Page 719 - Clinical Immunology_ Principles and Practice ( PDFDrive )

692 Part SIX Systemic Immune Diseases

estrogen in patients with stable disease may be safe; however, a including inception versus long-standing lupus cohorts, com-
subset of patients appears to have an estrogen-sensitive disease. munity versus academic settings, socioeconomic factors, and
Mild to moderate flare rates were significantly increased in ascertainment differences are also likely to contribute to observed
postmenopausal women treated with hormone replacement differences in the prevalence of clinical manifestations. Over
therapy. time, the course of lupus is characterized by flares and remissions
Most of what we understand about hormonal modulation of disease activity.
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of B-cell development comes from mouse studies. Estrogen
treatment of NZB/W and MRL/lpr mice or castration of male
lupus-prone mice exacerbates disease, whereas oophorectomy KEY CONCEPtS
of female mice ameliorates disease. Treatment of lupus-prone • Continued heightened awareness of systemic lupus erythematosus
mice with the selective estrogen receptor modulator tamoxifen to shorten the time between onset of symptoms and diagnosis will
also ameliorates disease. improve outcomes.
Estrogen and prolactin promote the loss of B-cell tolerance • Lupus is a disease characterized by recurrent flares.
in nonautoimmune mice. Estrogen results in diminished B-cell • Attentive monitoring even during periods of disease remission leads
responsiveness to BCR cross-linking and in less stringent negative to early recognition of impending flare, better control, and better
prognosis.
selection. Additionally, estrogen has also been reported to inhibit • Lupus is a chronic disease; the importance of a therapeutic partnership
activation-induced T-cell death by downregulation of Fas ligand between physicians and patients, emotional/social support, and patient
expression, thereby permitting increased numbers of autoreactive education cannot be overemphasized.
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T cells. Emerging data suggest that estrogen receptor signaling • Advances in understanding mechanisms of disease pathogenesis
promotes differentiation of DC into immune-competent DC correspond to advances in treatment strategies and development of
through increased expression of the transcription factor IRF4. 42 therapies with improved efficacy and safety profiles.
Elevated prolactin levels are reported in 20% of patients with
SLE, and increased prolactin exposure in lupus-prone mice
exacerbates disease activity. Whereas treatment of patients with The most common features of lupus are constitutional and
bromocriptine yielded equivocal results, treatment of NZB/W include fatigue, malaise, low-grade fever, anorexia, and lymph-
lupus mice with bromocriptine results in improved survival. adenopathy. These symptoms are believed to result from elevated
Transmembrane prolactin receptors are present on a variety of serum levels of inflammatory cytokines and may accompany
cells, including T and B cells. Upregulation of both Bcl-2 and other organ system manifestations of active disease, or they may
CD40 on B cells and CD40L on T cells occurs in response to occur in isolation. Although frequent, these symptoms are
prolactin, identifying pathways that may be involved in the nonspecific and do not aid in making the diagnosis of SLE.
prolactin-mediated rescue of autoreactive B cells. Symptoms of fatigue and malaise may also represent fibromyalgia,
Data on the microbiome demonstrate that sex hormones can which can co-occur with SLE or confound the diagnosis. 44
modulate its composition. Studies in murine lupus suggest that
androgens generate a microbiome that prevents the development Musculoskeletal Involvement
of lupus, whereas estrogen maintains a disease-permissive The musculoskeletal system is the most common organ system
microbiome. Studies of the microbiome in human disease are affected in SLE; joint pain is the presenting symptom in approxi-
just beginning. 43 mately 60–70% of patients, and 85% have joint involvement
after 5 years. 45
CLINICAL MANIFESTATIONS Arthritis and Arthralgia
CLINICaL PEarLS The pattern of joint involvement is usually symmetrical, affecting
the small joints of the hands, wrists, and knees. Pain in the
• Systemic lupus erythematosus (SLE) is a systemic disease with the ankles, elbows, shoulders, or hips or monoarticular involvement
potential to affect any organ system.
• Not all symptoms experienced by a patient with SLE are from SLE is less typical. In contrast to rheumatoid arthritis, morning
disease activity. Attribution is critical to determine before initiation of stiffness is typically limited to several minutes. Frequently, the
treatment. The differential diagnosis of a lupus flare mandates con- subjective complaints of pain are greater than the objective
sideration of infection, drug toxicities, or other etiologies. findings of warmth, swelling, and erythema. Lupus arthritis is
• Corticosteroid exposure should be minimized. characteristically nonerosive on X-ray and nondeforming.
• In the absence of data from randomized trials, use of aggressive Anticyclic citrullinated peptide antibodies occur frequently in
treatment must be balanced against associated toxicity. the rare patients with erosive arthritis. Some lupus patients
• SLE patients accumulate damage from both repeated episodes of
inflammatory disease and medication toxicities. Prompt recognition develop a nonerosive hand deformity with hypermobile joints
and appropriate treatment of disease flares should result in reduced secondary to tendon and ligamentous laxity (Jaccoud arthritis)
exposure to corticosteroids and immunosuppressive agents. (Fig. 51.3). Proliferative tenosynovitis, synovitis, small erosions
• SLE patients are at increased risk of developing atherosclerotic disease, not detectable on plain radiographs, and capsular swelling are
osteoporosis, malignancy, diabetes mellitus, and hypertension. It is features of joint and soft-tissue involvement that may be seen
essential to screen for and reduce modifiable risk factors. on MRI. The role of ultrasound and MRI in the evaluation of
musculoskeletal symptoms is not established.
Joint effusions, when they occur, are usually small. The fluid
The prevalence of the diverse clinical and laboratory features of is clear yellow with normal viscosity and forms a mucin clot. It
lupus varies in published reports (Table 51.2). Both genetic and is typically noninflammatory with a normal glucose level and a
environmental factors are likely to account for much of the white blood cell (WBC) count of less than 2000 cells/mL that
variability between cohorts. Characteristics of published cohorts, is predominantly lymphocytic. ANA performed on the synovial