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
Rheumatoid Arthritis
Rheumatoid arthritis is a chronic systemic autoimmune inflammatory disease associated with severe damage of the cartilage, bone, and joints. The disease progresses in a symmetrical manner. One of the most common clinical presentations of rheumatoid arthritis include polyarthritis of small joints of the hands, such as the proximal interphalangeal and metacarpophalangeal joints. Other affected areas may include the wrist, elbows, shoulders, hips, knees, angles, and metatarsophalangeal joints. Thus, rheumatoid arthritis is a painful disease, and both pharmacological and non-pharmacological treatments are significant in improving the quality of life of the patient. The goals of treatment include reduction of joint inflammation and pain, improve joint function, and prevent destruction of joints and deformations.
Rheumatoid arthritis begins with a complex interplay of environmental, genetic, and immunologic triggers that causes immune system dysregulation, leading to inflammation. However, its exact mechanism is poorly understood. T-cells, B-cells, and macrophages are immune cells that infiltrate the synovium, also known as the synovial membrane. The synovial membrane is the connective soft tissue membrane lining the inner surface of synovial joint capsules and houses blood vessels and lymphatics. It is an important tissue component that forms the joint. Infiltration of immune cells in the synovium contributes to the inflammatory nature of this disease. Destruction of the bone and cartilage of the joints and weakening of tendons and ligaments are expected thereafter. Further, B-cells produce auto-antibodies and secrete cytokines (IL-1, IL-6, IL-8, TNF) which further activate other antigen presenting immune cells. Secretion of chemokines induce chemotaxis whereas secretion of matrix metalloproteinases (MMPs), collagenase, and hydrolase leads to cartilage degradation. Essentially, the body is attacking the synovial lining of the joints. Overtime, the inflammation causes destruction of tissues, edema, and the development of pannus on the joint, which is extra tissue growth that is spongy. Development of pannus can cause pain and damage to the joints and surrounding cartilage, thereby decreasing mobility and affecting joint function.
One of the first-line therapies for the treatment of rheumatoid arthritis is the use of a disease-modifying antirheumatic drug, DMARD. DMARD reduces inflammation, reduces joint damage, and preserves joint function. Conventional DMARDs include methotrexate, hydroxychloroquine, and sulfasalazine. Biologic DMARDs include etanercept, adalimumab, abatacept, and tocilizumab, and are provided as an injection or intravenous infusion. New DMARDs on the market include tofacitinib, and are considered “targeted synthetic DMARDs.” Methotrexate, a conventional DMARD, reduces inflammation and slows down the individual’s overactive immune system. It is considered the gold standard or first-line treatment in individuals with moderate to high disease who have not taken a DMARD before. Methotrexate is a folic acid analog that competitively inhibits the enzyme, dihydrofolate reductase. As a result, the substrate, dihydrofolic acid, cannot bind to the enzyme. This inhibits the conversion of dihydrofolic acid to folinic acid, which is required for purine and pyrimidine metabolism, thereby inhibiting DNA and RNA synthesis. It also inhibits pro-inflammatory properties of T-cells, macrophages, endothelial cells, and fibroblast-like synoviocytes, which are all responsible for inflammation.
Monotherapy with methotrexate is preferred over combination treatments and other types of DMARDs due to lower incidence of side effects and flexibility in dosing. However, it is an immunosuppressive drug that requires regular blood tests, and can pose risk of hepatic impairment, cirrhosis, and bone marrow deterioration.
On the other hand, hydroxychloroquine (conventional DMARD) is reserved for those with mild symptoms. Hydroxychloroquine is an antimalarial drug that works by decreasing the secretion of monocyte-derived proinflammatory cytokines. Expected side effects include stomach pain and skin rashes. Individuals on this medication must consult with the ophthalmologist regularly as it can cause ocular toxicity, which decreases or blurs vision. Another conventional DMARD is sulfasalazine. Its mechanism of action is unclear. One reason is that the reduced form of sulfasalazine, sulfapyridine, reduces IL-8 and monocyte chemoattractant protein (MCP). Given that it is a sulfa and salicylate containing medication, it must be avoided in patients with sulfa allergies. Expected side effects include stomach pain and rash.
Moreover, corticosteroids or NSAIDs, such as aspirin, naproxen, ibuprofen, and etodolac, may be prescribed in addition to a DMARD to help relieve pain and inflammation. At high doses, aspirin inhibits prostaglandins, thereby reducing inflammation. NSAIDs inhibit cyclo-oxygenase, which prevents prostaglandin, prostacyclin, and thromboxane synthesis. It is important to note that NSAIDs do not reduce long-term, rheumatoid arthritis-induced damages of the joints, and it is imperative that a DMARD be prescribed for symptom management. Corticosteroids may also be prescribed due to its anti-inflammatory properties. It is more potent than NSAIDs, but has additional side effects. Thus, it is recommended for short-term use and at low doses during a flare-up or exacerbation of rheumatoid arthritis. Corticosteroids prevent the release of phospholipids and decrease eosinophil action, which decreases inflammation. Side effects of corticosteroid use include bone-thinning, weight gain, diabetes, and immunosuppression. To reduce side effects, it is recommended to gradually taper the dose upon improvement of symptoms. Abrupt discontinuation of injected or oral corticosteroid can initiate a rheumatoid arthritic flare-up or can lead to suppression of the hypothalamic-pituitary-adrenal axis, which may manifest as fatigue, immune system suppression, depression, and anxiety.
