ABSTRACT: Rheumatoid arthritis (RA) is a prevalent chronic, progressive, inflammatory autoimmune disease that affects not only the joints but also other organs, including the eyes, heart, and lungs. It is characterized by painful, tender, and swollen joints that can significantly affect a patient’s quality of life and productivity due to pain, stiffness, and sleep disturbances. Pain is often reported as the most debilitating symptom associated with RA. Pharmacologic therapies used in the treatment and management of RA include nonbiologic and biologic disease-modifying antirheumatic drugs and adjunctive agents such as immunosuppressants, corticosteroids, nonsteroidal anti-inflammatory drugs, and other analgesics. Pharmacists can educate patients and make clinical recommendations when warranted to improve clinical outcomes.
Rheumatoid arthritis (RA) a chronic, inflammatory, systemic autoimmune disease characterized by severe pain, joint stiffness, inflammation, deformity of joints, and loss of mobility.1,2 This progressive disease is linked with numerous physical, psychological, and economic burdens for affected patients, and impacts their families and the healthcare system as well. RA can negatively affect a patient’s overall quality of life, including productivity.1,2 Left untreated, RA can cause progressive joint destruction, resulting in disability and augmented rates of mortality.1
An estimated 1.5 million individuals in the United States have RA.3 Globally, the incidence of RA is about 0.5% to 1% in developed countries and 0.6% in the United States population.3,4 Statistics from various healthcare organizations also indicate that women are two to three times more likely to develop RA when compared with men, with the greatest incidence of RA occurring in women aged 65 years and older.3-6 Moreover, 75% of RA cases are diagnosed in women, and estimates are that 1% to 3% of women will develop RA at some point in their lifetime.7-9
Although RA can occur at any age, the onset of this disease is typically between the ages of 35 years and 60 years.1,2 It is important to note that RA can also occur in pediatric patients and young adults.1,2
The exact cause of RA is unknown; however, several factors have been identified that may contribute to its pathogenesis, including genetic, environmental, hormonal, immunologic, and infectious components.10 The most robust correlations have been observed with the following factors: female gender, having a family history of RA, and exposure to tobacco smoke (history of smoking).11 Socioeconomic, psychologic, and lifestyle elements may impact the development of RA and patient outcomes. Genetic factors account for an estimated 50% of RA cases.10,12 RA is considered to be the most common type of autoimmune arthritis.7
The onset of RA is typically insidious, often beginning with subtle symptoms, although sometimes RA manifests suddenly and can resemble an acute viral syndrome.4 Examples of systemic symptoms may include pain, swelling, and/or early morning stiffness in affected joints, generalized afternoon fatigue and malaise, anorexia, and weakness; occasionally, patients experience a low-grade fever.4,12 The degree of inflammation and pain in the joints vary from person to person.2,7,13 RA can also affect extra-articular sites such as the eyes, mouth, lungs, and heart.7,14
RA primarily involves synovial joints with symmetrical synovitis.15 If left uncontrolled, RA usually leads to joint destruction due to erosion of cartilage and bone.15 Since RA is a complex and progressive disease, patients with RA may experience periods of exacerbation of the disease known as flare-ups; however, with early intervention and treatment, patients may experience significant improvement in symptoms and some periods of remission.1,12,15 Early diagnosis and clinical intervention can be key to improving clinical outcomes, delaying disease progression and averting the development of irreversible joint damage and functional disability.15
Pain in RA
RA is linked with elevated levels of pain, impaired physical function, and diminished health-related quality of life.16,17 Patients with RA tend to have greater rates of morbidity, mortality, and disability.18 They frequently identify pain as their most bothersome symptom; approximately 70% rate pain relief as the uppermost or number-one priority compared with alleviating other RA symptoms.19 Pain impacts productivity and often leads to psychological distress and sleep disturbances—between 50% and 75% of RA patients report sleep disturbances due to pain.19,20 RA is a common cause of disability in the U.S.; rates of disability are directly proportional to the severity and duration of the RA.20-22 RA pain often persists in spite of optimal disease control, and stress can exacerbate pain episodes and contribute to depression and anxiety.18,23,24 Since pain from RA is usually believed to be a direct consequence of peripheral inflammation, healthcare providers have typically assessed pain as a marker of RA inflammation.25,26
