Bromocriptine in rheumatic and autoimmune diseases

Bromocriptine in Rheumatic and Autoimmune Diseases Robert W. McMurray Background and Objectives: Multiple lines of evidence support the concept that the anterior pituitary hormone prolactin has a pathogenic role in rheumatic and autoimmune diseases including, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Reiter’s syndrome, psoriatic arthritis, and uveitis. Conversely, the dopaminergic agonist bromocriptine appears to have therapeutic effects through suppression of pituitary prolactin secretion and, perhaps, through actions on peripheral dopamine receptors. This article reviews the experimental and clinical data supporting the therapeutic use of bromocriptine as a nonstandard or adjunctive therapy in rheumatic and autoimmune diseases. Methods: Data addressing the potential therapeutic role of bromocriptine in rheumatic and autoimmune diseases, as well as frequently associated comorbidities, was accumulated from the author’s work, online literature search of the National Library of Medicine, and references from these identified publications. Results: There have been a number of clinical therapeutic trials using 2.5 to 30 mg of bromocriptine per day in a single or divided dose, which have shown efficacy with minimal side effects in the treatment of rheumatic and autoimmune diseases. In RA, bromocriptine administration has induced immunosuppression of several immune parameters and has been associated with improvements in morning stiffness, grip strength, numbers of swollen/painful joints, and the Health Assessment Questionnaire disability index. In two blinded studies, bromocriptine reduced the number of SLE flares and was as effective as hydroxychloroquine in reducing lupus disease activity indices, respectively. In case reports, bromocriptine has been used successfully in the treatment of Reiter’s syndrome enthesopathy and psoriatic arthritis. The potential efficacy of bromocriptine in the treatment of uveitis and multiple sclerosis is suggested but remains to be verified. Conclusions: Double-blind, placebo-controlled studies are limited, but clinical observations and trials support the use of bromocriptine as a nonstandard primary or adjunctive therapy in the treatment of recalcitrant RA, SLE, Reiter’s syndrome, and psoriatic arthritis and associated conditions unresponsive to traditional approaches. Additional investigation is needed to verify this conclusion and extend preliminary results. Relevance: In patients with rheumatic and autoimmune diseases, bromocriptine may be a relatively safe and efficacious alternative therapy. Semin Arthritis Rheum 31:21-32. Copyright © 2001 by W.B. Saunders Company INDEX WORDS: Bromocriptine; prolactin; rheumatoid arthritis; lupus; autoimmunity.

From the Rheumatology Section, G.V. (Sonny) Montgomery VA Hospital and Division of Rheumatology and Molecular Immunology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS. Robert W. McMurray, MD: Associate Professor of Medicine, Rheumatology Section, G.V. (Sonny) Montgomery VA Hospital and Division of Rheumatology and Molecular Immunology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS.

Address reprint requests to Robert W. McMurray, Division of Rheumatology, L525 Clinical Sciences Building, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216. E-mail: [email protected] Copyright © 2001 by W.B. Saunders Company 0049-0172/01/3101-1041$35.00/0 doi:10.1053/sarh.2001.25482

Seminars in Arthritis and Rheumatism, Vol 31, No 1 (August), 2001: pp 21-32

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Table 1: Diseases Associated With Prolactin Abnormalities and/or Response to Bromocriptine Rheumatic diseases Rheumatoid arthritis Systemic lupus erythematosus Reiter’s disease Psoriatic arthritis Sjogren’s syndrome Scleroderma Fibromyalgia Restless legs syndrome Autoimmune diseases Uveitis Multiple sclerosis Endocrine diseases Premenstrual syndrome Hashimoto’s thyroiditis Diabetes mellitus Galactorrhea/amennorhea syndrome Prolactinoma Miscellaneous diseases Migraine headaches Depression Psoriasis Fatigue

