#94934: Rheumatoid Arthritis

The history and physical examination are the most sensitive and specific tools for RA diagnosis. Findings on general physical examination are normal except for an occasional low-grade fever (38°C) and a slightly elevated pulse rate. The characteristic patient with RA initially presents with complaints of pain and stiffness in multiple joints. There is prominent and prolonged morning stiffness (lasting more than one hour) that usually begins gradually with fatigue, loss of appetite, widespread muscle aches, and weakness [4,7,14].

After this initial presentation, joint pain appears. When the joint is not used for some time, it can become warm, tender, and stiff. After inflammation of the joint, increased synovial fluid is produced and the joint becomes swollen. There is accompanying soft tissue swelling, and joint pain is often felt bilaterally, affecting the fingers, wrists, elbows, shoulders, hips, knees, ankles, toes, and neck [7]. Though the joints are tender, the small joints of the hands and feet are not usually painful when the patient is at rest. Palmar erythema and prominent veins on the dorsum of the hand and wrist indicate increased blood flow. Distal interphalangeal joints are rarely involved. The temperature over the involved joints (except the hip) can be elevated, but there is usually no accompanying erythema. There are limitations in the range of motion, muscle strength, and function around inflamed joints.

In addition, soft, poorly delineated subcutaneous nodules (rheumatoid nodules) are often found in the extensor surface of the forearm. Soft, small lymph nodes are found occasionally in epitrochlear, axillary, and cervical areas [10]. Other symptoms that may present include anemia due to deficits in bone marrow production; eye burning, itching, and discharge; or lung inflammation (pleurisy) [4,7,10,14]. Joint destruction may occur within one to two years after the appearance of the disease.

The 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) joint working group recommends several laboratory tests for the diagnosis of RA, including rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti-cyclic citrullinated peptide (anti-CCP) antibody [13]. A positive rheumatoid factor is the most specific and sensitive laboratory marker of RA, as it is seen in about 70% to 80% of patients [4,10,14]. It is also present in many healthy individuals, patients with other rheumatic diseases, and individuals with chronic infections [11]. ESR is typically ≥30 mm/hour, and CRP level is typically ≥0.7 pg/mL. Both levels are associated with disease activity, and the CRP value over time correlates with radiographic progression [10,11,15]. The anti-CCP antibody test is a specific blood test available for diagnosing RA and distinguishing it from other types of arthritis [10,14]. The anti-CCP antibody test is a marker of ACPA and is positive in about 80% to 90% of patients; it can also be present in other diseases, including active tuberculosis, and is especially useful in early synovitis. While RA differs from person to person, individuals with rheumatoid factor, the anti-CCP antibody, or subcutaneous nodules tend to have more severe forms of the disease [10,11,14].

As noted, RA is a clinical diagnosis [16]. To date, biomarkers for the initial tissue processes that cause joint damage in RA lack prognostic accuracy and are therefore inadequate as stand-alone tests, but they can help to rule out other causes of arthritis when a patient has clinical features of RA [17]. In 2010, a multi-biomarker disease activity test, Vectra DA, was introduced. This test uses a unique algorithm to derive a composite score (1 to 100) based on the results of 12 blood protein biomarkers, including vascular cell adhesion molecule-1, epidermal growth factor, vascular endothelial growth factor A, interleukin-6 (IL-6), tumor necrosis factor (TNF) receptor type 1, matrix metalloproteinase-1 or collagenase-1, matrix metalloproteinase-3 or stromelysin-1, YKL-40, leptin, resistin, serum amyloid, and CRP [18,19]. Vectra DA has been independently verified and found to correlate well to disease activity measured with RA assessment tools (e.g., Disease Activity Score in 28 joints using the CRP level). The test is validated for use in adults already diagnosed with RA but is not intended to diagnose RA [20].

There are several other laboratory tests used in the differential diagnosis of RA. Complete blood count may reveal mild normochromic and either normocytic or microcytic anemia (hemoglobin 10 g/dL); white blood cell count and differential may reveal thrombocytosis [10,15]. Although baseline evaluation of renal and hepatic function is not sensitive or specific for RA, it is recommended because the findings will guide medication choices.

In certain instances, clinicians may perform an arthrocentesis in order to differentiate RA from other arthropathies [21]. Usual findings from synovial fluid aspiration that support a diagnosis of RA include straw-colored fluid with a significant number of fibrin flecks, synovial fluid ability to clot at room temperature, and 5,000–25,000 white blood cells (WBCs)/mm³ (5 to 25 × 10⁹/L) with 85% polymorphonuclear leukocytes (PML) [4,10]. In addition, bacterial cultures are negative, no crystals are present, and the synovial fluid glucose level is low [4,10].

