Rheumatoid Arthritis (RA)

The hallmark feature of rheumatoid arthritis (RA) is persistent symmetric polyarthritis (synovitis) that affects the hands and feet, though any joint lined by a synovial membrane may be involved. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can be significant. (See Presentation.)

No laboratory test results are pathognomonic for RA, but the presence of anti-cyclic citrullinated protein antibody (ACPA; often tested as anti-CCP) and rheumatoid factor (RF) is highly specific for this condition. (See Workup.)

Optimal care of patients with RA requires an integrated approach that includes nonpharmacologic therapies and pharmacologic agents such as nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and corticosteroids. (See Treatment, Guidelines, and Medication.)

Early therapy with DMARDs has become the standard of care; it not only can more efficiently retard disease progression than later treatment but also may induce more remissions. (See Treatment and Guidelines.) Many of the newer DMARD therapies, however, are immunosuppressive in nature, leading to a higher risk for infections. (See Treatment/Complications.)

Macrophage activation syndrome is a life-threatening complication of juvenile idiopathic arthritis (JIA) that necessitates immediate treatment with high-dose steroids and cyclosporine. (See Complications.)

The pathogenesis of RA is not completely understood. An external trigger (eg, cigarette smoking, infection, or trauma) that sets off an autoimmune reaction, leading to synovial hypertrophy and chronic joint inflammation along with the potential for extra-articular manifestations, is theorized to occur in genetically susceptible individuals.

The onset of clinically apparent RA is preceded by a period of pre-rheumatoid arthritis (pre-RA). The development of pre-RA and its progression to established RA has been categorized into the following phases[6] :

• Phase I -  Interaction between genetic and environmental risk factors of RA
• Phase II - Production of RA autoantibodies, such as rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP)
• Phase III - Development of arthralgia or joint stiffness without any clinical evidence of arthritis
• Phase IV – Development of arthritis in one or two joints (ie, early undifferentiated arthritis); if intermittent, the arthritis at this stage is termed palindromic rheumatism
• Phase V - Established RA

Not all individuals will progress through the full sequence of phases, and current research is investigating ways to identify patients who are at risk of progression, and to delay or prevent RA in those patients.[7]

Synovial cell hyperplasia and endothelial cell activation are early events in the pathologic process that progresses to uncontrolled inflammation and consequent cartilage and bone destruction. Genetic factors and immune system abnormalities contribute to disease propagation.

CD4 T cells, mononuclear phagocytes, fibroblasts, osteoclasts, and neutrophils play major cellular roles in the pathophysiology of RA, and B cells produce autoantibodies (ie, rheumatoid factors). Abnormal production of numerous cytokines, chemokines, and other inflammatory mediators has been demonstrated in patients with RA, including the following:

• Tumor necrosis factor alpha (TNF-α)
• Interleukin (IL)-1
• IL-6
• IL-8
• Transforming growth factor beta (TGF-ß)
• Fibroblast growth factor (FGF)
• Platelet-derived growth factor (PDGF)

Ultimately, inflammation and exuberant proliferation of the synovium (ie, pannus) leads to destruction of various tissues, including cartilage (see the image below), bone, tendons, ligaments, and blood vessels. Although the articular structures are the primary sites involved by RA, other tissues are also affected.

The cause of RA is unknown. Genetic, environmental, hormonal, immunologic, and infectious factors may play significant roles. Socioeconomic, psychological, and lifestyle factors may influence disease development and outcome.

Genetic factors

Genetic factors account for 50% of the risk for developing RA.[8] About 60% of RA patients in the United States carry a shared epitope of the human leukocyte antigen (HLA)-DR4 cluster, which constitutes one of the peptide-binding sites of certain HLA-DR molecules associated with RA (eg, HLA-DR beta *0401, 0404, or 0405). HLA-DR1 (HLA-DR beta *0101) also carries this shared epitope and confers risk, particularly in certain southern European areas. Other HLA-DR4 molecules (eg, HLA-DR beta *0402) lack this epitope and do not confer this risk.

Genes other than those of the major histocompatibility complex (MHC) are also involved. Results from sequencing genes of families with RA suggest the presence of several resistance and susceptibility genes, including PTPN22 and TRAF5.[9, 10] Researchers have identified more than 150 candidate loci with polymorphisms associated with RA, mainly related to seropositive disease.[11]

Juvenile idiopathic arthritis (JIA), also known as juvenile rheumatoid arthritis (JRA), is a heterogeneous group of diseases that differs markedly from adult RA. JIA is known to have genetically complex traits in which multiple genes are important for disease onset and manifestations, and it is characterized by arthritis that begins before the age of 16 years, persists for more than 6 weeks, and is of unknown origin.[12] The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene.[13]

Some investigators suggest that the future of treatment and understanding of RA may be based on imprinting and epigenetics. RA is significantly more prevalent in women than in men,[14, 15] which suggests that genomic imprinting from parents participates in its expression.[16, 17] Imprinting is characterized by differential methylation of chromosomes by the parent of origin, resulting in differential expression of maternal over paternal genes.[18]

Epigenetics is the change in DNA expression that is due to environmentally induced methylation and not to a change in DNA structure. Clearly, one research focus will be on environmental factors in combination with immune genetics.[11]

Infectious agents

For many decades, numerous infectious agents have been suggested as potential causes of RA, including Mycoplasma organisms, Epstein-Barr virus (EBV),[19] and rubella virus. This suggestion is indirectly supported by the following evidence:

• Occasional reports of flulike disorders preceding the start of arthritis
• The inducibility of arthritis in experimental animals with different bacteria or bacterial products (eg, streptococcal cell walls)
• The presence of bacterial products, including bacterial RNA, in patients’ joints
• The disease-modifying activity of several agents that have antimicrobial effects (eg, gold salts, antimalarial agents, minocycline)

Emerging evidence also points to an association between RA and periodontopathic bacteria. For example, the synovial fluid of RA patients has been found to contain high levels of antibodies to anaerobic bacteria that commonly cause periodontal infection, including Porphyromonas gingivalis.[20, 21]

Hormonal factors

Sex hormones may play a role in RA, as evidenced by the disproportionate number of females with this disease, its amelioration during pregnancy, its recurrence in the early postpartum period, and its reduced incidence in women using oral contraceptives. Hyperprolactinemia may be a risk factor for RA.[22]

Lifestyle and occupational factors

Tobacco use is the main lifestyle risk factor for RA.[23] Genetic factors can further increase risk: a smoker with two copies of HLA-SE is at 40-fold higher risk of developing RA. In former smokers, risk may not return to the level of non-smokers for up to 20 years after smoking cessation.[6]

Dietary risk factors for RA include the following[6] :

• Red meat intake
• Vitamin D deficiency
• Excessive coffee consumption
• High salt intake

A review of data from the Nurses' Health Study, which assessed 5 lifestyle factors (smoking, alcohol consumption, body mass index, physical activity, and diet), found that a healthier lifestyle was associated with lower risk of RA. The population attributable risk estimate was that 34% of incident RA was preventable if participants adopted ≥4 healthy lifestyle factors.[24]

Occupational risk

Schmajuk et al reported a strong association between coal mining, and other dusty trades involving silica exposure, with RA. For those in the highest-intensity ergonomic exposure group, the odds ratio for RA was 4.3.[25]

Immunologic factors

All of the major immunologic elements play fundamental roles in initiating, propagating, and maintaining the autoimmune process of RA. The exact orchestration of the cellular and cytokine events that lead to pathologic consequences (eg, synovial proliferation and subsequent joint destruction) is complex, involving T and B cells, antigen-presenting cells (eg, B cells, macrophages, and dendritic cells), and various cytokines. Aberrant production and regulation of both proinflammatory and anti-inflammatory cytokines and cytokine pathways are found in RA.

T cells are assumed to play a pivotal role in the initiation of RA, and the key player in this respect is assumed to be the T helper 1 (Th1) CD4 cells. (Th1 cells produce IL-2 and interferon [IFN] gamma.) These cells may subsequently activate macrophages and other cell populations, including synovial fibroblasts. Macrophages and synovial fibroblasts are the main producers of TNF-a and IL-1. Experimental models suggest that synovial macrophages and fibroblasts may become autonomous and thus lose responsiveness to T-cell activities in the course of RA.

B cells are important in the pathologic process and may serve as antigen-presenting cells. B cells also produce numerous autoantibodies (eg, RF and ACPA) and secrete cytokines.

The hyperactive and hyperplastic synovial membrane is ultimately transformed into pannus tissue and invades cartilage and bone, with the latter being degraded by activated osteoclasts. The major difference between RA and other forms of inflammatory arthritis, such as psoriatic arthritis, lies not in their respective cytokine patterns but, rather, in the highly destructive potential of the RA synovial membrane and in the local and systemic autoimmunity.

Whether these 2 events are linked is unclear; however, the autoimmune response conceivably leads to the formation of immune complexes that activate the inflammatory process to a much higher degree than normal. This theory is supported by the much worse prognosis of RA among patients with positive RF results.

Worldwide, the annual incidence of RA is approximately 3 cases per 10,000 population, and the prevalence rate is approximately 1%, increasing with age and peaking between the ages of 35 and 50 years. RA affects all populations, though it is much more prevalent in some groups (eg, 5-6% in some Native American groups) and much less prevalent in others (eg, Black persons from the Caribbean region).

First-degree relatives of individuals with RA are at 2- to 3-fold higher risk for the disease. Disease concordance in monozygotic twins is approximately 15-20%, suggesting that nongenetic factors play an important role. Because the worldwide frequency of RA is relatively constant, a ubiquitous infectious agent has been postulated to play an etiologic role.

Women are affected by RA approximately 3 times more often than men are.[14, 15] For example, a nationwide study from Norway reported that the point prevalence of RAl was 1.10% in women and 0.46% in men.[26] However, sex differences in RA diminish in older age groups.[14] In investigating whether the higher rate of RA among women could be linked to certain reproductive risk factors, a study from Denmark found that the rate of RA was higher in women who had given birth to just 1 child than in women who had delivered 2 or 3 offspring.[27] However, the rate was not increased in women who were nulliparous or who had a history of lost pregnancies.

Time elapsed since pregnancy is also significant. In the 1- to 5-year postpartum period, a decreased risk for RA has been recognized, even in those with higher-risk HLA markers.[28]

The Danish study also found a higher risk of RA among women with a history of preeclampsia, hyperemesis during pregnancy, or gestational hypertension.[27] In the authors’ view, this portion of the data suggested that a reduced immune adaptability to pregnancy may exist in women who are predisposed to the development of RA or that there may be a link between fetal microchimerism (in which fetal cells are present in the maternal circulation) and RA.[27]

The clinical course of RA is generally one of exacerbations and remissions. Approximately 40% of patients with this disease become disabled after 10 years, but outcomes are highly variable.[29] Some patients experience a relatively self-limited disease, whereas others have a chronic progressive illness.

Prognostic factors

Outcome in RA is compromised when diagnosis and treatment are delayed. Intervention with DMARDs in very early RA (symptom duration < 12 weeks at the time of first treatment) provides the best opportunity for achieving disease remission.[30] Better detection of early joint injury has provided a previously unappreciated view of the ubiquity and importance of early joint damage. Nonetheless, predicting the long-term course of an individual case of RA at the outset remains difficult, though the following all correlate with an unfavorable prognosis in terms of joint damage and disability:

• HLA-DRB1*04/04 genotype
• High serum titer of autoantibodies (eg, RF and ACPA)
• Extra-articular manifestations
• Large number of involved joints
• Age younger than 30 years
• Female sex
• Systemic symptoms
• Insidious onset

In a retrospective study that used logistic regression to analyze clinical and laboratory assessments in patients with RA who took only methotrexate, the authors found that measures of C-reactive protein (CRP) and swollen joint count after 12 weeks of methotrexate administration were most associated with radiographic progression at week 52.[31]

The prognosis of RA is generally much worse among patients with positive RF results. For example, the presence of RF in sera has been associated with severe erosive disease.[32, 33] However, the absence of RF does not necessarily portend a good prognosis.

Other laboratory markers of a poor prognosis include early radiologic evidence of bony injury, persistent anemia of chronic disease, elevated levels of the C1q component of complement, and the presence of ACPA (see Workup). In fact, the presence of ACPA and antikeratin antibodies (AKA) in sera has been linked with severe erosive disease,[32] and the combined detection of these autoantibodies can increase the ability to predict erosive disease in RA patients.[33]

RA that remains persistently active for longer than 1 year is likely to lead to joint deformities and disability.[34] Periods of activity lasting only weeks or a few months followed by spontaneous remission portend a better prognosis.

A study by Mollard et al of 8189 women in a US-wide observational cohort who developed RA before menopause found greater functional decline in postmenopausal women than in premenopausal ones; furthermore, the trajectory of functional decline worsened and accelerated after menopause.  However, ever-use of hormonal replacement therapy, ever having a pregnancy, and longer length of reproductive life were associated with less functional decline.[35]

Morbidity and mortality

Most data on RA disability rates derive from specialty units caring for referred patients with severe disease. Little information is available on patients cared for in primary care community settings. Estimates suggest that more than 50% of these patients remain fully employed, even after 10-15 years of disease, with one third having only intermittent low-grade disease and another one third experiencing spontaneous remission.

A systematic review and meta-analysis concluded that the relative risk of cardiovascular events in patients with RA was 1.55.[36] RA is associated with traditional and nontraditional cardiovascular risk factors. The leading cause of excess mortality in RA is cardiovascular disease, followed by infection, respiratory disease, and malignancies. The effects of concurrent therapy, which is often immunosuppressive, may contribute to mortality in RA. However, studies suggest that control of inflammation may improve survival.

Nontraditional risk factors appear to play an important role in cardiovascular morbidity and mortality. Myocardial infarction, myocardial dysfunction, and asymptomatic pericardial effusions are common; symptomatic pericarditis and constrictive pericarditis are rare. Myocarditis, coronary vasculitis, valvular disease, and conduction defects are occasionally observed. A large Danish cohort study suggested an increased risk of atrial fibrillation and stroke in patients with RA.[37]

Patients with RA are at significantly elevated risk for lymphoma, likely due to chronic inflammatory stimulation of the immune system.[38] A study using National Health and Nutrition Examination Survey (NHANES) data documented an increased risk for cancer in general in patients with RA. with an odds ratio of 1.632.[39] In contrast, an earlier study of 84,475 RA patients in California concluded that females were at significantly decreased risk for several cancers, including breast, ovary, uterus, cervix, and melanoma, while males had significantly higher risks of lung, liver, and esophageal cancer, but a lower risk of prostate cancer.[40]

The overall mortality in patients with RA is reportedly 2.5 times higher than that of the general age-matched population. In the 1980s, mortality among those with severe articular and extra-articular disease approached that among patients with 3-vessel coronary disease or stage IV Hodgkin lymphoma. Much of the excess mortality derives from infection, vasculitis, and poor nutrition.