A

CCUMULATING MEDICAL evidence (1-9) continues to establish that the anterior pituitary hormone prolactin has pathophysiologic roles in the development or persistence of several rheumatic and autoimmune diseases (Table 1). Anterior pituitary prolactin is a 200 amino acid hormone produced in, and secreted from, the anterior pituitary into the circulation (10,11). Peripheral prolactin, also identified as immunoreactive prolactin (irPRL) or lymphocyte prolactin, is produced and secreted locally by lymphocytes (12-13). Pituitary prolactin production and secretion is normally under inhibitory dopaminergic control, and serum concentrations are increased by estrogen, nursing, stress, chest wall stimulation, prolactin releasing factor, and a number of drugs (10,11). Factors regulating irPRL production and secretion are less well understood but may involve cytokines or lymphocyte activation (12,13). Serum prolactin concentrations rise during pubertal development in response to increasing estrogen surges, are higher in females than males, and

fall with menopause (10,11,14). However, a significant percentage of women develop microscopic prolactinomas in later life (15,16). Baseline prolactin concentrations are accentuated during pregnancy and peak in the postpartum nursing female, when mammary gland immunoglobulin production nears its maximum level. Traditional endocrinologic concepts define prolactin as a hormone crucial for mammary gland immune function, immunoactivation, and production of immunoglobulin by migratory gut-associated lymphoid tissue (14,17,18). Circulating prolactin binds to the prolactin receptor and its various isoforms, which are also expressed on lymphocytes (19-21), as might be expected for a receptor that belongs to the growth hormone, erythropoietin, and cytokine receptor superfamily (22,23). Signal transduction of the prolactin receptor leads to gene transcriptional regulation (20,21). Interestingly, the immunomodulatory drug cyclosporine antagonizes the binding of prolactin to T and B lymphocytes (24). There is substantial evidence (1-9) that prolactin has both acute and chronic effects on immune and autoimmune responses (Table 2). Accordingly, bromocriptine suppression of prolactin in animal models of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and uveitis modulates disease severity and outcomes (reviewed below). These studies have been extended to human diseases in which bromocriptine has been shown to suppress autoimmune responses and improve rheumatic and autoimmune disease manifestations in association with suppression of serum prolactin concentrations. Bromocriptine is an ergot alkaloid that binds to the dopamine receptor, thereby suppressing Table 2: Immunoregulatory Properties of Prolactin Activates protein kinase C Essential for T-cell proliferation Co-mitogenic with IL-2 Induces IL-2 receptor expression Supports IFN-␥ production through interferon regulatory factor-1 Stimulates antibody and autoantibody production Associated with increased percentages of total and CD2⫹ lymphocytes

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pituitary prolactin synthesis and release and lowering serum prolactin concentrations (25,26). Bromocriptine may also directly modulate T and B lymphocytes through the dopamine receptor (27,28). By virtue of its suppressive properties on the immunostimulatory hormone prolactin and its direct actions on T and B lymphocytes, bromocriptine has apparent therapeutic efficacy in the treatment of mild to moderate rheumatic and autoimmune disease. Herein we review bromocriptine’s pharmacology, proposed mechanisms of immunosuppression, disease-specific evidence of efficacy, and an approach to its use in the treatment of rheumatic and autoimmune diseases. PHARMACOLOGY OF BROMOCRIPTINE

Bromocriptine has rapid oral and mucosal absorption, reaches peak levels in 6 to12 hours, and is excreted primarily through the biliary route. Binding to the D2 dopaminergic receptor, bromocriptine has a wide variety of effects on motor function as well as suppression of prolactin release from the anterior pituitary (25,26). Additional effects on vasoreactivtiy appear to be dose and situation dependent, as bromocriptine appears to lower blood pressure (29,30). Typical dosing for humans is once or twice daily in a dosage ranging from 2.5 to 30 mg. Primarily used in the treatment of symptomatic prolactinomas since the 1960s, bromocriptine is typically well tolerated. The most common reported side effects are nasal stuffiness, dreaming, and headache, although in rare circumstances cerebral vasospasm and stroke or pleuropulmonary or retroperitoneal fibrosis has occurred (25,26). Bromocriptine is not teratogenic (31) and facilitates pregnancy in hyperprolactinemic amenorrhea (14,25,26). Bromocriptine has no significant drug interactions and has been used safely, as described below, with corticosteroids, hydroxychloroquine, and other immunosuppressives.

