Rheumatoid arthritis is a type of chronic autoimmune arthritis that primarily causes joint pain, stiffness, swelling, and decreased movement of the joints. It affects more than 1.3 million Americans, and approximately 75% of patients with rheumatoid arthritis are women. Around 1% to 3% of women may develop rheumatoid arthritis in their lifetime, which most often begins between the ages of 30 and 50 years.¹ Uncontrolled rheumatoid arthritis leads to inflammation that can damage cartilage leading to bone erosion and joint fusion.² Therefore, early treatment and well-controlled disease is necessary to avoid inflammation in joints that could lead to permanent damage.³ 

The exact cause of rheumatoid arthritis is unknown, but genetic, environmental, hormonal, immunologic, and infectious factors play large roles in its development. Indeed, genetic factors account for up to approximately 50% of rheumatoid arthritis cases, with strongest risks seen in first-degree relatives.⁴

The risk of developing rheumatoid arthritis has been associated with several alleles. One gene family, the HLA-DRB1 alleles found within the human major histocompatibility complex on chromosome 6, is consistently highlighted when seeking to identify the disease. The HLA-DRB1 alleles constitute the strongest genetic association and may contribute to 30% or greater of the total genetic component of rheumatoid arthritis.⁵ These HLA-DRB1 alleles contain a stretch of a conserved sequence of five amino acids and include HLA-DRB1*04, HLA-DRB1*01, and HLA-DRB1*10.^5,6 Genome-wide association studies have identified polymorphisms in other genes, such as PAD14, PTPN22, CTLA4, IL2RA, STAT4, TRAF1, CCR6, and IRF5, as being associated with rheumatoid arthritis.⁶ Further genome-wide association studies have identified even more loci that are consistently associated across ethnicities, such as PADI2 and NFKBIE.⁵

Many environmental factors are associated with rheumatoid arthritis development. The strongest environmental risk is exposure to tobacco. Indeed, exposure to smoking accounts for approximately 20% to 30% of the environmental risk.⁴ Other risks include female sex, exposure to silica, air pollution, a diet high in sodium, red meat, and iron, obesity, and low vitamin D intake. Factors associated with a decreased risk include fish and omega-3 fatty acid consumption, moderate alcohol intake, healthy diet, statin use, and oral contraceptive or hormone replacement use.⁴

Finally, a possible immunologic and infectious risk component exists for developing rheumatoid arthritis. Several specific organisms have been identified as possibly being associated with the pathogenesis of rheumatoid arthritis, including Porphyromonas gingivalis (P ging), Anaeroglobus and Prevotella species, and Aggregatibacter actinomycetemcomitans.⁴ These pathogens cause mucosal inflammation and may influence the early immunologic changes that lead to rheumatoid arthritis. This is an early area of investigation that requires more knowledge regarding the relationship between mucosal processes and the initiation of autoimmunity. In addition, it will be important to combine these factors to understand how mucosal processes relate to other risk factors for rheumatoid arthritis.⁴

The diagnosis of rheumatoid arthritis involves an examination of blood test results, joint and organ examinations, as well as a review of x-ray or ultrasound images. There is no single test available for its diagnosis. Blood tests are conducted to identify the presence of antibodies in the blood that may indicate the disease.¹ However, these antibodies can also be present in healthy individuals and can lead to a false positive outcome. Abnormal blood tests can show anemia, rheumatoid factor, antibodies to cyclic citrullinated peptides, and/or an elevated erythrocyte sedimentation rate. Although X-rays can be useful for detecting rheumatoid arthritis, the autoimmune disease may be within normal limits in its early stages. As such, imaging tests are typically more beneficial for measuring disease progress and severity.¹

In 2010, the American College of Rheumatology and European League Against Rheumatism published classification criteria for rheumatoid arthritis.⁷ In the new criteria set, classification as definite rheumatoid arthritis is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis which better explains the synovitis, and achievement of a total score of 6 or greater from the individual scores in the following four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1), and symptom duration (two levels; range 0–1).⁷

Dutch researchers developed a clinical prediction tool to help identify patients with undifferentiated arthritis who are at risk of progressing to rheumatoid arthritis. The clinical rule includes assigning points to various patient characteristics, including age, sex, distribution of involved joints, and more. The sum of the total points gives a score in which a score of 0 represents the lowest risk of rheumatoid arthritis and a score of 14 represents the highest risk.⁸

In 2021, the American College of Rheumatology (ACR) published a guideline update for the treatment of rheumatoid arthritis, which was intended to serve as a tool to support clinical and patient decision making.⁹ New topics included in this update are recommendations for administering methotrexate, using methotrexate in patients with subcutaneous nodules, pulmonary disease and nonalcoholic fatty liver disease, using rituximab in patients with hypogammaglobulinemia, and treating rheumatoid arthritis in patients with nontuberculous mycobacteria lung disease. The guidelines provide a general guidance for commonly encountered clinical scenarios, but individual treatment decisions should be made through a shared decision-making process based on the patients’ disease activity, values, goals, preferences, and comorbidities.⁹