Patient education and counseling help to reduce pain and disability and the frequency of physician visits. These may represent the most cost-effective intervention for RA.[41, 42]

Informing patient of diagnosis

With a potentially disabling disease such as RA, the act of informing the patient of the diagnosis takes on major importance. The goal is to satisfy the patient’s informational needs regarding the diagnosis, prognosis, and treatment in appropriate detail. To understand the patient’s perspective, requests, and fears, the physician must employ careful questioning and empathic listening.

Telling patients more than they are intellectually or psychologically prepared to handle (a common mistake) risks making the experience so intense as to trigger withdrawal. Conversely, failing to address issues of importance to the patient compromises the development of trust. The patient needs to know that the primary physician understands the situation and is available for support, advice, and therapy as the need arises. Encouraging the patient to ask questions helps to communicate interest and caring.

Discussing prognosis and treatment

Patients and families do best when they know what to expect and can view the illness realistically. Many patients fear crippling consequences and dependency. Accordingly, it is valuable to provide a clear description of the most common disease manifestations. Without encouraging false hopes, the physician can point out that spontaneous remissions can occur, a sizeable portion of patients achieve remission with therapy, and more than two thirds of patients live independently without major disability. In addition, emphasize that much can be done to minimize discomfort and to preserve function.

A review of available therapies and their efficacy helps patients to overcome feelings of depression stemming from an erroneous expectation of inevitable disability.[43] Even in those with severe disease, guarded optimism is now appropriate, given the host of effective and well-tolerated disease-modifying treatments that have become available.

Dealing with misconceptions

Several common misconceptions regarding RA deserve attention. Explaining that no known controllable precipitants exist helps to eliminate much unnecessary guilt and self-recrimination. Dealing in an informative, evidence-based fashion with a patient who expresses interest in alternative and complementary forms of therapy can help limit expenditures on ineffective treatments.

Another misconception is that a medication must be expensive to be helpful. Generic NSAIDs, low-dose prednisone,[29] and the first-line DMARDs are quite inexpensive yet remarkably effective for relieving symptoms, a point that bears emphasizing. The belief that one must be given the latest TNF inhibitor to be treated effectively can be addressed by a careful review of the overall treatment program and the proper role of such agents in the patient’s plan of care.

Active participation of the patient and family in the design and implementation of the therapeutic program helps boost morale and to ensure compliance, as does explaining the rationale for the therapies used.

The family also plays an important part in striking the proper balance between dependence and independence. Household members should avoid overprotecting the patient (eg, the spouse refraining from intercourse out of fear of hurting the patient) and should work to sustain the patient’s pride and ability to contribute to the family. Allowing the patient with RA to struggle with a task is sometimes constructive.

Supporting patient with debilitating disease

Abandonment is a major fear in these individuals. Patients are relieved to know that they will be closely observed by the primary physician and healthcare team, working in conjunction with a consulting rheumatologist and physical/occupational therapist, all of whom are committed to maximizing the patient’s comfort and independence and to preserving joint function. With occupational therapy, the treatment effort is geared toward helping the patient maintain a meaningful work role within the limitations of the illness.

Persons with long-standing severe disease who have already sustained much irreversible joint destruction benefit from an emphasis on comfort measures, supportive counseling, and attention to minimizing further debility. Such patients need help in grieving for their disfigurement and loss of function.

An accepting, unhurried, empathic manner allows the patient to express feelings. The seemingly insignificant act of touching does much to restore a sense of self-acceptance. Attending to pain with increased social support, medication, and a refocusing of attention to function is useful. A trusting and strong patient-doctor relationship can do much to sustain a patient through times of discomfort and disability.

For more information, see the Arthritis Center, as well as Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, and Rheumatoid Arthritis Medications.

The hallmark feature of rheumatoid arthritis (RA) is persistent symmetric polyarthritis (synovitis) that affects the hands and feet, although any joint lined by a synovial membrane may be involved. The severity of RA may fluctuate over time, but chronic RA most commonly results in the progressive development of various degrees of joint destruction, deformity, and a significant decline in functional status. Extra-articular involvement of organs such as the skin, heart, lungs, and eyes can also be significant.

Juvenile idiopathic arthritis (JIA), sometimes referred to as juvenile rheumatoid arthritis (JRA), is the most common form of childhood arthritis. In most patients, the immunogenic associations, clinical pattern, and functional outcome of JIA are different from those of adult-onset RA.

Patients with RA may report difficulty performing activities of daily living (ADLs), such as dressing, standing, walking, personal hygiene, or use of their hands. In addition to articular deterioration, constitutional symptoms (eg, fatigue, malaise, morning stiffness, weight loss, and low-grade fever) may be present.

In most patients, RA has an insidious onset. It may begin with systemic features (eg, fever, malaise, arthralgias, and weakness) before the appearance of overt joint inflammation and swelling. A small percentage (approximately 10%) of patients have an abrupt onset with the acute development of synovitis and extra-articular manifestations. Spontaneous remission may occur but is uncommon, especially after the first 3-6 months.

During the physical examination, it is important to assess for the following:

• Stiffness
• Tenderness
• Pain on motion
• Swelling
• Deformity
• Limitation of motion
• Extra-articular manifestations
• Rheumatoid nodules

Joint involvement is the characteristic feature of RA. In general, the small joints of the hands and feet are affected in a relatively symmetric distribution. In decreasing frequency, the metacarpophalangeal (MCP), wrist, proximal interphalangeal (PIP), knee, metatarsophalangeal (MTP), shoulder, ankle, cervical spine, hip, elbow, and temporomandibular joints are most commonly affected.

Affected joints show inflammation with swelling, tenderness, warmth, and decreased range of motion (ROM). Atrophy of the interosseous muscles of the hands is a typical early finding. Joint and tendon destruction may lead to deformities such as ulnar deviation, boutonniere and swan-neck deformities, hammer toes, and, occasionally, joint ankylosis.

Other commonly observed musculoskeletal manifestations include the following:

• Tenosynovitis (defined as inflammation of the tendon and its enveloping tendon sheath) and associated tendon rupture due to tendon and ligament involvement, most commonly involving the fourth and fifth digital extensor tendons at the wrist

• Periarticular osteoporosis due to localized inflammation

• Generalized osteoporosis due to systemic chronic inflammation, immobility, or corticosteroid therapy

• Carpal tunnel syndrome

Most patients with RA have muscle atrophy from disuse, which is often secondary to joint inflammation.

Examination of upper extremities

Fingers

The boutonniere deformity (see the image below) describes nonreducible flexion at the PIP joint along with hyperextension of the distal interphalangeal (DIP) joint of the finger.

This deformity occurs as a result of synovitis stretching or rupturing the PIP joint through the central extensor tendon, with concomitant volar displacement of the lateral bands. When the lateral bands have subluxed far enough to pass the transverse axis of the joint, they become flexors of the PIP joint. Hyperextension of the DIP joint occurs as the tendons shorten with time. A compensatory and reducible hyperextension may occur at the MCP joint. Consequences of boutonniere deformity are loss of thumb mobility and pincher grasp.

Swan-neck deformity of the finger describes hyperextension at the PIP joint with flexion of the DIP joint (see the image below).

This deformity may be initiated either (a) by disruption of the extensor tendon at the DIP joint, with secondary shortening of the central extensor tendon and hyperextension of the PIP joint, or (b) by volar herniation of the PIP joint capsule due to weakening from chronic synovitis, with subsequent tightening of the lateral bands and central extensor tendon. The lateral bands may become shortened over time and lie dorsally, limiting PIP flexion and ineffectively extending the DIP joint.

Tightness of intrinsic muscles (eg, the interossei and lumbricals) may cause major declines in finger mobility. This tightness is ascertained on examination when the PIP joint cannot be flexed while the MCP joint is fully extended but can be flexed while the MCP is in flexion (Bunnell test); primary PIP joint pathology is evident with the MCP joint in either position. For accurate assessment, the phalanx must be aligned with the metacarpal; when ulnar deviation at the MCP joint exists, the intrinsic muscles on the ulnar side are slack, allowing more motion.

Flexor tenosynovitis of the fingers is common and suggests a poor prognosis. “Triggering” of the finger occurs when thickening or nodule formation of the tendon interacts with the concomitant tenosynovial proliferation, trapping the tendon in a flexed position (stenosing tenosynovitis). Tendon rupture may occur as a consequence of infiltrative synovitis in the digit or bony erosion of the tendon at the wrist (especially the flexor pollicis longus). See Trigger Finger.

Arthritis mutilans (sometimes called opera glass hands) results if destruction is severe and extensive, with dissolution of bone. In the small joints of the hands, the phalanges may shorten, and the joints may become grossly unstable. Pulling on the fingers during examination may lengthen the digit in a manner resembling the opening of opera glasses, or the joint may bend in unusual directions merely under the pull of gravity.

Metacarpophalangeal joints

Two typical deformities that alter the alignment of the palmar skeletal arches and the stability of the fingers may occur at the MCP joints: volar subluxation and ulnar deviation (see the image below).

Most cases of ulnar deviation are accompanied by counterpoised radial deviation of the wrist, roughly proportional to the degree of ulnar deviation of the fingers. The volar plate is firmer and more substantial than other portions of the MCP joint capsule, thus effectively limiting extension and dorsal movement at the joint. The greater strength of the flexor muscles relative to the extensor muscles causes volar migration of the proximal phalanx after synovial-based inflammation has weakened ligament and tendon insertions about the MCP joint capsule.

Ulnar deviation occurs after synovitis has led to stretching and attenuation of the volar plate and collateral ligaments, allowing dislocation of the flexor tendon volarward and ulnarward. The supporting structures of the extensor tendons also may become attenuated or destroyed by synovial distention and invasion, loosening the tendons so that they no longer ride centrally and dorsally over the metacarpal head but move into the cleft between the MCP joints.

If the extensor tendon subluxation is beyond the transverse axis of the MCP joint, the tendon becomes a flexor at that joint, further limiting the active extension of the fingers.

Wrists

Multiple deformities may occur in the wrist. Disruption of the radioulnar joint with dorsal subluxation of the ulna (caput ulnae) as well as rotation of the carpus on the distal radius with an ulnarly translocated lunate are common. The combination of an ulnar drift of the fingers and carpal rotation is known as a zigzag deformity. Shortening of the carpal height (noted on radiographs), due in part to cartilage loss, is seen with rotational deformities.

Dorsal subluxation of the ulna often allows the ulnar styloid to be depressed volarly on examination, much as a piano key is depressed when played. It may lead to rupture of the extensor tendons of the little, ring, and long fingers because the end of the distal ulna is roughened secondary to erosion of bone and may abrade the tendons as they move during normal hand function, much as a rope is frayed when rubbed over a sharp rock (see the image below). This process is especially likely to lead to tendon rupture if tenosynovitis is present.

Entrapment neuropathy may result from synovitis about the flexor tendons. Entrapment of the median nerve as it passes through the carpal tunnel leads to decreased sensation on the palmar aspect of the thumb, index finger, and long finger and on the radial aspect of the ring finger; weakness and atrophy of the muscles in the thenar eminence also occurs. Entrapment of the ulnar nerve at the wrist, a less frequent event, causes decreased sensation over the little finger and the ulnar aspect of the ring finger and decreased interosseous muscle strength and mass.

Elbow

Elbow involvement is often detected by palpable synovial proliferation at the radiohumeral joint and is commonly accompanied by a flexion deformity, such as in contractures. Involvement of the olecranon bursa is common, as are rheumatoid nodules in the bursa and along the extensor surface of the ulna (see the image below).

Shoulders

RA commonly involves the shoulders and is manifested by tenderness, nocturnal pain, and limited motion. Initially, swelling occurs anteriorly, but it may be difficult to detect and is present on examination in only a minority of patients at any point in time.

Rotator cuff degeneration secondary to synovitis may limit abduction and rotation. Superolateral migration of the humerus occurs with complete tears. Glenohumeral damage results in pain with motion and at rest and typically leads to severely restricted motion or “frozen shoulder syndrome.” Acromioclavicular arthritis is not as frequent or as disabling as the other manifestations of this disease.

Examination of lower extremities

Ankles and feet

The ankle joint itself is rarely involved without midfoot or MTP involvement. Because it is a mortise joint, it does not often deform. Major structural changes occur in the midfoot and foot as a result of the combination of chronic synovitis and weight bearing. Posterior tibialis tendon involvement or rupture may lead to subtalar subluxation, which results in eversion and migration of the talus laterally. Midfoot disease leads to loss of normal arch contour with flattening of the feet.

The MTP joints are inflamed in most patients and, because of the heavy loads they bear, often become deformed over time. The great toe typically develops hallux valgus (a bunion); subluxation of the phalanx at the MTP joint of the other toes predominantly occurs dorsally. Toes may exhibit compensatory flexion due to a fixed length of the flexor tendons—so-called hammer toes. The second and third metatarsal heads commonly protrude and may become the primary weight-bearing surface at the MTP joints. Calluses and pain upon weight bearing result.

Knees

Affected knees may develop large effusions and abundant accumulation of synovium. Knee effusions and synovial thickening are common in RA and are easily detected during the early course of the disease. Persistent effusions may lead to inhibition of quadriceps function by spinal reflexes, resulting in subsequent atrophy.

Instability may develop after progressive loss of cartilage and weakening of ligaments; deformity may include genu valgus or varus, as well as flexion deformities. The patient’s energy expenditure for standing or walking increases substantially if there are flexion deformities of the knees.

Hips

The hips are commonly involved in RA; however, because of their deep location, their involvement is not always readily apparent early in the course of the disease. Hips are difficult to examine by means of direct inspection or palpation.

Limited motion or pain on motion and weight bearing are the hallmarks of hip involvement. The Patrick maneuver (flexion, external rotation, and abduction) is abnormal in this situation. A flexion deformity may be demonstrable by conducting a Thomas test, which is performed by flexing one hip (with the patient supine) while restricting pelvic motion by keeping the other hip in the neutral position on the examination table. If the hip cannot be maintained in the neutral position, a contracture is present.

Cervical spine

Cervical spine involvement (see the following image) usually affects C1-C2 and has the potential to cause serious neurologic consequences. Patients who are to undergo intubation or procedures that may involve manipulation of the neck should undergo careful evaluation of the cervical spine.

Neck pain on motion and occipital headache are common manifestations of cervical spine involvement. Most patients with cervical spine involvement (see the image below) have had the disease for more than 10 years.