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cytokine regulation, being comitogenic with IL-2 and stimulating IFN-␥ indirectly through interferon regulatory factor (IRF-1) (37-44). In contrast, bromocriptine-induced hypoprolactinemia is associated with suppression of classic T- and B-cell immune responses in rodents (27,28,34,40,43 and references therein), which is reversed by increased serum prolactin concentrations (32,34). In experimental models, bromocriptine administration has been associated with suppression of T lymphoproliferation, antibody and autoantibody production, and cytokine levels (34,35,43,44). These effects occur either indirectly, through suppression of serum prolactin concentrations, or directly, through modulation of lymphocyte function (27,28). A direct immunomodulatory effect of bromocriptine is refuted by available data (34,43,45). Pathways and mechanisms of prolactin and bromocriptine immunomodulation as well as potential bromocriptine effects on irPRL at the cellular level have not been completely elucidated and could conceivably overlap with bromocriptine’s effects on pituitary prolactin. In humans, the effects of bromocriptine on classic immune and autoimmune responses have not been studied in detail, but its administration appears to induce immunosuppression (46,47). Limited examination has shown an association between bromocriptine administration and altered T- and B-cell function (47), decreased autoantibodies (48,49), alteration in lymphocyte number and expression of surface molecules (47) (Table 3), and modulation of a variety of rheumatic and autoimmune disease manifestations (Table 4), which are reviewed below. Systematic study and doubleblind, placebo-controlled clinical therapeutic trials are scarce, although the potential benefits of bromocriptine therapy on autoimmunity have been

MECHANISMS OF BROMOCRIPTINE IMMUNOSUPPRESSION

Table 3: Immunosuppressive Properties of Bromocriptine

Administration of prolactin to hypophysectomized (32) or hypopituitary rodents (33) restores immune competence, suggesting that prolactin is immunostimulatory. Accordingly, immunosuppression associated with prolactin suppression can be overridden by administration of exogenous prolactin (34). Prolactin augments antibody production (35,36) and has a significant role in lymphoproliferation and

Bromocriptine suppresses: Lymphoproliferation IL-2 and other cytokine production Antibody production Autoantibody production Lymphocyte prolactin Prolactin-induced immunostimulatory properties

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Table 4: Therapeutic Efficacy of Bromocriptine in Rheumatic and Autoimmune Disease Disease

Bromocriptine Dose

RA

5-7.5 mg/d (up to 30 mg/d in some patients)

SLE

2.5-7.5 mg/d or tailored to prolactin ⬍1 ng/mL

Reiter’s syndrome

2.5-5 mg/d

Psoriatic arthritis

7.5-10 mg/d

Uveitis

2.5-3.75 mg/d

Multiple sclerosis

10 mg/d

Response Decreased morning stiffness Improved HAQ Increased grip strength Decreased numbers of painful/swollen joints Decreased disease activity as measured by SLAM Decreased disease flares Decreased fatigue Steroid tapering Reduced psychological distress Decreased arthritis and enthesopathy Pain reduction ESR reduction Decreased arthritis and skin manifestations Alleviation of iridocyclitis Reduction of recurrences Decreased autoantibodies Reduction or elimination of steroids Synergistic with cyclosporine Reduction in paroxysmal symptoms

Side Effects Minimal Nausea

Nasal stuffiness Dreaming Headache Nausea

None recorded

Reference(s) 59,60,61

75-77,82,83

85

Minimal

86-93

Minimal

95-102

None recorded

108

Abbreviations: HAQ, Health Assessment Questionnaire; SLAM, Systemic Lupus Activity Measure; ESR, erythrocyte sedimentation rate.

previously considered (1,6,46). Available patient data, as reviewed below, are congruent with that of animal models. The immunosuppressive action(s) of bromocriptine, in the setting of a relatively safe side effect profile, warrants its consideration for use as an adjunctive or nonstandard treatment in mild to moderate rheumatic and autoimmune disease. BROMOCRIPTINE IN RA

The potential efficacy of bromocriptine in the treatment of RA initially was shown in the collagen-induced (CIA) (50) and adjuvant-induced mouse models of arthritis (51). This data was extended into suppression of the postpartum exacerbation of CIA (50), although the interplay between immunostimulatory effects of prolactin (9) and the immunosuppressive effects of estrogen

