Epidemiology

EPIDEMIOLOGY AND PATHOPHYSIOLOGY

RA affects approximately 1% of adults all over the world.^1,2

• RA is the most common autoimmune disease, and the second most common form of arthritis compared to osteoarthritis (OA).^1-4
• The prevalence of RA in adult Americans was estimated at 1.29 million, down from the previous estimate of 2.1 million based on data from a 1995-2005 study.³
• RA can occur at any age⁴ CD4+ T cells that secrete IL-2, IL-6, and IFN-γ infiltrate the synovial membrane.

Individuals are usually diagnosed between the third and fifth decade of life and women are 2 to 3 times more likely to be diagnosed than men.

 

 

Pathophysiology

Rheumatoid arthritis (RA) is  a chronic autoimmune, inflammatory disease in which the immune system destroys synovial joints and accessory structures.^1,2,5-7 Although the exact cause of RA remains unknown, recent findings suggest a genetic basis for disease development.

• The interplay between genetic risk factors and environmental triggers is believed to be responsible for initiating an inflammatory process that ultimately manifests clinically by typical signs and symptoms of disease, such as joint swelling and tenderness⁵
• The rheumatoid joint contains numerous cell types that are involved in these inflammatory and destructive processes ^6,7.
• T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA.^8,9 Concurrently, CD4+ T cells that secrete IL-2 and IFN-γ infiltrate the synovial membrane
• Synovitis is caused by the influx or local activation, or both, of mononuclear cells (including T cells, B cells, plasma cells, dendritic cells, macrophages and mast cells) and by angiogenesis.⁸
• As synovial proliferation continues, the pannus invades from the joint margins, triggering cartilage thinning mediated in part by release of matrix metalloproteinases from synovial fibroblasts, in addition to chondrocyte mediated destruction and failure of repair mechanisms
• Bone destruction is also initiated through the activation of osteoclasts^5-7

 

Mechanism of Action of Disease-Modifying Antirheumatic Drugs (DMARDs)

The progressive joint damage of rheumatoid arthritis is caused by the release of pro-inflammatory cytokines by immune cells infiltrating the synovium. DMARDs work by modifying the immune system to decrease inflammation and prevent radiographic changes to the joint. There are three major classes of DMARDs used in the treatment of RA: conventional DMARDs (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine), biological DMARDs (TNF inhibitors and other monoclonal antibodies), and targeted DMARDs (baricitinib and tofacitinib). In addition to DMARDs, NSAIDs and corticosteroids may be used to treat the signs and symptoms of RA.

NSAIDs inhibit the generation of prostaglandin by blocking cyclooxygenase enzymes, COX-1 and COX-2. NSAIDs such as ibuprofen, naproxen, and celecoxib reduce acute inflammation, thereby decreasing pain and improving function. It is important to note that these drugs do not change the course of disease of RA or prevent joint destruction.¹¹

Corticosteroids, such as prednisone and methylprednisolone, have both anti-inflammatory and immunoregulatory activity. Corticosteroids are useful in early disease as temporary adjunctive therapy while waiting for the onset of DMARD activity. They may also be used as chronic adjunctive therapy in patients with severe disease not well controlled on NSAIDs and DMARDs.¹¹

Although NSAIDs and DMARDs improve the symptoms of active RA, only DMARD agents have been shown to alter the course of the disease and improve radiographic outcomes. In most cases, once a diagnosis of RA has been confirmed, DMARD therapy should be initiated. The presence of erosions or joint space narrowing on x-rays of the involved joints is a clear indication for DMARD therapy, but physicians should not wait for evidence of joint damage to begin therapy.¹²

Conventional DMARDs
Methotrexate, leflunomide, sulfasalazine, hydroxychloroquine

Methotrexate is considered the first-line DMARD agent for most patients with RA. The anti-inflammatory effects of methotrexate may be related to interruption of adenosine as well as other pathways. Its immunosuppressive effects are due to inhibition of dihydrofolate reductase, an enzyme involved in the metabolism of folic acid. It has a relatively rapid onset of action (6-8 weeks), good efficacy, favorable toxicity profile, ease of administration and low cost.^12,13