Clinical manifestations of early cervical spine disease consist primarily of neck stiffness that is perceived throughout the entire arc of motion. The atlantoaxial joint is a synovial-lined joint and is susceptible to the same proliferative synovitis and subsequent instability seen in the peripheral joints. Patients with severe destruction in the hands (arthritis mutilans) are very likely to have symptomatic cervical spine abnormalities, as are those patients taking significant amounts of corticosteroids for control of RA.

Neurologic involvement in the cervical spine ranges from radicular pain to a variety of spinal cord lesions that may result in weakness (including quadriparesis), sphincter dysfunction, sensory deficits, and pathologic reflexes.

Transient ischemic attacks (TIAs) and cerebellar signs may reflect vertebral artery impingement from cervical subluxation or basilar artery impingement from upward migration of the dens. Tenosynovitis of the transverse ligament of C1 may lead to C1-C2 instability. Myelopathy secondary to rupture of the transverse ligament may lead to neurologic deficits. Radiculopathy is most common at the C2 root, though symptomatic subluxations may occur at any level.

Symptoms of cervical myelopathy are gradual in onset and are often unrelated to either the development or the accentuation of neck pain. When neck pain does occur, it frequently radiates over the occipital region in the distribution of the C1-3 nerve roots. The Lhermitte sign, in which tingling paresthesia that descends through the thoracolumbar spine occurs as the cervical spine is flexed, is typically observed.

For more information, see Rheumatoid Arthritis of the Cervical Spine.

On physical examination, stiffness in patients with RA is determined by limitation of motion, which may vary with the time of day. However, stiffness that is due to articular surface derangement or soft tissue contractures about the joint does not vary with the time of day.

Severe stiffness in the hands may improve with heat, but it is most effectively relieved with active exercise. These modalities reduce stiffness immediately after application, but unfortunately, they do not prevent the return of stiffness.

Direct palpation can elicit joint tenderness, which can vary significantly among patients and with the method of application of force used. To minimize variation over time, the examiner should try to apply approximately the same pressure for each patient examined.

The enlarged synovial membrane, periarticular ligaments, and supporting structures are the major pain-sensitive structures. Muscles may also become tender, but rarely is this due to myositis. Muscle tenderness is not specific for RA. Severe muscle tenderness should suggest another differential diagnosis, including fibromyalgia or a regional pain disorder (see DDx). Bony prominences are generally tender; periarticular structures tend to be more vulnerable to palpation at these sites.

Pain on motion is often used as a surrogate for tenderness in joints that are not readily amenable to direct palpation because of overlying muscle and other tissues. Such areas include the cervical spine, shoulder, and hip.

Pain on motion of the joint may be due to noninflammatory processes that also interfere with the joint’s normal, almost frictionless motion, including damage of cartilage and bone. Additionally, joint instability or subluxation causes pain on motion because of musculotendinous imbalances across the joint. Documenting the positions of motion at which pain occurs can be useful.

In RA, enlargement of the synovial membrane is noted on physical examination as thickening of the synovium that may obscure joint margins. This thickening is most evident in the small joints of the hands and feet. In the MCP and MTP joints, the outline of the base of the proximal phalanx may become indistinct, and in the PIP joints of the fingers, a fusiform swelling is noted that is due to the anatomy of the synovial reflections (see the image below).

If synovial proliferation is abundant, the resultant soft-tissue mass may have a doughy texture on palpation. Such synovial proliferation is commonly identified in the PIP, MCP, elbow, ankle, MTP, and knee joints, as well as in the flexor tendons of the fingers, the common extensor compartment of the dorsal wrist, and the extensor carpi ulnaris tendon sheath.

Joint effusions may also contribute to swelling by distending the joint. When the effusion is put under increased pressure with joint flexion, the synovium may be forced between articular structures, with the result that a portion becomes trapped and separated from the rest of the joint, forming a Baker cyst (see the image below). More fluid is forced into the structure with subsequent loading of the distended joint, and a 1-way valve effect may prevent the fluid from returning to the joint.

Baker cysts may be seen in most peripheral joints and are most commonly recognized in the knee.[44] The larger the effusion, the more likely it is that a painful cyst will develop in the popliteal fossa. Rupture of a Baker cyst at the knee may resemble acute thrombophlebitis, with distal dissection of inflammatory joint contents along fascial planes as far as the ankle and dorsal foot.

Deformity of the joint may develop over time as articular and supporting structures are damaged by the inflammatory process. By the time deformity has developed, the diagnosis of RA is in little doubt; however, optimal management of RA requires that the inflammatory aspects of the arthritis be recognized before the development of deformity.

Loss of cartilage from proteolytic and mechanical degradation, combined with stretching and weakening of the periarticular ligaments and their attachments, allows forces acting across the joints to deform them. The small joints in the hands and feet are most commonly deformed in this manner; more than 10% of patients with RA develop deformity of the small joints of the hands within the first 2 years of the disease, and at least 33% develop such deformities over time. Joint instability is seen if disruption of supporting structures has occurred.

Limitation of motion occurs as a result of articular surface damage, joint and tendon sheath swelling, or alteration of joint supporting structures. Effusion may limit joint motion through pain or by causing sufficient tightness of the joint capsule to impede joint mobility. Fibrosis involving tendons and muscles may limit normal joint motion and result in flexion contractures. Joint deformities and subluxations invariably limit motion because of mechanical factors.

RA is a systemic disease, and most individuals with this condition experience extra-articular manifestations such as generalized malaise and fatigue. Rarely, a patient presents with extra-articular manifestations before the onset of arthritis. Some of these manifestations are more common in men (eg, pleural involvement, vasculitis, and pericarditis), but overall, the sex distribution of extra-articular manifestations of the disease is similar to that of RA.

Rheumatoid nodules

Rheumatoid nodules occur in approximately 25% of patients with RA, but in fewer than 10% of patients during the first year of the disease. These lesions are most commonly found on extensor surfaces or sites of frequent mechanical irritation.

The olecranon process, the proximal ulna, the back of the heel, the occiput, and the ischial tuberosities are common periosteal sites for rheumatoid nodule development. Nodules may also form in subcutaneous tissues of the fingers, in toe and heel pads, in tendons, and in viscera. Rheumatoid factor (RF) is almost invariably present in patients with rheumatoid nodules; the absence of RF suggests other diagnoses.

Frequently, there is a discrepancy between the level of articular inflammation and the progression of nodule formation. Patients with rheumatoid nodulosis have a great number of nodules, usually subcutaneous, and may have little active synovitis. In a similar fashion, patients whose articular inflammation responds well to treatment with methotrexate may have a seemingly paradoxical rapid increase in the number of nodules.

Effects on organ systems

RA affects several organ systems, as follows:

• Cutaneous
• Cardiac
• Pulmonary
• Renal
• Gastrointestinal (GI)
• Vascular
• Hematologic
• Neurologic
• Ocular

Subcutaneous nodules (rheumatoid nodules) develop in many RA patients whose RF value is abnormal, often over pressure points (eg, olecranon). Vasculitic lesions of the skin may manifest as palpable purpura or skin ulceration (eg, leg ulceration). Additionally, palmar erythema and pyoderma gangrenosum may be noted.

Cardiovascular morbidity and mortality are increased in patients with RA. Nontraditional risk factors appear to play an important role. Myocardial infarction, myocardial dysfunction, and asymptomatic pericardial effusions are common; symptomatic pericarditis and constrictive pericarditis are rare. Myocarditis, coronary vasculitis, valvular disease, and conduction defects are occasionally observed.

RA involvement of the lungs may take several forms, including pleural effusions, interstitial fibrosis, nodules, and bronchiolitis obliterans organizing pneumonia. Methotrexate therapy can induce interstitial fibrosis that may be difficult to distinguish from that which naturally occurs in patients with RA.

The kidneys usually are not directly affected by RA. Secondary involvement is common, including that due to medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], gold, and cyclosporine), inflammation (eg, amyloidosis), and associated diseases (eg, Sjögren syndrome with renal tubular abnormalities).

GI involvement, like kidney involvement, is often secondary to associated processes such as medication effects, inflammation, and other diseases. The liver may be affected in patients with Felty syndrome (ie, RA, splenomegaly, and neutropenia).

Vasculitic lesions can occur in any organ, but they are most commonly found in the skin. Lesions may present as palpable purpura, skin ulcers, or digital infarcts.

Some patients with active RA have an anemia of chronic disease. Several hematologic parameters parallel disease activity, including normochromic-normocytic anemia, thrombocytosis, and eosinophilia, though the last of these is uncommon. Leukopenia is a finding in patients with Felty syndrome.

Nerve entrapment is common, as with the median nerve in carpal tunnel syndrome. Vasculitic lesions, mononeuritis multiplex, and cervical myelopathy may cause serious neurologic consequences. Peripheral myopathy may be noted as well.

Keratoconjunctivitis sicca is common in individuals with RA, and this condition is often the initial manifestation of secondary Sjögren syndrome. The eye may also have episcleritis, uveitis, and nodular scleritis that may lead to scleromalacia.

RA itself is not fatal, but complications of the disease may shorten survival by years in some individuals. In general, RA is progressive and cannot be cured, but in some patients, the disease gradually becomes less aggressive, and symptoms may even improve. However, if bone and ligament destruction and any deformities have occurred, the effects are permanent.

Joint disability and pain with daily life are common. Affected joints can become deformed, and the performance of even ordinary tasks may be very difficult or impossible; these factors can severely affect patients’ quality of life. In addition, RA is a systemic disease that can affect other parts of the body in addition to joints. These effects include the following:

• Anemia

• Infections – Patients with RA are at greater risk for infections; immunosuppressive drugs further increase that risk

• GI problems – Patients with RA may experience stomach and intestinal distress; however, lower rates of stomach and colorectal cancers have been reported in RA patients

• Osteoporosis – This condition is more common than average in postmenopausal women with RA; the hip is particularly affected; the risk of osteoporosis appears to be higher than average in men with RA who are older than 60 years

• Lung disease – A small study found a high prevalence of pulmonary inflammation and fibrosis in patients with newly diagnosed RA, but this finding may be associated with smoking

• Heart disease – RA can affect blood vessels and increase the risk of coronary ischemic heart disease

• Sjögren syndrome – Keratoconjunctivitis sicca is a common complication of RA; oral sicca and salivary gland enlargement are less common

• Felty syndrome – This condition is characterized by splenomegaly, leukopenia, and recurrent bacterial infections; it may respond to disease-modifying antirheumatic drugs (DMARDs)

• Lymphoma and other cancers – RA-associated immune system alterations may play a role; aggressive treatments for RA may help prevent such cancers

No test results are pathognomonic for rheumatoid arthritis (RA); instead, the diagnosis is made by using a combination of clinical, laboratory, and imaging features. Criteria for diagnosis have been established by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR; now the European Alliance of Associations for Rheumatology),[45] Multiple measures have been developed for assesssing disease activity in RA, using patient report, clinician assessment, and/or laboratory findings. These measures can facilitate a treat-to-target approach. The ACR has published assessments and ratings of these measures; see Guidelines.[2]

Potentially useful laboratory studies in suspected RA fall into 3 categories—markers of inflammation, hematologic parameters, and immunologic parameters—and include the following:

• Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP) level
• Complete blood count (CBC)
• Rheumatoid factor (RF) assay
• Antinuclear antibody (ANA) assay
• Anti−cyclic citrullinated peptide (anti-CCP) antibody

The ESR and the CRP level are associated with disease activity. The CRP value over time correlates with radiographic progression.

Although viral infections may trigger RA, or mimic early RA, routine viral screening by serologic testing does not significantly facilitate the diagnosis of RA in patients with early RA, nor is it helpful as a potential identifier of disease progression.[46]

Hematologic parameters

The CBC commonly demonstrates anemia of chronic disease and correlates with disease activity; it improves with successful therapy. Hypochromic anemia suggests blood loss, commonly from the gastrointestinal (GI) tract (associated with the use of nonsteroidal anti-inflammatory drugs [NSAIDs]). Anemia may also be related to disease-modifying antirheumatic drug (DMARD) therapy.

Thrombocytosis is common and is also associated with disease activity. Thrombocytopenia may be a rare adverse event of therapy and may occur in patients with Felty syndrome. Leukocytosis may occur but is usually mild. Leukopenia may be a consequence of therapy or a component of Felty syndrome, which may then respond to DMARD therapy.

Immunologic parameters

Immunologic parameters include autoantibodies (eg, RF, anti-CCP antibodies, and ANA). RF is an immunoglobulin (Ig) M antibody directed against the Fc fragment of IgG that is present in approximately 60-80% of patients with RA over the course of their disease (but in fewer than 40% of patients with early RA). RF values fluctuate somewhat with disease activity, though RF titers generally remain high even in patients with drug-induced remissions.

RF is not specific for RA; it is also present in other connective tissue diseases, infections, and autoimmune disorders, as well as in 1-5% of healthy people. The presence of RF predicts radiographic progression of bone erosions, independent of disease activity.[47]

ANA assays are positive in approximately 40% of patients with RA. However, test results for antibodies to most nuclear antigen subsets are negative.

Assays for anti-citrullinated protein antibody (ACPA; often tested as anti-CCP) are used clinically for diagnosing RA. ACPA-positive and ACPA-negative RA may be 2 distinct disease subsets, with different underlying pathogeneses and risks.[48, 49] ACPA-positive patients may have a more erosive RA disease course than ACPA-negative patients.[50] However, a 2011 study suggests that reassessment of ACPA or IgM RF during the first year after onset of arthritis does not provide significant additional information.[51]

Initial studies of anti–mutated citrullinated vimentin (anti-MCV) assays reported sensitivity comparable to that of ACPA[52] ; however, subsequent studies have found the specificity of anti-MCV to be lower than that of ACPA.[53, 54, 55] Anti-MCV and anti-CCP levels may correlate with disease activity.[52, 56]

Studies of anti-CCP antibodies suggest a sensitivity and specificity as good as or better than those of RF, with an increased frequency of positive results in early RA. The presence of both anti-CCP antibodies and RF is highly specific for RA. Additionally, the presence of anti-CCP antibodies, like that of RF, indicates a worse prognosis.

A trial that tested for 4 novel RA biomarkers improved the diagnosis of early RA in patients who tested negative on conventional tests.[57] In the study comprising 293 RA patients, 97 healthy control subjects, and 87 rheumatic control patients with other arthritides, the panel of 4 biomarkers—UH-RA.1, UH-RA.9, UH-RA.14 and UH-RA.21—had 83% specificity for RA.[57] These markers were found in 37% of patients with early RA and 26% of those who were seronegative for RF and ACPA. The investigators suggested that in addition to an improved diagnosis in early RA, these biomarkers may also have prognostic significance.[57]

Pregnancy

RA often goes into remission during pregnancy. The presence of RF neither helps predict nor correlates with the outcome of arthritis during pregnancy. The ESR cannot be used to assess RA disease activity during pregnancy, because pregnancy alters the normal values. The volume expansion that occurs during pregnancy can result in lower hematocrit values.

