Articular manifestations of rheumatoid arthritis

INTRODUCTION — 

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune, inflammatory disorder of unknown etiology that primarily involves synovial joints. The arthritis is typically symmetric; if uncontrolled, it may lead to joint deformities due to erosion of cartilage and bone. The disease usually progresses from the periphery to more proximal joints and results in significant disability within 10 to 20 years in patients whose disease does not respond to treatment.

The symptoms of RA can affect patients' capacity to perform the activities of daily living (eg, walking, stairs, dressing, use of a toilet, getting up from a chair, opening jars, doors, typing) and those required in their occupation.

The major clinical features of RA, including the articular manifestations, are reviewed here. The systemic and extraarticular features and the diagnosis and differential diagnosis of RA are discussed in detail separately. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis".)

INITIAL CLINICAL PRESENTATION

Patterns of joint involvement — Rheumatoid arthritis (RA) most typically presents as polyarticular disease and with a gradual onset, but some patients can present with acute onset, intermittent or migratory joint involvement, monoarticular disease, or a proximal joint arthritis mimicking polymyalgia rheumatica (PMR).

Typical (classic) rheumatoid arthritis

●Time course – Classic RA typically has a gradual onset, but some patients can present with acute onset.

●Symptoms – Classic RA presents with joint pain and swelling, especially of the small joints of the hands, wrist, and forefoot, along with morning stiffness and decreased grip strength [1].

●Examination – Synovial thickening is detected by a "boggy" feel to a swollen joint, and effusion by demonstrating fluctuance. Heat and redness are not prominent features of RA, although an involved joint is often perceptibly warmer on careful examination.

●Symmetry – Symmetrical involvement of joints is a characteristic feature, although this may be less apparent early in the disease. The severity of joint disease and consequent deformity is sometimes notably asymmetrical, which may be due to unilateral overuse of a dominant limb, or joint protection of a limb resulting from neurologic disease.

Palindromic rheumatism — The onset of RA is episodic in a few patients, with one to several joint areas being affected sequentially for hours to days, alternating with symptom-free periods that may last from days to months; this episodic pattern is often referred to as a separate diagnosis known as "palindromic rheumatism."

●Relation to RA – The proportion of patients presenting with palindromic rheumatism who progress to develop RA or another well-defined disease varies between studies. In one study of 60 patients with palindromic rheumatism followed over 20 years, 40 (67 percent) developed RA [2]. In another study, among 147 such patients seen in a tertiary referral center, 41 were eventually diagnosed with RA (28 percent) and four with other disorders (three with systemic lupus erythematosus and one with Behçet syndrome) [3].

A response among patients with palindromic rheumatism to hydroxychloroquine (HCQ), which is also used for the treatment of RA, further supports the possibility that palindromic rheumatism can be a presenting feature of RA. The use of HCQ in such patients may also reduce the risk of progression to RA. One retrospective study of 113 patients with palindromic rheumatism found that those who received HCQ were 20 percent less likely to develop a chronic rheumatic disease [4].

●Risk factors – Patients with palindromic rheumatism have similar predisposing genetic risk factors to patients with a more typical persistent presentation of RA and exhibit a similar dose effect of carriage of certain human leukocyte antigen (HLA) alleles [3]. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Familial and genetic risk factors'.)

The presence of anti-citrullinated peptide/protein antibodies (ACPA), a serologic finding that is common in RA, might predict progression of palindromic rheumatism to RA, but evidence evaluating this possibility has been mixed [5]. In one study involving 61 patients followed for a mean of five-and-a-half years, ACPA testing was performed within a year of symptom onset, and antibodies were present in 83 percent of patients who progressed to definite RA but in only 19 percent of those whose disease did not [6,7]. However, in another study, a majority of those with palindromic rheumatism also had ACPA, but there was no significant difference in the frequency of ACPA between patients with persistent palindromic rheumatism and those who subsequently developed RA [8]. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies (ACPA)'.)

