Official reprint from UpToDate www.uptodate.

com 2012 UpToDate

Clinical fea

e of he ma oid a h i i
Sec ion Edi o James R O'Dell, MD Dep Edi o Paul L Romain, MD

A ho PJW Venables, MA, MB BChir, MD, FRCP RN Maini, BA, MB BChir, FRCP, FMedSci, FRS Di clo e

All topics are updated as new evidence becomes available and our peer review process is complete. Li e a e e ie c en h o gh: feb 2012. | Thi opic la pda ed: dic 6, 2011. INTRODUCTION Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown etiology that primarily involves joints. The arthritis is symmetrical, may be remitting, but if uncontrolled may lead to destruction of joints due to erosion of cartilage and bone which leads to deformity. The disease usually progresses from the periphery to more proximal joints, and in patients who do not fully respond to treatment, results in significant locomotor disability within 10 to 20 years. Many of the clinical features that are discussed in this topic review are used in the clinical diagnosis of RA and also serve as classification criteria for RA. The latter are used to define patient populations with RA for clinical or other research purposes. The diagnosis and classification of RA are presented separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".) The following is a summary of characteristic clinical features, some of which are also useful for diagnostic and/or classification purposes: Morning stiffness for at least one hour and present for at least six weeks Swelling of three or more joints for at least six weeks Swelling of wrist, metacarpophalangeal, or proximal interphalangeal joints for at least six weeks Symmetric joint swelling Hand x-ray changes typical of RA that include erosions or bony decalcification Rheumatoid subcutaneous nodules Rheumatoid factors or anti-citrullinated peptide/protein antibodies Elevated acute phase reactants (erythrocyte sedimentation rate or C-reactive protein) CLINICAL PRESENTATIONS Polyarticular disease with a gradual onset, intermittent or migratory joint involvement, and a monoarticular onset are different types of clinical presentations of RA. In addition, extraarticular manifestations may be present. Patients need to be questioned regarding how the arthritis has affected their 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), the type of job they have, and their ability to do their job. T pical "cla ic" RA The disease onset is usually insidious, with the predominant symptoms being pain, stiffness, and swelling of many joints [1]. Typically, the metacarpophalangeal and proximal interphalangeal joints of the fingers, interphalangeal joints of the thumbs, the wrists, and metatarsophalangeal joints of the toes are sites of arthritis early in the disease. Other joints of the upper and lower limbs, such as the elbows, shoulders, ankles, and knees are also commonly affected [2,3]. Morning stiffness is a common feature of those with active RA; it has been defined as the following: "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" [4]. Morning stiffness, or stiffness after any prolonged period of inactivity, is also seen in virtually all inflammatory

arthropathies and myopathies [5]. However, morning stiffness lasting more than one hour reflects a severity of joint inflammation that rarely occurs in diseases other than RA. Up to one-third of patients have the acute onset of polyarthritis associated with prominent myalgia, fatigue, low grade fever, weight loss, and depression. Occasionally, the syndrome of polymyalgia rheumatica may be present. 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. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".) Palind omic he ma i m The onset of RA is episodic in a few patients, with one to several joint areas being affected sequentially for hours to days, with symptom free periods that may last from days to months; an episodic pattern referred to as "palindromic rheumatism." Patients with palindromic rheumatism have similar predisposing genetic risk factors and exhibit a dose effect of carriage of certain HLA alleles, as do patients with a more typical persistent presentation of RA [6]. (See "Epidemiology, risk factors for, and possible causes of rheumatoid arthritis", section on 'Genetic susceptibility'.) 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 [7]. In another study, among 147 such patients seen in a tertiary referral center, 41 were eventually diagnosed with RA (28 percent) and 4 with other disorders (3 with systemic lupus erythematosus and 1 with Behet s disease) [6]. In one study, a majority of those with palindromic rheumatism also had anti-citrullinated peptide/protein antibodies (ACPA), a serologic finding that is common in RA [8]. In another study, ACPA were positive in 83 percent of patients who progressed to definite RA [9]. (See "Clinically useful biologic markers in the diagnosis and assessment of outcome in rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.) Use of antimalarial drugs may reduce the risk of progression to RA. One retrospective study of 113 such patients found that those who received antimalarials were 20 percent less likely to develop a chronic rheumatic disease [10]. Monoa h i i Persistent single joint arthritis (monoarthritis), frequently of a large joint such as the knee, shoulder, hip, wrist, or ankle, may be the sole manifestation 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, the approach to such patients is that for any patient with monoarticular arthritis. (See "Evaluation of the adult with monoarticular pain".) E aa ic la in ol emen Extraarticular features of RA, including anemia, fatigue, subcutaneous ("rheumatoid") nodules, pleuropericarditis, neuropathy, episcleritis, scleritis, splenomegaly, Sjgren's syndrome, vasculitis, and renal disease, may occur during the course of the disease These and other systemic and extraarticular manifestations are presented in more detail separately. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".) Most patients with extraarticular manifestations also have the classic joint symptoms of RA. Rarely, patients present with extraarticular disease in the absence of clinical arthritis. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".) In addition, a proportion of patients complain of persistent nonarticular symptoms, such as generalized aching, stiffness, bilateral carpal tunnel syndrome, loss of weight, depression, and fatigue (the last simulating chronic fatigue syndrome). This constellation of symptoms may antedate the onset of polyarthritis by many months. DISTRIBUTION OF JOINT INVOLVEMENT RA eventually affects the peripheral joints in almost all patients. Involvement of axial and central joints, such as the interfacetal and atlantoaxial joints of the neck, acromioclavicular [11], sternoclavicular, temporomandibular, cricoarytenoid joints, and shoulders and hips is less common, occurring in 20 to 50 percent of patients. 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, an

