Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that affects 1% of the world’s adult population. For years, RA was considered a benign disease; however, recent studies have shown the deleterious effects on mobility and functional capacity, as well as the persistence of the inflammatory process. It is estimated that 50% of patients with RA are unable to work within 10 years of onset, representing a significant economic and social impact.
The pathophysiology of RA involves chronic inflammation of the synovial membrane (a tissue that aligns the inner surface of joints), which can destroy articular cartilage. The disease begins with infiltration of the synovial membrane in several joints with T cells, B cells and monocytes (immune cells). This process is preceded by activation of endothelial cells and growth of new blood vessels. The expansion of synovial and macrophage cells leads to a hyperplastic synovial mucosa.
This expanded synovial membrane (pannus) invades the periarticular bone at the cartilage-bone junction, leading to bony erosion and cartilage degradation. Molecules such as pro-inflammatory cytokines, including interleukin 6 (IL-6), promote local inflammation and bony damage. These events lead to the clinical disease expression, signs, and symptoms such as chronic pain, inflammation, weakness, and restricted movement.
What are the current rheumatoid arthritis treatment strategies?
Nowadays, rheumatoid arthritis treatment is guided until remission or a state of at least low disease activity, which should be attained within 6 months. The strategic approach to defining treatment is based on choice of target. A target sustained indicates that remission or low disease activity was maintained for at least 6 months, whereas a target failure is defined as reaching the treatment goal, but not maintaining the goal after reaching it.
Therefore, if the goal is achieved, treatment is continued, but if the goal is not achieved, treatment moves on to the next line. If the target is maintained, the disease is considered to be in the remission phase, and attempts are made to reduce the dose or increase the intervals between treatments. In addition, the therapy may be continued according to the patient’s or physician’s preference.
The standard therapy is methotrexate as first-line treatment, often combined with glucocorticoids, although only 40% to 50% of patients achieve remission or at least low disease activity with this regimen. When methotrexate is contraindicated, the alternative is to use leflunomide or sulfasalazine.
Second-line treatment consists of a combination of two different disease-modifying antirheumatic drugs. This combination may be a conventional drug plus either a biologic, such as a human monoclonal antibody, or a drug that acts directly on a specific target, such as tofacitinib. In the event of failure to achieve targets under second-line treatment, third-line treatment, which consists of the same conventional drug plus a different and unused biologic or targeted drug, may be initiated.
Small molecule JAK inhibitors:
Janus kinase (JAK) inhibitors are promising in treating RA and several other inflammatory conditions, as the JAK/STAT signaling pathway is known to be involved in RA pathogenesis. These medications come in pill form, and patients can use them in combination with other RA drugs. Results from two studies presented at the EULAR 2021 Virtual Congress demonstrated that JAK inhibitors and biologics are effective in the treatment of RA.
To date, four JAK inhibitors have been approved for use:
- Xeljanz (tofacitinib; Pfizer): FDA (2012), EMA (2017)
- Olumiant (baricitinib; Eli Lilly): FDA (2018), EMA (2017)
- Rinvoq (upadacitinib, AbbVie): FDA (2019), EMA (2019)
- Jyseleca (filgotinib, Gilead): EMA (2020)
Anti-IL-6 receptor antibodies:
IL-6 plays a key role in the induction of immunological abnormalities and in the development of joint and systemic inflammation RA. Overproduction of IL-6 is found in the synovial fluid and blood of patients, and this excess correlates with disease activity and joint destruction.
The cytokine IL-6 mediates a broad spectrum of immunological responses in inflammatory diseases. Synthesis of this cytokine is beneficial and contributes to the host defence, but persistent dysregulated IL-6 production is implicated in the pathogenesis of chronic inflammation, including RA.
Considering that IL-6 is involved in the development, manifestations, and common comorbidities of patients’ RA due to its inflammatory profile, the benefits of IL-6 inhibition seem to be associated with improving manifestations of the disease such as pain, fatigue, and anaemia. Compared with anti-tumor necrosis factor (TNF) monotherapy (adalimumab), monotherapies of IL-6 receptor antibodies (sarilumab and tocilizumab) show better clinical efficacy. When conventional drugs are poorly tolerated or contraindicated, anti-IL-6 receptor antibodies are more effective in treating RA.
Tocilizumab and sarilumab are humanized monoclonal antibodies directed against the IL-6 receptor. They were approved by the FDA in 2010 and 2017, respectively. Studies have reported the effects of tocilizumab and sarilumab monotherapies on patient-reported outcomes over 24 weeks. The clinical trials AMBITION and MONARCH showed that both drugs improved quality of life, including physical functioning, bodily pain, vitality, social functioning, and mental health.
The future of therapeutics for rheumatoid arthritis:
Although these antibody therapies are effective, new studies are being conducted to find innovative treatments and alternatives for patients who respond inadequately to current approaches. Several recent clinical trials and scientific publications have shown new possibilities for rheumatoid arthritis treatment.
A Phase II trial of ABBV-3373 completed in August 2020 showed an improvement in disease activity. ABBV-3373, developed by AbbVie, is a novel antibody-drug conjugate consisting of an anti-TNF antibody and a proprietary glucocorticoid receptor modulator (GRM) that does not elicit systemic glucocorticoid effects that is under development for the treatment of RA and other immune-mediated diseases.
Another innovative drug is RC-18, a novel recombinant fusion protein targeting B lymphocyte stimulator (BLys). RC-18 is in Phase III trials in the European Union and United States. Phase I results show promise for use as an alternative for patients who respond inadequately to methotrexate.
Another interesting approach is the administration of apoptotic cells. Cell-based therapeutic approaches are currently being developed in RA, as early-stage apoptotic cells have direct and indirect anti-inflammatory properties and may be beneficial for joint inflammation. Furthermore, it has been shown that apoptotic cells could be administered with standard treatments. A Phase I/II clinical trial to verify the effectiveness of this therapy is planned to be conducted in France with an estimated study completion date of December 2022.
Final considerations and future outlook:
Rheumatoid arthritis is a chronic autoimmune disease that can affect quality of life with social and physical effects. Many new mechanisms of action are being investigated that have the potential to change the rheumatoid arthritis treatment landscape, opening the potential for additional and more effective treatment options when first-line drugs prove inadequate for a patient. Intensive research is being conducted to better understand the causes and mechanisms that lead to RA.
Although a cure is not in sight, it is possible to achieve permanent remission or freedom from disease activity and prevent joint damage in most — but not all — cases. Significant progress has been made over the last decade in development of IL-6 and JAK inhibitors. Therapies currently under clinical investigation are targeting alternative pathways, with the goal of more effectively relieving symptoms and preventing disease progression.
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