Monoarthritis — Persistent single-joint arthritis (monoarthritis), frequently of a large joint such as the wrist, knee, shoulder, hip, or ankle, may be the sole manifestation of RA or may herald the onset of polyarticular disease. There may be a history of joint trauma as an apparent initiating event. The interval between monoarthritis and polyarthritis may extend from days to several weeks in patients whose disease progresses. Until polyarthritis develops, such patients should be evaluated as any patient presenting with monoarticular arthritis. (See "Monoarthritis in adults: Etiology and evaluation".)

Proximal joint arthritis — Occasionally, some patients may present predominantly with proximal joint stiffness suggestive of PMR. When this occurs in the absence of clinically detectable synovitis, the distinctive clinical features of RA may not develop until months or even years later.

Other patients may have features suggestive of PMR in addition to features of polyarticular RA. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica", section on 'Clinical features' and "Clinical manifestations and diagnosis of polymyalgia rheumatica", section on 'Differential diagnosis'.)

Morning stiffness — Morning stiffness is a common feature of those with active RA; it can be defined as "slowness or difficulty moving the joints when getting out of bed or after staying in one position too long, which involves both sides of the body and gets better with movement" [9].

Morning stiffness lasting more than one hour reflects a severity of joint inflammation that rarely occurs outside of active inflammatory arthritis. Morning stiffness, or stiffness after any prolonged period of inactivity ("gelling phenomenon"), is seen in virtually all inflammatory arthropathies and is not specific for RA [10].

Other symptoms

●Other symptoms may include generalized aching, stiffness, weight loss, depression, and fatigue. In some patients, persistent extraarticular symptoms may antedate the onset of polyarthritis by many months; these symptoms include generalized aching, stiffness, symptoms of bilateral carpal tunnel syndrome, loss of weight, depression, and fatigue (the last simulating chronic fatigue syndrome, also known as myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]).

●Patients with extraarticular RA may have additional symptoms reflecting specific organ involvement (eg, subcutaneous ["rheumatoid"] nodules, pleuropericarditis, airway and parenchymal lung diseases, neuropathy, episcleritis, scleritis, splenomegaly, Sjögren's disease, vasculitis). Involvement of the musculoskeletal system other than joints (eg, bone and muscle) and of extraarticular organs (eg, skin, eyes, lungs, heart, and others) occurs in approximately 40 percent of patients with RA over the course of the disease. In addition, patients may rarely present with extraarticular disease in the absence of clinical arthritis.

●In up to one-third of patients with disease onset after age 60 (historically termed "elderly-onset RA"), the acute onset of polyarthritis is associated with prominent myalgia, fatigue, low-grade fever, weight loss, and depression.

The systemic and extraarticular manifestations of RA are discussed in detail separately. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

SPECIFIC JOINT INVOLVEMENT — 

The key features of early rheumatoid inflammation are pain and swelling of the affected joints due to synovial hypertrophy or effusion.

The characteristic joint deformities are late manifestations of disease that result from the physical stresses and damage to the local anatomy of involved joints. Symmetrical involvement of joints is a characteristic feature, although this may be less apparent early in the disease.

Upper extremity — Rheumatoid arthritis (RA) eventually affects the peripheral joints in almost all patients. Typically, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the fingers, the interphalangeal joints of the thumbs, and the wrists are sites of arthritis early in the disease [11,12].

Hands — The main signs of disease can often be found in the hands early in the course of RA [13]. In patients with RA, pain and soft tissue swelling of the small joints of the hands leads to a number of findings on physical examination, including the following:

●Dorsal swelling – The whole hand may be swollen in very acute RA, with pitting edema over the dorsum giving rise to the "boxing glove" appearance. More often, this swelling is localized around the involved joint.

●Palmar changes – Palmar erythema may be present (as with any peripheral arthritis). Occasionally, thickening of the flexor tendons can be detected by palpation of the palm; this finding is due to synovitis of the tendon sheaths ("tenosynovitis"). Nodules may form along the palmar tendon sheaths, resulting in the tendon sheath catching (or triggering) and an inability to fully extend the finger. The nodules may cause tendon rupture, especially of the extensor pollicis longus (extensor of the distal interphalangeal [DIP] joint of the thumb).