observation that may be attributed to increased structural damage to joints related to unilateral overuse of a dominant limb, or joint protection of a limb resulting from neurologic disease. The pattern of joint involvement may also be diagnostically useful. As an example, involvement limited to the distal interphalangeal joints is usually due to osteoarthritis, whereas proximal interphalangeal involvement can reflect either RA or osteoarthritis. Squeeze tenderness at the MCP and MTP joints and palpable synovial thickening at these joints are characteristic of RA. CLINICAL COURSE 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. As an example, 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. Finally, extraarticular disease may be prominent in a subset of patients. Pa e n of p og e ion Variation is also seen in the course of disease activity and the rapidity of structural damage to joints [12]. 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. Disease activity may not abate in about 10 to 20 percent of cases. Remission has been reported in a small proportion of patients with a well established diagnosis of RA [13]. In our experience, however, this is very rare without disease modifying antirheumatic drugs (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 [14]. Some clinical features that can be assessed early in the course of RA may be predictive of the likelihood of achieving a remission with DMARD treatment. Patients with less initial disease activity, less disability, lower levels of acute phase reactants, absence of RF and antibodies to citrullinated peptides (ACPA), and less radiographic joint damage when initially evaluated, are more likely to achieve a remission when treated with DMARDs within the first year of disease [14]. Di ea e ac i i e c al 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 can (and does) vary. This variation in part reflects the endogenous rhythms of the disease process but is mainly the result of therapeutic interventions. Thus, periods of spontaneous exacerbations and quiescence, characterized by an increase (a "flare") or decrease in symptoms, are modulated by both the beneficial effects of drug therapy and withdrawal of therapy due to loss of efficacy or side effects. In contrast, structural damage is cumulative and irreversible. The degree of damage is closely linked to inflammation and hence to disease activity, but is also associated with degeneration and repair [15]. 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. Remi ion Rarely, disease activity is absent; in this circumstance, the disease is said to be in remission. Attempts to define clinical remission for clinical trials and in clinical practice, 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 League Against Rheumatism (EULAR) [16,17]. A complete lack of joint pain, swelling, and tenderness may be impossible to achieve in patients who have developed structural damage of the joints, despite actual remission in the rheumatoid disease process, and is not required by the ACR/EULAR criteria. (See "Assessment of rheumatoid arthritis activity in clinical trials