For patients with chronic extremity joint pain and suspected rheumatoid arthritis, the American College of Radiology recommends x-ray as the imaging study of choice for evaluation.

(https://acsearch.acr.org/docs/3097211/Narrative Last Accessed: April 24, 2023)

Strength of Recommendation: 9 (Usually appropriate)

Popular imaging tests for RA include joint ultrasound, magnetic resonance imaging (MRI), and joint x-rays. Imaging studies may show normal findings or osteopenia and erosions near joint spaces in early disease; wrist and ankle films are useful as baselines for comparison with future studies [10,22]. Implementing the modern treatment strategy in RA (i.e., early initiation and optimal adjustments of aggressive therapies) requires methods for early diagnosis and sensitive monitoring of the disease process.

In RA clinical trials and routine management, conventional radiography is the pivotal method for diagnosing and monitoring structural joint damage. It is inexpensive, readily available, easily reproducible, and allows easy serial comparison for assessment of disease progression [11]. However, it is insensitive to bone damage at its earliest stages and incapable of capturing synovitis. In comparison with radiography, MRI offers assessment of bone damage with improved sensitivities to early pathology and changes in joint structure [11]. With increased use of MRI, it has been found that joints occasionally exhibit MRI evidence of synovitis in the absence of symptoms [22]. In addition, detailed assessment of soft tissue changes, including synovitis and tenosynovitis, is possible, and MRI findings are of prognostic value for the long-term radiologic outcome. Ultrasonography, although less specific and sensitive in RA diagnosis than MRI, offers comparable information on both inflammatory and destructive changes in RA finger and toe joints.

MRI and ultrasonography have significantly increased detection of early joint damage, assessment of synovial inflammation, and therapeutic management of patients with RA. Clinicians should be familiar with the MRI and sonographic appearances of early RA in the small synovial joints of the appendicular skeleton. Sonography provides a way to detect synovitis, whereas MRI allows a more intricate approach to the small synovial joints of the appendicular skeleton.

A number of different medical conditions may be considered in the differential diagnosis of RA (Table 1) [16,28,29,30]. These include:

Early in the course of RA, self-limited viral syndromes should be considered, especially hepatitis B and C, parvovirus, rubella (infection or vaccination), and Epstein-Barr virus [28,29,30]. At any time, systemic lupus erythematosus, psoriatic arthritis, and reactive arthritis may present diagnostic challenges. This requires a targeted history and examination to elucidate associated clinical symptoms, such as rashes, oral ulcers, nail changes, dactylitis, urethritis, and renal, pulmonary, gastrointestinal, or ophthalmologic complications [4,28]. Remitting rheumatoid factor-negative symmetrical synovitis with pitting edema and paraneoplastic syndromes should be considered in elderly patients with fulminant-onset RA [29]. Chronic tophaceous gout may also mimic severe nodular RA. Hypothyroidism not only causes many rheumatic manifestations but also occurs commonly in conjunction with RA and, therefore, should be kept in mind [29].

According to the American College of Rheumatology, a treat-to-target approach is strongly recommended over usual care for patients who have not been previously treated with biologic or targeted synthetic DMARDs.

(https://onlinelibrary.wiley.com/doi/10.1002/acr.24596 Last Accessed: April 24, 2023)

Strength of Recommendation/Level of Evidence: Strong/Low

DMARDs are the current standard of pharmaceutical care for RA, and their choice for a patient should be determined by several factors, including patient compliance, disease severity, physician experience, and the presence of various comorbidities. Table 3 provides a list of the most commonly used DMARDs and their most common adverse effects [37,38,39,197].

In DMARD-naïve patients with moderate-to-high disease activity, the American College of Rheumatology strongly recommends methotrexate monotherapy over hydroxychloroquine, sulfasalazine, biologic DMARD, or targeted synthetic DMARD monotherapy.

(https://onlinelibrary.wiley.com/doi/10.1002/acr.24596 Last Accessed: April 24, 2023)

Strength of Recommendation/Level of Evidence: Strong/Low or very low

Methotrexate is the most commonly prescribed DMARD and is still considered the "anchor drug" for the treatment of RA [33,42,197]. Leflunomide, a competitive inhibitor of an intracellular enzyme needed for de novo pyrimidine synthesis, is a newer DMARD with comparable efficacy that can be substituted for methotrexate and may be particularly useful for patients with intolerance of or contraindications to methotrexate; methotrexate is still the preferred initial DMARD due to its utility as an anchor in combination regimens, its lower cost, and its greater dosing flexibility [10,33,43,44,197]. Patients who have failed monotherapy with methotrexate may benefit from the addition of leflunomide, either with methotrexate or other DMARDs [33,36,44]. Other commonly prescribed DMARD medications include hydroxychloroquine, minocycline, and sulfasalazine; the anti-TNF biologic agents adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab; and the non-TNF biologic agents abatacept, anakinra, rituximab, and tocilizumab [42]. Sulfasalazine and hydroxychloroquine are anti-malarial medications that are often prescribed as first-line therapy. However, the treatment effects of the anti-malarial medications may take weeks or months in order to be effective [39,45]. In more severe cases (i.e., moderate or high disease activity and poor prognostic features), combination therapy with two or three DMARDs is used as immediate first-line treatment [33,39,45,197].