●Restricted range of motion – The range of movement of involved joints is restricted, and loss of active flexion may be so severe that the patient is unable to oppose the fingertips to the palm.

●Reduced grip strength – Reduced grip strength, which is common, can be a surprisingly sensitive indicator of early disease, as well as a useful parameter in the evaluation of disease activity and progression. However, these findings can be found in other forms of inflammatory arthritis. Additionally, a number of factors (eg, joint pain, tendon involvement, nerve compression, and muscle wasting) that contribute to a weak grip, which makes this finding somewhat nonspecific.

●Squeeze tenderness – In patients with early RA, grasping the MCP joints and applying gentle pressure (the "squeeze test") may elicit pain when other physical findings associated with synovitis are less apparent.

●Carpal tunnel syndrome – Between 1 and 5 percent of patients present with carpal tunnel syndrome. Affected patients develop dysesthesia and muscle weakness of the first three fingers and the radial side of the fourth finger. A positive Tinel or Phalen sign is usually present. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis".)

●Deformities – The characteristic joint deformities appear in more established chronic RA. These findings include MCP subluxation, ulnar deviation or "ulnar drift," swan neck and Boutonniere deformities of the fingers (picture 1A-C), and the "bow string" sign (prominence of the tendons in the extensor compartment of the hand). Occasionally, patients present with extensor tendon rupture, most commonly affecting the thumb or little or ring fingers of either hand. The nails and fingertips may show evidence of digital infarcts in patients with rheumatoid vasculitis. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Cutaneous vasculitis'.)

Wrists, elbows, and shoulders — All of the upper-extremity joints may be involved in RA, including the wrists, elbows, and shoulders. Wrist involvement is often seen early in the disease course.

●Wrists – The wrist is probably the most common upper-extremity joint to be involved other than the small joints in the hand. Early in the disease, there is a loss of extension. Late changes due to erosive damage lead to volar subluxation and radial drift of the carpus, resulting in increasing prominence of the ulnar styloid and lateral deviation [14]. Tendon rupture can also occur at the wrist. Synovitis of the wrist may present as carpal tunnel syndrome even in very early disease when swelling may not be particularly evident.

●Elbows – The elbow is frequently affected, with loss of extension (fixed flexion) both in early and late disease (image 1). An effusion or synovitis may be detected as a bulge between the head of the radius and the olecranon. A compressive neuropathy of the ulnar nerve, with dysesthesias of the fourth and fifth fingers, can result from elbow synovitis. Olecranon bursitis is also common (picture 2). Destruction of the joint may occur due to erosion of cartilage and bone.

The extensor surface of the elbow is the most common site for subcutaneous rheumatoid nodules (picture 3). These should always be visually examined and palpated for in view of their diagnostic and prognostic importance. (See "Rheumatoid nodules".)

●Shoulders – The shoulder, being more proximal, tends to be involved later in the disease and may be less common due to the widespread use of biologic disease-modifying antirheumatic drugs (DMARDs) [15]. The most common site for erosions is the superolateral aspect of the humerus [15].

Disease in the glenohumeral joint leads to painful restriction of movement resembling a capsulitis and can result in the development of a "frozen" shoulder. This will typically cause pain at night, when the patient lies on the affected shoulder and marked restriction of range of motion due to the accompanying pain. Rotator cuff injury is common. Effusions are relatively rare, but when they occur, they may be detected in the anterior glenohumeral joint as a filling of the depression under the clavicle anterior to the head of the humerus.

Lower extremity — Lower-extremity joints are often involved in RA, particularly in the forefoot and ankles; the knees and hips may also be affected, but hip involvement tends to occur in more severe or longstanding disease. Synovitis in the knee may predispose to the development of popliteal (Baker's) cysts.

