain relief than adalimumab or placebo," he explained. In addition, baricitinib "showed a similarly rapid median time to reach pain response thresholds, regardless of baseline pain severity."

At week 24, pain reduction was similar with baricitinib and adalimumab for patients with residual C-reactive protein levels of 3 mg/L or less. However, for patients with levels higher than 10 mg/L, "there was a large differential favoring baricitinib over adalimumab for pain reduction," Dr Taylor reported.

The researchers developed models to identify how much pain relief could be attributed to a reduction in inflammation and how much could be attributed to other factors.

For indirect effects on inflammation, they were able to show similar improvements with TNF blockade and JAK1/JAK2 inhibition. "In contrast, the direct effect of some other contributory factors was greater with baricitinib," he reported.

After the presentation, a member of the audience pointed out that it appeared that about 50% of the pain reduction was associated with decreases in inflammatory markers and swollen joint counts, and the remaining 50% could be attributed to other factors. Dr Taylor confirmed that the estimation was correct.

Another audience member asked whether the researchers accounted for the approximately 30% of people with rheumatoid arthritis who have fibromyalgia.

"We did not directly account for it in this study," Dr Taylor replied, "but I can tell you they had high baseline disease activity, inflammatory markers, and high swollen joint counts."

Patients come because they hurt. And if we don't address their discomfort, we're not truly taking care of them. Dr David Borenstein

"It's very interesting to see that a JAK1/2 inhibitor has the potential to work independently on pain, above and beyond what it addresses in terms of inflammation," said session comoderator David Borenstein, MD, from the George Washington University Medical Center in Washington, DC.

"It did seem, at least with this initial group, that baricitinib had a greater reduction in pain than a TNF inhibitor alone," he told Medscape Medical News, but the findings are still early.

Future studies should try to determine the mechanism, because an agent that addresses both inflammation and pain could be beneficial, said Dr Borenstein.

"It isn't enough just to control inflammation and stiffness," he explained. "Patients come because they hurt. And if we don't address their discomfort, we're not truly taking care of them."

In our diseases, pain appears to be multifactorial, he added. "It can be nociceptive, damage to a joint, and/or neuropathic because you damage a nerve that is in a joint. Then, how your brain responds to having this discomfort and the upregulation of sensitization make the total package."

However, it is unlikely that one agent will address the multiple pain pathways in rheumatoid arthritis. "I asked the presenters what they would use, and it ends up probably being a potpourri of therapies," Dr Borenstein added.

The study was funded by Eli Lilly and Incyte Corporation. Dr Taylor is a consultant for AbbVie and Eli Lilly and reports receiving research grants from Eli Lilly. Dr Borenstein has disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2017 Annual Meeting: Abstract 855. Presented November 5, 2017.

Follow Medscape on Twitter @Medscape and Damian McNamara @MedReporter

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