Biologic agents (anti-TNF and non-TNF) have been used since 1998 and are now a well-established form of DMARD therapy [42]. Non-TNF agents are generally only used if TNF-alpha inhibitors fail to control disease or if they are contraindicated [33,197]. The TNF-alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab) block the proteins responsible for the inflammation process and are given subcutaneously or intravenously, thereby lowering TNF-alpha levels, which are elevated in the synovial fluid in patients with RA [4,10,14,36]. Treatment with anti-TNF therapies also significantly improves the anemia associated with RA [39,46,47]. Etanercept is a soluble TNF-alpha-receptor fusion protein, with some studies showing comparable long-term treatment effects to methotrexate [10,48]. However, etanercept elicits more rapid symptom improvement, often within two weeks [39]. A systematic review found that etanercept plus methotrexate was more efficacious than either drug alone and that the combination slowed joint radiographic progression after up to three years of treatment [49]. Infliximab is another anti-TNF-alpha antibody that has shown greater response than placebo (52% versus 17%) in patients who had a poor response to methotrexate [50,51]. Results from one controlled trial found that infliximab plus methotrexate produced a significant reduction in MRI evidence of synovitis and erosions at one year, and at two years, functional and quality of life benefits were sustained, despite withdrawal of infliximab [52]. Adalimumab, a recombinant TNF-alpha antibody, has an additive effect when taken with methotrexate [53].

Certolizumab pegol is a humanized antigen-binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol and is administered subcutaneously [54]. It is the only anti-TNF pegylated Fab' approved for use in RA, either as monotherapy or with other DMARDs. Because of certolizumab pegol's unique structure, certain cytotoxic effects (e.g., complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) seen with other anti-TNF agents (adalimumab, infliximab, and etanercept) do not occur [54]. Certolizumab pegol also does not actively transfer across the placenta; although it has been used safely during pregnancy in humans (and in animal studies), this agent should only be used if clearly needed. Moderate-to-high-quality evidence from randomized controlled trials indicate that certolizumab pegol, alone or combined with methotrexate, is beneficial in the treatment of RA for improved quality of life, increased chance of remission of RA, and reduced joint damage as seen on x-ray [55].

Golimumab is an anti-TNF-alpha antibody similar to adalimumab and infliximab [54]. One study found that golimumab had a similar safety profile as the other anti-TNF agents, but that the 100-mg dose showed higher incidences of serious infections, demyelinating events, and lymphoma than 50 mg [56]. A follow-up to this study reported safety of golimumab through year five, which was consistent with previously reported findings at the third year, but with similarly higher incidences of tuberculosis, lymphoma, opportunistic infections, and demyelination [57].

The non-TNF agents (abatacept, anakinra, rituximab, and tocilizumab) are specific white blood cell modulators that work to control inflammation. Abatacept decreases the number of T-cells, which reduces the activation of other cells in the inflammatory process. Abatacept is given once a month either subcutaneously or intravenously [4,10,14]. Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist that has been found to be more effective than placebo when administered alone or in combination with methotrexate in several randomized controlled trials [39,46]. Anakinra, anti-TNF therapies, and denosumab (a nuclear factor-kappa B [RANK] ligand inhibitor) have the demonstrated ability to improve RA-associated osteoporosis and joint space erosions [39; 46]. Overall, indirect comparisons between anakinra and most other biologic DMARDs reveal that anakinra is associated with a significantly lower risk of adverse events; however, it is associated with skin irritation at the injection site, increased infection risk, and leukopenia [39; 58]. Rituximab is a B-cell surface receptor antibody that has shown promise in several studies. It is given intravenously twice a year and reduces the number of abnormal B-cells produced in patients with RA [59]. Response rates and time to relapse vary significantly among individuals treated with rituximab. One study evaluated these variables among 17 patients with RA [60]. Eight patients were seropositive for RF; nine were seronegative for RF. Both groups were treated with two cycles of rituximab, and all patients were re-evaluated following treatment. Rituximab was re-administered when disease relapse was confirmed by clinical laboratory measures. CD20+ cells and CD2-receptor expression levels were estimated at initiation, relapse, and re-evaluation time points and compared between the two groups. Compared with the seronegative group, patients with seropositive disease responded more favorably to treatment with rituximab and demonstrated a longer time to relapse [60]. Additional research is needed on rituximab to address concerns about the efficacy, optimum dose, safety, prediction of response, and pregnancy outcomes [61].