●Feet and ankles – Foot involvement, especially of the metatarsophalangeal (MTP) joints, is common in early disease, with a pattern that mirrors that occurring in the hand. Involvement of the feet is typically under-recognized, making it imperative for the clinician to closely inspect the bare feet. Foot and ankle involvement is associated with the following characteristics:

•Dorsal foot swelling – Involvement of the tarsus and the associated tendon sheaths is also common, leading to diffuse edema and erythema over the dorsum of the foot.

•Dorsal ankle swelling – Arthritis of the ankle can lead to a diffuse swelling around the tibiotalar joints, which may be red and edematous. These findings may be wrongly attributed to fluid retention or an infective cellulitis of the skin.

•MTP tenderness – Tenderness of the MTP joints may be marked, resulting in the tendency to bear weight on the heels and hyperextend the toes. The fifth MTP is the most frequently involved, and swelling of this joint may be most readily appreciated on examination. Grasping the MTP joints and applying gentle pressure (the "squeeze test") may elicit pain when other physical findings associated with synovitis are less apparent.

•Heel pain – Heel pain may be associated with retrocalcaneal bursitis or tarsal tunnel syndrome, caused by impingement of the posterior tibial nerve. Tarsal tunnel syndrome is also associated with paresthesia of the toes and is important because it can be diagnosed by ultrasound and treated by local injection or surgical release. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Tarsal tunnel syndrome'.)

•Painful inversion/eversion – Involvement of the taurus and associated tendon sheaths may also lead to pain on inversion or eversion of the foot and ankle.

•Joint deformities – Erosive damage results in lateral drift of the toes and plantar subluxation of the metatarsal heads (picture 4), resulting in "cock-up" deformities. The latter may be palpable as bony lumps on the sole with associated callosities.

●Knees – The knee manifests many changes in RA.

•Synovial thickening – Synovial thickening is easily detected at the knee, extending the suprapatellar recess around the patella.

•Effusion – Effusion is a common feature of knee involvement and can be elicited by patellar tap.

•Restricted movement – Restriction of movement, particularly flexion, is also a common physical finding.

•Ligamentous laxity – Ligamentous laxity leading to deformities and quadriceps atrophy may occur, if knee synovitis is not controlled.

•Joint deformities – Erosion of the femoral condyles and tibial plateau can result in either genu varus or genu valgus.

•Popliteal cysts – Patients with RA may develop popliteal (Baker's) cysts, which can be detected by inspection and palpation of the popliteal fossa (picture 5) [16]. Ruptured Baker's cysts extending down the calf are of clinical importance because they can resemble a deep vein thrombosis or acute thrombophlebitis [17]. A history of arthritis, morning stiffness, lack of a palpable occluded venous cord, and edema below the posterior of the knee all suggest a Baker's cyst. Ultrasonography is generally used for the detection of intact or ruptured Baker's cysts (image 2A-B), and they can be readily imaged by magnetic resonance imaging (MRI), although historically a ruptured Baker's cyst was usually demonstrated using arthrography (picture 6) [18]. (See "Popliteal (Baker's) cyst".)

●Hips – Involvement of the hips typically occurs only in longstanding disease. Hip disease is most frequently manifested as pain in the groin, thigh, or low back, or referred to the knee on standing or movement. Restriction of movement, detected by "log-rolling the leg" or rotation of the hip, also may be seen. Pain in the lateral thigh suggests trochanteric bursitis. (See "Greater trochanteric pain syndrome (formerly trochanteric bursitis)".)

Axial skeleton

●Cervical spine – Severe disease of the cervical spine (particularly C1 to C2) may cause serious neurologic compromise, generally in patients with longstanding disease. Symptoms of pain and stiffness in the neck are the most typical manifestation, but disease affecting the joints of the cervical spine can be of critical clinical importance, as longstanding disease may lead to instability and cause symptoms related to subluxation such as neck pain, stiffness, and radicular pain. If the subluxation is causing spinal cord compression, there may be signs of long tract involvement such as hyperreflexia or upgoing toes on Babinski testing. The clinical manifestations of cervical spine subluxation and the approach to diagnosis and management are discussed in detail separately. (See "Cervical subluxation in rheumatoid arthritis".)

