The introduction of tumor necrosis factor (TNF) inhibitors in the late 1990s revolutionized the treatment of rheumatic diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), providing patients with another therapeutic option when conventional therapies were ineffective. However, when these diseases fail to respond to anti-TNF therapy, it is still difficult to determine the next best course of action.
“One of the big challenges we have in treating psoriatic arthritis, and I would say rheumatoid arthritis was fine, is how to manage patients who have failed their first biologic therapy,” Christopher Ritchlin, MD, MPH, professor of allergy, immunology; and rheumatology at the University of Rochester, Rochester, New York, he said Medscape Medical News. “In the case of both RA and PsA, it’s quite often an anti-TNF agent.”
For approximately 30-40% of patients, TNF-blocker therapy is discontinued due to non-response or intolerance. Doctors can switch to another targeted biological or synthetic disease-modifying antirheumatic drug (DMARD) or add another conventional DMARD, such as methotrexate. Now, several case studies and promising results from Phase 2 clinical trials suggest that combining two biologics could be an alternative strategy to improve patient response to treatment. However, concerns about safety and higher costs remain.
Target multiple mechanisms of action
Rheumatic conditions affect multiple areas of the body and involve different signaling pathways, said Ritchlin, who also heads the Clinical Immunology Research Unit at the University of Rochester. PsA, for example, affects the skin, peripheral joints, axial skeleton, and entheses.
“The question is, are these various manifestations multiple? [ones] are they often seen in a patient who is likely to respond to single pathway targeted therapy?” he said.
Combination therapies have been effective in treating leukemia and lymphoma as well as HIV infection, writes Melek Yalin Mutlu, MD, and colleagues at the Friedrich Alexander University Erlangen-Nuremberg and Erlangen University Hospital, Erlangen, Germany, in a review on the combination of biological DMARDs in the treatment of RA and PsA. The review was published on April 17 in Articular bone spine.
“Cumulative evidence on the success of combination therapies in various diseases supports a similar approach in rheumatology, and concurrent or sequential blockade of multiple mechanisms that generate or propagate arthritis could theoretically improve efficacy,” the authors write. “On the other hand, targeting multiple targets in the immune system carries a risk of adverse events, with infection being a major concern.”
Clinical trials failed
Clinical trials of combination biological therapies for rheumatic disease have been attempted previously, but these combinations have not shown superior efficacy and increased the patients’ risk of infection. A study published in 2004 compared monotherapy with the TNF inhibitor etanercept (Enbrel) to the combination of etanercept and anakinra (Kineret), an interleukin-1 (IL-1) antagonist, in 244 patients with active RA despite methotrexate therapy. The researchers found no statistically significant difference in achieving 20 percent improvement in the modified American College of Rheumatology (ACR20), ACR50, or ACR70 response criteria between the groups receiving etanercept and anakinra and those receiving etanercept alone. There were nine serious infections among patients treated with etanercept and anakinra, including one death due to pneumonia. There were no serious infections in the etanercept monotherapy group.
In another rheumatoid arthritis study, 121 patients were given etanercept 25 mg twice a week and were randomly assigned to also receive either a placebo or low-dose abatacept (Orencia), a T-cell costomulation inhibitor There was no significant difference in disease improvement between the two groups, although the rate of serious adverse events was nearly six times higher in the etanercept-abatacept group (16.5% vs 2.8%).
Those studies had a “chilling effect on the whole field for a few years,” Brian Feagan, MD, senior scientific director of gastrointestinal contract research firm Alimentiv in London, Ontario, Canada, told Medscape. People were reluctant to try new biological combinations, due to fears that these safety issues would plague subsequent trials.
But a recent phase 2 study, led by Feagan, suggests that some combinations may be effective. In the Janssen-sponsored VEGA study, researchers found that a combination of guselkumab (Tremfya), an IL-23 inhibitor, and golimumab (Simponi), an anti-TNF agent, was more effective than either drug used as monotherapy for initial induction treatment for moderate to severe ulcerative colitis. Importantly, there was no difference in adverse events between any of the groups. This same combination therapy is now being tested for patients with active PsA in Janssen’s AFFINITY study, for which Ritchlin is a principal investigator.
