Rheumatoid Arthritis

Rheumatoid Arthritis

Ioannis Tassiulas

Stephen A. Paget


  • Rheumatoid arthritis (RA) is a chronic, systemic, immune-mediated inflammatory disease that affects at least twice as many women as men. Although RA affects predominantly the joints, epidemiologic studies have unearthed disturbing information about the true potential of this disease: RA leads to joint damage within the first 2 years; causes marked functional limitation; and shortens life by 5 to 7 years due to premature atherosclerosis.

  • Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP): RF is an immunoglobulin M (IgM) antibody against the Fc portion of an IgG molecule, and is the main serologic marker of the disease found in 75% to 80% of patients. Another important disease-specific auto antibody, anti-CCP antibody has been recognized and serves as a sensitive and specific diagnostic and prognostic tool in the early stages of the disease, when patients may not yet have developed RF in their serum.

  • Cytokines and immune cell networks have been identified as important mediators in the pathogenesis and perpetuation of inflammation in RA. This information has been successfully translated into the development of new and significantly more effective targeted treatments in the form of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) antagonists.



There is substantial experimental evidence that the initiation of RA is a T-cell–mediated, antigen-specific process. The arthritogenic antigen has not yet been defined but it could be either an exogenous antigen, such as a viral protein, or an endogenous protein such as citrullinated peptides.

II. The synovial membrane

in patients with RA is characterized by hyperplasia, increased vascularity, and an infiltrate of inflammatory cells, primarily CD4+ T cells, which are the main orchestrators of cell-mediated immune responses. The histologic appearance of the synovium in RA is not specific, as a similar picture is seen in other inflammatory arthritides, such as psoriatic arthritis. One characteristic feature of RA is the invasion of and damage to cartilage, bone, and tendons by an infiltrating inflammatory synovial tissue mass called the pannus.


  • CD4+ T cells constitute most T cells in the rheumatoid synovium. Often they form lymphoid aggregates in the subintimal area. B lymphocytes are also present in the synovium, where they are surrounded by T cells in follicle formation. B cells process autoantigen and contribute to the inflammatory process. B cells can differentiate into plasma cells and produce RF under the influence of T cells and cytokines, such as IL-6 and B-lymphocyte–stimulating factor (BLyS), which are found in rheumatoid synovium.

  • Activated macrophages and dendritic cells, both important in antigen presentation, are also found and are important sources of proinflammatory cytokines such as TNF-α and IL-1. Neutrophils are found predominantly in the synovial fluid, and are important mediators of tissue damage via the release of various enzymes.


Cytokines are local protein mediators involved in cell growth and activation, inflammation, immunity, and differentiation. The important role of cytokines in the pathogenesis of RA has been demonstrated by the effectiveness of therapies that target TNF-α and IL-1, and emerging data have identified additional cytokines such as IL-6 and IL-15 as potential therapeutic targets in RA.

  • TNF-α and IL-1 are produced mainly by monocytes/macrophages and are potent stimulators of mesenchymal cells such as synovial fibroblasts, osteoclasts, and
    chondrocytes that release tissue-destroying matrix metalloproteinases (MMPs). TNF-α is considered to be the master regulator of the inflammatory cascade in rheumatoid synovium.

  • A number of anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β are also detected in the rheumatoid synovium and synovial fluid, but are unable to downregulate the inflammatory response either because they are present in low concentrations or their action is blocked or altered in this inflammatory environment.

  • Enzymes, such as MMPs, which degrade matrix proteins, and complement proteins, which participate in acute inflammation, are effector molecules that mediate tissue destruction.


  • RFs are antibodies that bind to the Fc portion of IgG. The mechanisms initiating RF production and its exact role in disease pathogenesis have still not been established. RF is found in the serum of 75% to 80% of patients with RA (who are therefore called “seropositive”), is locally produced in the synovial membrane, and may be present in the serum of patients with other diseases characterized by B cell or immune hyperactivity, such as chronic hepatitis C infection, bacterial endocarditis, and systemic lupus erythematosus (SLE). The presence of high RF titers is associated with severe, erosive disease, a worse functional outcome, rheumatoid nodules, other extra-articular disease manifestations, and human leucocyte antigen (HLA)-DR4 positivity.

  • Anti-CCP antibodies are detected in up to two-thirds of patients with RA sera and in less than 5% of controls. Anti-CCP antibodies show the highest disease specificity (95%) for RA of any antibody known. They are already present in patients with early RA and predict the development of more severe disease. Their sensitivity is comparable to RF occurring in 50% to 75% of patients with established disease. Their role in the pathogenesis of RA is unknown.