●Other axial and central joints – Involvement of axial and central joints is uncommon; such joints include the interfacetal and atlantoaxial joints of the neck as well as the acromioclavicular [19], sternoclavicular, temporomandibular, and cricoarytenoid joints.

Involvement of the facet joints of the lumbar spine and occasionally discitis has been reported to occur in RA, both from radiographic and post-mortem studies [20]. However, in clinical practice, it is important to exclude more common and serious causes of back pain, such as vertebral compression fractures associated with low bone mass, before attributing back pain to rheumatoid involvement of the lumbar spine.

Cricoarytenoid joint — Cricoarytenoid joint involvement may be asymptomatic or cause symptoms of hoarseness and/or inspiratory stridor in patients with RA. In studies conducted prior to the use of biologic DMARDs for RA, direct laryngoscopy studies reported the prevalence of cricoarytenoid joint involvement at 30 to 50 percent, and potentially higher in studies using advanced imaging techniques. As an example, one study from 1984, involving 45 patients with RA, found laryngeal involvement in 32 percent by laryngoscopy and 54 percent by computed tomography (CT) [21]. While the current prevalence of cricoarytenoid joint involvement in patients with RA is unclear, in our experience, modern treatment approaches have made it rare.

LABORATORY FINDINGS — 

A number of abnormalities are present in the blood and synovial fluid of patients with rheumatoid arthritis (RA) that reflect the presence of systemic and intraarticular inflammation and the autoimmune features of the disorder; these include inflammatory joint fluid, anemia of chronic inflammation, the presence of rheumatoid factor (RF) and anti-citrullinated peptide/protein antibodies (ACPA), and evidence of an acute phase response that tends to correlate with the degree of disease activity.

●Synovial fluid – Synovial fluid examination in affected joints usually reveals an inflammatory effusion. (See "Synovial fluid analysis" and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation and diagnosis'.)

•Leukocytes – In a patient with active RA, the synovial fluid typically demonstrates a leukocyte count between 1500 and 25,000/cubic mm characterized by a predominance of polymorphonuclear cells [22]. Cell counts in excess of 25,000 may indicate the presence of coexisting infection, although they can also be found in patients with very active disease [23,24].

•Complement – Additional findings in RA synovial fluid are low C3 and C4 complement levels in contrast to higher levels found in the blood. However, these are not routinely obtained in clinical settings.

•Glucose – Historically, synovial fluid glucose levels in RA have been noted to be low relative to simultaneous blood glucose measurement, but such testing is not useful in clinical practice.

●Hematologic abnormalities – Common hematologic abnormalities associated with active RA include anemia of chronic inflammation, thrombocytosis, and sometimes a mild leukocytosis. There is an increased risk of lymphoproliferative disease, including non-Hodgkin lymphoma. Felty syndrome, with neutropenia and splenomegaly, and large granular lymphocyte leukemia are very infrequent.

The hematologic features of RA are described in detail separately. (See "Hematologic complications of rheumatoid arthritis" and "Clinical manifestations and diagnosis of Felty syndrome" and "Large granular lymphocyte leukemia in rheumatoid arthritis".)

●Autoantibodies – Approximately 75 to 80 percent of patients with RA test positive for RF, ACPA, or both; patients with RA and such antibodies are defined as having "seropositive RA," and the presence of the antibodies has diagnostic, therapeutic, and prognostic implications. While RF and ACPA have similar sensitivity, ACPA are much more specific for RA compared with RF. Approximately a quarter to a third of patients with RA have antinuclear antibodies as well [25]. While the prognostic importance of antinuclear antibodies in RA is not established, clinicians should recognize that SSA antibodies in an RA patient also confer risk of neonatal lupus and heart block [25]. Other autoantibody responses to post-translationally modified proteins have been observed in RA, though their clinical utility has not been defined.