RA pain manifests due to mechanisms including inflammation, peripheral and central pain processing, disease progression, and structural changes within the joint, which characteristically occur in the small joints of the hands, wrists, and feet, and sometimes the elbows, shoulders, neck, knees, ankles, or hips.25,26 Pain is often due to an interaction between joint pathology and processing of pain signals via the peripheral nerves and spinal and supraspinal pain pathways.25-27
As researchers have gained a deeper understanding of the biological mechanisms correlated to the pathogenesis of RA, the early use of various therapy options including conventional and biologic disease- modifying antirheumatic drugs (DMARDs) have the ability to improve symptoms and diminish or prevent disease flare-ups.15 However, although randomized, controlled trials have reported that considerable reduction in pain is often correlated with the use of DMARDs, many patients still experience clinically significant grades of pain and discomfort despite treatment.26,28 Pain may be the result of nociceptive/inflammatory mechanisms, but neuropathic pain descriptors have also been reported and are independently linked with worse self-reported physical and mental health.29,30 One study reported that 38.4% of patients continued to experience moderate-to-severe pain even though they were taking biologic therapies.31
Although there is no cure for RA, newer treatments have significantly enhanced therapeutic outcomes for patients. According to the two current guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), treatment of RA typically includes pharmacologic therapy and a multitreatment approach including a combination of nonpharmacologic measures such as adequate nutrition, physical therapy, emotional support, exercise, and rest.12 The overall goals of treatment are to improve patients’ quality of life by reducing pain, diminishing symptoms, reducing functional limitations, thwarting joint damage, and diminishing complications of the disease.12,32-35 In some cases, patients may require surgery.12,32 The Arthritis Foundation notes that in order to meet the aforementioned goals, clinicians should implement the following strategies when possible: 1) begin early and aggressive therapy to diminish or halt inflammation; 2) use a treat-to-target method to work toward remission; and 3) maintain tight control of therapy to minimize level of inflammation.3
Pharmacologic therapies used in the treatment and management of RA include the nonbiologic and biologic DMARDs and adjunctive agents such as immunosuppressants, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and other analgesics.12,13,19,32 The early use of DMARDs is considered the standard of care in treating RA, since it may thwart progression of RA more effectively than later treatment and may induce more remissions.12,13,19,32 Ideally, pharmacologic therapy should tightly control inflammation, with the overall goal of achieving either remission or low disease activity.32 The treat-to-target strategy, which consists of frequent evaluation to achieve this goal, is a strong recommendation supported by available treatment guidelines (TABLE 1).35
When no contraindications are present, the use of methotrexate in conjunction with folic acid is the standard of care for initial therapy because of its known efficacy and safety as initial monotherapy or combination treatment.32 Due to their swift onset of action, NSAIDs are commonly used on an as-needed basis for analgesia.32
Glucocorticoids (GC) are used extensively during acute disease flares/exacerbations either orally or as intra-articular injections for relief of pain and to quickly reduce swelling and inflammation.1,32,35 Guidelines recommend that oral GCs be reserved for short-term use (i.e., up to 3 to 4 months) only and should be tapered as soon as possible to prevent adverse drug reactions (ADRs).1,32,35 Additionally, recommendations for controlling inflammation on a long-term basis include the use of DMARDs tailored to patient needs.1,32 Examples of pharmacologic agents that are commonly prescribed for the treatment of RA can be found in TABLE 2.
Recent News About RA Treatment Guidelines
Due to ongoing developments since the last update in 2016 for the treatment of RA, including approval of novel therapies and efficacy and safety data from clinical trials, EULAR updated some guidelines in 2019.12,34 These updates can be found at https://ard.bmj.com/content/79/6/685.full.