Tocilizumab blocks the attachment site for IL-6, effectively preventing the cytokine from activating an immune response [62]. The agent is administered as a monthly IV infusion. Adjusting the dose frequency of tocilizumab may be a useful strategy [63,64]. Tocilizumab appears to have a similar safety profile as other non-TNF biologic agents. Rheumatoid neutrophilic dermatitis and psoriasis-like eruption have been reported in patients taking tocilizumab for RA treatment [64,65]. Tocilizumab should be combined with a DMARD [33,66,197]. Regarding signs and symptoms, physical function, and joint damage, there is some evidence to support the efficacy of tocilizumab monotherapy; however, it is not recommended at this time [33,66,197]. In 2012, a targeted agent, tofacitinib, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with RA with inadequate response to methotrexate [67]. Tofacitinib is an oral Janus kinase inhibitor and is the first in the class to be approved for the treatment of RA. The approved dose is 5 mg twice daily, but this may be decreased to one 5-mg dose daily in the presence of moderate-to-severe renal impairment, moderate hepatic impairment, or coadministration of certain antifungals [41]. Tofacitinib can be used either as monotherapy or in combination with methotrexate or other nonbiologic DMARDs [41,67]. Boxed warnings related to risks for serious infection, tuberculosis, and lymphoma and other malignancies have been issued for this agent [41].

Unfortunately, many of the available RA treatments can also cause serious side effects [68]. Because biologics have significant side effects and are expensive, patients with mild or moderate disease are often first treated with methotrexate (unless contraindicated) or other conventional DMARDs [42]. Induction of malignancy is a concern when RA is treated with biologic therapy, as patient immune systems are suppressed; however, a 2014 systematic safety literature review found that the overall risk for malignancy is not significantly increased, with the exception of melanoma (adjusted hazard ratio: 1.5) [4,10,14,68,69,70]. A follow-up review conducted in 2016 confirmed these findings [71]. Biologics are associated with an increased risk of infection, especially tuberculosis and herpes zoster reactivation [39,53,70,71]. Patients should be evaluated for latent tuberculosis infection before drug administration and monitored for signs and symptoms of active tuberculosis [4,10,14,36,41]. Patients at risk of hepatitis B virus infection should be evaluated for carrier status before adalimumab initiation; any live vaccine should not be concurrently administered in these patients [72]. Vaccination with live attenuated vaccines (e.g., herpes zoster) should be undertaken prior to initiation of TNF and non-TNF biologics [36].

NSAIDs, glucocorticoids, or cyclooxygenase-2 (COX-2) inhibitors are often used concurrently to treat RA-associated joint pain and inflammation. However, they do not alter the disease course and should not be used as single therapy.

Potential side effects are a consideration with these medications as well. Patients taking NSAIDs should be monitored for long-term NSAID-associated complications such as gastrointestinal bleeding, cardiovascular problems (e.g., myocardial infarction, stroke), and gastric ulcers and bleeding. COX-2 inhibitors block an inflammation-promoting enzyme called cyclooxygenase; this drug class was initially believed to work as well as traditional NSAIDs, but with fewer stomach problems. However, myocardial infarction and stroke reports have prompted the FDA to re-evaluate the risks and benefits of the COX-2 inhibitors. Although certain COX-2 inhibitors (such as celecoxib) are still available, they are labeled with strong warnings and a recommendation for prescribing the lowest possible dose for the shortest possible duration [41].

Corticosteroids reduce joint swelling and inflammation, and a glucocorticoid injection is a safe and highly effective, but temporary, intervention for single-joint treatment. Infectious arthritis should be ruled out before injections are performed. Steroid dosages equivalent to less than 10 mg of prednisone daily are highly effective for relieving RA symptoms and can slow joint damage [73]. Corticosteroids should be considered when initiating or changing conventional DMARDs, in different dose regimens and routes of administration, but should be tapered as rapidly as clinically feasible due to potential long-term side effects, including osteoporosis, cataracts, Cushingoid symptoms, and blood glucose level abnormalities [33]. The ACR recommends that patients being treated with glucocorticoids take 1,200–1,500 mg of calcium and 800–1,000 IU of vitamin D daily to prevent glucocorticoid-induced osteoporosis [74]. Symptoms may recur with steroid discontinuation, especially when high dosages are used. Therefore, the agents should be withdrawn slowly, over one month or more, to avoid rebound effects [75]. Systemic steroids often are used as "bridging therapy" during the initiation of DMARDs therapy before their action is noted; some of the newer DMARDs have a relatively rapid onset of action, making this method less necessary [33].