These serologic features of RA are reviewed in detail separately. (See "Biologic markers in the assessment of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation and diagnosis'.)

●Acute phase response – Measures of the acute phase response, including the erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP), are usually elevated in patients with active disease, and the degree of elevation in a given patient tends to correlate with disease activity; however, mild disease activity is sometimes present without such abnormalities.

ESR and CRP in RA and the acute phase response are discussed in more detail separately. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Erythrocyte sedimentation rate' and "Biologic markers in the assessment of rheumatoid arthritis", section on 'C-reactive protein' and "Acute phase reactants".)

IMAGING — 

Patients with rheumatoid arthritis (RA) develop joint space narrowing and bony erosions, which are typically evaluated using plain radiographs of the hands and feet (see 'Plain film radiography' below). Erosions of cartilage and bone can also occur in some other forms of inflammatory and gouty arthropathy and are therefore not necessarily diagnostic of RA. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.)

MRI studies and ultrasonography are more sensitive than radiography for the detection of changes resulting from synovitis, but additional research is ongoing to determine the prognostic importance of changes observed with these studies that are not evident radiographically. (See 'Magnetic resonance imaging' below and 'Ultrasonography' below.)

Plain film radiography — Progressive radiographic changes occur in the affected joints of patients with active disease, including periarticular osteopenia, joint space narrowing, and bone erosions. Deformities, including joint subluxation, and secondary degenerative changes may occur with an active disease course.

Plain radiographs are often normal early in disease, and the early changes evident on plain films may include only soft tissue swelling and periarticular osteopenia (image 3A-C). To be detected by plain radiography, erosions must have eroded through the cortex of the bone around the margins of the joint. In some patients, erosions occur first in the ulnar styloid (image 4A-B) or metatarsophalangeal (MTP) joints (image 5A-B). Joint space narrowing may also be present. Radiographic evidence of joint injury in patients with early RA is often greater in the dominant than the nondominant hand [26]. Similar asymmetry in joint damage has long been observed in patients with hemiplegia [27]. With extreme destruction, the severity of erosions may reach a level beyond which further progression cannot be assessed radiographically, despite the presence of ongoing joint damage [28].

In studies done in the late 1980s and early 1990s, erosions in the metacarpophalangeal (MCP) (image 6A-B and image 7) and proximal interphalangeal (PIP) joints (image 8A-B) were identified by plain radiography in 15 to 30 percent of patients in the first year of the disease. By the end of the second year of disease in patients who did not respond to therapy, the cumulative incidence of erosions was 90 percent [29,30].

Magnetic resonance imaging — MRI is a more sensitive technique than plain radiography for identifying bone erosions and evidence of active RA (eg, bone marrow edema, synovial hypertrophy).

●Bone erosions – When radiography and MRI were compared in a group of 55 patients with early arthritis, MRI identified seven times as many erosions in the MCP and PIP joints than plain radiography [31]. MRI also may detect bone erosions earlier in the course of the disease than is possible with plain films [32]. As an example, approximately 45 percent of patients with symptoms for only four months were found to have erosions detected by this method [33]. A similarly increased sensitivity of MRI has also been noted for early RA of the forefoot [34]. However, the prognostic significance of erosions only detected by MRI is not clear [35].

●Bone marrow edema – Decreased signal from the bone marrow on T1-weighted images and enhancement of the marrow with gadolinium administration is interpreted as bone marrow edema. The presence of marrow edema on MRI is predictive of later development of erosive disease [36].

●Synovial hypertrophy – It is also possible to identify and estimate the quantity of hypertrophic synovial tissue using MRI. The presence of MRI-detected synovial proliferation correlates with the later development of bone erosions [37]. Use of this imaging technique outside of research settings may be hastened by the development of MRI scanners that are designed specifically for imaging the extremities, but clinical indications for the use of such techniques remain uncertain [38,39].

