Sara E. Walker

Inflammatory central nervous system disease in lupus-prone MRL/lpr mice: comparative histologic and immunohistochemical findings

The brains of pathogen-free autoimmune MRL/lpr, NZBWF1 and NZB mice were examined for central nervous system (CNS) inflammation in premoribund 8-week-old animals and at ages when active systemic lupus erythematosus (SLE) was present. CNS inflammation was observed only in MRL/lpr mice. Immunohistochemical studies of brains from young MRL/lpr mice found that infiltrates were composed primarily of CD4+ cells. Older MRL/lpr mice (22 and 26 weeks of age) had CD4+ cells predominantly, but CD8+ and B220+ cells were also present. Perivascular leakage of IgG was a prominent and unexpected finding in the MRL/lpr model. Congenic MRL/+ mice with late-onset autoimmunity had no inflammatory cells in brain tissue, and there was no perivascular staining with IgG or albumin. Our findings suggest that MRL/lpr mice are a useful model for studies of lupus-associated CNS inflammatory disease, and perivascular leakage may be a primary mechanism for entry of IgG into the brain.

Age, depressive symptoms, and rheumatoid arthritis

OBJECTIVE To examine the relationship between age and depression in persons with rheumatoid arthritis (RA). METHODS Two separate outpatient cohorts of persons with RA were studied. In both studies, the Center for Epidemiological Studies Depression Scale was administered to all subjects, and the prevalence of depressive symptoms was determined by age group. In the second study, data on additional measures of disease activity, pain, life stress, and coping were collected for use in multiple linear regression analyses. RESULTS In both samples, a significant correlation between age and depression was found; younger persons (age < or = 45 years) with RA were significantly more depressed, even after controlling for potentially confounding variables such as sex, marital status, antidepressant medication, arthritis medication, functional class, and disease duration. CONCLUSION The findings show that younger persons with RA are at higher risk for depressive symptoms than their older counterparts.

Review : Prolactin: a stimulator of disease activity in systemic lupus erythematosus

It is accepted that estrogen and testosterone have the potential to affect the severity of autoimmunity in animal models’ and humans with systemic lupus erythematosus (SLE)2,3. More recently, the anterior pituitary hormone, prolactin, has been shown to have immune-stimulating propertieS4 and high concentrations of prolactin were associated with accelerated disease in Fez I hybrid New Zealand Black X New Zealand White (NZB/NZW) mice, which develop a lupus-like disorders. When NZB/NZW females were made chronically hyperprolactinemic by pituitary transplantation, the animals died prematurely with autoimmune renal disease. In contrast, treatment with the prolactin-suppressing drug, bromocriptine, was beneficial6. Hyperprolactinemia has also been linked to human lupus. Abnormal elevations of serum prolactin have been reported in 22% of women with SLE , in pregnant women with lupus flares8 and in men with SLE9. The authors recently evaluated four women with chronic hyperprolactinemia who also developed SLE: in two instances, lupus appeared I or 6 months after bromocriptine therapy was stoppedlo. This article will review the effects of two patterns of hyperprolactinemia: prolonged, pituitary implant-induced prolactin elevation and episodic ’physiologic’ hyperprolactinemia in the NZB/NZW mouse model of lupus. The authors will discuss the reported associations between SLE and hyperprolactinemia, and describe recent experience with chronically hyperprolactinemic women who have developed SLE. If hyperprolactinemia is deleterious, are normal levels of prolactin harmful in SLE? In this review, the proposal will be considered that physiological concentrations of circulating prolactin, falling within the accepted range of normal values, chronically promote disease activity in the SLE patient. Long-term use of a prolactin-suppressive drug would therefore be a reasonable form of adjunct treatment of SLE. Preliminary analyses of a recent therapeutic trial have advanced this supposition. The authors found that bromocriptine, which inhibits pituitary secretion of prolactin, was associated with remission in selected patients with active SLE 11. z

Prolactin levels and antinuclear antibody profiles in women tested for connective tissue disease.