Non-pharmacological treatment includes regular physical activity. Although rheumatoid arthritis may impair joint mobility, inactivity can further weaken muscle strength and lead to loss of joint function. It is important that the individual performs regular physical activity, such as walking, swimming, cycling, or tai chi, as it can preserve and restore movement of joints and increase strength as well as endurance. Working alongside a physical therapist may also help improve joint mobility and function. Specific types of therapy may include balance training for the prevention of falls, and orthotics, which are foot device/shoe wear recommendations to reduce foot pain and improve walking.
In conclusion, to improve the quality of life of the individual and manage rheumatoid arthritis symptoms, both pharmacological and non-pharmacological therapy are used in an effort to reduce pain and inflammation, preserve joint function, and improve mobility.
References
Bullock, Jacqueline, et al. “Rheumatoid Arthritis: A Brief Overview of the Treatment.” Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre, 2 Sept. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6422329/.
Chauhan, Krati, et al. “Rheumatoid Arthritis: A Brief Overview of the Treatment.” Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre, pubmed.ncbi.nlm.nih.gov/30173215/. Accessed 6 June 2023.
Cronstein, Bruce N., and Thomas M. Aune. “Methotrexate and Its Mechanisms of Action in Inflammatory Arthritis.” Nature News, 17 Feb. 2020, www.nature.com/articles/s41584-020-0373-9.
“Hand Rheumatoid Arthritis.” Physiopedia, www.physio-pedia.com/Hand_Rheumatoid_Arthritis. Accessed 6 June 2023.
“Patient Education: Rheumatoid Arthritis Treatment (Beyond the Basics).” UpToDate, www.uptodate.com/contents/rheumatoid-arthritis-treatment-beyond-the-basics#H402960751. Accessed 6 June 2023.
“Rheumatoid Arthritis Treatment Guidelines.” Rheumatoid Arthritis Treatment Guidelines, www.arthritis.org/diseases/more-about/rheumatoid-arthritis-treatment-guidelines. Accessed 6 June 2023.
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Rheumatoid Arthritis is a chronic inflammatory disorder that can have a major impact on quality of life. In some people, this condition can damage many different body systems such as skin, eyes, lungs, heart, and blood vessels. The cause of this condition is when a person’s immune system mistakenly attacks the body’s own tissues. Rheumatoid arthritis is progressive and affects the lining of the synovial joints which causes painful swelling that can lead to bone erosion and joint deformity. If untreated, this can lead to significant pain, deformity, loss of manual function and deterioration in overall quality of life. The inflammation caused by rheumatoid arthritis can cause physical disabilities even with new types of medications having improved treatment options. Many of the treatment options for rheumatoid arthritis are NSAIDs, corticosteroids, methotrexate, tumor necrosis factor inhibitors, interleukin 1 inhibitors, rituximab, abatacept, and more. There has recently been data supporting the use of Janus Kinase Inhibitors in the treatment of rheumatoid arthritis. Some janus kinase inhibitors are upadacitinib, baricitinib, and tofacitinib. This is probably the most recent new drug class being tested for the use of this condition.
There are many trials on the use of janus kinase inhibitors. The ORAL scan trial was 24 month trial undertaken to evaluate the efficacy and safety of tofacitinib in patients with active rheumatoid arthritis that have an inadequate response to methotrexate. In this trial, there were seven hundred seventy-nine patients randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo switching to tofacitinib 5 mg twice daily with stable background methotrexate or placebo switching to 10 mg twice daily with stable background methotrexate. Patients receiving placebo switched to tofacitinib at month 3 or month 6 based on if they were not responding to treatment. In this trial, they evaluated clinical efficacy, structural progression, and treatment-emergent adverse events. Out of the 797 patients that were treated, 539 completed 24 months of treatment which was about 67.6 percent. The proportion of patients in whom remission or low disease activity was achieved according to the 4-variable disease activity score in 28 joins using erythrocyte sedimentation rate, clinical disease activity index, or simplified disease activity index, Boolean remission, and health assessment questionnaire disability index scores were maintained from month 12 to month 24 and were similar between the tofacitinib dosages. The safety events were also similar in type and frequency and were consistent with previous reported data. In this study, they found that the treatment of rheumatoid arthritis using janus kinase inhibitors like tofacitinib in combination with methotrexate would best sustain the effects of clinical and radiographic treatment. There was limited structural damage observed at months 12 and 24. The safety profile in this study was consistent with previous tofacitinib studies. This was a study that was conducted soon after tofacitinib has been approved for the use in the treatment of patients with moderate to severe rheumatoid arthritis. I believe studies like the ORAL scan study can help contribute to progressing treatment options for rheumatoid arthritis in the future.
References:
1. van der Heijde D, Strand V, Tanaka Y, Keystone E, Kremer J, Zerbini CAF, Cardiel MH, Cohen S, Nash P, Song YW, Tegzová D, Gruben D, Wallenstein G, Connell CA, Fleischmann R; ORAL Scan Investigators. Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study. Arthritis Rheumatol. 2019 Jun;71(6):878-891. doi: 10.1002/art.40803. Epub 2019 Apr 24. PMID: 30666826; PMCID: PMC6593705.
2. “Rheumatoid Arthritis.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 18 May 2021, https://www.mayoclinic.org/diseases-conditions/rheumatoid-arthritis/symptoms-causes/syc-20353648.