and clinical practice", section on 'Remission'.) The current ACR/EULAR definitions of remission include use of either the Simplified Disease Activity Index (for clinical trials) or the Clinical Disease Activity Index (in clinical practice). Alternatively, the definition of remission for clinical trials can be met in patients with scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) all 1. The CRP can be excluded in clinical practice. Achieving a clinical remission does not 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 [18]. A majority (52 percent) remained in remission during two years of follow-up. Despite inapparent clinically active disease, one new erosion in a previously unaffected joint appeared in 14 percent of these patients. Because the past remission criteria of the ACR included measures of fatigue and required at least two months of sustained response, they had not been applied widely in clinical trials [13]. Measures using the Disease Activity Score (DAS <1.6 or DAS28 <2.4 or 2.6) to define remission were previously also proposed [19-21]. PHYSICAL FINDINGS The key features of early rheumatoid inflammation are pain and swelling of the affected joints. Painful inflammation is demonstrated either by local tenderness from pressure applied on the joint or by pain on moving the joint. Swelling may be due to synovial hypertrophy or effusion. Synovial thickening is detected by a "boggy" feel to a swollen joint, and effusion by demonstrating fluctuation. Heat and redness (the other signs of Celsus) are not prominent features of RA, although an involved joint is often perceptibly warmer on careful examination. The characteristic joint deformities are late manifestations of disease that result from the physical stresses and local anatomy of involved joints. The hand The main signs of disease can often be found in the hands early in the course of RA [22]. Symmetrical effusions and soft tissue swelling around the metacarpophalangeal joints and proximal interphalangeal joints typically occur, although distal interphalangeal involvement can be seen later in the disease [23]. These joints are tender to the touch and exhibit a restricted range of movement. 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") (picture 1). Nodules may form along the palmar tendon sheaths, resulting in the tendon sheath catching (or triggering) and in an inability to fully extend the finger. The nodules may cause tendon rupture, especially of the extensor pollicis longus (extensor of the DIP joint of the thumb). Other physical signs include the following: Reduced grip strength can be a surprisingly sensitive indicator of early disease, as well as a useful parameter in the evaluation of disease activity and progression. However, the multiplicity of factors (joint pain, tendon involvement, nerve compression, and muscle wasting) that contribute to a weak grip makes this assessment rather nonspecific. The whole hand may be swollen in very acute RA, with pitting edema over the dorsum giving rise to the "boxing glove" appearance. 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 finger tips to the palm. 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's or Phalen's sign is usually present. (See "Clinical manifestations and diagnosis of carpal tunnel syndrome".) The characteristic joint deformities appear in more established chronic RA. These findings include ulnar deviation or "ulnar drift" swan neck or Boutonniere deformities of the fingers (picture 2A-B), or the "bow string" sign (prominence of the tendons in the extensor compartment of the hand). Occasional patients present with extensor tendon rupture, most commonly affecting the thumb, little or ring fingers of either hand. The nails and fingertips should also be examined in every patient for evidence of digital infarcts.

The ppe limb All of the upper extremity joints may be involved in RA. The wrist is probably the most common to be involved. 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 [24]. Tendon rupture can also occur at the wrist. The elbow is frequently affected, with loss of extension (fixed flexion) both in early and late disease (picture 3). 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. Destruction of the joint may occur due to erosion of cartilage and bone. The elbow is the most common site for subcutaneous rheumatoid nodules. These should always be looked and felt for in view of their diagnostic and prognostic importance. The shoulder, being more proximal, tends to be involved later in the disease. As an example, one prospective study assessed shoulder involvement over time in 74 patients with RA [25]. At 15 years, 55 percent had developed radiographic evidence of erosive glenohumeral joint disease [25]. The most common site for erosions was the superolateral aspect of the humerus. 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. 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. The lo e limb Foot involvement is common in early disease, with a pattern which mirrors that occurring in the hand. Tenderness of the metatarsophalangeal joints may be marked, resulting in the tendency to bear weight on the heels and hyperextend the toes. Erosive damage results in lateral drift of the toes, and plantar subluxation of the metatarsal heads, resulting in "cock-up" deformities. The latter may be palpable as bony lumps on the sole with associated callosities. Involvement of the tarsus and the associated tendon sheaths is also common, leading to pain on inversion or eversion of the foot and diffuse edema and erythema over the dorsum of the foot. Heel pain may be associated with retrocalcaneal bursitis tarsal tunnel syndrome, caused by impingement of the posterior tibial nerve. Tarsal tunnel syndrome is also associated with paresthesiae of the toes and is important because it is readily diagnosed by ultrasound and treated by local injection or surgical release. Two rare but easily missed causes of heel pain are Achilles tendon rupture or calcaneal stress fracture [26,27]. 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. The knee manifests many changes in RA. Synovial thickening is easily detected at the knee, often extending around the patella. Effusion is a common feature of knee involvement and can be elicited by patellar tap. Restriction of movement, particularly flexion, is also a common physical finding. In addition, ligamentous laxity leading to deformities and quadriceps atrophy is frequently observed. The popliteal fossa should always be palpated for evidence of a popliteal (Baker's) cyst [28]. Ruptured Baker's cysts extending down the calf are of clinical importance because they can resemble a deep vein thrombosis or acute thrombophlebitis [29]. 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. Traditionally, a ruptured Baker's cyst is demonstrated by arthrography, though it can now be reliably demonstrated by ultrasonography or magnetic