In a November 2020 press release, ACR announced that it would preview the updated draft guidelines for RA management at its ACR Convergence 2020 annual meeting.36,37 These guidelines update previous guidelines based upon the latest clinical data available. A summary of the clinical recommendations for pharmacologic treatment of RA includes critical updates to the previous guideline released in 201536:
• Recommendations highlight initiating patients on methotrexate and continuing with the treatment in place of promptly changing to another DMARD.
• A conditional recommendation based on the ADRs associated with corticosteroids is aimed at reducing the use of steroids to treat RA inflammation, due to the serious ADRs associated with this class of drugs. The panel indicated that this recommendation is meant to encourage rheumatologists to limit use of steroids as much as possible.36
• There is a shift from past recommendations to expand to triple therapy before beginning a biologic. “Now, it is recommended that rheumatologists add a biologic or a targeted synthetic DMARD instead of changing patients to triple therapy,” the ACR stated.36
• There will be novel, detailed recommendations regarding tapering of drug therapies and treatment in certain patient populations that were not in previous guidelines and will cover conditions such as subcutaneous nodules, pulmonary disease, nonalcoholic fatty liver disease, persistent hypogammaglobulinemia and nontuberculous mycobacterial lung disease.36
The final version is not yet available; further information on the 2020 RA guideline updates can be found on the ACR website.37
Nonpharmacologic measures for RA include rest, application of heat or cold to relieve pain or stiffness, stress-reduction techniques, counseling, and patient-support services. The use of splints to protect and strengthen joints is recommended. Patients should be encouraged to consider physical therapy and exercise, when feasible, to sustain joint mobility, decelerate loss of muscle mass, and strengthen the muscles around the joints with movement exercises that are less stressful for the joints, such as swimming, yoga, and tai chi.12-14,32 Additionally, applying heat- and cold-packs before and after exercise minimizes painful symptoms.12,14,32 Patients should be encouraged to join support groups so that they can learn more about RA and how to cope with both the physical and emotional aspects as well as gain more insight into controlling this progressive disease.
The CDC recommends these self-management strategies for RA pain:38
1. Inquire about arthritis management strategies from various patient-education resources.
2. Remain active and implement exercise into daily routine, if feasible (research demonstrates that physical activity reduces pain, enhances productivity, and delays disability for adults with arthritis, including RA).
3. Maintain a healthy weight, and lose weight if needed.
4. Maintain routine healthcare visits with a rheumatologist.
5. Protect joints from injuries, and use supportive devices such as braces or splints if warranted.
More information can be found on the CDC website.
The Role of the Pharmacist
When counseling patients, pharmacists can be instrumental in identifying those at risk for or exhibiting the early signs of RA and encourage them to seek medical evaluation if warranted. Pharmacists can also enhance clinical outcomes by educating patients about RA medications, provide information from the various manufacturers about patient savings/financial assistance programs, and direct patients to patient-education/teaching resources (see SIDEBAR). They can also remind patients about the importance of adherence to therapy and routine follow-up with their rheumatologist to monitor response to therapy. Pharmacists can screen for possible drug/drug interactions and potential contraindications, as well as monitor for and educate patients about possible adverse effects.
During counseling, pharmacists should discuss the details of medications with patients regarding dosage, storage, and administration, including injection training, warnings and precautions, and potential adverse effects. They can also educate patients about the black box warnings associated with several classes of DMARDs. For example, some DMARDs are associated with serious infections that can lead to hospitalization or death, including tuberculosis and bacterial infections, invasive fungal, viral, and other opportunistic infections, as well as increased risk of lymphoma and other malignancies. Patients should be advised to watch closely for signs of infection and to alert their rheumatologists immediately if they exhibit any of the following symptoms: fevers, chills, cough lasting more than 3 weeks, coughing up blood, unexplained weight loss, fatigue, or other symptoms that could signify the start of infection.39
Prior to initiating therapy, patients should be reminded to discuss with their rheumatologist the recommended tuberculosis screenings, other necessary laboratory tests, and monitoring parameters. Pharmacists should also remind patients that before initiating pharmacologic treatment with either nonbiologic or biologic DMARDs, they should receive not only the pneumococcal, hepatitis, and influenza vaccinations (as indicated in the 2008 ACR recommendations) but also vaccinations for human papillomavirus and herpes zoster virus .12 Patients should be instructed to avoid live vaccine formulations as indicated in the prescribing information of many DMARDs. Patients should be urged to keep a current list of all medications including prescription medications for other conditions, OTC drugs, nutritional supplements, and alternative remedies and consult their primary care provider before taking any medications to avoid potential drug interactions or contraindications.