Ultrasonography — Ultrasonography is another sensitive alternative imaging technique for estimating the degree of inflammation and the volume of inflamed tissue. In particular, ultrasonography can also be used to assess the MTP joints, which may become affected early in the course of disease but can be difficult to assess by physical examination alone [40].

Direct comparison of color Doppler ultrasonography and contrast-enhanced MRI in one study of 29 patients demonstrated agreement regarding the presence or absence of inflammation between the two techniques in 75 percent of the joints of the hands and wrists [41]. Both imaging modalities found features of inflammation in joints that were neither tender nor swollen on physical examination. However, the clinical importance of these findings remains to be determined.

Ultrasound evaluation for bone erosions and synovitis is described in more detail separately. (See "Musculoskeletal ultrasonography: Clinical applications", section on 'Joints'.)

CLINICAL COURSE

Patterns of progression — Rheumatoid arthritis (RA) shows a marked variation of clinical expression in individual patients (table 1). These differences may be apparent in the number of involved joints and pattern of joint involvement, fluctuations in disease activity and ability to achieve remission, and the rate of progression and extent of structural damage. Some patients may have mainly small joints or large joints affected. A given patient may also have only a few or almost all joints involved. In addition, extraarticular disease may be prominent in a subset of patients. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Functional outcomes'.)

The prognosis associated with RA is discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Prognosis'.)

Disease activity versus structural damage — The concept of disease activity is based upon the state of the underlying inflammatory response and may be distinguished from the destructive process that leads to irreversible damage of the joint (table 2):

●Disease activity – Disease activity can (and does) vary. Variations in disease activity impact the rapidity of structural damage to joints [42]. Most patients show fluctuation of disease activity over periods lasting weeks to months. This corresponds to an increase or decrease in symptoms of arthritis, a pattern which may recur throughout the course of the disease. This variation in part reflects the endogenous rhythms of the disease process but is mainly the result of therapeutic interventions. The early initiation of disease-modifying antirheumatic drugs (DMARDs) improves the likelihood of attaining clinical remission, although sustained remission occurs in the minority of patients. Subsequent tapering of DMARDs (due to intolerance or patient/clinician preference) or loss of efficacy may lead to exacerbations of disease activity that may result in structural damage if not treated effectively. Drug-free remission, defined as clinical remission without requiring DMARD therapy, is very rare [43,44]. (See 'Remission' below.)

●Damage – Structural damage is cumulative and irreversible. The degree of damage is closely linked to disease activity (ie, resulting from disease activity) but is also associated with mechanical stressors leading to joint degeneration [45]. As structural damage progresses, the detection of variation in disease activity by clinical examination becomes increasingly difficult. At these later stages, symptoms and signs of inflammation, such as pain, stiffness, tenderness, swelling, and joint effusions, may be caused either by continuing rheumatoid disease or as a secondary result of mechanical and degenerative change.

Remission — Disease remission occurs when there is little or no evidence of clinical disease activity. However, achieving remission does not entirely preclude the development of further erosive changes. This was illustrated in a retrospective study of 187 patients who were in remission for six months and whose clinical course and radiographic findings were subsequently followed [46]. A majority (52 percent) remained in remission during two years of follow-up. However, despite inapparent clinically active disease, one new erosion in a previously unaffected joint appeared in 14 percent of these patients.

In our experience, reaching and maintaining remission is very rare without DMARDs. As an example, among 191 patients treated with such drugs beginning within a year of disease onset, 48 (25 percent) met criteria for remission after three years of treatment, and 38 (20 percent) after five years of DMARD therapy [47]. The likelihood of achieving remission with DMARD treatment within the first year of disease was greater in patients with less initial disease activity, less disability, lower levels of acute phase reactants, absence of rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA), and less radiographic joint damage.

