Rheumatoid Arthritis: Pathogenesis and Treatment

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5-1% of the global population [1]. Its pathological hallmark is synovial inflammation caused by immune cells (lymphocytes, leukocytes and others) that infiltrate the joint compartment, where pro-inflammatory cytokines, prostaglandins, and protein-degrading enzymes are released. The resulting chronic inflammation causes thickening of the synovial lining and invasion of fibrovascular tissue into the underlying cartilage and subchondral bone. Atrophy of cartilage and bone result in progressive loss of joint function [1,2].

The prodromal stage of RA involves a loss of self-tolerance, where B-cells produce autoantibodies (rheumatoid factor and anti-citrullinated protein). Both substances may be detectable in serum several years before the onset of symptoms.

The pathogenesis of RA is summarized in Figure 1. Genetic and environmental factors, which remain poorly defined, contribute to inflammation of the synovium and infiltration of T-cells and other immune cells into the tissue. Autoreactive CD4 T cells activate macrophages, triggering the release of inflammatory cytokines (interleukins 1, 6, 17 and TNFa) that induce collagen-degrading enzymes (matrix metalloproteinases; MMPs) and RANK ligand. RANK ligand triggers bone resorption by activating osteoclasts [3].

**Figure 1. Pathogenesis of RA** involves the infiltration of T-cells and other immune cells into the joint tissue initiates inflammation. Autoreactive CD4 T cells activate macrophages, triggering the release of inflammatory cytokines that induce collagen destruction and erosion of the subchondral bone. Tumor necrosis factor alpha (TNF-α) is a pivotal pathogenic driver and target of modern pharmacotherapies.

Despite the complexity of the disease, the current therapeutic landscape remains focused on blocking the function of inflammatory cytokines themselves. This can be achieved non-specifically with NSAIDs and corticosteroids, but with limited efficacy and dose-dependent toxicities. TNF-α is an attractive target because it upregulates adhesion molecules, promotes leukocyte influx, stimulates the production of IL-1 and IL-6, and shifts bone metabolism to a catabolic state.

Conservative therapies for RA include NSAIDs, which inhibit COX-1 and COX-2-mediated biogenesis of prostaglandin E2 and other eicosanoids. NFΚB inhibitors (curcumin, boswellic acids) indirectly down-regulate the transcriptional activation of TNF-α and IL-6 genes, but are far less potent than currently available prescription drugs targeting these proteins (see Biologics, below). To learn how these compounds and other natural products modify the inflammatory response, click here.

Corticosteroids, such as prednisone and methylprednisone, repress genes involved in immune activation. Predinsone is highly effective for flares, but continuous use increases the risk of infection and other adverse effects.

More advanced therapies include DMARDs (disease-modifying antirheumatic drugs) which slow the course of disease progression and reduce joint damage. Examples include methotrexate (Trexall), leflunomide (Arava), and sulfasalazine (Azulfidine). Targeted synthetic DMARDs like baricitinib (Olumiant) and tofacitinib (Xeljanz) are used when these agents are not effective. These drugs have a relatively narrow therapeutic index due to significant immunosuppression.

Biologics are genetically engineered proteins that selectively and directly block previously “undruggable” mediators of the inflammatory response (e.g. TNF-α). Etanercept (Enbrel), a soluble form of the TNF receptor, binds to TNF and keeps it from functioning (i.e. binding to its cognate receptor). Similarly, adalimumab (Humira) is an antibody that binds to TNF-α and prevents it from activating its receptor. While highly selective, biologics still suppress the immune system and therefore carry many of the same adverse effects as DMARDs.^1,2

Dietary interventions, such as anti-inflammatory diets⁴ and omega-3 fatty acids⁵ have shown promise in attenuating RA. Significant differences in gut microbiota between patients with RA versus controls suggests that favorably shifting gut bacteria through diet should also be considered.^5.

Further Reading

2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. https://www.rheumatology.org/Portals/0/Files/2021-ACR-Guideline-for-Treatment-Rheumatoid-Arthritis-Early-View.pdf

Gioia C, Lucchino B, Tarsitano MG, Iannuccelli C, Di Franco M. Dietary Habits and Nutrition in Rheumatoid Arthritis: Can Diet Influence Disease Development and Clinical Manifestations? Nutrients. 2020 May 18;12(5):1456. https://www.mdpi.com/2072-6643/12/5/1456

References

2. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. https://www.rheumatology.org/Portals/0/Files/2021-ACR-Guideline-for-Treatment-Rheumatoid-Arthritis-Early-View.pdf

3. Image courtesy of BioRender.com.

4. Vadell AKE, Bärebring L, Hulander E, Gjertsson I, Lindqvist HM, Winkvist A. Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA)-a randomized, controlled crossover trial indicating effects on disease activity. Am J Clin Nutr. 2020 Jun 1;111(6):1203-1213.

5. Dourado E, Ferro M, Sousa Guerreiro C, Fonseca JE. Diet as a Modulator of Intestinal Microbiota in Rheumatoid Arthritis. Nutrients. 2020 Nov 14;12(11):3504.