(52) are significant in this complex hormonal milieu (9,14). Several recent studies have supported a role for prolactin in the development and disease activity of RA (53-55). Although prolactin concentrations were not measured, postpartum exacerbations of RA have been associated with nursing (56), which is a hyperprolactinemic, hypoestrogenic state (10,14). Prolactin is also produced by synoviuminfiltrating T lymphocytes and was associated with induction of excessive synovial cell functions in patients with RA. It was shown in vitro that bromocriptine suppressed lymphocyte prolactin as well as synovial lymphocyte proinflammatory cytokines (eg, IL-6) and proliferation (57). An attempt at extending these studies to humans was disappointing, as reported by Dougados et al, in which combination bromocriptine and cyclospor-

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ine therapy of RA patients was not efficacious (58). In this study of 6 patients, the absence of demonstrated efficacy may have occurred because of the lack of significant serum prolactin suppression (prolactin concentrations were not documented), patient selection bias, or early dropout of several patients (58). Although initially disappointing, these results may not be truly representative of a role for prolactin in RA. Recent open-label studies of bromocriptine administration to RA patients with mild to moderate disease activity have been more successful (59-61). In 9 patients with active RA, bromocriptine administration (3.75 to 30 mg/d) for 3 months significantly suppressed serum prolactin concentrations (59,60). Bromocriptine induced a significant depression of the peripheral blood mononuclear cells (PBMC) response to antigen and mitogen (P ⫽ .008). In-vitro PBMC production of IL-2, nitric oxide, and polyamines also decreased significantly. These immunologic changes correlated significantly with improvements in the Health Assessment Questionnaire (HAQ) disability index (r ⫽ 0.68; P ⫽ .04) and grip strength (r ⫽ 0.7; P ⫽ .02), and the group as a whole experienced significant improvement of morning stiffness, grip strength, and the HAQ disability index. Four individuals achieved clinical improvement according to the American College of Rheumatology definition. Some patients experienced nausea as a minor side effect; no major side effects of bromocriptine administration were reported. These results suggest that bromocriptine treatment induced a significant depression of in-vitro immune function in RA patients and that these changes were related to parameters of disease activity. In a separate study (61), 5 mg bromocriptine at bedtime was administered to 5 patients with refractory RA who had failed to respond to previous treatment with at least 2 disease-modifying antirheumatic drugs. Three of the 5 patients showed more than 25% improvement in the number of tender and swollen joints at 12 weeks of treatment. However, in only 2 patients was improvement maintained through 6 months. One patient dropped out of the study because of acute exacerbation of RA 4 weeks after initiation of bromocriptine. The remaining patient did not show any significant clinical changes. No correlation was found between serum prolactin levels and disease activity over time.

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These studies suggest that some patients with refractory RA might improve with bromocriptine. The open-label nature of these studies precludes definitive conclusions but provides a basis for further investigation. The use of bromocriptine in larger doses in larger groups of patients and in controlled, double-blind studies may help elucidate the role of bromocriptine in the treatment of RA. These preliminary studies suggest that bromocriptine may be an efficacious adjunctive or primary treatment in RA uncontrolled by first-line therapy. BROMOCRIPTINE IN SLE

A pathophysiologic role for prolactin in human SLE is controversial, evidenced by a number of studies with variable statistical power (62-69). However, a recent comparison of statistically evaluable studies supports a significant, although perhaps not causal, association between prolactin and SLE disease activity (69). Potential actions and interactions with estrogen (9,10,43) confound a complete understanding of prolactin in SLE. Nevertheless, in murine models of SLE, bromocriptine suppresses immunoglobulin levels, autoantibodies, and immune-complex glomerulonephritis and significantly improves survival (43,44,70,71). In animal models, bromocriptine administration also has been associated with decreased T lymphoproliferation and cytokine production (43,44). The potential efficacy of bromocriptine in the treatment of human SLE was first realized with its use for a movement disorder in an SLE patient (72) and further suggested by observations of SLE patients with prolactinomas whose disease symptoms resolved with bromocriptine treatment (73-76) and recurred upon its discontinuation (75). In an openlabel, 6-month study, 7 patients with SLE and normal or elevated serum prolactin concentrations improved within a 3-month period of bromocriptine (2.5 to 7.5 mg) administration and serum prolactin inhibition. A transient but significant reduction in anti-DNA antibodies and sustained significant reductions in Systemic Lupus Activity Measure (SLAM) scores and cholesterol were observed during bromocriptine treatment. Significant improvements also were noted in fatigue, lupus headache, arthralgias, and skin rash, regardless of normal or elevated entry serum prolactin concentration (ie, reduction of prolactin from physiologic or elevated concentrations to ⬍1 ng/mL was asso-