Other studies have also yielded promising results. One study enrolled 51 adults with active RA who were all receiving stable doses of either a TNF-blocker or etanercept or adalimumab (Humira) and methotrexate. Patients were randomly assigned to receive a course of rituximab (Rituxan) or placebo. The researchers found that the safety profile of this TNF inhibitor/methotrexate/rituximab combination was “consistent” with the safety profiles of previous studies of dual methotrexate/rituximab combinations without any TNF inhibitor; there were no new safety signals. At 24 weeks, 30% of the rituximab group achieved ACR20, compared with 17% of the placebo group. A total of 12% of the rituximab group achieved ACR50, compared with 6% of the group receiving placebo.
“B-cell depletion is fundamentally different from cytokine inhibition and even co-stimulation blockade, making an additive effect more likely,” write Mutlu and colleagues in their review. Reports have also suggested possible benefits of the combination of a TNF inhibitor and an IL-17 inhibitor in the treatment of rheumatoid arthritis and PsA, as well as of the combination of a TNF inhibitor and an IL-23 antagonist for the PSA.
While these combinations require controlled clinical trials, “there are some smoke signals out there that this might be an effective strategy for some patients,” Ritchlin said.
In addition to the AFFINITY study, two clinical trials are ongoing in France. The first, CRI-RA, is evaluating the combination of baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, and adalimumab. While baricitinib is not a biologic, as it is a targeted synthetic DMARD, the therapy is more potent than conventional DMARDs and the same potential safety concerns apply. However, the use of a combination of tofacitinib (Xeljanz) and several biologics has been reported for RA patients; no serious side effects were reported in the 11 months of therapy. The randomized, placebo-controlled trial began in July 2021 and will enroll 178 patients. The estimated completion date of the study is July 2025.
“Of note, baricitinib does not directly block downstream TNF signaling, although an indirect effect on TNF production is likely,” reads the CRI-RA entry on clinicaltrials.gov. “Targeting multiple inflammatory cytokines in combination may lead to more effective treatment and better clinical responses in RA patients than current second-line strategies.”
The second study, titled SEQUENS-RA, is evaluating the use of TNF blockers followed by abatacept for RA patients who test positive for anti-citrullinated protein autoantibodies (ACPAs). In the past, the combination of a TNF blocker and abatacept has not led to promising results, but in this study, the drugs will be administered sequentially.
“Although abatacept has shown a very good tolerance profile that may be superior to other bDMARDs [biologic DMARDs]rheumatologists may be reluctant to use it as a first-line bDMARD as there is a belief of slower efficacy than other bDMARDs or JAK inhibitors,” according to the clinical trial description. inflammatory phase, the use of TNF inhibitors, followed by abatacept to induce immunological remission, would optimize the response and tolerance of ACPA-positive patients with RA.”
The randomized study of 220 participants began in November 2022. The estimated date for completion of the study is November 2025.
Finding the right patients
Although these trials had some promising results, the difference in efficacy between biologic monotherapy and dual therapy was mostly moderate, write Mutlu and coauthors. Identifying disease subtypes for which there may be an increased likelihood of response to dual biologic treatment, especially multidrug-resistant types, could improve efficacy in future studies, they argue. “The good effects of bDMARD combinations in resistant patients indeed point in this direction, although they have been observed in uncontrolled studies,” note the authors.
Insurance coverage remains a “major challenge” for these dual therapies due to the higher expense, Ritchlin noted. More targeted therapies could help convince these companies to pay for these therapies.
“I would argue that if we were able to demonstrate a phenotype of a patient that would respond to biologics and not monotherapies, [then] many companies would be inclined towards this kind of approach,” he said.
Ritchlin reports financial relationships with AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Eli Lilly, Novartis and UCB. Feagan reports financial relationships with AbbVie, Amgen, Janssen, Pfizer, Takeda and many other pharmaceutical companies.
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