Historically, the diagnosis of RA was based on the 1987 American College of Rheumatology (ACR) criteria.[58] Those criteria were intended to discriminate established RA from other definite rheumatologic disorders; they lacked the sensitivity to identify early inflammatory arthritis. With the recognition that early therapeutic intervention significantly improves clinical outcomes and reduces irreversible joint damage and disability, this lack of sensitivity was acknowledged to be significant.

Consequently, in 2010 the ACR and the European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism; EULAR) published new classification criteria for RA.[45] According to the ACR/EULAR criteria, patients who should be tested are those with at least 1 joint with definite clinical synovitis that is not better explained by another disease (eg, lupus, psoriatic arthritis, gout). The 2010 ACR/EULAR classification system is a score-based algorithm for RA that incorporates the following 4 factors:

• Joint involvement
• Serology test results
• Acute-phase reactant test results
• Patient self-reporting of the duration of signs and symptoms

Joint involvement consists of swelling or tenderness upon examination. The presence of synovitis may be confirmed on imaging studies. Points are allocated as follows:

• 1 large joint (ie, shoulders, elbows, hips, knees, ankles) = 0 points

• 2-10 large joints = 1 point

• 1-3 small joints (with or without involvement of large joints), such as MCP, PIP, second to fifth MTP, thumb interphalangeal (IP), and wrist joints = 2 points

• 4-10 small joints (with or without involvement of large joints) = 3 points

• More than 10 joints (at least 1 small joint, plus any combination of large and additional small joints or joints such as the temporomandibular, acromioclavicular, or sternoclavicular) = 5 points

At least 1 serology test result is needed for RA classification. Points are allocated as follows:

• Negative rheumatoid factor (RF) and negative anti−citrullinated protein antibody (ACPA; in the ACR/EULAR criteria set, tested as anti−cyclic citrullinated peptide [anti-CCP]) = 0 points

• Low-positive RF or low-positive ACPA = 2 points

• High-positive RF or high-positive ACPA = 3 points

Serology test results are defined as follows:

• Negative – International unit (IU) values that do not exceed the upper limit of normal (ULN) for the reporting laboratory or assay
• Low-positive – IU values that exceed the ULN but are no more than 3 times the ULN for the reporting laboratory or assay
• High-positive – U values > 3 times higher than the ULN for the reporting laboratory or assay
• When RF is available only as a positive or negative finding, a positive result should be scored as low-positive RF.

At least 1 test acute-phase reactant test result is needed for classification. Local laboratory standards determine which results are normal and which are abnormal. Points are allocated as follows:

• Normal C-reactive protein (CRP) and normal erythrocyte sedimentation rate (ESR) = 0 points
• Abnormal CRP or abnormal ESR = 1 point

Points for the patient’s self-reporting of the duration of signs or symptoms of synovitis in clinically involved joints are allocated as follows:

• Shorter than 6 weeks = 0 points
• 6 weeks or longer = 1 point

The highest possible score is 10 points. Patients with a total score of 6 or higher are classified as having definite RA.

A systematic literature review by Radner et al concluded that the ACR/EULAR criteria have a pooled sensitivity for RA of 0.82 (95% confidence index [CI], 0.79-0.84) and a specificity of 0.61 (95% CI, 0.59-0.64). These authors' review of research that directly compared the 2010 ACR/EULAR criteria with 1987 ACR criteria found that the ACR/EULAR criteria had higher overall sensitivity (+0.11 compared with 1987 criteria) at the cost of lower overall specificity (-0.04).[59]

Radiography remains the first choice for imaging in RA; it is inexpensive, readily available, and easily reproducible, and it allows easy serial comparison for assessment of disease progression.[60] Views of the hands, wrists, knees, feet, elbows, shoulders, hips, cervical spine, and other joints should be assessed with radiography when indicated (see the images below). Erosions may be present in the feet, even in the absence of pain and in the absence of erosions in the hands.

Magnetic resonance imaging (MRI) provides a more accurate assessment and earlier detection of lesions than radiography does[61] ; however, the cost of the examination and the small size of the joints involved militate against its widespread use. MRI is used primarily in patients with abnormalities of the cervical spine (see the images below); early recognition of erosions on the basis of MRI images has been sufficiently validated.

In recent decades, rheumatologists have increasingly incorporated musculoskeletal ultrasound (US) into the management of RA in clinical practice.[62, 63, 64] US has multiple roles in this setting. In patients with musculoskeletal symptoms but without clinical synovitis, it can help predict progression to RA. In patients with early undifferentiated, US can help predict the development of persistent arthritis and facilitate differential diagnosis of RA versus other types of arthritis, such as psoriatic arthritis. In patients with established RA, US can be used to assess response to therapy and to evaluate new symptoms. In patients with RA in remission, it can detect subclinical inflammation.[63]

Ultrasonography allows recognition of effusions in joints that are not easily accessible (eg, the hip and, in obese patients, the shoulder) and of cysts (Baker cysts). It can be used to to guide articular and periarticular aspiration, injection, or biopsy (see the image below). High-resolution gray-scale (B-mode) US can identify synovial proliferation, and is superior to plain radiographs for detecting bone and cartilage. Doppler US can demonstrate joint vascularity, active inflammation, and neovascularization.

Hand

Hand imaging in RA can include radiography, MRI, ultrasonography, and computed tomography (CT), though the last of these plays only a minimal role. Radiography is the mainstay of imaging RA in the hands: It is inexpensive and easily reproducible, and it allows easy serial comparison for assessment of disease progression. Its main disadvantage is the absence of specific radiographic findings in early disease; erosions may only be visualized later.

MRI is sensitive than radiography to early changes in RA, and in the appropriate clinical setting, it is more accurate than plain radiography in the diagnosis of the disease. However, a systematic literature review concluded that widespread use of MRI for the diagnosis of early RA and for helping determine the prognosis of early RA is not currently recommended, though MRI bone edema may be predictive of progression in certain RA populations.[65]

Ultrasonography has been applied to the assessment of RA with the goal of improving on the current standard of conventional radiography. Like MRI, ultrasonography serves as an early diagnostic tool and can help in evaluating the cause of joint swelling in a patient with RA.[66, 67] However, the results of one study suggested that NSAID use may mask the ultrasonographic gray scale and power Doppler signal in the assessment of synovitis in RA, resulting in lower scoring despite continuing disease activity.[68]

See Rheumatoid Arthritis Hand Imaging for complete information on this topic.

Spine

Spinal imaging in RA involves radiography, MRI, and CT. As with hand imaging in RA, the mainstay of imaging remains plain radiography. Only about 50% of patients with radiographic evidence of atlantoaxial subluxation are actually symptomatic.

The role of plain radiography is to establish whether the patient has risk factors for cord compression. The major role for CT and MRI is in preoperative assessment of the 2 main indications for surgical intervention—namely, neurologic deficit and severe pain.[69, 70] Although CT scanning can document bone damage and alignment abnormalities, especially with more detailed multiplanar reconstruction, MRI has become the preferred modality for evaluation of the spinal cord and neural elements.[71]

See Rheumatoid Arthritis Spine Imaging for complete information on this topic.

Consider joint aspiration when making the definitive diagnosis of RA or when ruling out coexistent infection or crystal arthritis in an acutely swollen joint. New-onset monoarticular arthritis or an unusual pattern of a joint flare in a patient with RA should encourage strong consideration of joint aspiration and synovial fluid analysis.

Analysis of synovial fluid includes Gram staining, cell count, culture, and assessment of overall appearance. In patients with RA, analysis typically reveals inflammation (white blood cell [WBC] count > 2000/µL, generally in the range of 5000-50,000/µL). Usually, neutrophil predominance (60-80%) is observed in the synovial fluid (in contrast with mononuclear cell predominance in the synovium). Because of a transport defect, glucose levels of synovial fluids (as well as pleural and pericardial fluids) in patients with RA are often low compared with serum glucose levels.

Early in the course of the RA disease process, there is an influx of inflammatory cells into the synovial membrane, with subsequent angiogenesis, proliferation of chronic inflammatory (mononuclear) cells and resident synovial cells, and marked histologic changes—a 2-cell-layer lining membrane changes to a thickened membrane that often has villous projections into the joint space (see the images below).

The lymphoplasmacytic infiltration of the synovium with neovascularization seen in RA is similar to that seen in other conditions characterized by inflammatory synovitis. Early rheumatoid nodules are characterized by small-vessel vasculitis and later by granulomatous inflammation.

In 2019, the ACR published revised recommendations for the measurement of disease activity in RA, for clinical use at the point of care. The ACR assessed the feasibility of various measures, based on the number of items included in the measure, time to complete, need for provider joint counts, need for laboratory testing, commercial availability, and need for advanced imaging. The guidelines identified the following 5 measures as preferred for regular use in most clinic settings[2] :

• 28-joint Disease Activity Score, using either the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level (DAS28-ESR/CRP)
• Clinical Disease Activity Index (CDAI)
• Simplified Disease Activity Index (SDAI)
• Routine Assessment of Patient Index Data 3 (RAPID3)
• Patient Activity Scale-II (PAS-II)

In addition, the following measures met a minimum standard for regular use:

• Disease Activity Score (DAS)
• Patient-derived DAS28
• Hospital Universitario La Princesa Index (HUPI)
• Multi-biomarker Disease Activity Score (MBDA score, VECTRA DA)
• Rheumatoid Arthritis Disease Activity Index (RADAI)
• Rheumatoid Arthritis Disease Activity Index 5 (RADAI-5)
• Routine Assessment of Patient Index Data 5 (RAPID5)

All of the recommended measures result in a continuous index with defined ranges for low, moderate, or high disease activity or clinical remission.[72] See Table 3, below.

Table 3. Rheumatoid Arthritis Disease Activity Cutoffs (Open Table in a new window)

Remission

A joint ACR/EULAR guideline on remission criteria for RA, first published in 2011 and updated in 2022, includes two definitions, one a Boolean-based definition and the other based on a composite index of RA activity, either the SDAI or the CDAI (the latter omits CRP). The Boolean-based definition requires that the patient satisfy all of the following to be considered in remission[3] :

• Tender joint count of 1 or less 
• Swollen joint count of 1 or less 
• Patient global assessment of 2.0 or less (on a 0-10 scale)
• Optional: CRP 1 mg/dL or lower

To be considered in remission using the traditional index definition, the patient must have an SDAI score of less than 3.3, or a CDAI score of 2.8 or lower.[3]

Optimal care of patients with rheumatoid arthritis (RA) consists of an integrated approach that includes both pharmacologic and nonpharmacologic therapies. Many nonpharmacologic treatments are available for this disease, including exercise, diet, massage, counseling, stress reduction, physical therapy, and surgery. Active participation of the patient and family in the design and implementation of the therapeutic program helps boost morale and ensure compliance, as does explaining the rationale for the therapies used.

Medication-based therapies comprise several classes of agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), and corticosteroids. Early therapy with DMARDs has become the standard of care, because it can both retard disease progression more efficiently than later treatment and, potentially, induce more remissions.[73, 74, 75]

A treat-to-target approach is recommended for RA, with the target being low disease activity or remission, as determined by validated instruments for measuring disease activity (see Workup/Measures of Disease Activity).[5, 4] Online calculators are available for the following RA disease activity measures:

• Clinical Disease Activity Index for RA (CDAI)
• DAS28-CRP for Rheumatoid Arthritis
• DAS28-ESR for Rheumatoid Arthritis
• Simplified Disease Activity Index for RA (SDAI)

In pregnant patients with RA, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care. However, some of the medications used in treating RA can have adverse effects on the fetus and may have to be discontinued several months before conception is planned.

Surgical procedures used in the treatment of RA include the following:

• Synovectomy
• Tenosynovectomy
• Tendon realignment
• Reconstructive surgery or arthroplasty
• Arthrodesis

Once a diagnosis of RA is made, the main treatment goals are to control disease activity and slow the rate of joint damage, in addition to minimizing pain, stiffness, inflammation, and complications. Pharmacologic therapies that are used include nonbiologic and biologic DMARDs and adjunctive agents such as corticosteroids, NSAIDs, and analgesics.

A study by Callhoff et al found that biologic agents were significantly more effective than nonbiologic treatments in improving physical function in RA. The meta-analysis of 35 studies that included 8733 treated patients with RA and 4664 controls determined that more than 50% of patients treated with biologics experienced clinically relevant improvement. Etanercept and rituximab were the most effective treatments, both in patients who had never before taken antirheumatic drugs and in those who had shown an inadequate response to them.[76]

The immunosuppressive effects of DMARDs place patients with RA at greater risk of infection and of more serious complications of infection. ACR guidelines provide recommendations on vaccinations in children and adults with RA or other rheumatic and musculoskeletal diseases, including RA, including guidance on coordination of immunosuppressive medication use with vaccination scheduling.[77]

Early DMARD therapy

DMARDs can be classified into nonbiologic and biologic agents. The nonbiologic DMARDs include the following:

• Hydroxychloroquine (HCQ)
• Azathioprine (AZA)
• Sulfasalazine (SSZ)
• Methotrexate (MTX)
• Leflunomide
• Cyclosporine
• Gold salts
• D-penicillamine
• Minocycline

The recognition of tumor necrosis factor–α (TNF-α) and interleukin (IL)-1 as central proinflammatory cytokines has led to the development of biologic agents that block these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions. Biologic DMARDs include agents such as adalimumab, certolizumab, etanercept, golimumab, and infliximab.

DMARDs represent the most important measure in the successful treatment of RA. These agents can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be used as bridging therapy to reduce pain and swelling.

Many studies have revealed that early treatment of RA (ie, within months of onset) with DMARDs not only can retard disease progression more efficiently than later treatment but also may induce more remissions.[73, 74, 75] Thus, early DMARD therapy (< 6 months after the onset of symptoms) has become the standard of care.[78] Patients with early forms of arthritis should be evaluated by and, if necessary, referred to physicians who are experienced in the diagnosis and treatment of RA.

