MONARCH TRIAL: Sarilumab
Sarilumab is a biologic disease-modifying antirheumatic drug (bDMARD) that targets cytokines for the treatment of patients with rheumatoid arthritis. This monoclonal antibody targets cytokines IL-6R and inhibits IL-6 mediated signaling. The presence of IL-6R in the synovial fluid of patients with rheumatoid arthritis has been linked with systemic inflammation, fatigue, and joint destruction. Rheumatoid arthritis is commonly treated with synthetic DMARDS such as methotrexate as first-line therapy, but many patients have built up an intolerance or have not mounted an adequate response to the therapy. Adalimumab, another biologic disease-modifying antirheumatic drug, like sarilumab, is globally approved for the treatment of rheumatoid arthritis and has proven successful in patients who do not respond well to methotrexate. Adalimumab targets TNF-a, a different target than sarilumab for the treatment of rheumatoid arthritis. The MONARCH trial was conducted to compare the efficacy and safety of sarilumab and adalimumab monotherapy in patients who did not reach clinical remission on synthetic DMARD therapy.
The MONARCH trial was a multicenter, randomized, active-controlled, double-blind, double-dummy, phase 3 superiority trial conducted in multiple countries that ran for 24 weeks. Inclusion criteria for patients included patients greater than 18 years of age, who fulfilled American College of Rheumatology (ACR)/European League Against Rheumatism Classification Criteria for RA and ACR class I–III functional status; had active RA, and either intolerant or considered inappropriate for continued treatment with methotrexate. The primary efficacy endpoint was a change from baseline in disease-joint activity using erythrocyte sedimentation rate (ESR). Other secondary efficacy endpoints included DAS28-ESR remission, Health Assessment Questionnaire-Disability Index (HAQ-DI); ACR 20% (ACR20), 50% (ACR50) and 70% (ACR70) responses; Medical Outcomes Short Form 36 Health Survey (V.2) (SF-36) physical component summary (PCS) score and mental component summary (MCS) score and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Clinical Disease Activity Index (CDAI). Safety was measured by assessing treatment-emergent adverse events, serious adverse events reported by investigators, as well as lab tests.
Within this study, the primary endpoint was reached. Sarilumab at a dose of 200 mg every 2 weeks was superior to adalimumab 40 mg every 2 weeks with a mean change from baseline to week 24 in DAS28-ESR of -1.08 with a 95% confidence interval. In comparison to adalimumab, the odds of reaching remission were three times more likely with sarilumab at week 12 and five times more likely at week 24. In terms of safety, the adverse events reported in both groups were similar, as well as the rate of discontinuation between the groups.
Biologics for the treatment of rheumatoid arthritis offers new options for patients who are not getting the help they need from older therapies such as methotrexate. This trial showed that sarilumab was superior to adalimumab in the reduction of disease activity with no large difference in safety. One of the most important things in patients suffering from rheumatoid arthritis is their ability to perform functional tasks without pain and fatigue. Compared to adalimumab, patients who received sarilumab reported a greater improvement in daily activities with less pain. Biologic therapy targeting different cytokines that play a role in the pathogenesis of rheumatoid arthritis is changing the way of life for patients who are plagued by this disease.
References:
1. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847. doi:10.1136/annrheumdis-2016-210310
2. Emery P, Rondon J, Parrino J, et al. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(5):849-858. doi:10.1093/rheumatology/key361
Summary of Rheumatoid Arthritis:
Rheumatoid Arthritis (RA) is an autoimmune disorder whereby the immune system mistakenly attacks healthy cells in the body which subsequently causes painful swelling and inflammation in different areas of the body. The primary site commonly affected by RA are the joints and can inflame multiple joints at once, therefore leading to painful hands, wrists and knees. In addition to affecting joints and causing pain/inflammation in these areas, rheumatoid arthritis can also extend and cause complications in areas such as the lungs, heart and eyes.
While the search to identify a single trigger for RA is still ongoing, there have been a number of epidemiological and genetic studies that have been conducted, yielding valuable insights into possible pathophysiological reasons for why one develops RA. One of the most common theories regarding the pathogenesis of RA originated in the early 1980s, when a correlation between rheumatoid arthritis and class II MHC antigens was identified. Specifically, the epitope present in HLA-DR4, was found to engage with T-cell receptors and showed a hypervariable region with highly conserved characteristics in sequence and charge, which is now thought to account for about 30% of RA’s genetic risk.