Through patient education, pharmacists can empower patients with the knowledge they need to make informed decisions about their health, take an active role in managing their RA, and improve their overall quality of life by working toward and maintaining remission and reducing or preventing RA exacerbations.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
1. Köhler BM, Günther J, Kaudewitz D, Lorenz HM. Current therapeutic options in the treatment of rheumatoid arthritis. J Clin Med. 2019;8(7):938.
2. CDC. Rheumatoid arthritis (RA). www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Accessed February 12, 2021.
3. Arthritis Foundation. Rheumatoid arthritis. www.arthritis.org/diseases/rheumatoid-arthritis. Accessed February 16, 2021.
4. Kontzias A. Rheumatoid arthritis (RA). Musculoskeletal and connective tissue disorders. MSD Manual Professional Version. www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/rheumatoid-arthritis-ra. Accessed January 4, 2021.
5. Wasserman AM. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2011;84(11):1245-1252.
6. National Institute for Health and Care Excellence (NICE). Rheumatoid arthritis in adults: management. 2018. www.nice.org.uk/guidance/ng100/resources/rheumatoid-arthritis-in-adults-management-pdf-66141531233989. Accessed February 16, 2021.
7. American College of Rheumatology. Rheumatoid arthritis. Updated March 2019. www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritis. Accessed January 5, 2021.
8. Brigham and Women’s Hospital. Rheumatoid arthritis overview. www.brighamandwomens.org/medicine/rheumatology-immunology-allergy/arthritis-and-joint-diseases-center/rheumatoid-arthritis-symptoms-and-treatment. Accessed January 5, 2021.
9. Nierengarten M. The empowered patient’s guide to rheumatoid arthritis. Practical Pain Management. Updated December 10, 2020. www.practicalpainmanagement.com/patient/conditions/rheumatoid-arthritis/understanding-rheumatoid-arthritis-symptoms-causes. Accessed January 5, 2021.
10. Carlens C, Hergens MP, Grunewald J, et al. Smoking, use of moist snuff, and risk of chronic inflammatory diseases. Am J Respir Crit Care Med. 2010;181(11):1217-1222.
11. Deane KD, Demoruelle MK, Kelmenson LB, et al. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3-18.
12. Smith H. Rheumatoid arthritis. Medscape. Updated February 7, 2020. https://emedicine.medscape.com/article/331715-overview#a4. Accessed January 6, 2021.
13. Bullock J, Rizvi SAA, Saleh AM, et al. Rheumatoid arthritis: a brief overview of the treatment. Med Princ Pract. 2018;27(6):501-507.
14. U.S. National Library of Medicine. Medline Plus. Rheumatoid arthritis. https://medlineplus.gov/rheumatoidarthritis.html. Accessed February 16, 2021.
15. Alivernini S, Tolusso B, Petricca L, et al. Rheumatoid arthritis. Mosaic of autoimmunity. Published March 29, 2019. www.sciencedirect.com/science/article/pii/B9780128143070000463?via%3Dihub. Chapter 46. Accessed January 6, 2021.
16. Strand V, Kaine J, Alten R, et al. Associations between Patient Global Assessment scores and pain, physical function, and fatigue in rheumatoid arthritis: a post hoc analysis of data from phase 3 trials of tofacitinib. Arthritis Res Ther. 2020;22:243.