Occasionally, surgery is needed to correct severely affected joints. Surgeries serve to relieve joint pain, correct deformities, and modestly improve joint function [4,10,14]. The most successful locations of surgery are those performed on the knees and hips [4,10,14]. The first surgical treatment performed is a synovectomy, which removes part or all of the joint lining (synovium). This procedure may only provide temporary relief, but it can be effective for patients for whom pharmacologic treatment has not resulted in improvements. Surgeries performed in later-onset disease include total joint replacement with a joint prosthesis. In extreme cases, total knee or hip replacement can have enhanced importance, making the difference between a dependent or independent lifestyle for a patient.

There are a significant number of total joint replacements performed each year in the United States, and the procedures are considered relatively safe and effective. However, some patients will experience prosthesis failure. Risk factors for failure include male gender, age younger than 55 years at the time of surgery, obesity, and the presence of comorbidities. In terms of factors related to the surgeon, greater procedure volume (both of the surgeon and the facility), prosthesis choice, and surgical technique (e.g., proper alignment of the prosthesis) all contribute to better patient outcomes [76]. It is important to note that both knee and hip replacement are associated with a high risk of deep vein thrombosis (DVT) and pulmonary embolism compared with other surgeries. Without prophylaxis, DVT will develop in most patients [77]. Therefore, prophylactic treatment, usually with either low-molecular-weight heparin or warfarin, is recommended for patients undergoing one of these procedures, unless contraindications are present. In general, total joint replacement is reserved for patients for whom other treatments have been ineffective.

Range-of-motion exercises and individualized exercise programs prescribed by a physical therapist can also delay the loss of joint function. Joint protection techniques, heat and cold treatments, and splints or orthotic devices to support and align joints may be of assistance [4,10,14]. Some therapists will use specialized devices to apply deep heat or electrical stimulation to reduce pain and improve joint mobility [4,10,14]. Occupational therapists can construct splints for the hand and wrist and teach patients with RA how to protect and use their joints most effectively. In addition to physiotherapy, occupational therapists can also show patients with RA how to better cope with limitations that can affect their daily tasks at work and at home. For example, many clinicians have recommended frequent rest periods between activities and proper sleeping habits (e.g., 8 to 10 hours of sleep per night) [78].

The use of complementary and alternative medicine (CAM) is on the rise among the general population, and its use for the treatment of RA is extremely commonplace among individuals in the United States, despite a lack of evidence for the long-term benefit of many of these practices [79,80,81]. According to the National Institutes of Health, 40.9% of patients with RA used CAM in 2012, compared with 24.1% in the healthy population. Some estimate the prevalence of CAM use among patients with RA to be as high as 90% [82,83,84]. A 2014 survey of 855 African American patients with RA found that 98% had ever engaged in CAM activities, 95% had ever used CAM treatments, and 51% had visited a CAM provider [85]. CAM use varies significantly between cultural/social groups, and as such, it may be difficult to draw overall prevalence data from this study. However, it is known that patients with symptoms of severe pain are more likely to engage in self-treatment, nutritional supplementation, and unconventional approaches to coping and healing than those with less symptomatic arthritis [79]. CAM use among the elderly has many potential implications, including altered pharmacokinetics, comorbidities, and polypharmacy of potentially toxic drugs [86]. Patients may also choose alternatives because conventional medicine offers no cure, symptoms persist despite conventional therapy, CAM offers a relatively favorable risk/benefit ratio compared with pharmacotherapy, and/or their culture or society supports the use of CAM. Nearly 15% of CAM users cite healthcare costs as an impetus [87,88].

Despite the fact that no evidence exists to support the use of CAM for long-term improvement in RA, short-term relief of symptoms is often realized with various CAM therapies [79]. CAM encompasses a wide range of therapeutic practices, from modified diets and the use of herbal medications (HMs) and other natural products (NPs) to yoga and tai chi exercises. Other therapies, such as acupuncture, biofeedback, chiropractic medicine, homeopathy, hypnosis, massage, meditation, naturopathy, osteopathy, prayer, and traditional cultural medicine (e.g., Chinese, Native American, Ayurveda, Siddha, Unani), are all considered CAM because they fall outside the realm of conventional Western medicine; however nonvitamin, nonmineral natural products are the most commonly used category of CAM, followed by deep breathing, meditation, and massage therapy [87]. For healthcare professionals, the major significance of CAM use (especially HMs and NPs) by patients with RA is that it goes unreported about 50% to 70% of the time, and some modalities can modify the efficacy of medications being taken concurrently or cause serious adverse effects when combined with pharmaceuticals [81]. Most often, patients say they are simply not asked about use, but are generally forthcoming about CAM with their physicians when discussion is initiated. A very small minority feel that healthcare professionals are ignorant and skeptical of CAM and will only admonish them for use; nonetheless, inquiring about CAM, while remaining nonjudgmental, is advised to gain a clear understanding of all the factors involved.