resonance imaging [30] (picture 4 and picture 5). Erosion of the femoral condyles and tibial plateau can result in either genu varus or genu valgus. Involvement of the hips typically occurs only in well established disease. Hip disease is most frequently manifested as pain in the groin, thigh, 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. The a ial kele on Cervical spine joints are the most clinically important joints in the axial skeleton in RA and may cause pain and stiffness of the neck. Long standing disease may lead to instability and cause symptoms such as neck pain, stiffness, radicular pain, related to subluxation. If the subluxation is causing spinal cord compression, there may be signs of long tract involvement such as hyperreflexia or up going 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".) C icoa enoid join Nearly 30 percent of patients with RA have involvement of the cricoarytenoid joint; symptoms may include hoarseness and an inspiratory 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 and anti-citrullinated peptide antibodies. Synovial fluid examination typically reveals an inflammatory effusion, with a leukocyte count typically between 1500 and 25,000/cubic mm characterized by a predominance of polymorphonuclear cells [31]. Cell counts in excess of 25,000 may occur in very active disease, but levels over 25,000 should alert the clinician to the increased possibility of coexisting infection [32,33]. Additional findings in RA synovial fluid are low glucose, low C3 and C4 complement levels, and protein levels approaching those in serum, but these tests are generally not obtained in clinical practice. (See "Synovial fluid analysis and the diagnosis of septic arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation for suspected RA'.) Other laboratory features of RA are reviewed in detail elsewhere. (See "Hematologic manifestations of rheumatoid arthritis" and "Clinically useful biologic markers in the diagnosis and assessment of outcome in rheumatoid arthritis".) IMAGING Patients with RA develop joint space narrowing and bony erosions, which are best observed in 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. Erosions of cartilage and bone are among the cardinal features of RA. However, they can also occur in some other forms of inflammatory and gouty arthropathy and are, therefore, not diagnostic of RA in and of themselves. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.) Magnetic resonance imaging (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. 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 [34]. Plain film adiog aph To be detected by plain radiography, erosions must have eroded through the cortex of the bone around the margins of the joint. Erosions in the metacarpophalangeal and proximal interphalangeal joints can be 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 do not respond to therapy, the cumulative incidence of erosions is 90 percent [35,36]. In some patients, erosions occur first in the ulnar styloid or MTP joints. MR imaging Magnetic resonance imaging (MRI) is a more sensitive technique than plain radiography for identifying 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 metacarpophalangeal and proximal interphalangeal joints than plain radiographs [37]. However, the clinical significance of erosions only detected by MRI awaits

