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For rheumatoid arthritis patients who cannot tolerate methotrexate, combination therapy isn't often an option. This study offers a new approach for these patients.
When it comes to treating rheumatoid arthritis, combination therapy is often the go-to regimen. However, not all patients can tolerate methotrexate. Instead, they turn to monotherapy.
A new study published in the Annals of the Rheumatic Diseases compared the efficacy and safety of prescribing sarilumab monotherapy with adalimumab monotherapy in rheumatoid arthritis patients who cannot tolerate or do not respond to methotrexate. They discovered sarilumab performs better than adalimumab.
“The results showed that, overall, sarilumab monotherapy demonstrated superiority to adalimumab monotherapy in patients with active rheumatoid arthritis. These patients had been inappropriate candidates for continued treatment with methotrexate due to intolerance or inadequate responses,” said Gerd Burmester, M.D., a rheumatologist with CharitÃ©-University Medicine in Berlin. “Sarilumab monotherapy resulted in a reduction of disease activity, and improvement in signs and symptoms, and physical function. The overall incidences of adverse events and serious adverse events were similar between groups, as was the rate of infections and serious infections.”
Approximately 30 percent of rheumatoid arthritis patients rely on biologics as monotherapy because they have an intolerance or contraindications to combination therapy, Dr. Burmester said. Many factors could prevent them from benefiting from combination therapy, including pregnancy, breastfeeding, heavy alcohol consumption, renal or lung disease, or an infection, such as herpes zoster.
If this group participates in combination therapy, they could develop gastrointestinal, hepatic, dermatologic, and neurological adverse events, cytopenia, and methotrexate-induced pneumonitis. At the same time, nausea and dizziness are possible.
Addressing the Problem
To determine which monotherapy regimen might be best - sarilumab or adalimumab - researchers designed a randomized, active-controlled, double-blind, double-dummy, Phase III superiority trial called MONARCH.
Researchers divided enrolled participants into two groups: 184 received 200 mg of sarilumab biweekly, and 185 received 40 mg of adalimumab biweekly for 24 weeks. Patients received each monotherapy subcutaneously via pre-filled matching syringes.
The primary endpoint was a change from baseline in 28-joint disease activity scores using erythrocyte sedimentation rate at 24 weeks.
Based on the study findings, sarilumab out-performed adalimumab at the primary endpoint (-3.28 vs. -2.20; p<0.0001). In fact, sarilumab-treated participants much higher American College of Rheumatology 20/50/70 response rates (71.7%/45.7%/23.4%) than adalimumab (58.4%/29.7%/11.9%).
In addition, at week 24, more sarilumab patients than adalimumab achieved Clinical Disease Activity Index remission (7.1% vs. 2.7%) and low disease activity (41.8% vs. 24.9%).
However, sarilumab patients experienced slightly more adverse events (64.1%) than adalimumab (63.6%). Neutropenia and injection site reactions occurred with sarilumab, and headache and worsening rheumatoid arthritis appeared with adalimumab. Incidences of infection were similar between both monotherapies.
According to the results, sarilumab patients had a three times greater chance at week 12 of achieving DAS28-ESR remission (OR: 2.61, 95% CI 1.31 to 5.20; nominal p=0.0051) and roughly five times greater at week 24 (OR: 4.88; 95% CI 2.54 to 9.39; p<0.0001).
Sarilumab also revealed a greater efficacy than adalimumb in the Clinical Disease Activity Index (CDAI), a measure of clinical response independent of acute-phase reactants that could favor interleukin-6 inhibition. These patients had lower mean CDAI scores at weeks 12 and 24 than did adalimumab recipients – week 24: -28.9 vs. -25.2; difference: -3.74; 95% CI -6.02 to -1.47; nominal p=0.0013.
The ACR 20/50/70 response was also greater in the sarilumab population than the adalimumab group. Differences were noticed as early as week 8. The mean HAQ-DI improvement from baseline to week 24 was also greater in the sarilumab group (-0.61 vs. -0.43; difference: -0.18; 95% CI -0.31 to -0.06; p=0.0037). Additionally, sarilumab participants had much greater improvement in SF-36 PCS than adalimumab with improvements showing up as early as week 12.
Between sarilumab and adalimumab, the incidence of adverse events (~64% for both groups) and serious adverse events (6.5% with adalimumab and 4.9% with sarilumab), and discontinuations (7.1% with adalimumab and 6.0% with sarilumab) were largely similar. Infection rates were also close – 27.7% for adalimumab and 28.8% for sarilumab.
Injection site reactions happened more often with sarilumab (9.2%) than with adalimumab (4.3%). As a result, two sarilumab patients discontinued participation in MONARCH.
Sarilumab patients also experienced more neutrophil counts <1.0 G/L than participants receiving adalimumab monotherapy. Overall, 8.7% of the sarilumab patients and 1.1% of adalimumab patients reported an absolute neutrophil count (ANC) between ≥0.5 and 1 G/L. An additional 1.6% of sarilumab participants experienced an ANC of <0.5 G/L. The results showed no link between neutrophil count decreases and infection risk. Infection rates between both groups were close – 27.7% for adalimumab and 28.8% for sarilumab.
With alanine aminotransferase (ALT), increases between 1 and 3-times the upper limit of normal was 33.7% for the sarilumab group. It was 21.2% for the adalimumab group. The mean ALT increase at week 24 was higher for the sarilumab group (6.1 IU/L) than with the adalimumab group (2.1 IU/L).
The adalimumab group also experienced more adverse events with serum lipid elevations. Of those patients, 4.3% reported an event while it was 1.6% of sarilumab patients.
The MONARCH study did have limitations, however. Even though sarilumab added to methotrexate performed better than a placebo and methotrexate, the study didn’t evaluate radiographic outcomes after sarilumab monotherapy was compared with adalimumab monotherapy.
In addition, the study didn’t compare the effectiveness of sarilumab monotherapy with sarilumab combined with methotrexate. But, since patients who couldn’t tolerate methotrexate were the primary intended study target, analyzing the addition of sarilumab to methotrexate wouldn’t have been feasible.
Burmester, Gerd R, et al. “Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomized double-blind, parallel-group phase III trial,” Annals of the Rheumatic Diseases. Nov. 17, 2016. DOI: 10.1136/annrheumdis-2016-210310.
Soliman MM, et al. “Impact of concomitant use of DMARDs on the persistence with anti-TNF therapies in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register,” Annals of the Rheumatic Diseases. Feb. 17, 2011. DOI: 10.1136/ard.2010.139774