Lymphadenopathy accompanying rheumatoid arthritis (RA).

Rheumatoid arthritis is common disease, affecting 0.8% of the world’s population (1). Approximately 2 million people in the United States have RA. Women develop the disease 3 to 5 times more often than do men (1,2). This sex difference becomes less prominent in older patients. There is no racial preference. Although RA can affect patients at any age, approximately 80% of patients develop RA between 35 and 50 years of age (2).

Rheumatoid arthritis is a systemic, autoimmune disease that can affect many organ systems, but it is best known for joint disease. The cause of RA is unknown, but it appears to be multifactorial (3). Environmental factors are involved. Smoking is associated with an increased risk of developing RA (1,4,5). Episodes of disease severity, and reactivation of disease after an interval of quiescence, appear to be related to stress. A genetic component is also involved in RA pathogenesis (3). The disease can run in families. First-degree relatives of patients with RA have a greater risk of developing disease, up to four times higher. Approximately 20% to 25% of monozygotic twins can both develop RA, much higher than the rate of concordance for dizygotic twins. Approximately 75% of patients with RA have an association with expression of certain HLA molecules, with the most prominent being HLA-DR1 or HLA-DR4 (3).

Infectious agents also have long been suspected, but not proven, as inciting the synovitis of RA (6). Possible infectious agents suggested include Epstein-Barr virus (EBV), cytomegalovirus, parvovirus, rubella virus, Mycoplasma, and others. Although the exact cause of RA is not known, the inciting agent is not ultimately responsible for the long-term consequences of disease. Instead, the patient’s own immune system attacks the synovium (7). Activated T cells, mostly CD4+, which appear to first arrive at the synovium, along with B cells, plasma cells, macrophages, and fibroblasts in the synovium, release their various intracellular products such as cytokines, interleukins (particularly IL-1), tumor necrosis factor α (TNFα), interferon-γ, growth factors, and enzymes (e.g. proteases, collagenase). This is accompanied by the accumulation of exudative fluid within the joints, containing many neutrophils. The end result of these events is extensive damage to joint cartilage, bone, surrounding ligaments, tendons, and muscles, with eventual scarring and loss of range of motion and function. Rheumatoid factor (RF) and circulating immune complexes that may be produced within the affected joints can activate the complement cascade and cause of damage to various organ systems and possible vasculitis. Amyloidosis can also complicate the clinical course of patients with RA.

In this chapter, the focus is on pathologic changes that occur in lymph nodes in patients with RA. Lymphadenopathies, some with similar histologic changes, may occur in other, related conditions, such as juvenile RA (Still disease) (8) and adult-onset Still disease (8,9).

Patients with RA often present insidiously with fatigue, anorexia, generalized weakness, and vague musculoskeletal symptoms; fever also can occur (10). The nonspecific nature of these symptoms often leads to a delay in diagnosis, on the average of months up to a year. Eventually, several joints become affected in a symmetric fashion, with small joints (hands and feet) being more often involved than large joints. When fully developed, affected joints are painful, tender, enlarged, and associated with stiffness (particularly in the morning). The clinical course of patients with RA, although usually and eventually progressive, is highly variable with periods of remission and reactivation (or flares). As there is no current gold-standard physical finding or laboratory test for the diagnosis of RA, the American College of Rheumatology has issued a set of seven criteria, of which four are needed to establish the diagnosis of RA (11). These criteria include: (a) morning stiffness of at least 1 hour’s duration; (b) arthritis involving three or more joints; (c) arthritis of hand joints; (d) symmetrical distribution of arthritis; (e) presence of rheumatoid nodule(s); (f) positive RF; and (g) radiologic changes of hands and feet (e.g. erosions, osteopenia) (11). However, these criteria may not be met in patients with RA early in the course of their disease (10).

According to these criteria, lymph node involvement in RA patients is not an important criterion for diagnosis, not does it alter therapy, and lymph node biopsy is rarely performed in RA patients. Nevertheless, lymphadenopathy can occur in 50% to 75% of patients with RA at some point in the course of their disease (12,13). Lymphadenopathy can be localized or systemic, range from mild to severe, and is not restricted to lymph nodes draining affected joints. Sudden onset of lymphadenopathy in RA patients can lead to the clinical suspicion of malignant lymphoma, prompting lymph node biopsy (12).

The axillary, cervical, and supraclavicular lymph nodes are most often involved, but enlarged inguinal, epitrochlear, and preauricular lymph nodes and enlarged lymph nodes in the forearm, thigh, and other unusual places have been found (12,14,15). The lymph nodes are palpable, mobile, and nontender. Episodes of fever, anemia, and weight loss are often associated with rheumatoid lymphadenopathy. The spleen can be moderately enlarged (in 5% to 20% of cases). Some patients may have Felty syndrome, characterized by the combination of RA, splenomegaly, and cytopenias (usually neutropenia, but anemia and thrombocytopenia can also occur). Polyclonal hypergammaglobulinemia and cryoglobulinemia are common (5).

Risk of lymphoma is increased in patients with RA, approximately 2 times greater than the normal population (16,17). The risk is higher for Hodgkin lymphoma than it is for
non-Hodgkin lymphoma (18). However, assessment of lymphoma risk is complicated by therapy in RA patients, as certain treatments may be associated with an increased risk of subsequent lymphoproliferative disorders. One class of therapeutic agents, known as disease-modifying antirheumatic drugs, includes methotrexate. However, the risk of lymphoma in RA patients treated with methotrexate is controversial. In one study that assessed risk of lymphoma in RA patients in the era before common use of methotrexate, risk of non-Hodgkin lymphoma was similar to the present day risk, suggesting that methotrexate therapy does not increase lymphoma risk (19). (Lymphoproliferative disorders associated with prolonged methotrexate therapy for various autoimmune diseases are discussed in Chapter 45.) Recent reports have also been published of lymphoproliferative disorders occurring in patients treated with biologic agents, such as antibodies against TNFα (20). However, increased lymphoma risk as a result of anti-TNFα antibody therapy is not clearly established at the time of writing.

Most non-Hodgkin lymphomas occurring in RA patients are of B-cell lineage, and diffuse large B-cell lymphoma is, by far, the most common type (21,22). A wide variety of other types of non-Hodgkin lymphoma have been reported rarely in RA patients, including T-cell lymphomas. Cases of Hodgkin lymphoma have been of classical type, either nodular sclerosis or mixed cellularity (21,22). The etiology of the increased risk of lymphomas in RA is unknown. As these patients have elevated EBV viral loads and other evidence of immune deficiency (23), similar to patients with other types of immune deficiency (e.g. posttransplant), EBV has been suggested as the culprit. However, most non-Hodgkin lymphomas in RA patients are not associated with EBV, thus suggesting that other factors are involved (23).