Attempts to define clinical remission for clinical practice and in clinical trials, in order to understand better the natural history of RA and the effects of therapy, have resulted in provisional definitions of remission by a joint effort of the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [48-50]. These definitions take into account that a complete lack of joint pain, swelling, and tenderness may be impossible to achieve in patients who have developed structural damage of the joints or who have other medical conditions, despite actual remission in the rheumatoid disease process. The absence of all such symptoms and findings is not required by the ACR/EULAR criteria, and revised criteria endorse a less stringent patient global assessment cutoff. The ACR/EULAR (2022 revision) definitions of remission include use of the Clinical Disease Activity Index, Simplified Disease Activity Index, or Boolean 2.0 remission (which requires tender joint count swollen joint count, C-reactive protein (CRP; in mg/dL) ≤1, and patient global assessment [0 to 10 scale] ≤2) [50]. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Criteria for remission'.)

Strategies for managing patients with RA in remission are discussed in detail elsewhere. (See "Overview of the management of rheumatoid arthritis in adults", section on 'Tapering medications in patients with sustained remission'.)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)" and "Patient education: Hand pain (The Basics)")

●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Initial presentation – Rheumatoid arthritis (RA) most typically presents as polyarticular disease and with a gradual onset, but some patients can present with acute onset, intermittent or migratory joint involvement ("palindromic rheumatism"), monoarticular disease, or a proximal joint arthritis mimicking polymyalgia rheumatica (PMR). Morning stiffness is a common feature, and many patients will also note generalized aching, stiffness, weight loss, depression, and fatigue, which may antedate the onset of arthritis. Other symptoms may be caused by extraarticular manifestations of RA. (See 'Initial clinical presentation' above.)

●Distribution of joint involvement – RA eventually affects the peripheral joints in almost all patients. Symmetrical joint involvement is characteristic, although this may be less apparent early in the disease. The pattern of joint involvement may also be diagnostically useful. Squeeze tenderness at the metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints and palpable synovial thickening at these joints are characteristic of RA. (See 'Patterns of joint involvement' above.)

•Upper extremity – All of the upper-extremity joints may be involved in RA, although hand and wrist involvement is often seen early in the disease course.

•Lower extremity – Forefoot and ankle disease is common in RA; synovitis in the knees may predispose to the development of popliteal (Baker’s) cysts.

•Axial skeleton – Severe disease of the cervical spine (particularly C1 to C2) may cause serious neurologic compromise, generally in patients with longstanding disease. Involvement of axial and central joints is otherwise less common, and investigation of other causes of such symptoms should be pursued.

•Cricoarytenoid joint – Approximately 30 percent of patients with RA have involvement of the cricoarytenoid joint, which may be asymptomatic but can also lead to hoarseness and stridor.

●Laboratory findings – A number of abnormalities are present in the blood and synovial fluid of patients with RA. These include changes reflecting systemic and intraarticular inflammation, and the autoimmune features of the disorder, including the presence of rheumatoid factors (RF) and anti-citrullinated protein/peptide antibodies (ACPA). (See 'Laboratory findings' above.)

●Imaging findings – Patients with RA develop joint space narrowing and bony erosions, which are often observed in plain radiographs of the hands and feet. These may already be present when first seen by a clinician but more usually become evident over time with ongoing synovitis beyond the first few months of disease. MRI and ultrasound are more sensitive imaging modalities than plain radiographs. (See 'Imaging' above.)

●Variation in clinical course and pattern of presentation – RA shows a marked variation of clinical expression in individual patients (table 1). This difference may be apparent in the number and pattern of joint involvement and whether extraarticular disease is prominent. Variation is also seen in the course of disease activity and the rapidity of structural damage to joints. (See 'Clinical course' above and 'Patterns of progression' above.)

●Disease activity versus structural damage – The concept of disease activity is based upon the state of the underlying inflammatory response and may be distinguished from the irreversible damage of the joint that results from this inflammatory response (table 2). In a minority of patients, disease activity is absent; in this circumstance, the disease is said to be in remission but typically continues to require disease-modifying antirheumatic drug (DMARD) therapy. (See 'Disease activity versus structural damage' above and 'Remission' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS and PJW Venables, MA, MB BChir, MD, FRCP, who contributed to earlier versions of this topic review.