Nonbiologic DMARDs

In terms of frequency of remissions and time to onset of action, MTX and SSZ are the most active compounds and provide the best risk-benefit ratios. MTX, either alone or in combination with other agents, has become the standard of care for moderate to severe RA.[5, 4]

In 2013, the US Food and Drug Administration (FDA) approved the first single-dose, self-administered, disposable MTX subcutaneous autoinjector (Otrexup).[79] Otrexup is indicated for adults with severe, active RA who have either responded inadequately to or cannot tolerate first-line therapy, as well as for children with active polyarticular juvenile idiopathic arthritis (JIA) (also known as juvenile rheumatoid arthritis).[79]

Triple therapy—MTX, SSZ, and HCQ—may provide greater improvement in disease activity compared with MTX monotherapy, but has the disadvantages of less convenience and greater cost.[4] In a meta-analysis of 158 trials, triple therapy was found to have a statistically significant benefit of inhibiting joint damage compared with oral MTX alone. Also, there was no statistically significant difference in prevention of joint damage between triple therapy and MTX in combination with a biologic (adalimumab, certolizumab, etancercept, or inflximab) or the combination of MTX and tofacitinib.[80]

The results of a retrospective cohort study found that the use of HCQ may decrease the risk of diabetes in patients with RA. Further studies are needed to determine its preventive role in other patients at high risk for diabetes.[81] The results of a retrospective cohort study involving 121,280 patients found a lower adjusted risk of diabetes mellitus among individuals with RA or psoriasis who started a TNF inhibitor or HCQ than among those taking other nonbiologic DMARDs.[82]

A multinational retrospective study that compared new use of HCQ (n=956,374) with new use of SSZ (n=310,350) in adults with RA found no excess risk of severe adverse events with either drug over the first 30 days of therapy. With long-term use, however, HCQ appeared to be associated with higher cardiovascular mortality (calibrated hazard ratio [HR] 1.65; 95% confidence index [CI] 1.12–2.44]).[83]

Leflunomide is the most recent addition to the nonbiologic DMARDs and has activity similar to that of SSZ and MTX. It may be used in patients with contraindications to, or intolerance of, MTX.[5]

Minocycline may act as a DMARD through its action as a matrix metalloproteinase inhibitor (MMPI). Injectable gold salts and penicillamine rarely induce sustained remission and thus have largely been supplanted by more effective agents.

Biologic DMARDs: TNF inhibitors

The TNF inhibitors, which bind TNF and thus prevent its interaction with its receptors, include the following:

• Etanercept
• Infliximab
• Adalimumab
• Certolizumab
• Golimumab

Precautions and adverse effects

Biologic agents are expensive. Consensus statements do not recommend their use until at least one nonbiologic DMARD, usually MTX, has been administered without sufficient success. In clinical trials, as many as 70% of patients achieve significant responses, but remissions are not usually observed.[84]

Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies (ANAs), occasional drug-induced lupuslike syndromes, and infections (including tuberculosis). Rarely, demyelinating disorders and bone marrow suppression occur. Immunogenicity, such as the development of anti-drug antibodies, has been shown to occur with adalimumab and infliximab, potentially leading to decreased drug efficacy. Concomitant use of MTX may reduce the frequency of anti-drug antibody development.[85]

Acute and chronic infections, demyelinating disorders, class III or IV heart failure, and recent malignancies are contraindications to the use of TNF inhibitors. Thoroughly searching for latent tuberculosis using purified protein derivative (PPD) testing or an interferon (IFN) gamma release assay (IGRA), with or without chest radiography, is recommended before these agents are started.

Patients taking anti-TNF agents must avoid live-virus vaccines. Giving live vaccines to patients receiving immunosuppressive drugs leads to a higher risk for serious infection.

The results of one study noted that the use of anti-TNF therapy may double the risk of septic arthritis in patients with RA, with the risk being highest in the early months of therapy. Although not significantly influenced by anti-TNF therapy, previous joint replacement surgery was also noted as a risk factor for septic arthritis.[86]

Hepatitis B virus (HBV) reactivation can occur in both hepatitis B surface antigen (HBsAg)–positive and HBsAg-negative/hepatitis B core antibody (anti-HBc)-positive patients with detectable occult HBV infection during anti−TNF-α therapy. Antiviral prophylaxis may effectively reduce this reactivation.[87]

In three Swedish registries that analyzed the cancer risk in 6366 RA patients taking TNF inhibitors, no increased risk of cancer with these agents was observed.[88] These patients were compared with 61,160 biologics-naive RA patients, 5989 patients starting MTX, 1838 patients starting DMARD combination therapy, and the general Swedish population. Of patients taking TNF inhibitors, 240 developed first-time cancer, yielding a relative risk (RR) of 1.00 compared with the biologics-naive cohort. Similar RRs were shown with the other cohorts.

TNF inhibitors versus MTX

In one study, bone erosions showed a higher rate of repair in RA patients treated with TNF inhibitors than in patients treated with MTX.[89] After a 1-year follow-up, bone erosions in the group treated with TNF blockers showed a mean width of 2 mm and a mean depth of 2.3 mm; the MTX-treated group showed a mean width of 2.4 mm and a mean depth of 2.4 mm. Deeper lesions in the TNF-inhibitor group were also particularly prone to repair when compared with more shallow lesions.[89]

Van Vollenhoven et al reported that in patients with early RA who have MTX-treatment failure, the addition of a TNF antagonist was superior to the addition of conventional DMARDs.[90] In this study, 258 patients with early RA who did not achieve low disease activity after 3-4 months of MTX (up to 20 mg/wk) were randomized to receive additional treatment (in addition to MTX)  with SSZ and HCQ or with infliximab.

In the SSZ and HCQ group, 32 of 130 (25%) achieved the primary outcome, defined as a good response according to the European Alliance of Associations for Rheumatology (EULAR); in the infliximab group, 50 of 128 (39%) attained the primary outcome.[90]

A systematic review by Visser et al suggested that an initial oral MTX dose of 15 mg/wk, with escalation of 5 mg/mo to achieve target doses of 25-30 mg/wk or maximum tolerable doses, was the optimal evidence-based dosing strategy.[91] Starting at higher initial doses or escalating too rapidly may be limited by toxicity. Conversion from oral to subcutaneous (SC) administration of MTX is suggested for patients who have an inadequate response to oral therapy.

Adalimumab

The TNF-α inhibitor adalimumab is approved for use as monotherapy or in combination with MTX or other nonbiologic DMARDs. A double-blind controlled 52-week trial in 619 patients with active RA who had an incomplete response to MTX found that the addition of adalimumab provided better disease control than placebo. In an open-label extension study, patients in the original placebo arm who were switched to adalimumab experienced inferior radiographic, functional, and clinical outcomes after 5 years, compared with the patients in the original adalimumab arm, thus demonstrating the disadvantage of delaying anti-TNF therapy.[92]

According to data from a study of 221 consecutive RA patients, adalimumab blood levels of 5 to 8 μg/mL have the greatest effect on disease activity. In the study, adalimumab trough levels greater than 8 μg/mL had no additional beneficial effect on disease activity[93] Study participants were treated with 40 mg adalimumab subcutaneously every other week for 28 weeks and stratified according to whether or not they were taking concomitant MTX. Patients treated with concomitant MTX reached recommended blood levels at lower adalimumab doses. At 28-week follow-up, mean adalimumab levels were 4.1 μg/mL in patients receiving monotherapy and 7.4 μg/mL in patients receiving concomitant MTX.[93] MTX might contribute to increasing adalimumab blood levels by reducing inflammation and lowering the number of binding targets for adalimumab.

Certolizumab

Fleischmann et al found that monotherapy with certolizumab effectively reduced the signs and symptoms of active RA in patients in whom DMARD therapy had failed.[94] In this study, 200 patients were randomized on a 1:1 basis to receive certolizumab 400 mg or placebo every 4 weeks for 24 weeks. At 24 weeks, 45.5% of the certolizumab group achieved a 20% improvement, according to ACR criteria, compared with 9.3% of the placebo group. Statistically significant differences were observed as early as week 1 through week 24.[94]

A study by Smolen et al found that certolizumab plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression.[95] In this study, 619 patients were randomized to receive certolizumab 400 mg at weeks 0, 2, and 4, followed by 200 mg or 400 mg plus MTX every 2 weeks or placebo plus MTX every 2 weeks.

Significantly more patients who received certolizumab 200 mg (57.3%) or 400 mg (57.6%) achieved 20% improvement by ACR criteria than did those who received placebo (8.7%).[95] Radiographic progression was significantly inhibited with certolizumab 200 mg or 400 mg, as compared with placebo. When compared with placebo plus MTX, certolizumab plus MTX significantly relieved signs and symptoms, improved physical function, and inhibited radiographic progression in patients with RA.[95]

Golimumab

Golimumab is a human anti−TNF-α monoclonal antibody that inhibits TNF-α bioactivity, thereby modulating immune activity in patients with RA. Using a modified intention-to-treat analysis, researchers demonstrated that golimumab plus MTX is more efficacious than MTX alone (and that golimumab alone is about as efficacious as MTX alone) in reducing disease signs and symptoms in MTX-naive patients.[96]

In this 52-week, randomized, double-blind, placebo-controlled study, which was was followed by an open-label extension through 5 years, 637 patients were randomized to receive placebo plus MTX (group 1), golimumab 100 mg subcutaneously (SC) plus placebo (group 2), golimumab 50 mg SC plus MTX (group 3), or golimumab 100 mg SC plus MTX (group 4).[96] Intent-to-treat analysis showed no significant differences in the primary endpoint between group 1 and groups 3 and 4 combined, indicating efficacy of subcutaneous golimumab. The incidence of serious adverse events was similar across all groups.

In 2013, the FDA approved golimumab for intravenous (IV) use.[97, 98, 99] Approval was supported by a phase 3 study of 592 patients with moderately to severely active RA who had been receiving background MTX for at least 3 months.

In this study, 58.5% (n = 231/395) of patients receiving treatment with golimumab IV plus MTX experienced significant improvements in signs and symptoms at week 14 compared with 24.9% of patients receiving placebo plus MTX (n = 49/197).[99] Improvement was demonstrated by at least a 20% increase in ACR 20 score, the study’s primary endpoint. A higher proportion of patients receiving golimumab plus methotrexate achieved at least a 50% improvement in ACR criteria (ACR 50) at week 14 (30%) compared with patients receiving placebo plus MTX (9%).

The rate of adverse events and serious adverse events, respectively, at week 24 were 53% and 4% in the golimumab group and 49% and 2% in the placebo group.[97, 98] The most common adverse events were "infections and infestations," including upper respiratory tract infection (> 5% of patients), urinary tract infection, and nasopharyngitis. Exacerbation of RA occurred in 5.6% of patients receiving placebo plus MTX.[97]

At week 52, the rate of adverse events and serious adverse events in the golimumab group were 65% and 9%, respectively.[97] No serious opportunistic infections occurred through week 52. However, in the golimumab group, a single case of tuberculosis was reported, and a patient died from a myocardial infarction secondary to community-acquired pneumonia.[97]

Biologic DMARDs: non-TNF agents

Rituximab

Rituximab is most often used in combination with MTX. It has been shown to be effective for reducing signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to therapy with one or more TNF inhibitors.[100, 101, 102] The ORBIT study in 295 biological-treatment naive patients with RA found that initial treatment with rituximab is noninferior to initial TNF inhibitor treatment, and is cost saving over 12 months.[103]

Treatment with rituximab may deplete CD20+ B cells. A study by Bingham et al suggested that polysaccharide and primary immunizations should be administered before rituximab infusions in order to maximize immunization responses.[104] After administration of pneumococcal polysaccharide vaccine, a 2-fold rise in titers against 1 or more pneumococcal serotypes occurred in 57% of RA patients receiving rituximab and MTX, but in 82% of those receiving MTX alone.

Decreased response to a neoantigen (keyhole limpet hemocyanin [KLH]) was also seen in the rituximab-treated patients (47% vs 93%).[104] However, the ability to maintain a positive delayed-type hypersensitivity to a Candida albicans skin test was comparable in both treatment groups, as was response to tetanus toxoid.

Anakinra

Anakinra is a recombinant nonglycosylated form of the human IL-1 receptor antagonist (IL-1ra). IL-1ra occupies the IL-1 receptor without triggering it and prevents receptor binding of IL-1. In clinical trials, patients treated with anakinra were significantly more likely to demonstrate a American College of Rheumatology 20% improvement response (ACR20), compared with those receiving placebo.[105]

Abatacept

Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. CD28 interaction provides a signal needed for the full T-cell activation that is implicated in RA pathogenesis.

Maintenance doses of abatacept may be administered as a monthly intravenous (IV) infusion or by the patient as a weekly SC injection.[106] In patients with RA who have previously had treatment failure with anti-TNF therapy, abatacept has been shown to demonstrate consistent safety and efficacy that are maintained from 6 months to 5 years of therapy.[107]

A head-to-head phase IIIb randomized noninferiority trial found that SC abatacept and SC adalimumab were equally effective in RA patients, with comparable safety (though adalimumab was associated with more injection-site reactions).[108] Adding either treatment to background methotrexate produced similar ACR20 rates and similar rates of radiographic nonprogression. In view of these findings, clinicians may reasonably conclude that the 2 agents are substantially equivalent for treating RA.

Tocilizumab

Tocilizumab, an IL-6 receptor inhibitor, is available as either an IV infusion or SC injection. It is indicated for moderate-to-severe active RA in adults who have had an inadequate response to 1 or more TNF-antagonist therapies. It may be used either alone or in combination with MTX or other DMARDs. However, Dougados et al found that in patients with active RA, combination therapy with IV tocilizumab and MTX did not yield better clinical results than tocilizumab monotherapy and combination therapy was more often associated with transaminase increases.[109]

In patients with inadequate response to TNF inhibitors, tocilizumab treatment results in significant, clinically meaningful, rapid, and sustained improvements in a number of patient-reported outcomes.[110, 111] A 2012 consensus statement confirmed the efficacy and safety of IL-6 pathway blockade in adult rheumatoid arthritis.[112]

In 2013, the FDA approved an SC injection of tocilizumab that can be self-administered after proper training. The SC formulation has been shown to be as effective as the IV infusion and has the same safety profile, except for increased injection site reactions with SC administration.[111]

Sarilumab

Also an IL-6 inhibitor, sarilumab is a human monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). It is approved for adults with RA who have had an inadequate response or intolerance to one or more DMARDs. Administration is by SC injection every 2 weeks. Sarilumab may be prescribed as monotherapy or with MTX or other conventional DMARDs.

Approval of sarilumab was based on the MOBILITY and TARGET trials. In the MOBILITY study, patients treated with sarilumab plus MTX had reduced signs and symptoms and improved physical function, and demonstrated significantly less radiographic progression of structural damage, compared with placebo plus MTX. At 24 weeks of treatment, the ACR20 score was 66% for sarilumab 200 mg, 58% for sarilumab 150 mg, and 33% for placebo.[113]

The TARGET study combined sarilumab with a DMARD. Results showed reduced signs and symptoms and improved physical function compared with placebo plus DMARD. Results were similar to the MOBILITY trial. At 24 weeks, ACR20 was 61% for sarilumab 200 mg, 56% for sarilumab 150 mg, and 34% for placebo.[114]

Tofacitinib

Janus kinases (JAKs) consist of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor–receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression.