elucidation. MRI also may detect bone erosions earlier in the course of the disease than is possible with plain films [38]. As an example, approximately 45 percent of patients with symptoms for only four months were found to have erosions detected by this method [39]. 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 [40]. A similarly increased sensitivity of MRI has also been noted for early RA of the forefoot [41]. 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 [42]. 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 [43,44]. Ul a onog aph Ultrasonography is another alternative for estimating the degree of inflammation and the volume of inflamed tissue. 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 [45]. Both imaging modalities found features of inflammation in joints that were neither tender nor swollen on physical examination. The clinical importance of these findings remains to be determined. Ultrasonography can also be used to assess the MTP joints, which may become affected early in the course of disease [46]. 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 5th to 6th 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 10th to 12th 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 information: Rheumatoid arthritis (The Basics)" and "Patient information: Hand pain (The Basics)") Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Complementary therapies for rheumatoid arthritis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS The onset of rheumatoid arthritis (RA) is usually insidious, with the predominant symptoms being pain, stiffness, and swelling of many joints. Onset may occasionally be intermittent or with migratory joint involvement, or onset may be monoarticular. RA may adversely affect a patient s capacity to perform the activities of daily living. (See 'Clinical presentations' above and 'Typical "classic" RA' above and 'Palindromic rheumatism' above and 'Monoarthritis' above.) Extraarticular features of RA, including anemia, fatigue, subcutaneous ("rheumatoid") nodules, pleuropericarditis, neuropathy, episcleritis, scleritis, splenomegaly, Sjgren's syndrome, vasculitis, and renal disease, may occur during the course of the disease. (See 'Extraarticular involvement' above and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".) RA eventually affects the peripheral joints in almost all patients. Involvement of axial and central joints is less common, occurring in 20 to 50 percent of 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 MCP and MTP joints and palpable synovial

thickening at these joints are characteristic of RA. (See 'Distribution of joint involvement' above.) 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.) 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). Rarely, disease activity is absent; in this circumstance, the disease is said to be in remission. (See 'Disease activity versus structural damage' above and 'Remission' above.) The key features of early rheumatoid inflammation are pain and swelling of the affected joints. Painful inflammation is demonstrated either by local tenderness from pressure applied on the joint or by pain on moving the joint. Swelling may be due to synovial hypertrophy or effusion. Synovial thickening is detected by a "boggy" feel to a swollen joint, and effusion by demonstrating fluctuation. (See 'Physical findings' above and 'The hands' above and 'The lower limb' above and 'The axial skeleton' above and 'Cricoarytenoid joint' above.) 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 and anti-citrullinated peptide antibodies. (See 'Laboratory findings' above.) Patients with RA develop joint space narrowing and bony erosions, which are best observed in radiographs of the hands and feet. These may already be present when first seen by a physician but more usually become evident over time with ongoing synovitis beyond the first few months of disease. (See 'Imaging' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001; 358:903. 2. Fleming A, Crown JM, Corbett M. Early rheumatoid disease. I. Onset. Ann Rheum Dis 1976; 35:357. 3. Jacoby RK, Jayson MI, Cosh JA. Onset, early stages, and prognosis of rheumatoid arthritis: a clinical study of 100 patients with 11-year follow-up. Br Med J 1973; 2:96. 4. Lineker S, Badley E, Charles C, et al. Defining morning stiffness in rheumatoid arthritis. J Rheumatol 1999; 26:1052. 5. Edworthy SM. Morning stiffness: sharpening an old saw? J Rheumatol 1999; 26:1015. 6. Maksymowych WP, Suarez-Almazor ME, Buenviaje H, et al. HLA and cytokine gene polymorphisms in relation to occurrence of palindromic rheumatism and its progression to rheumatoid arthritis. J Rheumatol 2002; 29:2319. 7. Koskinen E, Hannonen P, Sokka T. Palindromic rheumatism: longterm outcomes of 60 patients diagnosed in 1967-84. J Rheumatol 2009; 36:1873. 8. Salvador G, Gomez A, Vinas O, et al. Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism. An abortive form of rheumatoid arthritis? Rheumatology (Oxford) 2003; 42:972. 9. Russell AS, Devani A, Maksymowych WP. The role of anti-cyclic citrullinated peptide antibodies in predicting progression of palindromic rheumatism to rheumatoid arthritis. J Rheumatol 2006; 33:1240. 10. Gonzalez-Lopez L, Gamez-Nava JI, Jhangri G, et al. Decreased progression to rheumatoid arthritis or other connective tissue diseases in patients with palindromic rheumatism treated with antimalarials. J Rheumatol 2000; 27:41. 11. Lehtinen JT, Kaarela K, Belt EA, et al. Incidence of acromioclavicular joint involvement in rheumatoid