17. Walsh DA, McWilliams DF. Pain in rheumatoid arthritis. Curr Pain Headache Rep. 2012;16:509-517.
18. Grabovac I, Haider S, Berner C, et al. Sleep quality in patients with rheumatoid arthritis and associations with pain, disability, disease duration, and activity. J Clin Med. 2018;7(10):336.
19. Bas DB, Su J, Wigerblad G, Svensson CI. Pain in rheumatoid arthritis: Models and mechanisms. Pain Manag. 2016;6(3):265-284.
20. Nicassio P, Ormseth S, Kay M, et al. The contribution of pain and depression to self-reported sleep disturbance in patients with rheumatoid arthritis. Pain. 2012;153(1):107-112.
21. de Souza S, Bansal, RK, Galloway J. Managing patients with rheumatoid arthritis. BDJ Team. https://doi.org/10.1038/bdjteam.2017;4:1706.
22. Park Y, Chang M. Effects of rehabilitation for pain relief in patients with rheumatoid arthritis: a systematic review. J Phys Ther Sci. 2016;28(1):304-308.
23. Cakirbay H, Bilici M, Kavakci O, et al. Sleep quality and immune functions in rheumatoid arthritis patients with and without major depression. Int J Neurosci. 2004;114:245-256.
24. Lee YC, Chibnik LB, Lu B, et al. The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2009;11:R160.
25. Walsh DA, McWilliams DF. Mechanisms, impact and management of pain in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(10):581-592.
26. Zhang A, Lee YC. Mechanisms for joint pain in rheumatoid arthritis (RA): from cytokines to central sensitization. Curr Osteoporos Rep. 2018;16(5):603-610.
27. Bas DB, Su J, Wigerblad G, Svensson CI. Pain in rheumatoid arthritis: models and mechanisms. Pain Manag. 2016;6(3):265-284.
28. Altawil R, Saevarsdottir S, Wedren S, et al. Remaining pain in early rheumatoid arthritis patients treated with methotrexate. Arthritis Care Res (Hoboken). 2016;68:1061-1068.
29. Lee YC. Effect and treatment of chronic pain in inflammatory arthritis. Curr Rheumatol Rep. 2013;15(1):300.
30. Roche PA, Klestov AC, Heim HM. Description of stable pain in rheumatoid arthritis: a 6-year study. J Rheumatol. 2003;30(8):1733-1738.
31. Vergne-Salle P, Pouplin S, Trouvin AP, et al. The burden of pain in rheumatoid arthritis: impact of disease activity and psychological factors. Eur J Pain. 2020;24(10):1979-1989.
32. Sparks JA. Rheumatoid arthritis. Ann Intern Med. 2019;170(1):ITC1-ITC16.
33. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26.
34. Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.
35. Moreland L, Cannella A. General principle and overview of management of rheumatoid arthritis in adults. UpToDate. Updated December 2020. www.uptodate.com/contents/general-principles-and-overview-of-management-of-rheumatoid-arthritis-in-adults?search=rheumatoid%20arthritis%20treatment&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed January 5, 2021.
36. American College of Rheumatology press release. New rheumatoid arthritis guideline emphasizes maximizing methotrexate and biologics, minimizing steroids. Published November 6, 2020. www.newswise.com/articles/new-rheumatoid-arthritis-guideline-emphasizes-maximizing-methotrexate-and-biologics-minimizing-steroids. Accessed January 7, 2021.
37. American College of Rheumatology. Rheumatoid arthritis. 2020 Rheumatoid arthritis guideline. www.rheumatology.org/Practice-Quality/Clinical-Support/Clinical-Practice-Guidelines/Rheumatoid-Arthritis. Accessed February 16, 2021.
38. CDC. Arthritis. Key public health messages. Reviewed February 2019. www.cdc.gov/arthritis/about/key-messages.htm. Accessed January 6, 2021.
39. Johns Hopkins Arthritis Center. Signs and symptoms of infection with biologic medications. Published February 21, 2016. www.hopkinsarthritis.org/arthritis-news/signs-and-symptoms-of-infection-with-biologic-medications. Accessed February 20, 2021.
To comment on this article, contact email@example.com.