Hyperprolactinemia has been reported in some patients with active systemic lupus erythe matosus (SLE). To determine if there was an association between selected autoantibodies and hyperprolactinemia, we assayed prolactin concentrations in sera from women sub mitted to a reference antinuclear antibody laboratory. Autoantibody-positive samples were separated into groups that contained antibodies to double-stranded DNA (anti-DNA), anti bodies to SSA/Ro (anti-SSA/Ro), or antibodies to both SSA/Ro and SSB/La (anti-SSA/Ro- SSB/La). Results were compared with autoantibody-negative sera from age-matched women, submitted to the same laboratory. We also compared the study groups with a separate cohort of 84 healthy women who were not referred for autoantibody testing. Elevated prolactin levels were clustered in 20% of sera from anti-DNA-positive women ≤50 years of age. Twenty-one percent of anti-SSA/Ro-SSB/La-positive women < 50 years of age were hyperprolactinemic. Four of the 15 hyperprolactinemic women identified in this survey had no known cause of elevated prolactin. In the other 11 individuals, secondary causes such as hypothyroidism, pregnancy, chronic renal failure, and medications may have accounted for high serum prolactin values. We also examined sera by Western blot, to determine if immunoblot patterns were associated with elevated serum prolactin concentra tions. The hyperprolactinemic sera yielded novel bands migrating at 70 kd, 32 kd, and 16.5 kd. This study confirmed the reported associations of hyperprolactinemia with SLE and Sjögrens syndrome. Multiple factors appeared to contribute to elevated serum prolactin levels in women with connective tissue diseases, and the presence of hyperprolactinemia was related to unique findings on immunoblot analysis.Sjögrens syndrome (SS) is a chronic autoimmune rheumatic disorder characterized by lymphocytic infiltration and destruction of exocrine glands, mainly of salivary and lacrimal glands, leading to dryness of mouth and eyes. It can occur either alone (primary SS) or in association with almost every systemic autoimmune rheumatic SS). Usually, SS patients have slowly progressive disease confined in exocrine glands, however, in approximately one third of primary SS patients the disorder presents a systemic and progressive course with involvement of diverse extraglandular sites and in a small but significant number of patients with lymphoid neoplasia development. Although the aetiology of SS remains unknown, chronic immune system stimulation is thought to play a central role in the pathogenesis of the disorder, as illustrated by several indices of immunological hyperactivity, including various autoantibodies, polyclonal hypergammaglobulinemia and circulating paraproteins. To date, treatment of SS remains largely empirical and symptomatic, and no clinical trial has been proved capable to change the course of the disease. Hydroxychloroquine has been successfully applied for the treatment of arthralgias, myalgias and general constitutive symptoms of SS patients. In an initial small open study, hydroxychloroquine administration has been shown to improve features of immunological hyperreactivity, such as hypergammaglobulinaemia and autoantibody levels. However, large prospective double-blind studies are still needed to assess the long-term efficacy of hydroxychloroquine in preventing extraglandular involvement and lymphoma development in primary SS patients.

Prolactin and autoimmune disease

A number of reports have shown that PRL is an immune-stimulating hormone that is capable of stimulating organ-specific inflammatory disease in humans. More recently, hyperprolactinemia has been associated with the active phase of the immune-complex-mediated autoimmune disease, systemic lupus erythematosus. The theory that PRL contributes substantially to disease activity was upheld in the NZB/W mouse model of spontaneous, hormone-sensitive lupus. Implanted pituitary glands resulted in hyperprolactinemia, accelerated proteinuria, high levels of circulating IgG, and premature death. Therapeutic studies with NZB/W mice, as well as anecdotal evidence from a small number of patients, have provided evidence that PRL suppressive therapy may be beneficial in selected cases of autoimmune disease.

