Challenges in Managing and Preventing Rheumatoid Arthritis Pain

Yvette C. Terrie, BS Pharm, RPh


US Pharmacist. 2021;46(3):42-48. 

In This Article

Abstract and Introduction


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

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

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 2015:[36]

  • 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]