Aside from supplementation with several specific types of oils, the only complementary therapy currently endorsed by the U.S. Department of Health and Human Services for patients with RA is to consume a nutritious, balanced diet [89]. Some argue that the typical American diet, which is based on animal proteins (many of which are now devoid of significant levels of nutrients and/or are heavily processed) and typically consisting of high levels of animal fats (e.g., cheese, butter, ice cream) and simple carbohydrates promotes inflammation. However, others argue that restricting the intake of good quality food sources of nutrients, such as fish and real cheese, can lead to dietary deficiencies. A growing body of evidence supports the belief that proper nutrition from food, or more specifically, avoidance or correction of nutritional deficiencies, can prevent the development of inflammatory disorders in genetically predisposed individuals. One group of researchers writes that, "diet can affect transgenerational gene expression via 'reversible' heritable epigenetic mechanisms" [90]. It is believed that certain anti-inflammatory bioactive food components (e.g., carotenoids, organosulfurs, polyphenols, phytosterols, tocopherols, tocotrienols) can lessen the rates and negative effects of acetylation, methylation, oxidation, phosphorylation, ribosylation, SUMOylation, and ubiquitination.

One food-sourced supplement, fish oil, is a proven, powerful RA therapy and contains several bioactive components, such as the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). A 2010 meta- and mega-analysis of randomized controlled trials confirmed the efficacy of fish oil for the relief of joint pain and found a significantly reduced use of anti-inflammatory drugs in patients with long-standing RA [91]. A 2015 randomized controlled trial examined the effects of high versus low doses of fish oil in early RA by employing a treat-to-target protocol of combination DMARDs [92]. DMARD-naïve patients with RA of less than 12 months' duration were randomized to either fish oil at high dose (5.5 g/day) or low dose (0.4 g/day), considered the control. All patients received methotrexate, sulfasalazine, and hydroxychloroquine, with doses adjusted to account for disease activity and toxicity. Reported results included lower failure of triple DMARD therapy and significantly greater remission in the high-dose group compared with the control group, with no differences in dose of methotrexate, health assessment results, or adverse events [92].

NSAIDs can cause an increased cardiovascular risk, and reduced morbidity and mortality among participants in the research groups was also attributable to fish oil supplementation, as atherosclerosis and NSAID use are both reduced with this therapy. Past research was limited to long-standing cases of RA; it is unclear whether fish oil can prevent joint damage in recent-onset RA [91,93]. Though fish oil is most often studied, krill oil (from a small, shrimp-like crustacean) has also shown similarly beneficial results [94]. It should be noted that concerns over bleeding risks (e.g., hemorrhagic stroke) related to a high intake of fish oil have been shown to be unfounded [95]. However, blood thinning is a side effect, and patients should be advised to eat foods rich in vitamin K1 while taking these supplements.

Other HMs and NPs have received attention for the treatment of RA and have been or are currently being studied, including gamma-linolenic acid (from evening primrose, borage, and black currant), thunder god vine extract (used in traditional Chinese medicine), nettle leaf, turmeric, frankincense, ginger, and green tea. However, the results are either inconsistent or inconclusive or the risk profile of the product is of concern [81]. Thunder god vine, in particular, has many negative side effects in large doses [88]. Mind-body therapies, such as tai chi, yoga, meditation, biofeedback, imagery, and relaxation, have shown positive correlations with coping and mood disorders associated with RA, but have no significant, lasting effects on pain and the other physical symptoms of RA [81]. The danger to patients who rely exclusively on CAM for the treatment of recent-onset RA is that the disease will progress unchecked.

In addition to the medical management of RA, several lifestyle changes may improve symptom severity and decrease the number of flare-ups. The National Institute of Arthritis and Musculoskeletal and Skin Disorders recommends advising patients regarding rest and exercise, use of orthotic devices, stress reduction, and healthful diet [4].

RA may cause inflammation of the outer cardiac lining (pericarditis) and cardiac muscle (myocarditis), leading to congestive heart failure. In a population-based cohort study, patients with RA had a significantly higher risk of cardiovascular disease than those without RA [113]. More than half of the patients 50 to 59 years of age and all of those older than 60 years of age with a new diagnosis of RA had a more than 10% increased risk of cardiovascular disease within 10 years of RA onset.