JAK inhibitors modulate the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. These signals maintain the inflammatory condition in RA. Inhibition of JAKs reduces production of and modulates proinflammatory cytokines central to RA.

Tofacitinib is an oral JAK inhibitor[115] that was approved by the FDA in 2012 as second-line treatment for moderate to severe active RA.[116] The indication is specific for patients who have had an inadequate response to or are intolerant of MTX. Tofacitinib may be given as monotherapy or in combination with MTX or other nonbiologic DMARDs. It should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine or cyclosporine).

Tofacitinib has been associated with reductions in signs and symptoms of RA and improvement in physical function.[117] Fleischmann et al demonstrated that ACR criteria for a 20% response were met in 59.8% of patients receiving monotherapy with tofacitinib 5 mg twice daily, compared with 26.7% of patients receiving placebo.[118] Health Assessment Questionnaire Disability Index (HAQ-DI) reduction was also greater in the tofacitinib group (−0.50 points) than in the placebo group (−0.19 points).

In another study, in which 717 patients who received stable MTX doses over 12 months were randomized to also receive 5 mg or 10 mg of tofacitinib orally twice daily, adalimumab 40 mg every 2 weeks, or placebo, ACR 20% response rates at 6 months were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%).[119]

A once-daily 11-mg extended-release dosage form was approved by the FDA in 2016 as an alternative to the 5-mg twice-daily regimen.

However, a randomized trial by Ytterberg et al found that although the efficacy of tofacitinib is similar to that of TNF inhibitors, risks of major adverse cardiovascular events, cancers, and certain opportunistic infections (eg, herpes zoster, tuberculosis) were higher with tofacitinib.[120]

The trial compared tofacitinib at a dose of 5 mg twice daily (n=1455) or 10 mg twice daily (n=1456) with a TNF inhibitor (n=1451) in patients with active RA despite MTX treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Incidence rates of major adverse cardiovascular events with the combined tofacitinib doses versus a TNF inhibitor were 3.4% vs 2.5%, respectively (hazard ratio [HR], 1.33], while rates of cancers were 4.2% versus 2.9%, respectively (HR 1.48) for cancers.[120]

Baricitinib

The FDA approved a second JAK inhibitor, baricitinib (Olumiant), in 2018 as a second-line treatment of moderately to severely active RA in adults who have had an inadequate response to one or more TNF antagonists. Baricitinib may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs. It should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine or cyclosporine).

The dosage of baricitinib is one 2-mg tablet daily. The FDA declined to approve 4-mg tablets, citing safety concerns. The drug's prescribing information will contain a boxed warning about the risk for serious infections, malignancies, and thrombosis.[121]

Approval of baricitinib was supported by the RA-BUILD, RA-BEYOND, and RA-BEACON phase III clinical trials. The RA-BUILD study was a double-blind 24-week study that included 684 biologic DMARD–naïve patients with RA and inadequate response or intolerance to 1 or more conventional synthetic DMARDs. At week 12, 62% of patients taking baricitinib 4 mg achieved ACR20 response, compared with 39% of those taking placebo (P ≤0.001).[122]

In the RA-BEYOND study,  radiographic progression at 24 and 48 weeks was statistically significantly lower for either baricitinib 2 or 4 mg compared with placebo. However, only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomized to placebo when observed at week 48.[123]

In the RA-BEACON study (n=527), patients with RA received baricitinib 2 mg, baricitinib 4 mg, or placebo in addition to conventional DMARDs they were currently taking. Patients in the study had demonstrated an inadequate response or intolerance to at least one TNF inhibitor therapy. Study participants could have undergone prior therapy with other biological DMARDs. At week 12, patients taking baricitinib had significantly higher ACR20 response rates (49%, versus 27% for placebo) and gains in all individual ACR20 component scores.[124]

Upadacitinib 

Another JAK inhibitor, upadacitinib, was approved in 2019 for moderately to severely active RA in adults who have had an inadequate response or are intolerant to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiological DMARDs.

Approval was based on data from the SELECT phase 3 RA program that enrolled over 4000 patients with moderate to severe RA across 5 studies. In the SELECT-MONOTHERAPY study, 598 or 648 patients completed the study. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients in the continued methotrexate group, 147 (68%) of 217 patients receiving upadacitinib 15 mg, and 153 (71%) of 215 patients receiving upadacitinib 30 mg (p < 0.0001 for both doses vs continued methotrexate).[125]

The SELECT-COMPARE study evaluated safety and effectiveness of upadacitinib compared with adalimumab (each with methotrexate) over 48 weeks. Results showed low disease activity, clinical remission, and improvements in pain and function remained superior for upadacitinib compared with adalimumab at 26 weeks and also from weeks 26 to 48.[126]

Combination DMARD therapy

In clinical trials, 30-70% of patients using DMARDs, either as monotherapy or in combination therapy, achieve partial responses, as determined by the ACR disease activity score. Currently, it is not possible to predict which patients will not have a treatment response.

In clinical practice, three strategies are employed to reduce disease activity as much as possible in patients whose disease does not respond or in those with clinical responses that are regarded as insufficient:

• Increasing the dose of medication
• Switching to other DMARDs
• Initiating combination therapy

Because patients may require 2-3 months to achieve a full response to DMARDs, decisions regarding changes in medication are often delayed until that time.

Combination therapy appears to be helpful in patients whose disease partly or completely fails to respond to DMARD monotherapy. One study found that in patients with early, active RA, combination DMARD therapy with downward titration or intensive triple-DMARD combination therapy is more cost-effective than DMARD monotherapy.[127] Several combinations have proved successful without posing unexpected added risks; most include MTX (eg, MTX plus SSZ plus HCQ, MTX plus leflunomide, or MTX plus biologic DMARDs).

MTX combined with infliximab[128] or rituximab[129] yields a better response than monotherapy does. MTX combined with etanercept provides a higher rate of meaningful clinical response. MTX combined with cyclosporine, though not a commonly used combination, results in greater clinical improvement than MTX alone. Triple therapy with MTX, SSZ, and HCQ may provide substantially greater clinical improvement than either MTX alone or SSZ plus HCQ.[130]

In new-onset early RA, the use of MTX in combination with biologic DMARDs—mainly, TNF inhibitors—has not shown sufficient superiority to MTX with or without additional conventional synthetic DMARDs to justify first-line use. In the VEDERA (Very Early Versus Delayed Etanercept in Patients With RA) trial, remission rates with etanercept plus MTX versus treat-to-target MTX (with etanercept added in patients not in remission at 24 weeks) were 38% vs 33% at week 24 and 52% vs 38% at week 48, respectively (odds ratios 1.6, 95% CI 0.8-3.5, P=0.211). The study data suggested that delaying etanercept until failure of methotrexate was linked to poorer response to etanercept; that finding requires validation.[131]

The VEDERA results failed to confirm the large effect size (30%) suggested in previous exploratory analysis of first-line TNF inhibitor plus MTX compared with treat-to-target MTX. This highlights the fact that even when clinicians incorporate all the recommended treat-to-target strategies in treatment-naïve patients with early RA (ie, symptoms for ≤12 months), a ceiling effect exists.[131]

The toxicities of these drug combinations are rarely more significant than those occurring with any of the individual agents used alone, though liver and bone marrow toxicity may be increased if MTX and leflunomide are combined.

Adverse effects

When used with appropriate clinical and laboratory control monitoring, combination therapy with the above agents is usually well tolerated. Adverse events typically become rarer after the first 2-3 months of therapy. Most adverse events are reversible with cessation of the drugs or with reduction of the doses.

The most important and most common adverse events are as follows:

• Liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, and D-penicillamine)
• Kidney toxicity (cyclosporine, parenteral gold salts, and D-penicillamine)
• Pneumonitis (MTX)
• Allergic skin reactions (gold compounds and SSZ)
• Autoimmunity (D-penicillamine, SSZ, and minocycline)
• Infections (azathioprine and cyclosporine)

Antimalarial agents may cause ocular toxicity. In addition to an assessment of renal and liver function, it is recommended that baseline ophthalmologic screening for patients using these agents should include an evaluation for visual impairment and a recording of near visual acuity.[132] In 2011, the American Academy of Ophthalmology issued Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy.

Complications of DMARD treatment

Patients with an established diagnosis of RA who are being treated with DMARDs, particularly those treated with combination therapy, including biologic agents such as TNF antagonists, may present with serious infections, malignancies, or both.[133, 134, 135] Additionally, adverse events from RA medications may include liver toxicity, renal toxicity, bone marrow depression, lung inflammation, and skin manifestations.

TNF precautions and mortality

Patients taking anti-TNF agents must avoid live-virus vaccines (eg, measles-mumps-rubella [MMR], HZV, varicella-zoster virus [VZV], and bacillus Calmette-Guérin [BCG] vaccines) to avoid the potential for serious infection.

A large national prospective cohort study over a mean of 4 years demonstrated that anti-TNF therapy for RA was not associated with a significant increase or decrease in mortality when compared with standard nonbiologic DMARD therapy.[136] The results from another study confirmed that the risk of serious infection and malignancy is not increased in patients receiving anti-TNF therapy when the patients have early RA and have not been previously treated with MTX or other DMARDs.[137]

In a systematic review and meta-analysis reporting on the risk of malignancy in patients with RA treated with TNF inhibitors, the data reviewed showed that these agents did not increase the risk of malignancy, particularly lymphoma; however, they did appear to increase the risk of skin cancer, including melanoma.[138]

Corticosteroids

Corticosteroids are potent anti-inflammatory drugs that are commonly used in patients with RA to bridge the time until treatment with DMARDs is effective.[5, 139] These agents are effective adjuncts to DMARD or NSAID therapy. Timely dose reductions and cessation are important because of the adverse effects associated with long-term steroid use. Corticosteroids can be administered by oral, IV, or intra-articular routes.

When Buttgereit et al studied circadian rhythms in 288 patients with active RA, half of whom were randomly assigned to a modified-release (MR) prednisone tablet and the other half to an immediate-release (IR) prednisone tablet, there was a clinically relevant reduction of morning stiffness of the joints with the MR product as compared with the IR product.[140]

A 9-month extension of the same study showed that the MR prednisone taken at bedtime was well tolerated and provided a sustained improvement.[141] A third study that added low-dose MR prednisone to existing DMARD treatment also showed improvements in RA signs and symptoms, including a reduction in morning stiffness as compared with baseline (35% vs 55%).[142]

A comparison of high-dose IV steroids with infliximab in the 18-month randomized, double-blind IDEA study found similar rates of remission induction and sustained remission, as well as the time to sustained remission, with the two agents.[143] The study, which included 112 patients with new-onset DMARD-naïve RA, compared the efficacy of infliximab and IV steroid therapy, both in combination with methotrexate, as remission induction in early RA, followed by a treat-to-target approach.

Adverse effects

One study found that the use of corticosteroids was associated with heart failure in patients with RA, independent of cardiovascular risk factors and coronary heart disease (CHD). Those patients who currently used MTX showed a lower risk of heart failure.[144]

Nonsteroidal anti-inflammatory drugs

NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. However, they do not retard joint destruction and thus are not sufficient to treat RA when used alone. Like corticosteroids, NSAIDs can be reduced in dose or discontinued with successful DMARD therapy.

The several dozen NSAIDs that are available can be classified into several different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac.

In the early 1990s, a second isoform of COX was discovered (COX-2). COX-1 has a protective role, particularly in the stomach, whereas COX-2 is strongly upregulated during inflammation. Traditional NSAIDs are nonselective COX inhibitors, inhibiting both COX-1 and COX-2. Several coxibs (selective COX-2 inhibitors) were developed that had a significant preference for COX-2 over COX-1. Currently, however, only one COX-2 inhibitor remains on the US market—namely, celecoxib.

Adverse effects

Coxibs, with their selectivity for COX-2, have been shown to be clinically efficacious and produce less gastrointestinal (GI) toxicity, the major adverse event related to the use of nonselective COX inhibitors (ie, NSAIDs). Other adverse effects, such as water retention, hypertension, and abnormal transaminase levels, are observed with both nonselective COX inhibitors and selective COX-2 inhibitors.

Whether and to what degree nonaspirin NSAIDs, coxibs, or both have increased cardiovascular toxicity has not been definitively settled. An analysis of 6 placebo-controlled trials comparing celecoxib with placebo found that the risk of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic events increased after celecoxib treatment in a dose-dependent fashion.[145]

Analgesics

Acetaminophen, tramadol, codeine, opiates, and various other analgesic medications can also be used to reduce pain. These agents do not affect swelling or joint destruction.

Experimental therapies

Despite significant advances over the past decades, RA continues to be a chronic disease. It remains active in many patients whose conditions partially or completely fail to respond to DMARDs. Therefore, the vigorous search for new therapeutic agents continues.

Several new CD20 B-cell−targeted biologic agents are under investigation, including atacicept, AMG 623, B3-FCc, Br3-Fc, belimumab, epratuzumab, ofatumumab, ocrelizumab, and TRU-015. Small molecules directed at enzymes involved in signal transduction of TNF and other proinflammatory cytokines are effective in treating RA.

A phase II study reported that in comparison with placebo, fostamatinib, an inhibitor of spleen tyrosine kinase (Syk), reduced disease activity in RA patients who did not have a response to MTX therapy.[146] However, a phase III study reported a lower level of response to fostamatinib than the phase II study, with statistically significant but not clinically significant improvements in the ACR20 compared with placebo at 24 weeks and no significant difference in the modified total Sharp/van der Heijde score of radiographic damage.[147]

Inhibition of matrix metalloproteinases (MMPs), though initially unsuccessful, could prove to be efficacious, as could inhibition of osteoclast activation. Apheresis procedures are also being investigated. High-dose immunosuppression combined with autologous stem cell transplantation has been used in study protocols for patients whose conditions are resistant to other therapies.

Acute presentations in patients with RA are generally because of an exacerbation of known disease or manifestations in other organ systems or other disease sequelae. Patients presenting with an initial onset of previously undiagnosed possible RA require symptomatic treatment with NSAIDs and rapid referral for definitive diagnosis and institution of DMARD therapy. A delay of as little as 2-3 months in initiating joint-sparing therapy can result in significant irreversible joint damage measured radiographically at 5 years.

In patients with known disease, increased pain, edema, and dysfunction are characteristics of rheumatoid flare (exacerbation). Flares may be local or systemic in nature. Laboratory evaluation may reveal elevation in acute-phase reactants. Treatment consists of rest, NSAIDs, DMARDs, short courses of steroids (2-4 weeks), and, possibly, intra-articular steroid injections. Pain relief is important and may necessitate short-term use of narcotic analgesics.

Felty syndrome

Felty syndrome is a triad of RA, neutropenia, and splenomegaly. Patients with Felty syndrome are prone to serious bacterial infections that result in higher morbidity and mortality than those reported for other patients with RA. Prompt diagnosis and initiation of antibiotic therapy are required.