According to the guidelines, disease-modifying antirheumatic drugs (DMARDs) are the most effective treatment options for treating rheumatoid arthritis. Their timely initiation can prevent joint damage. The conventional synthetic disease-modifying antirheumatic drug (csDMARD) hydroxychloroquine is recommended for initial treatment in patients with rheumatoid arthritis with low disease activity. However, the csDMARD methotrexate is recommended as the initial treatment of patients with rheumatoid arthritis and moderate or high disease activity. If patients do not achieve low disease activity with methotrexate, triple therapy with the addition of sulfasalazine and hydroxychloroquine is as effective as adding a biologic or targeted synthetic medication, but with a slower response.⁹

The newest therapeutic approach to rheumatoid arthritis approved by the FDA involves using Janus kinase (JAK) inhibitors. The ACR guideline updated its recommendations on using JAK inhibitors when csDMARDs are ineffective. Currently approved JAK inhibitors include tofacitinib, baricitinib, and upadacitinib. Other JAK inhibitors that have been investigated include peficitinib, filgotinib, decernotinib, ruxolitinib, and itacitinib.^10,11 Phase 4 studies investigating JAK inhibitors include the RA-BRANCH, RA-BRIDGE, CLOSEUP, and RINVOQ trials.^12–15

The goal of rheumatoid arthritis management is to begin an aggressive drug treatment plan to prevent joint damage. The 2016 update of the European League Against Rheumatism recommends that patients who present with arthritis and are at risk of persistent arthritis should be started on DMARDs as early as possible, even if they do not fulfill classification criteria for an inflammatory rheumatologic disease.¹⁶ Of the DMARDs available, methotrexate should be the first treatment strategy. Rheumatologists should be the primary point of care for patients with early arthritis.¹⁶

Rheumatoid arthritis management has made great progress over the last decades, but the mechanisms underlying the inflammatory process and the pharmacological effects of therapeutic molecules are still not completely understood. A more thorough understanding of why some patients become less responsive over time, how different therapies have comparable efficacies, detecting pre-rheumatoid arthritis and establishing an early treatment, and improving the efficacy and safety of treatments are necessary to fulfill unmet needs in the field.

1. Rheumatoid Arthritis. American College of Rheumatology. Updated December 2021. Accessed April 6, 2023. https://rheumatology.org/patients/rheumatoid-arthritis
2. Rheumatoid Arthritis. Cleveland Clinic. Updated February 18, 2022. Accessed April 6, 2023. https://my.clevelandclinic.org/health/diseases/4924-rheumatoid-arthritis
3. Rheumatoid arthritis - Complications. National Health Service. Updated March 8, 2023. Accessed April 6, 2023. https://www.nhs.uk/conditions/rheumatoid-arthritis/complications/
4. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3-18. doi:10.1016/j.berh.2017.08.003
5. Dedmon LE. The genetics of rheumatoid arthritis. Rheumatology. 2020;59(10):2661-2670. doi:10.1093/rheumatology/keaa232
6. Chauhan K, Jandu JS, Brent LH, Al-Dhahir MA. Rheumatoid Arthritis. StatPearls Publishing; 2023. Accessed April 6, 2023. https://www.ncbi.nlm.nih.gov/books/NBK441999/
7. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580-1588. doi:10.1136/ard.2010.138461
8. Mochan E, Ebell MH. Predicting rheumatoidarthritis risk in adults with undifferentiated arthritis. Am Fam Physician. 2008;77(10):1451-1453. https://www.aafp.org/pubs/afp/issues/2008/0515/p1451.html
9. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2021;73(7):1108-1123. doi:10.1002/art.41752
10. Radu AF, Bungau SG. Management of Rheumatoid Arthritis: an overview. Cells. 2021;10(11):2857. doi:10.3390/cells10112857
11. You H, Xu D, Zhao J, et al. JAK inhibitors: prospects in connective tissue disease. Clin Rev Allergy Immunol. 2020;59(3):334-351. doi:10.10007/s12016-020-08786-6.
12. A randomized, controlled pragmatic phase 3b/4 study of baricitinib in patients with rheumatoid arthritis. ClinicalTrials.gov. Published September 12, 2019. Updated March 7, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT04086745. https://clinicaltrials.gov/ct2/show/NCT04086745
13. A randomized, active-controlled, parallel-group, phase 3b/4 sstudy of baricitinib in patients with rheumatoid arthritis. ClinicalTrials.gov. Published April 16, 2019. Updated March 24, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT03915964. https://clinicaltrials.gov/ct2/show/NCT03915964
14. Canadian real-life post-marketing observational study assessing the effectiveness of upadacitinib for treating rheumatoid arthritis (CLOSEUP). ClinicalTrials.gov. Published October 5, 2020. Updated January 18, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT04574492. https://clinicaltrials.gov/ct2/show/NCT04574492
15. Post-marketing surveillance to evaluate the safety and effectiveness of upadacitinib in Korean patients. ClinicalTrials.gov. Published September 9, 2020. Updated March 29, 2023. Accessed April 9, 2023. ClinicalTrials.gov identifier NCT04541810. https://clinicaltrials.gov/ct2/show/NCT04541810
16. Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis. 2017;76(6):948-959. doi:10.1136/annrheumdis-2016-210602