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.

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.

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.

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.

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

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.