How is RA Diagnosed:
When it comes to diagnosing RA, healthcare providers often refer to the 2010 American College of Rheumatology/European League Against Rheumatology (ACR/EULAR) classification criteria as a guide for diagnosis. However, not all RA patients will meet these criteria during the initial stages of their disease but could still be suitable candidates for treatment. Based on the criteria found in the ACR/EULAR, a diagnosis of “definite RA” relies on the presence of synovitis in at least one joint, the absence of another explanation/diagnosis that better explains the synovitis, and a cumulative score of 6 (out of a potential 10) from the individual scores across four domains. The highest score found in each domain is the number that is used in this calculation. The domains considered in this calculation include the number and site of involved joints, any serological abnormalities (RF or ACPA), symptom duration of at least six weeks and an elevated acute phase response, indicated by ESP or CRP levels above the upper limit of normal.
Pre-treatment screenings for RA:
Before beginning treatment for RA, rheumatologists usually conduct a pre-treatment evaluation to identify any contraindications to non biologics, targeted synthetic small molecules or DMARDs. The following are some of the evaluations that are conducted prior to initiation of RA treatment:
General testing - Baseline bloodwork consisting of a CBC, Scr, ESR and CRP levels are usually collected. For patients who will possibly be receiving IL-6 or JAK inhibitors, baseline lipid levels are also collected.
Hepatitis virus screening - This is done in all patients without a known history of hepatitis infection. Presence of Hepatitis B or C is screened prior to treatment with DMARDs or JAK inhibitors
Ophthalmologic screening for hydroxychloroquine use: A comprehensive baseline ophthalmologic screening is conducted prior to treatment with hydroxychloroquine to monitor for any ocular toxicity that may occur due to treatment. This screening includes a thorough examination of the retina with pupil dilation and automated visual field testing.
Treatment Options:
There are a number of different treatment options available for RA, therefore individual patient factors must be considered before initiating treatment. Factors such as the level of disease activity, presence of any comorbidities and patient preferences must be considered before prescribing a treatment to a RA patient.
The first-line treatment for RA often consists of a DMARD (disease-modifying antirheumatic drug), usually Methotrexate (MTX). MTX is administered as a once-weekly dose, typically administered orally. Usual dosing begins at 7.5 mg to 15 mg once weekly, however the dose may be escalated as needed to appropriately manage the patient’s symptoms and disease control. However, unfortunately, MTX does have a number of contraindications for use such as women who may become pregnant, women who are pregnant, patients with liver disease or excessive alcohol intake and patients with severe renal impairment (eGFR < 30 mL/min). For patients with these contraindications, there are alternatives to MTX available such as Leflunomide, Sulfasalazine and Hydroxychloroquine.
For symptomatic breakthrough treatment of RA, NSAIDs or glucocorticoid medications are usually recommended to quickly treat inflammation without providing long-term control. Common examples of NSAIDs that are used to treat breakthrough RA include Ibuprofen 2400 to 3200 mg/day, Naproxen 1000 mg/day or Meloxicam 15 mg/day. It is recommended that NSAIDs are administered at their full anti-inflammatory doses as the first-line treatment for patients with breakthrough RA symptoms, unless contraindicated due to GI, renal or CV conditions. Another option, as aforementioned, are glucocorticoids. Although glucocorticoids are usually given in addition to NSAIDs, they can be used alone to treat active symptoms. Prednisone is the most common glucocorticoid prescribed and is usually dosed between 5 to 20 mg/day, depending upon the severity of the symptoms.
Resources:
Rheumatoid Arthritis. Centers for Disease Control and Prevention. April 7, 2022. Accessed April 13, 2024. https://www.cdc.gov/arthritis/types/rheumatoid-arthritis.html.
RA Pathophysiology. Johns Hopkins Arthritis Center. March 27, 2019. Accessed April 13, 2024. https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/.
Baker J. Diagnosis and differential diagnosis of rheumatoid arthritis. UpToDate. March 21, 2024. Accessed April 13, 2024. https://www-uptodate-com.jerome.stjohns.edu/contents/diagnosis-and-differential-diagnosis-of-rheumatoid-arthritis?search=rheumatoid+arthritis&topicRef=7516&source=see_link#H2293005574.
2010 RA Classification Tree Format . American College of Rheumatology. Accessed April 13, 2024. https://rheumatology.org/api/asset/bltc4dbe994c49eac11.
Cohen S. Initial treatment of rheumatoid arthritis in adults. UpToDate. January 5, 2024. Accessed April 13, 2024. https://www-uptodate-com.jerome.stjohns.edu/contents/initial-treatment-of-rheumatoid-arthritis-in-adults?search=rheumatoid+arthritis&topicRef=7516&source=see_link#H919605925.
Rheumatoid Arthritis. Mayo Clinic. January 25, 2023. Accessed April 13, 2024. https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/diagnosis-treatment/drc-20353653.