A biopsychosocial model of disability in rheumatoid arthritis

OBJECTIVE To test and cross-validate a model using disease activity, pain, and helplessness to predict future psychological and physical disability in persons with rheumatoid arthritis (RA) across time. METHODS Measures of disease activity, pain, helplessness, psychological function, and physical function were collected from 63 males with RA at baseline, 3 months, and 6 months. Path analytic methods were used to examine longitudinal relationships among these variables. RESULTS Path analysis revealed that pain and helplessness were significant mediators of the relationship between disease activity and future disability in RA; the predictive model withstood two cross-validations. CONCLUSION The findings suggest that pain and helplessness are key biopsychosocial variables that affect the development of disability in RA.

Stress Management in Rheumatoid Arthritis: What Is the Underlying Mechanism?

OBJECTIVE To test whether change in cognitive-behavioral variables (such as self-efficacy, coping strategies, and helplessness) is a mediator in the relation between cognitive behavior therapy and reduced pain and depression in persons with rheumatoid arthritis (RA). METHODS A sample of patients with RA who completed a stress management training program (n = 47) was compared to a standard care control group (n = 45). A path analysis testing a model including direct effects of comprehensive stress management training on pain and depression and indirect effects via change in cognitive-behavioral variables was conducted. RESULTS The path coefficients for the indirect effects of stress management training on pain and depression via change in cognitive-behavioral variables were statistically significant, whereas the path coefficients for the direct effects were found not to be statistically significant. CONCLUSION Decreases in pain and depression following stress management training are due to beneficial changes in the arenas of self-efficacy (the belief that one can perform a specific behavior or task in the future), coping strategies (an individuals confidence in his or her ability to manage pain), and helplessness (perceptions of control regarding arthritis). There is little evidence of additional direct effects of stress management training on pain and depression.

Estrogen and Autoimmune Disease

Estrogenic hormones possess both immunostimulating and immunosuppressive properties. In systemic lupus erythematosus (SLE), pregnancy is associated with disease flares. In some situations, exogenous estrogen predisposes to development of new SLE, flares of preexisting SLE, and thromboses in susceptible individuals. In contrast, treatment with exogenous estrogen protects postmenopausal rheumatoid arthritis (RA) patients from active RA and osteoporosis. The search for estrogen-like compounds with anti-inflammatory properties may expand treatment options in RA.

Mood states and disease activity in patients with systemic lupus erythematosus treated with bromocriptine

We tested mood states in patients with systemic lupus erythematosus (SLE) treated with the prolactin-lowering drug, bromocriptine. Bromocriptine was given to seven patients in an open-label study to test its effects on active SLE. Two independent measures of SLE activity, the SLE Activity Measure (SLAM) and the SLE Disease Activity Index (SLEDAI), were scored and the Symptom Questionnaire (SQ) mood survey was administered at entry and at 6 monthly follow-up visits. The SLAM and SLEDAI scores improved significantly during treatment. Two of the four mood scales in the SQ (Anxiety Scale and Anger – Hostility Scale) showed significant improvement compared to the entry value at least once during treatment. Significant improvement was also observed in the Total Distress Score, which is the sum of the four scales and is a more sensitive measure of distress than the score of an individual scale. Depression, anxiety, somatic complaints, and total distress correlated positively with SLAM and/or SLEDAI scores. The Anxiety Scale and the Total Distress Score improved with treatment and did correlate positively with SLE activity. In contrast, the Anger – Hostility Scale improved with treatment but did not correlate with SLE activity.

Treatment of systemic lupus erythematosus with bromocriptine

Prolactin, a lactogenic hormone, is a cytokine and an inportant link between the immune and endocrine systems. Prolactin stimulated disease in autoimmune NZB/NZW mice. Treatment of the mice with the prolactin-lowering dopamine agonist, bromocriptine, suppressed anti-DNA and prolonged life spans. These findings have been applied to humans with systemic lupus erythematosus (SLE). An open-label study, a double blind study, and a study comparing bromocriptine to hydroxychloroquine provided evidence that bromocriptine therapy reduced flares and suppressed disease activity in SLE.