  • Twin and family studies. Family studies have shown that siblings of individuals affected with RA have a twofold to fourfold risk of developing disease themselves, when compared with unrelated individuals. Studies of mono- and dizygotic twins have shown disease concordance rates of 12% to 15% and 4%, respectively. These twin concordance figures show that the risk of disease in relatives of affected individuals is conferred by shared genetic factors but also emphasizes that genetics is not the sole determinant.

  • The major histocompatibility complex (MHC). In genetic studies, RA is strongly linked to haplotypes containing the MHC class II antigens HLA-DR4 and HLA-DR1. On further molecular characterization, the association was confined to a short sequence in the HLA-DRβ1 gene that codes for the RA epitope in amino acid positions 67 through 74 (the “shared epitope”). Some of the HLA-DRβ1 alleles (HLA-DRβ1 *0401, *0404, and *0408, in general populations and some others in specific ethnic groups) are RA-associated alleles. The main function of MHC class II molecules is to present antigenic peptides to CD4+ T cells. These MHC genes are related not only to the initiation of the disease but also to its course and severity.


Most studies of the prevalence of RA are based on cross-sectional population studies. Several estimates of between 0.5% and 1% have been obtained in studies across Europe, North America, Asia, and South Africa. There is a greater prevalence of the disease in certain native North American populations. In contrast, RA appears to be exceptionally rare in rural African black populations, and in certain Chinese groups. RA is two to three times more common in women than in men, but over the age of 50 years, the distribution of disease frequency becomes more equal between the two sexes. Although the disease is most common between the ages of 40 and 60 years, in one-third of patients, RA develops after the age of 60 years.



A careful clinical evaluation is the most important step in the diagnosis and successful management of RA.

  • History. Diffuse, symmetric joint pain and swelling affecting the small peripheral joints are the most common presenting symptoms. These symptoms are often associated with prolonged (>1 hour) morning stiffness and generalized fatigue. Interestingly, RA is not associated with fever. If fever is a prominent clinical manifestation, alternative diagnoses such as viral arthritis, systemic infections, or SLE should be entertained. A history of RA in other members of the family should heighten suspicion that the patient’s symptoms could be an expression of early RA. Evaluation of the patient’s functional status using a number of self-report questionnaires, such as the Stanford Health Assessment Questionnaire (HAQ), is very important because it has been shown to correlate significantly with disease activity, mortality, pain, functional outcome, and psychosocial factors.

  • Musculoskeletal system. The key signs of early joint inflammation in RA are those of tenderness and swelling. These may be associated with local heat, but erythema is not a common feature of rheumatoid inflammation. Although the disease may begin in an asymmetrical or monoarticular fashion, RA will eventually evolve within weeks or a few months into a symmetric inflammatory arthritis involving the wrists, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands, elbows, shoulders, hips, knees, ankles, and the small joints of the feet. The joint is considered “active” if it is tender on pressure or painful on passive movement. Joint swelling may be periarticular or intra-articular. Intra-articular swelling is associated with the detection of a joint effusion. Early changes include prominence of the ulnar styloid, and later deformities resulting from combinations of joint and tendon damage may evolve, including ulnar deviation, boutonniere, and swan neck deformities. Flexor tenosynovitis can lead to triggering of the fingers and eventually there may be rupture of tendons. Extensor tenosynovitis is seen as swelling over the dorsum of the wrist. Carpal tunnel syndrome may result from pressure on the median nerve by swollen flexor tendons, and may present as paresthesias, pain, or motor dysfunction in the radial aspect of the hand. Similarly, cubital tunnel syndrome or tarsal tunnel syndrome can occur as the result of compression of the ulnar nerve at the elbow or of the posterior tibial nerve at the ankle, respectively. Olecranon bursitis often presents as swelling at the tip of the elbow; synovial extensions, known as Baker’s cysts, project from the knee to the medial calf region; occasionally, these cysts may rupture and the fluid may dissect inferiorly, resulting in a clinical picture that may mimic phlebitis. Spinal disease is usually limited to the cervical region, and in patients with severe and longstanding disease may lead to atlanto–axial subluxation and cord compromise.