Baker cysts

Ruptured Baker cysts are often confused with deep vein thrombosis (DVT). Baker cysts often occur fairly early in the course of the disease, with pain, edema, and inflammation in the posterior knee and calf. The diagnosis is best made with ultrasonography. Treatment includes rest, elevation, needle puncture of the calf, knee joint aspiration, and referral.

Carpal tunnel syndrome

Carpal tunnel syndrome (median nerve compression neuropathy) is evinced by pain or paresthesias in the median nerve distribution of the hand, a positive Phalen or positive Tinel test, or positive findings on electromyography (EMG). Therapy includes rest, temporary immobilization, NSAIDs, and surgery.

Pregnancy

Pregnancy alters the immune state, and often—though not always—ameliorates disease activity in women with RA.[148, 149] No specific guidelines address obstetric monitoring in patients with RA.

Because few available data suggest a significant risk of preterm birth, preeclampsia, or fetal growth restriction in pregnant patients with RA, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care (eg, stabilizing the disease before conception and using drugs safe for pregnancy and lactation).[150]

Medications considered low-risk in pregnancy include immunomodulating drugs, low-dose corticosteroids, antimalarial agents, SSZ, and azathioprine. Fetal toxicity is rarely associated with HCQ at the dosage used for RA and connective tissue disease (6.5 mg/kg body weight).[151] Anakinra may be used until conception.

Before therapy is initiated, patients should be counseled about the teratogenicity and adverse effects of the medications used to treat RA. NSAIDs should be avoided in the third trimester. MTX is contraindicated in pregnancy, because it is an abortifacient and has teratogenic effects, including craniofacial abnormalities, limb defects, and central nervous system (CNS) defects such as anencephaly, hydrocephaly, and meningomyelopathy, especially with first-trimester exposure.[152] Leflunomide is also contraindicated. Both MTX and leflunomide should be discontinued at least 3 months before pregnancy, and blood levels of leflunomide should be assessed.

Use of anti-TNF drugs during pregnancy is not covered by current guidelines.[153, 5, 4] Stopping TNF inhibitors at conception has been recommended.[150] However, TNF inhibitors do not cross the placenta until the end of the second trimester. Thus, concern over possible effects on the development of the fetal immune system has led to the suggestion, in the inflammatory bowel disease literature, that anti-TNF drugs can continue from conception through the first trimester but should be stopped during the second trimester.[154]

Analysis of data from the health registries in Denmark and Sweden determined that women who received anti-TNF agents during pregnancy had a slightly higher risk of having children with birth defects. However, the increased risk was not statistically significant.[155]

Patients may need a reminder about the importance of using contraception during DMARD therapy and about the necessity of discontinuing some of these medications several months before conception is planned. In addition to discontinuance, some patients who take DMARDs may require treatment with other medications to enhance their clearance.

Patients with RA must be monitored closely after delivery because of the potential for arthritis flareups to occur during the postpartum period.

For complete information on this topic, see Rheumatoid Arthritis and Pregnancy.

Goals of rehabilitation for RA patients include the following:

• Relief of pain
• Improvement in range of motion (ROM)
• Enhancement of strength and endurance
• Prevention or correction of deformities
• Provision of counseling and educational services

Nonpharmacologic therapeutic modalities that are available to the physiatrist to assist patients in achieving these goals include the following[156, 157, 158] :

• Splints and orthotics
• Assistive equipment
• Joint-protection and energy-conservation techniques
• Education
• Therapeutic exercise programs

Heat and cold therapies

Application of heat, either superficial or deep, is an effective modality for the relief of joint pain and stiffness caused by RA. In addition, it is used to treat joints in preparation for ROM, stretching, and muscle-strengthening exercises. Superficial and deep heating methods have been shown to raise the intra-articular temperature in patients with RA. Heat may be delivered via the following:

• Moist hot packs
• Electric mittens
• A hot shower
• Spas
• Ultrasonography
• Diathermy
• Paraffin

Cold is preferable for treatment of an acutely inflamed joint. Application of cold results in decreased pain and decreased muscle spasm. Cold may be delivered via ice packs, ice sticks, topical sprays, or ice water.

Orthotics and splints

Orthotic devices play an important role in the rehabilitation management of patients with RA. These devices are used to decrease pain and inflammation, improve function, reduce deformity, and correct biomechanical malalignment.

Lower-extremity orthoses are prescribed to provide stability and proper alignment or to shift weight-bearing off the affected limb. The most common orthoses used for the lower extremity involve the foot and ankle joints.

Approximately 80% of patients affected by RA have significant foot involvement. These problems are easily accommodated by providing a deep, wide, soft leather shoe. A metatarsal pad or bar is typically used to remove weight from painful metatarsophalangeal (MTP) joints, and a rocker-bottom sole can be used to facilitate rolloff. Hindfoot pronation should be addressed with custom inserts.

Knee orthoses may be used to control the following problems:

• Edema
• Pain
• Patellar misalignment
• Hyperextension
• Collateral or cruciate ligament instability

Therapeutic exercise

Fatigue and decreased endurance are frequent symptoms in patients with RA. When these patients are compared with age-matched subjects who do not have RA, a reduction in aerobic capacity and muscle strength is noted, both because of the disease itself and because of the lack of physical activity in these patients. Thus, exercise is an important part of rehabilitation management of RA.

Aerobic conditioning in affected patients (if tolerated) improves maximum oxygen uptake and decreases perceived exertion at submaximal workloads, reportedly without causing adverse effects in the joints. In addition, patients undergoing long-term endurance training have been known to feel less isolated, to take less sick leave, and to develop improved function in activities of daily living (ADLs). Patients with well-controlled RA should be encouraged to engage in 30 minutes of daily aerobic exercise several times a week.

A 21-week study by Katz et al in 96 patients with RA found that providing a pedometer and step-monitoring diary, with or without a step target,  increased activity levels and decreased fatigue. A control cohort that received education only showed a trend toward decreased steps.[159]

Muscle atrophy often accompanies RA and is exacerbated by inactivity, bed rest, splints, and medications. Isometric exercises restore and maintain strength in affected patients without producing pain. Resistance exercises may be initiated when the isometric program has been well established and when the patient is free of pain.[160]

In a review addressing hand function in RA patients, O’Brien suggested that strengthening hand exercises could yield significant improvements in the overall functioning of patients with this disease.[161] If surgery is not an option, medical management should be pursued in conjunction with rather thorough physical therapy in order to maintain and preserve hand function.[161]

Occupational therapy

Occupational therapy can be very useful for patients with RA.[162] Occupational therapy is initiated to help patients achieve the following:

• Using joints and tendons efficiently without stressing these structures

• Decreasing tension on the joints with specially designed splints

• Coping with daily life through adaptations to the patients’ environment and the use of different aids

An occupational therapist may work in conjunction with the physical therapist to ensure that patients are able to meet their goals. The occupational therapist may also assist in the recommendation and use of splints and orthotics, especially when the upper extremity is affected.

Upper-extremity orthoses may be classified as either static or dynamic. Static splints are used to support a weak or unstable joint, to rest a joint for pain relief, or to maintain functional alignment. Dynamic splints traditionally have been used to manage the postoperative hand, but they may also be used to increase manual dexterity. The most commonly used splints for the hand are the finger-ring splint and the thumb-post splint. The functional wrist splint and the resting hand splint are commonly used for wrist splinting.

Adaptive equipment

Many assistive devices are available to patients with RA and are used to maximize function, maintain independence, reduce joint stress, conserve energy, and provide pain relief. Equipment is available to assist patients with transfers, dressing, feeding, toileting, cooking, and ambulation. Physical and occupational therapists can assist with training in the use of adaptive equipment.

Joint-protection education

Joint-protection education provides the patient with techniques and recommendations for preventing joint overuse and avoiding of biomechanical torques that excessively bend the joint.[156] The use of adaptive equipment is important. Other components of a good joint-protection program include the following:

• Maintenance of good posture
• Avoidance of overuse during inflammation
• Modification of tasks to decrease joint stress
• Use of appropriate splints

Energy-conservation education

Fatigue is a major component of RA, and it is due to the systemic nature of the disease, as well as to the decreased cardiovascular endurance observed in patients with this inflammatory disorder.

The goal of energy conservation techniques is to save energy while maximizing function. Adaptive equipment is an essential part of this program. Other elements include maintaining joint ROM and strength, improving cardiovascular fitness, and taking short rest periods during the day. Every individual with RA should implement joint-protection and energy-conservation programs into his or her lifestyle.

Williams et al found that in older women with either RA or osteoarthritis of the lower limb, an individualized home program of balance-training exercise can improve balance and gait stability.[163] In this study, 39 women (mean age, 69.3 years) underwent a 4-month program of balance exercises conducted by a physical therapist. Before exercise training, 64% of patients reported having had fallen during the previous 12 months, and 42% of patients had a moderate fall-risk score.

After the 4-month program, the patients demonstrated improvement on most balance measurements, including their fall-risk score and measurements of activity level, fear of falling, functional reach, and step width.[163] Improvements were also seen in patients’ body mass index (BMI) and in their sit-to-stand rising index.

Surgical intervention in patients with RA can relieve pain, correct deformity, and improve function.[156] A number of surgical procedures are available to obtain these goals, such as myofascial techniques, excisions, reconstructions, joint fusions, and joint replacements. The timing of surgery is a complex decision; the patient’s age, stage of disease, and level of disability, as well as the location of the involved joints, must be considered. Early surgical intervention may help maintain a patient’s functional level of independence.

Deformities of the hand or wrist lead to loss of the ability to grip, grasp, and pinch, often leaving the patient unable to perform the activities of daily living. The surgical treatments for RA of the hand and wrist include the following:

• Synovectomy
• Tenosynovectomy
• Tendon realignment
• Reconstructive surgery or arthroplasty
• Arthrodesis

Cervical spine instability may develop in patients with established RA who have degeneration of the ligaments and bone in the C-spine area. Degeneration of the transverse ligament can lead to instability at the C1-C2 level. Minor trauma can lead to neurologic sequelae due to inherent instability.

Exercise caution in evaluating RA patients after minor falls, motor vehicle accidents, or other injuries. Cervical spine injury may occur spontaneously. Patients with long-standing disease may need careful evaluation perioperatively to detect any cervical spine instability before neck manipulation or intubation during surgery. Patients with RA of the cervical spine who have refractory pain, clearly evident neurologic compromise, or intrinsic spinal cord signal changes on magnetic resonance imaging (MRI) are generally candidates for surgical intervention.

For more information on these topics, see Hand and Wrist Surgery in Rheumatoid Arthritis and Rheumatoid Arthritis of the Cervical Spine.

Studies in Muslim patients have reported improvement in RA disease activity associated with the intermittent fasting practiced during Ramadan (ie, from sunrise to sunset for a month).[164, 165, 166] Ben Nessib et al compared Disease Activity Scores (DAS) 28 assessed 6 months before starting Ramadan fasting and the second after at least 7 days of fasting in 36 patients with RA, and recorded a decrease from 4.3 to 3.5 (P <  0.001).[165] A subsequent study by this group in 35 patients demonstrated that the positive effects of fasting can persist for as long as 3 months.[166]

Classification and disease activity measures

Updated guidelines on following aspects of rheumatoid arthritis (RA) management have been published:

• Classification – American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR; now the European Alliance of Associations for Rheumatology), 2010 (see Workup/Diagnostic Criteria) ^[45]
• Measurement of RA disease activity – ACR, 2019 (see Workup/Measures of Disease Activity) ^[2]
• Remission criteria – ACR/EULAR, 2022 (see Workup/Measures of Disease Activity) ^[3]

Treatment

The ACR and EULAR regularly update their clinical practice guidelines on the pharmacologic management of RA. As general principles, guidelines from both organizations stress the importance of early initiation of therapy, shared decision making, and a treat-to-target approach, with frequent monitoring of treatment response. Both organizations offer similar recommendations on use of disease-modifying antirheumatic drugs (DMARDs).[4, 5]

ACR recommendations for initiation of treatment in DMARD-naïve patients with moderate to high disease activity are as follows[4] :

• Methotrexate monotherapy is strongly recommended over hydroxychloroquine or sulfasalazine; biologic DMARD (bDMARD) or targeted synthetic DMARD (tsMARD) monotherapy; or methotrexate plus a non–tumor necrosis factor (TNF) inhibitor bDMARD or tsDMARD
• Methotrexate is conditionally recommended over leflunomide; dual or triple conventional synthetic DMARD (csDMARD) therapy; or the combination of methotrexate with a TNF inhibitor

The ACR conditionally recommends against initiating short-term (< 3 mo) glucocorticoids along with a csDMARD, and strongly recommends against longer-term glucocorticoids.

ACR recommendations for initiation of treatment in DMARD-naïve patients with low disease activity are as follows:

• Hydroxychloroquine is conditionally recommended over other csDMARDs
• Sulfasalazine is conditionally recommended over methotrexate
• Methotrexate is conditionally recommended over leflunomide

In patients with moderate to high disease activity who have been treated with csDMARDs other than methotrexate, the ACR conditionally recommends methotrexate monotherapy over the combination of methotrexate with a bDMARD or tsDMARD

ACR treat-to target recommendations are as follows:

• A minimal initial treatment goal of low disease activity is conditionally recommended over a goal of remission.
• For patients taking oral methotrexate who are not at target, switching to subcutaneous methotrexate is conditionally recommended over adding or switching to alternative DMARD(s)
• For patients taking maximally tolerated doses of methotrexate who are not at target, the addition of a bDMARD or tsDMARD is conditionally recommended over triple therapy (ie, addition of sulfasalazine and hydroxychloroquine).
• For patients taking a bDMARD or tsDMARD who are not at target, switching to a bDMARD or tsDMARD of a different class is conditionally recommended over switching to a bDMARD or tsDMARD belonging to the same class.

ACR recommendations regarding discontinuation of DMARD therapy are as follows:

• For patients who are at target for at least 6 months, continuation of all DMARDs at their current dose is conditionally recommended over a dose reduction of a DMARD, dose reduction is conditionally recommended over gradual discontinuation of a DMARD, and gradual discontinuation is conditionally recommended over abrupt discontinuation of a DMARD.
• Gradual discontinuation of sulfasalazine is conditionally recommended over gradual discontinuation of hydroxychloroquine for patients taking triple therapy who wish to discontinue a DMARD.
• For patients taking methotrexate plus a bDMARD or tsDMARD who wish to discontinue a DMARD, gradual discontinuation of methotrexate is conditionally recommended over gradual discontinuation of the bDMARD or tsDMARD.

