Lymphadenopathy associated with systemic lupus erythematosus (SLE).

Lupus lymphadenopathy; lupus lymphadenitis.

Systemic lupus erythematosus has a worldwide distribution, with differences in prevalence related to race, geography, and sex (1,2). In North America, the overall prevalence of SLE ranges from 15 to 50 per 100,000 persons in the general population (1,2). However, the disease is more frequent in blacks/African Americans, Hispanics, and Indians/Native Americans than in whites/Caucasians (1,2). The frequency is three to four times greater in African Americans than it is in Caucasians (1). In a study done in Hawaii, the frequency of SLE (per 100,000) was 24.1 for Chinese, 19.9 for Filipinos, 18.2 for Japanese, and 5.8 for Caucasians (3). The severity of SLE also appears to be greater in non-Caucasian populations (1). The prevalence of SLE shows a marked sex preference, being 3.5 times more common in women than men (2,4). Age of onset is usually in the second to fourth decades, with the median age often between 20 and 30 years, but all ages can be affected (2,4).

Systemic lupus erythematosus is an autoimmune disease of unknown cause characterized by abnormal immune regulation resulting in the development of autoantibodies and immune complexes that damage a wide variety of organ systems.

Systemic lupus erythematosus has a complex, multifactorial pathogenesis. There is evidence for a genetic predisposition. If a person has SLE, other family members have an increased frequency of developing SLE compared with the general population (5). If a monozygotic twin has the disease, the concordance rate for the other twin developing SLE is approximately 25% to 50%, compared with a substantially lower concordance rate for dizygotic twins of <5% (5). A subset of SLE patients has inherited deficiency of one or more of the complement components (particularly C1q, C2, or C4) (4,6). Patients with SLE have a higher frequency of HLA-DR2 or HLA-DR3. Polymorphisms of the Fcγ receptor genes (FcγRIIA and FcγRIIIA) are reported. In SLE families, linkage analysis has identified certain chromosomal regions that are likely to be the site of genes involved, such as chromosome locus 1q23 (the site of FcγRIIA) (6).

Environmental factors, although less well characterized and understood, also appear to be involved. Approximately two-thirds of SLE patients are photosensitive (4). In women of childbearing age, the prevalence of SLE is seven to nine times greater in women than in men, compared with the 3:1 ratio in young girls or older women who are postmenopausal.

The clinical course of SLE patients is variable, with periods of relative quiescence and exacerbation (4,7). However, prolonged remissions in which symptoms completely resolve and no therapy is required are uncommon and are rarely permanent. The clinical features of SLE are pleomorphic, affecting most of the major organ systems (4,7). Constitutional symptoms occur in almost all patients and include fever, fatigue, malaise, and weight loss. Musculoskeletal symptoms such as arthralgia, myalgia, and arthritis are almost always present. Approximately 75% of patients develop skin manifestations, of which the best known in the malar or “butterfly” rash over the cheeks and the bridge of the nose. Other types of skin rash, oral ulcers, vasculitis, alopecia, and panniculitis also can occur less often. Most SLE patients have hematologic abnormalities including anemia of chronic disease and other cytopenias. The cardiopulmonary system is often affected, in approximately 60% of patients, with pleuritis and pericarditis most common. Neurologic or renal symptoms occur in approximately half of SLE patients. The most common neurologic manifestation is cognitive dysfunction. In the kidney, glomerulonephritis is caused by immune complexes trapped in mesangial cells and the glomerular basement membrane.

With this wide array of variable manifestations, the diagnosis of SLE is based on a number of clinical and laboratory criteria that were first developed in 1982 and revised in 1997 (8). There are 11 criteria, of which four must be present for diagnosis. These criteria include: (a) malar rash; (b) discoid rash; (c) photosensitivity; (d) oral ulcers; (e) arthritis; (f) serositis; (g) renal dysfunction; (h) neurologic disorder; (i) hematologic abnormalities (e.g. cytopenias); (j) immunologic abnormalities (e.g., antibodies to double stranded DNA, anti-Sm, antiphospholipid); and (k) presence of antinuclear antibodies. However, in early cases of SLE, all of these criteria may not be met.

Lymphadenopathy is common in SLE patients, either localized or generalized, and can be marked (2,9). Lymphadenopathy is associated with more active disease, higher titers of anti–double stranded DNA antibodies, and lower serum complement levels (2). Cervical lymph nodes are most often involved (43%), followed by mesenteric (21%), axillary (18%), inguinal (17%), and retroperitoneal lymph nodes (9). Pulmonary hilar and mediastinal lymphadenopathy in SLE has also been reported (10). In 12% of cases, the lymphadenopathy is generalized (9). Patients with lymphadenopathy tend to be younger than those without, and the prevalence of lymph node involvement is higher in children than in adults (2,10,11).

The frequency of lymph node biopsy in SLE patients has dropped off substantially over the years, as the diagnosis of SLE can be established on the basis of clinical criteria and serologic testing (8). In addition, the frequency of lymphadenopathy
in SLE patients also may have decreased over time. For example, in a 1943 study by Fox and Rosahn, 66.7% of 210 SLE cases reviewed had lymphadenopathy (9). In a more recent study of SLE, lymphadenopathy was present in 26% of patients (2). The higher frequency of lymphadenopathy in earlier studies may have been related to the lack of effective immune-modulating therapy during that era. A considerable number of autopsy cases were also included in those earlier studies, which may have allowed increased detection of involved lymph nodes. The lower frequency of lymphadenopathy in more recent studies may be a consequence of the effect of steroids and other therapies (2).

Clinically, the most common indication for lymph node biopsy is when lymphadenopathy develops or increases in size suddenly or unexpectedly, for example, in a patient who had relatively quiescent or well controlled disease prior to development of enlarged lymph nodes. In this scenario, biopsy may be performed to exclude lymphoma or infection (12). The risk of lymphoma is three to four times higher in SLE patients as compared with the general population (13). Both non-Hodgkin lymphoma and Hodgkin lymphoma have been reported in SLE patients (13,14,15,16,17). Most lymphomas in arising in SLE patients are of B-cell lineage and diffuse large B-cell lymphoma is most common (15). However, other histologic types of non-Hodgkin lymphoma have been reported more than occasionally in SLE patients, including follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and plasma cell neoplasms (16,17). Isolated cases of other histologic types of lymphoma, including peripheral T-cell lymphoma, also have been described in the setting of SLE (16).