Sulfasalazine has similar efficacy to methotrexate in reducing the signs and symptoms of RA and slowing radiographic damage. It may be given in combination with methotrexate and hydroxychloroquine as “triple therapy.” Its mechanism of action is unknown but may involve folate depletion.¹³

Leflunomide has a similar efficacy to methotrexate and may be used in patients who are intolerant or have failed methotrexate therapy. It may also be used in combination with methotrexate in patients with no preexisting liver disease. Its mechanism of action is not known but may involve inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase enzyme.¹³

Hydroxychloroquine is an antimalarial drug that has limited ability to prevent joint damage as monotherapy. Use should be limited to patients with very mild, seronegative, and nonerosive disease. It is usually used in combination with methotrexate or with methotrexate and sulfasalazine as “triple therapy.” Its mechanism of action is unknown but it is proposed that hydroxychloroquine may affect antigen presentation.¹⁴

TNF Inhibitors
Etanercept, infliximab, adalimumab, certolizumab pegol, golimumab

Tumor necrosis factor alpha (TNF) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is produced locally within the joint by immune cells infiltrating the synovium and TNF is found in large quantities in a rheumatoid joint. TNF is one of the critical cytokines that mediates joint damage by stimulating the production of additional inflammatory mediators and enhancing immune cell recruitment to the joint. TNF inhibitors are biological molecules that bind to TNF and prevent the cytokine from binding to its receptor. There are currently five TNF inhibitors FDA approved for the treatment of RA: etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab. Etanercept is a soluble TNF receptor-Fc immunoglobulin fusion construct, infliximab, adalimumab, and golimumab are monoclonal antibodies, and certolizumab pegol is an anti-TNF antigen binding domain-polyethylene glycol construct. While these drugs differ in structure, the efficacy and safety of TNF inhibitors is similar across the class in reducing the signs and symptoms of RA and preventing radiographic joint damage when used alone or in combination with methotrexate.¹⁵

JAK Inhibitors
Baricitinib, tofacitinib, upadacitinib

As the understanding of the molecular basis of cytokine action was developed, it was discovered that interferons, many interleukins, and colony-stimulating factors all use the same method of signal transduction, the JAK/STAT pathway.¹⁶  Janus kinases (JAKs) are a family of intracellular tyrosine kinases that are activated when cytokines and interferons released by immune cells bind to cell-surface receptors.¹⁷ Once activated by a cytokine signal, JAK phosphorylates a transcription factor known as STAT (Signal Transducer and Activator of Transcription) that binds to DNA and drives the expression of genes involved in the inflammatory process.  Abnormal activation of JAK/STAT signaling is a critical event in the pathogenesis and progression of RA.¹⁸ JAK inhibitors, such as baricitinib and tofacitinib, and upadacitinib, block the kinase activity of JAK and prevent cytokine-mediated immune activity.

Other Biological DMARDs
Abatacept, rituximab, tocilizumab, anakinra

Abatacept is a T-cell costimulatory blocker that interferes with the interactions between antigen-presenting cells (APCs) and T lymphocytes, decreasing T-cell activation. Abatacept has a high affinity for CD28, a costimulatory protein on the surface of T cells. If CD28 does not bind to CD80 and CD86 on the surface of APCs, T cells do not become activated, even in the presence of antigen.¹⁹

Rituximab is a monoclonal antibody that causes a rapid and sustained depletion of circulating B cells by binding to CD20 on the B cell surface. B cells within a rheumatic joint can activate T cells and secrete cytokines, thereby promoting inflammation. Rituximab is effective in decreasing the signs and symptoms of RA and slowing radiographic progression in patients who have failed TNF inhibitor therapy.²⁰

Tocilizumab is an IL-6 inhibitor that binds to soluble and membrane-bound IL-6 receptors. IL-6 is a pro-inflammatory cytokine produced by T- and B- cells, monocytes and fibroblasts, and has been implicated in T-cell activation and antibody secretion. IL-6 is also produced by synovial and endothelial cells in the joints, contributing to the inflammation of RA.²¹

Anakinra is an IL-1 receptor antagonist that can be used alone or in combination with non-biologic DMARDs. IL-1 is another proinflammatory cytokine that promotes cartilage degradation and is a potent stimulus to osteoclasts, leading to bone erosion.²²

REFERENCES

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