arthritis: a 15 year endpoint study. J Rheumatol 1999; 26:1239. 12. Masi AT. Articular patterns in the early course of rheumatoid arthritis. Am J Med 1983; 75:16. 13. Pinals RS, Baum J, Bland J, et al. Preliminary criteria for clinical remission in rheumatoid arthritis. Bull Rheum Dis 1982; 32:7. 14. Gossec L, Dougados M, Goupille P, et al. Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study. Ann Rheum Dis 2004; 63:675. 15. Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis Rheum 1998; 41:1571. 16. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011; 63:573. 17. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011; 70:404. 18. Molenaar ET, Voskuyl AE, Dinant HJ, et al. Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum 2004; 50:36. 19. van Gestel AM, Anderson JJ, van Riel PL, et al. ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology. J Rheumatol 1999; 26:705. 20. Aletaha D, Ward MM, Machold KP, et al. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum 2005; 52:2625. 21. van der Heijde D, Klareskog L, Boers M, et al. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results. Ann Rheum Dis 2005; 64:1582. 22. Rheumatoid arthritis contemporary patient management series, 2nd, Gordon, DA (Eds), Medical Examination Publishing, New York 1985. 23. Jacob J, Sartoris D, Kursunoglu S, et al. Distal interphalangeal joint involvement in rheumatoid arthritis. Arthritis Rheum 1986; 29:10. 24. Hastings DE, Evans JA. Rheumatoid wrist deformities and their relation to ulnar drift. J Bone Joint Surg Am 1975; 57:930. 25. Lehtinen JT, Kaarela K, Belt EA, et al. Incidence of glenohumeral joint involvement in seropositive rheumatoid arthritis. A 15 year endpoint study. J Rheumatol 2000; 27:347. 26. Rask MR. Achilles tendon rupture owing to rheumatoid disease. Case report with a nine-year follow-up. JAMA 1978; 239:435. 27. Semba CP, Mitchell MJ, Sartoris DJ, Resnick D. Multiple stress fractures in the hindfoot in rheumatoid arthritis. J Rheumatol 1989; 16:671. 28. Gerber, NJ, Dixon, AS. Synovial cysts and juxta-articular bone cysts. Semin Arthritis Rheum 1974; 3:323. 29. Kraag G, Thevathasan EM, Gordon DA, Walker IH. The hemorrhagic crescent sign of acute synovial rupture. Ann Intern Med 1976; 85:477. 30. Torreggiani WC, Al-Ismail K, Munk PL, et al. The imaging spectrum of Baker's (Popliteal) cysts. Clin Radiol 2002; 57:681. 31. Dougados M. Synovial fluid cell analysis. Baillieres Clin Rheumatol 1996; 10:519. 32. Krey PR, Bailen DA. Synovial fluid leukocytosis. A study of extremes. Am J Med 1979; 67:436. 33. Kortekangas P, Aro HT, Tuominen J, Toivanen A. Synovial fluid leukocytosis in bacterial arthritis vs. reactive arthritis and rheumatoid arthritis in the adult knee. Scand J Rheumatol 1992; 21:283. 34. Kuper IH, van Leeuwen MA, van Riel PL, et al. Influence of a ceiling effect on the assessment of radiographic progression in rheumatoid arthritis during the first 6 years of disease. J Rheumatol 1999; 26:268. 35. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum 1992; 35:26. 36. Fuchs HA, Kaye JJ, Callahan LF, et al. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989; 16:585.