The 1987 revised American Rheumatology Association criteria for the classification of RA were developed for epidemiologic purposes (Table 29-1). However, because of the high sensitivity and specificity of these criteria in the classification of RA they are useful to consider at the time of clinical diagnosis. Of the seven criteria, the presence of four is sufficient for classifying a patient as having RA. The first four criteria must be present for at least 6 weeks. The natural history of individuals who do or do not meet the criteria for classification for RA may vary greatly from self-limiting disease, to mild, to severe form of the disease (Table 29-2). When faced with a patient with polyarthritis, the physician must keep in mind the many other conditions resembling RA. It is important to distinguish such disorders from RA as early as possible, because the correct and timely diagnosis of RA is fundamental to the application of optimal management.


In the past, extra-articular disease manifestations occurred in 40% of patients during the course of the disease. More recently, in the setting of more aggressive treatment early in the course of RA, these have become much less common.

  • Subcutaneous nodules appear in 5% to 10% of seropositive patients. Nodules develop most commonly on pressure areas, including the elbows, finger joints, ischial
    and sacral prominences, occipital scalp, and Achilles tendon and are associated with active and more severe disease. Nodules may regress during treatment with disease-modifying drugs [disease-modifying antirheumatic drugs (DMARDs)], usually as RA improves. Paradoxically, methotrexate treatment may result in an increase in nodules, particularly over finger tendons, despite improvement in the overall disease activity. Capillary nailfold infarcts may be seen if rheumatoid vasculitis develops.

    Table 29-1 Criteria for the Classification of Rheumatoid Arthritis

    Criterion Definition
    Morning stiffness Morning stiffness in and around the joints lasting at least 1 h before maximal improvement
    Arthritis of three or more joint areas At least three joint areas simultaneously have had soft tissue swelling or fluid observed by a physician. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints
    Arthritis of hand joints
    Symmetric arthritis
    At least one area swollen in a wrist, MCP, or PIP joint Simultaneous involvement of the same joint areas on both sites of the body
    Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions, observed by a physician
    Serum rheumatoid factor Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive for <5% of normal control subjects
    Radiographic changes Radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs
    MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.

  • Eye involvement. Keratoconjunctivitis sicca (dry eyes) is the most common eye abnormality, but scleritis and scleromalacia perforans may be associated with extensive disease activity.

    Table 29-2 Mild, Moderate, and Severe Rheumatoid Arthritis

    Mild disease

    • Fewer than 10 actively inflamed joints
    • No impairment of daily activities
    • No radiographic evidence of erosions or joint space narrowing
    • No joint deformities
    • No extra-articular manifestationt

    Moderate disease

    • 10–15 actively inflamed joints
    • Symptomatic fatigue or some limitations of daily activities
    • Radiologic evidence of erosions or joint space narrowing
    • Mild/moderate joint deformities
    • Mild extra-articular manifestations (e.g., anemia of chronic disease and nodules)

    Severe disease

    • More than 15 actively inflamed joints
    • Significant impairment of daily activities
    • Significant joint destruction and/or need for surgery
    • Serious extra-articular manifestation (e.g., vasculitis)

  • Pulmonary involvement. Pleurisy and pleural effusions may be bilateral in 25% of patients. Parenchymal pulmonary nodules, diffuse interstitial pulmonary fibrosis and bronchiolitis obliterans, and organizing pneumonia are associated with severe active disease. Upper airway obstruction in RA may be caused by inflammation of the cricoarytenoid joint and presents with sore throat, hoarseness, dysphagia, pain with speech, sensation of a foreign body in the throat, and difficulty with the inspiratory phase of respiration.

  • Cardiac manifestations include pericarditis, myocarditis, valvulitis, nodule formation with arrhythmia, amyloidosis, and vasculitis. More than 40% of patients with RA have premature atherosclerosis.

  • Peripheral neuropathy and central nervous system disease can be manifestations of rheumatoid vasculitis.

  • Felty’s syndrome (granulocytopenia, splenomegaly, and recurrent infection) and Sjögren’s syndrome may coexist with RA and often occur in patients with active, systemic disease.

  • A rare but potentially organ-threatening and life-threatening polyarteritis nodosa (PAN)-like systemic vasculitis called RA vasculitis or malignant RA is occasionally seen in patients with high serum titers of RF and nodules.

  • Adult-onset Still’s disease. Adult-onset Still’s disease is a systemic inflammatory disorder characterized by quotidian, spiking fevers typically accompanied by a salmon-colored evanescent rash, arthritis, and multiorgan involvement.

Jul 29, 2016 | Posted by in RHEUMATOLOGY | Comments Off on Rheumatoid Arthritis
Premium Wordpress Themes by UFO Themes