Overall, patients with RA have an estimated 50% increased risk of cardiovascular-related morbidity and mortality. They are less likely to report angina symptoms than those without RA, and they are more likely to experience both unrecognized myocardial infarction and sudden cardiac death [113,114]. This increased risk is closely linked to RA disease severity and chronic inflammation and is largely either over- or underestimated by traditional risk calculators (e.g., Framingham Risk Score) that evaluate traditional cardiovascular risk factors (e.g., hypertension, hyperlipidemia, smoking, diabetes mellitus, physical inactivity), which are highly prevalent among patients with RA [114,115].

Although the risk of coronary artery disease in patients with RA cannot be fully explained by the increased incidence of traditional coronary artery disease risk factors, the impact of traditional risk factors on the risk of cardiovascular disease appears to be different in the RA population than in the non-RA population [116,117]. For example, patients with RA have a higher atherosclerotic burden, with up to a 2.5-fold increase in coronary and aortic calcifications, with the chronic systemic and/or vascular inflammation of RA being an independent cardiovascular disease risk factor [118]. RA has also been associated with increased arterial stiffness and endothelial dysfunction, which may contribute to the development of heart failure by increased myocardial afterload and reduced coronary flow reserve [119,120]. Left ventricular concentric remodeling and systolic and diastolic left ventricular dysfunction also are found in patients with RA [121,122,123]. Patients with RA are more likely to display significantly elevated levels of circulating cardiac biomarkers (e.g., troponins, pro-B-type natriuretic peptides) that are recognized as strong predictors of cardiac diseases, including heart failure [124].

Pulmonary manifestations are also seen in patients with RA, occurring in approximately 30% to 40% of patients. In approximately 10% to 20% of these patients, involvement of the respiratory system is the first manifestation of RA [110]. There are several types of potential pulmonary manifestations of RA: pleural disease, interstitial pneumonitis, and fibrosis. Pleural effusions and pulmonary rheumatoid nodules are the most common manifestations, along with high rheumatoid factor titers [125,126,127]. Pleuritis is more often found in autopsies of patients with RA than in living patients. In about 20% of patients, pleuritis develops concurrently with RA onset [127]. Although pleuritic pain is not usually a major complaint, the effusions may be large enough to cause dyspnea. Pulmonary fibrosis can either be slowly progressive or result from pulmonary inflammatory disease; on physical exam of the lungs, they present with fine, diffuse, dry rales.

Early in the disease, patients with RA may develop pulmonary mononuclear cell infiltrate-associated interstitial lung disease; in later phases of interstitial lung disease, these patients develop pulmonary fibrosis [127,128]. Symptomatic interstitial lung disease occurs in approximately 3% to 14% of patients with RA, whereas detailed pulmonary function testing and autopsy studies have indicated that 35% to 60% of patients with RA have evidence of interstitial lung disease and pulmonary fibrosis [111,129,130]. Risk factors for the development of interstitial lung disease include smoking and disease severity (as measured by a disability assessment), although some studies found no correlation between disease severity and interstitial lung disease in patients with RA [130,131]. Patients with RA who smoke are at a higher risk for fibrotic complications in the lungs than are patients in the general population.

Vasculitis is a term used to group extra-articular complications of RA that are related to inflammatory vascular disease. The initial pathologic change in RA often includes inflammatory changes in medium and small blood vessels. These patients can develop skin ulcerations, infections, or neuropathy affecting the brain, nerves, and heart, consequently causing stroke, myocardial infarction, or heart failure [4,10,14]. Retinal vasculitis, a potentially disabling condition, also has been reported [132]. Systemic rheumatoid vasculitis, one of the most feared complications of RA, has become less prevalent in recent decades. This decline in rheumatoid vasculitis likely relates to the marked improvement in therapy resulting from widespread use of methotrexate and the new biologic agents. The associated neuropathy is of a distal sensory or sensorimotor type. Dermatologic manifestations may include nail-fold infarcts, skin ulcerations, or gangrene [133]. There is a strong association between rheumatoid factor levels and the development of vasculitis in patients with RA, usually caused by intravascular deposition of immune complexes containing rheumatoid factor and immunoglobulin from complement-mediated vascular damage [111,134,135,136].

Ocular involvement is another major manifestation of RA, usually manifesting as scleritis, development of anterior uveitis, and peripheral ulcerative keratitis (corneal melt) [137,138]. These disorders are associated with inflammatory cytokines produced by ocular mononuclear cell infiltrates [138,139]. There appears to be a correlation between RA disease scale and scleritis development [140]. However, unlike many other systemic RA manifestations, ocular involvement may be independent of RA disease activity [141]. Patients with RA can also develop secondary Sjögren syndrome, associated with keratoconjunctivitis sicca (dryness of the conjunctiva and cornea) [142]. There is an association between rheumatoid factor levels and keratoconjunctivitis sicca in patients with RA [143]. Secondary Sjögren syndrome is also associated with salivary and lacrimal gland inflammatory changes with mononuclear cell infiltration [137,142].