37. Klarlund M, Ostergaard M, Jensen KE, et al. Magnetic resonance imaging, radiography, and scintigraphy of the finger joints: one year follow up of patients with early arthritis. The TIRA Group. Ann Rheum Dis 2000; 59:521. 38. McQueen FM. The use of MRI in early RA. Rheumatology (Oxford) 2008; 47:1597. 39. McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998; 57:350. 40. McQueen FM, Benton N, Perry D, et al. Bone edema scored on magnetic resonance imaging scans of the dominant carpus at presentation predicts radiographic joint damage of the hands and feet six years later in patients with rheumatoid arthritis. Arthritis Rheum 2003; 48:1814. 41. Ostendorf B, Scherer A, Mdder U, Schneider M. Diagnostic value of magnetic resonance imaging of the forefeet in early rheumatoid arthritis when findings on imaging of the metacarpophalangeal joints of the hands remain normal. Arthritis Rheum 2004; 50:2094. 42. McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement. Ann Rheum Dis 1999; 58:156. 43. Ejbjerg BJ, Narvestad E, Jacobsen S, et al. Optimised, low cost, low field dedicated extremity MRI is highly specific and sensitive for synovitis and bone erosions in rheumatoid arthritis wrist and finger joints: comparison with conventional high field MRI and radiography. Ann Rheum Dis 2005; 64:1280. 44. Naraghi AM, White LM, Patel C, et al. Comparison of 1.0-T extremity MR and 1.5-T conventional highfield-Strength MR in patients with rheumatoid arthritis. Radiology 2009; 251:829. 45. Terslev L, Torp-Pedersen S, Savnik A, et al. Doppler ultrasound and magnetic resonance imaging of synovial inflammation of the hand in rheumatoid arthritis: a comparative study. Arthritis Rheum 2003; 48:2434. 46. Szkudlarek M, Narvestad E, Klarlund M, et al. Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: comparison with magnetic resonance imaging, conventional radiography, and clinical examination. Arthritis Rheum 2004; 50:2103. Topic 7502 Version 8.0

GRAPHICS
Na al hi o and p ogno i of RA

70 percent of joint erosions detectable by x-ray of hands and feet occur in the first two years of disease At 20 years, over 60 percent of RA patients belong to functional class III (significantly impaired, selfcaring, using aids, requiring joint replacements) or class IV (loss of independence, requiring daily care) Increased evidence of:
Infections C ardiovascular disease Lymphomas

Life-expectancy of RA less than age-sex matched control populations, especially in patients with:
Polyarticular disease Systemic extra-articular disease Persistent disease activity (high ESR, C RP) Rheumatoid factor and circulatory immune complex positivity HLA-DR & chain 'shared epitope' (especially bialleic)

men of di ea e ac i i

in he ma oid a h i i

S mp om
Duration of morning stiffness Pain score (visual analogue scale) Fatigue - severity (visual analogue scale) Patient's global score of disease activity (visual analogue scale)

Ph

ical e amina ion

Number of swollen joints Number of tender joints Degree of swelling and/or tenderness Extra-articular disease:
Minor nodules, episclertis, pure sensory neuropathy, pleruropericardial disease Major vasculitis, Felty's syndrome, motor neuropathy, interstitial lung disease

Labo a o
Elevated erythrocyte sedimentation rate Increased C-reactive protein Anemia (in the absence of chronic blood loss or hematuria) Leukocytosis Thrombocytosis Abnormal liver function tests (low albumin, raised alkaline phosphate) in the absence of drug toxicity or liver disease Inflammatory joint fluid (high polymorph count, low complement, fibrin)

Imaging
Low bone mineral density (juxta-articular, vertebrae, pelvis) in absence of glucocorticoid therapy or known cause

Teno

no i i in he ma oid a h i i

Ultrasonography of the fingers of a patient with rheumatoid arthritis showing tenosynovitis of the extensor tendons. An inflamed common tendon sheath of the wrist may also be observed. Courtes of Peter H Schur, MD.

S no ial hickening of he me aca pophalangeal join

Bilateral swelling of the MCP joints is evident in this patient with rheumatoid arthritis. Note also the mild swan neck deformities present in several fingers, particularly the left middle and fifth fingers. Courtes of Patrick J Venables, MD.

S elling of he me aca pophalangeal join igh hand

of he

Swelling of the MCP joints, moderate MCP flexion, and swan neck deformities are evident in this patient with rheumatoid arthritis. Courtes of Patrick J Venables, MD.

RA of he elbo

Lateral view of the elbow in a patient with rheumatoid arthritis (RA) reveals soft tissue swelling and osteopenia with destruction of the elbow joint (arrows). There are also secondary proliferative bony changes, which have arisen due to joint space destruction. Courtes of Jonathan Kruskal, MD.

Bake ' c

Ultrasonography of the knee showing a Baker's cyst in a patient with rheumatoid arthritis. The cyst is compressing the popliteal artery (arrow). Courtes of Peter H Schur, MD.

Bake ' c

Ultrasonography of the knee showing a Baker's cyst in a patient with rheumatoid arthritis. Calcifications (arrows) may be observed within the cyst. Courtes of Peter H Schur, MD.

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