The ACR guidelines also include specific recommendations for patients with the following:

• Subcutaneous nodules
• Pulmonary disease
• Heart failure
• Lymphoproliferative disorder
• Hepatitis B infection
• Nonalcoholic fatty liver disease (NAFLD)
• Persistent hypogammaglobulinemia without infection
• Previous serious infection

EULAR guidelines include the following recommendations for DMARD use[5] :

• Therapy with DMARDs should be started as soon as RA is diagnosed.
• In every patient, the treatment target should be sustained remission or low disease activity.
• Patients with active disease should receive monitoring every 1–3 months; if no improvement occurs within at most 3 months, or the target has not been reached by 6 months, therapy should be adjusted.
• Methotrexate should be part of the initial treatment strategy . Leflunomide or sulfasalazine should be considered when methotrexate is contraindicated. If those three agents are contraindicated or not tolerated and the patient has early, mild disease (ie, without poor prognostic factors), hydroxychloroquine may be used.
• Short-term use of glucocorticoids should be considered when initiating or changing csDMARDs, but should be tapered and discontinued as rapidly as clinically feasible.
• If the treatment target is not achieved with the first csDMARD strategy and poor prognostic factors are absent, other csDMARDs should be considered. If poor prognostic factors are present, a bDMARD should be added; Janus kinase (JAK) inhibitors may be considered, but pertinent risk factors must be taken into account.
• bDMARDs and tsDMARDs should be combined with a csDMARD; in patients who cannot use csDMARDs as co-medication, interleukin-6 (IL-6) pathway inhibitors and tsDMARDs may have some advantages compared with other bDMARDs.
• If a bDMARD or tsDMARD has failed, treatment with another bDMARD or a tsDMARD should be considered; if a TNF or IL-6 receptor inhibitor therapy has failed,  an agent with another mode of action or a second TNF inhibitor or IL-6 receptor inhibitor may be used.
• After glucocorticoids have been discontinued and the patient is in sustained remission, dose reduction of DMARDs may be considered.

Optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach that includes both nonpharmacologic and pharmacologic therapies. The following pharmacologic agents are commonly used in RA:

• Nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs)
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Analgesics
• Corticosteroids

Class Summary

DMARDs represent the most important measure in the successful treatment of rheumatoid arthritis. These agents can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.

Leflunomide (Arava)

Leflunomide is indicated for the treatment of active RA to reduce signs and symptoms, inhibit structural damage and improve physical function. Corticosteroids, aspirin, or other NSAIDs may be continued during leflunomide use. Leflunomide is contraindicated in women who are or may become pregnant.

Leflunomide is a pyrimidine synthesis inhibitor that blocks autoimmune antibodies and reduces inflammation. It also inhibits dihydroorotate dehydrogenase, an enzyme in the de novo pyrimidine synthesis pathway and has antiproliferative activity. 

Sulfasalazine (Azulfidine, Azulfidine EN-tabs)

Sulfasalazine (SSZ) is indicated for the treatment of patients with RA who have had an inadequate response to salicylates or other NSAIDs. It acts locally to decrease inflammatory response and systemically inhibits prostaglandin synthesis.

SSZ delayed-release tablets do not have an immediate response; therefore, concurrent treatment with NSAIDs or other analgesics is recommended at least until the effect of the delayed-release tablets is apparent. The initial dosage is 0.5-1 g/day. The dosage can be adjusted to a dose of 3 g/day after 12 weeks if an adequate clinical response is not seen.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine (HCQ) is approved for the treatment of acute or chronic RA. The initial dosage is 400-600 mg/day; dosages should be computed on the basis of patient body weight. If a good clinical response is seen over a period of 4 to 12 weeks, the dosage can be reduced by 50% and continued at a level of 200-400 mg/day. The risk of retinopathy is greater when this dosage is exceeded. It should be noted that each 200 mg tablet contains only 155 mg of active drug.

Patients must have a baseline eye examination (including color and vision testing, funduscopic examination, and visual-field testing) performed before starting HCQ therapy. Most rheumatologists recommend an HCQ eye examination every 6-12 months.

Rituximab (Rituxan)

Rituximab is most often used in combination with methotrexate (MTX). It has been shown to be effective at reducing signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to therapy with 1 or more tumor necrosis factor (TNF) antagonists. Treatment with rituximab may deplete CD20+ B cells. The usual regimen consists of 2 intravenous (IV) infusions of 1000 mg, separated by 2 weeks, in combination with MTX.

Class Summary

DMARDs represent the most important measure in the successful treatment of RA.

Methotrexate (Rheumatrex, Trexall, Otrexup)

MTX is a folic acid antagonist that is approved for the management of severe active RA in patients who have had an insufficient therapeutic response to or are intolerant of an adequate trial of first-line therapy, including full-dose NSAIDs. It inhibits dihydrofolic acid reductase, which ultimately interferes with DNA synthesis, repair, and cellular replication.

Tocilizumab (Actemra)

Tocilizumab is an IL-6 receptor inhibitor. It is indicated for moderate to severe active RA in adults who have had an inadequate response to 1 or more TNF-antagonist therapies. It has been approved as an IV infusion or SC injection that may be used alone or in combination with MTX or other DMARDs. 

Sarilumab (Kevzara)

Human monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). It is administered as a SC injection. May be prescribed as monotherapy or with methotrexate or other conventional DMARDs.

Azathioprine (Imuran)

Although azathioprine is not a first-line agent, it is sometimes used in the treatment of active RA to reduce signs and symptoms, particularly in patients who may have coinciding connective tissue diseases, such as systemic lupus erythematosus. Aspirin, NSAIDs, or low-dose glucocorticoids may be continued during treatment with azathioprine. The mechanism whereby azathioprine affects autoimmune diseases is unknown; however, it works primarily on T cells.

The initial dosage is 1 mg/kg/day (50-100 mg/day) given as a single dose or in divided doses twice daily. The dosage may be increased by 0.5 mg/kg/day at 6-8 weeks and thereafter at 4-week intervals, up to a maximum dosage of 2.5 mg/kg/day. Azathioprine is available in tablet form for oral administration or in 100-mg vials for IV injection.

Cyclosporine (Gengraf, Neoral)

Although cyclosporine is approved for the treatment of patients with severe active RA in which the disease has not adequately responded to MTX, it is not commonly used to treat RA, because of its nephrotoxicity. When cyclosporine is used, patients' renal function must be closely monitored.

Cyclosporine can be used in combination with MTX in RA patients who do not have an adequate response to MTX alone.

Anakinra (Kineret)

Anakinra is a recombinant, nonglycosylated form of the human interleukin (IL)-1 receptor antagonist (IL-1Ra) that is indicated for reducing signs and symptoms and slowing the progression of structural damage of moderately to severely active RA that has failed treatment with 1 or more DMARDs. Anakinra can be used alone or in combination with DMARDs other than TNF-blocking agents.

Abatacept (Orencia)

Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. CD28 interaction provides a signal needed for the full T-cell activation that is implicated in RA pathogenesis.

This agent is approved for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA. Abatacept can be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

Class Summary

The recognition of TNF-α and IL-1 as central proinflammatory cytokines has led to the development of agents that block either these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions.

The TNF inhibitors, which bind TNF and thus prevent its interaction with its receptors, include etanercept, infliximab, golimumab, certolizumab, and adalimumab. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually MTX, has been administered without sufficient success.

Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, the emergence of antinuclear antibodies (ANAs), occasional drug-induced lupuslike syndromes, and infections. Rarely, demyelinating disorders and bone marrow suppression occur.

Acute and chronic infections, demyelinating disorders, New York Heart Association (NYHA) class III or IV heart failure, and recent malignancies are contraindications for the use of TNF inhibitors. A thorough search for latent tuberculosis using chest radiography or purified protein derivative (PPD) testing is recommended before these agents are started. Patients taking anti-TNF agents must avoid live-virus vaccines to avoid the risk of serious infection.

Infliximab (Remicade, Inflectra, infliximab-dyyb, Renflexis, infliximab-abda, Ixifi, infliximab-qbtx)

Infliximab, a chimeric monoclonal antibody against TNF-α, is approved for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA, in combination with MTX. This agent binds to cells that express membrane TNF. FDA approved infliximab-dyyb, infliximab-abda, and infliximab-qbtx as biosimilars and not as an interchangeable drug.

Etanercept (Enbrel, Erelzi, etanercept-szzs)

Etanercept, a bivalent p75–TNF receptor linked to the Fc portion of human immunoglobulin G (IgG), is approved for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA. It can be given alone or in combination with MTX. This agent binds lymphotoxin (formerly termed TNF-β) in addition to soluble TNF-α. 

Golimumab (Simponi, Simponi Aria)

Golimumab, a human monoclonal antibody to TNF-α, inhibits TNF-α bioactivity, thereby modulating immune activity in patients with RA. It is approved for the treatment of adults with moderately to severely active RA, in combination with MTX. It may be administered as either a SC injection every month, or as an IV infusion every 2 months following 2 once monthly doses. Golimumab should be given in combination with MTX.

Certolizumab (Cimzia)

Certolizumab is a pegylated anti−TNF-α agent, which results in disruption of the inflammatory process in RA. It is indicated for the treatment of adults with moderately to severely active RA. 

Adalimumab (Amjevita, Cyltezo, Humira, Hadlima, Hyrimoz, Adalimumab-atto, Adalimumab-adbm, Adalimumab-bwwd, Adalimumab-adaz)

Adalimumab is a recombinant human IgG1 monoclonal antibody that is specific for human TNF. It binds specifically to TNF-α and blocks interaction with p55 and p75 cell-surface TNF receptors. It is indicated to reduce inflammation and inhibit progression of structural damage in moderate to severe RA, alone or in combination with MTX or other nonbiologic DMARDs. This agent is reserved for those who experience an inadequate response to 1 or more DMARDs. Adalimumab can be used alone or in combination with MTX or other DMARDs. FDA approved adalimumab-atto, adalimumab-adbm, adalimumab-adaz, adalimumab-bwwd, as biosimilars and not as interchangeable drugs.

Class Summary

Janus kinase (JAK) pathway inhibitors consist of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoieses and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression.

Tofacitinib (Xeljanz, Xeljanz XR)

Tofacitinib is an oral JAK inhibitor. It is indicated as second-line treatment for moderate to severe active RA in patients with an inadequate response to or intolerance of MTX. Tofacitinib may be used as monotherapy or in combination with MTX or other nonbiologic DMARDs, but it should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine and cyclosporine). Tofacitinib is a JAK inhibitor that modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

Baricitinib (Olumiant)

Oral JAK inhibitor indicated for moderately to severely active RA as second-line treatment in adults who have had an inadequate response to one or more TNF-antagonists. It may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs. It should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine or cyclosporine).

Upadacitinib (Rinvoq)

Indicated for moderately to severely active RA in adults who have had an inadequate response or are intolerant to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiological DMARDs.

Class Summary

Although tetracyclines are not typically used to treat RA, the ACR recommends minocycline monotherapy in patients with a disease duration shorter than 24 months who have low disease activity and no poor prognostic factors.[148, 153]

Minocycline (Dynacin, Minocin)

The anti-inflammatory effects of minocycline may result from inhibition of inflammatory cell migration and transformation of lymphocytes.

Class Summary

NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. However, they do not retard joint destruction and therefore are not sufficient to treat RA when used alone. Like corticosteroids, NSAIDs can be reduced in dose or discontinued with successful DMARD therapy. These agents decrease intraglomerular pressure and decrease proteinuria.

The several dozen NSAIDs available can be classified into several different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, celecoxib, and diclofenac.

Ibuprofen (Advil, Motrin)

Ibuprofen is indicated for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Naprosyn, Aleve, Anaprox, Anaprox DS, Naprelan)

Naproxen is used to relieve mild to moderate pain. This agent inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Diclofenac (Voltaren, Cambia)

Diclofenac is one of a series of phenylacetic acids that have demonstrated anti-inflammatory and analgesic properties in pharmacologic studies. It is believed to inhibit COX, which is essential in the biosynthesis of prostaglandins.

Ketoprofen

Ketoprofen is used to relieve mild to moderate pain and inflammation. It reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors.

Celecoxib (Celebrex)

Celecoxib is approved for the relief of signs and symptoms of RA. It primarily inhibits COX-2, which is considered an inducible isoenzyme (induced during pain and inflammatory stimuli). Inhibition of COX-1 may contribute to NSAID gastrointestinal (GI) toxicity. At therapeutic concentrations, celecoxib does not inhibit COX-1, thus potentially resulting in decreased GI toxicity. Administer the lowest possible dose for each patient. Use of celecoxib has been associated with an increased risk of cardiovascular toxicity.

Class Summary

Analgesics such as acetaminophen may be used in patients with RA.

Acetaminophen (Tylenol)

Acetaminophen is used for analgesia in patients with documented hypersensitivity to aspirin or NSAIDs, those with upper GI disease, and those who are taking oral anticoagulants. This agent does not have anti-inflammatory properties.

Class Summary

Tramadol has been used to reduce pain in patients with RA. However, this agent only provides analgesic effects and does not have anti-inflammatory properties.

Tramadol (Ultram)

The immediate-release formulation of tramadol is approved for the management of moderate to moderately severe pain in adults. The extended-release formulation is used for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of pain for an extended period of time. Tramadol and its active metabolite (M1) binds to mu-opiate receptors in the central nervous system causing inhibition of ascending pain pathways, altering perception of and response to pain.

Class Summary

Topical agents such as diclofenac can provide analgesia for patients with RA. This agent is commonly used in patients who experience acute pain.

Diclofenac topical (Voltaren)

Diclofenac topical gel is approved in patients with osteoarthritis at a dosage of 32 g/day applied over all affected joints. It has also been used to provide analgesic effects in patients with RA.

Class Summary

Corticosteroids are potent anti-inflammatory drugs commonly used in patients with RA to bridge the time until DMARDs become effective. Prednisone dosages as high as 10 mg/day are typically used, but some patients may require even higher dosages. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.

Prednisone (Prednisone Intensol, Rayos)

Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Circadian (ie, bedtime) administration of modified-release prednisone (Rayos) has been shown shown to decrease morning stiffness with RA.

Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability. It is as adjunctive therapy for short term administration (for an acute episode or exacerbation) in RA.

Prednisolone (Orapred ODT, Pediapred)

Prednisolone controls or prevents inflammation by controlling the rate of protein synthesis, suppressing the migration of PMNs and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at the cellular level. It is as adjunctive therapy for short term administration (for an acute episode or exacerbation) in RA.

Class Summary

Chelation therapy in RA may suppress inflammation and arthritis by depressing T-cell activity.

Penicillamine (Cuprimine, Depen)

Penicillamine depresses circulating IgM rheumatoid factor and T-cell activity (but not B-cell activity). It is indicated in patients with severe, active RA who have failed to respond to an adequate trial of conventional therapy.