Osteopenia and osteoporosis are very common extra-articular complications in patients with RA [144]. The development of osteopenia in patients with RA appears to occur independent of corticosteroid use and is directly linked to elevated levels of the RANK ligand expressed by T cells, which promotes osteoclastic bone resorption [144,145,146]. Osteopenia in RA is directly associated with inflammation markers [146]. The periarticular osteopenia that occurs in patients with RA is likely related to high local levels of IL-1 and TNF-alpha, which are produced in inflamed RA synovium and augment RANK ligand production [147].

Hematologic abnormalities, especially anemia, are present in the majority of patients with RA [148,149]. Anemia of chronic disease is commonly present in patients with RA, and its severity is directly related to high levels of inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6 [148,150,151,152]. Thrombocytosis is another common hematologic finding, correlating with disease activity and inflammation markers [153,154]. High rheumatoid factor and disease activity level (as measured by physical exam and by CRP and ESR levels) is seen with the development of Felty syndrome (defined by the presence of RA, splenomegaly, and neutropenia), large granulocytic leukemia, and non-Hodgkin lymphoma in patients with RA [148,155].

Rheumatoid nodules occur in 20% of patients with RA [156]. Most commonly they are subcutaneously developed in pressure areas (e.g., the elbows and finger joints). In addition, they can occasionally affect internal organs elsewhere in the body, including pleura, lungs, meninges, and larynx [156].

The mature rheumatoid nodule has a central area of necrosis rimmed by a corona of palisading fibroblasts that is surrounded in turn by a collagenous capsule with perivascular collections of chronic inflammatory cells. Careful histologic study suggests that development of the nodule is mediated through affected small arterioles and resulting complement activation and terminal vasculitis [157]. This immunologic response is linked to proliferation of resident histiocytes and fibroblasts and to an influx of macrophages from the circulation [158]. Rheumatoid factor is almost always found in the serum of patients with rheumatoid nodules, which are rarely present in the absence of obvious arthritis [158].

Cervical spine (atlanto-axial) instability may be observed in patients with established RA who have both degeneration of the ligaments and bone in the cervical spine [159]. Transverse ligament degeneration may lead to C1–C2 level instability [4,7,10,14]. As a result of this inherent instability, minor trauma can lead to neurologic sequelae. Thus, patients with RA must be examined carefully after minor falls, motor vehicle accidents, or other injuries. In addition, cervical spine injury may occur spontaneously [4,7,10,14]. Cervical proprioception was found to be impaired in patients with RA and related to the existence of atlanto-axial subluxations and balance problems [160].

The earliest and most common symptom of cervical subluxation is pain radiating up into the occiput [161]. Two other serious, but less common, clinical patterns include slow progressive quadriparesis with sensory loss in the hands and medullary dysfunction associated with vertical penetration of the dens. In addition, paresthesias in the shoulders and arms may occur with head movement [162].

Language and cultural barriers have the potential for far-reaching effect, given the growing percentages of racial/ethnic populations. As noted, patient understanding of the risks and benefits of treatment options is an essential aspect of the care of patients with RA, and it must be assured that all patients have a clear understanding of the concepts discussed. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

According to U.S. Census Bureau data from 2021, more than 13.6% of Americans (45.2 million) are foreign-born, and 8.3% of the population (25.9 million) speak English less than "very well" [169]. Clinicians should ask their patients what language they prefer for their medical care information, as some individuals prefer their native language even though they have said they can understand and discuss symptoms in English [170]. Translation services should be provided for patients who do not understand the clinician's language. "Ad hoc" interpreters (i.e., family members, friends, bilingual staff members,) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, clinicians should check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [171]. Even when allowed by law, the use of a patient's family member or friend as an interpreter should be avoided, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [171]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [171]. Individuals with limited English language skills have actually indicated a preference for professional interpreters rather than family members [172].

Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [173]. A systematic review of the literature showed that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters, and many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [174,175].

Clinicians should use plain language in their discussions with their patients who have low literacy or limited English proficiency. They should ask them to repeat pertinent information in their own words to confirm understanding, and reinforcement with the use of low-literacy or translated educational materials may be helpful.

Although RA is a physical disease, its effects on a patient's life are wide-ranging, affecting mental health, self-esteem, and ability to function socially and occupationally [4]. Many of the issues that arise for these patients are the result of dealing with a chronic, incurable illness. The problems associated with chronic illness will ultimately color the various domains of a patient's life, including physical, psychologic, economic, and social dimensions.