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ciated with improvement in disease activity). Subsequent discontinuation of bromocriptine and rebound of serum prolactin concentrations to normal or supernormal concentrations were followed by flares of SLE activity within 1 to 3 months as documented by significant increases in SLAM scores. Nasal stuffiness, dreaming, and headaches were reported side effects, and no drug interactions with concomitant administration of nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids were reported (75). In a related open-label study (77) evaluating psychological distress of SLE patients, anxiety and anger-hostility were significantly improved compared with the entry value at least once during bromocriptine treatment. Significant improvement also was observed in the total psychological distress score, which is the sum of the 4 scales and is a more sensitive measure of psychological distress than the score of an individual scale. Depression, anxiety, somatic complaints, and total distress correlated positively with SLAM and/or SLE Disease Activity Index (SLEDAI) scores in this study (77). It is well established that bromocriptine has efficacy in the treatment of recalcitrant depression (78-81) and, therefore, may be a useful psychotropic as well as immunosuppressive agent in patients with SLE. These promising results have subsequently been verified by 2 double-blind studies. Alvarez-Nemegyei et al (82) showed in a double-blind, placebocontrolled study that bromocriptine reduces SLE flares and facilitates corticosteroid tapering. The objective of this study was to investigate the efficacy and safety of bromocriptine as an adjunct to conventional treatment in SLE. Bromocriptine was administered at a fixed daily dosage of 2.5 mg to 66 patients with active SLE. Patients were followed up at a mean of 12.5 months, and disease activity was assessed with the SLEDAI and numbers of flares. Serum prolactin levels were obtained at intervals during the study. Patients were allowed to take prednisone and immunosuppressive drugs during the study. Thirty-six patients were treated with bromocriptine and 30 controls received placebo. Sixteen patients left the study during the treatment period: 5 in each group left the study because of adverse effects, 5 became pregnant, and 1 patient who took placebo died with central nervous system lupus. Four patients in the bromocriptine treatment group and 3 in the placebo group

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were lost to follow-up. At entry, serum prolactin was 24.8 ng/mL ⫾ 18.4 (mean ⫾ standard deviation [SD]) in the bromocriptine treatment group. This value fell to 5.8 ⫾ 9.0 after 12 months of treatment. Corresponding prolactin values in controls were 23.7 ⫾ 22.1 pretreatment and 20.3 ⫾ 14 after 12 months. Prolactin levels in bromocriptinetreated subjects were significantly lower than levels in control subjects after 3, 6, 9, and 12 months of treatment. The SLEDAI score on the fifth protocol visit was decreased significantly in the bromocriptine group versus the controls. Although the absolute number of flares in each group was similar, the mean number of flares/patient/month decreased significantly in the bromocriptine group compared with the control group. These results further suggest that long-term treatment with lowdose bromocriptine appears to be a safe and effective means of decreasing flares in patients with SLE (82). These results were further verified by the study of Walker et al (83) who showed in a doubleblinded trial that bromocriptine is as efficacious as hydroxychloroquine in the treatment of active SLE (83). In this comparison, bromocriptine-induced suppression of serum prolactin to ⬍1 ng/mL was associated with a significant decrease in mean SLAM score, a nonstatistically significant reduction in SLEDAI, and a reduction in corticosteroid use. These changes were comparable to those induced by 1-year treatment with hydroxychloroquine (83). Therefore, bromocriptine, either alone or in combination with other immunosuppressives, appears to be a safe and effective treatment for SLE and may address difficult-to-treat symptoms such as fatigue and lupus headaches. Although specific mechanisms of action remain to be elucidated, the responses of SLE manifestations to bromocriptine suggest that prolactin stimulates disease activity and that prolactin and gonadal hormone monitoring may have significant implications for the management (84). BROMOCRIPTINE IN REITER’S SYNDROME AND PSORIATIC ARTHRITIS

Scattered case reports of bromocriptine administration to patients with Reiter’s syndrome (85) and psoriatic arthritis (86-93) have suggested that bromocriptine may have clinical efficacy in the treatment of these seronegative spondyloarthropa-

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thies, although its efficacy is not universal (92). Clinical observations of elevated prolactin concentrations in Reiter’s syndrome (85) and the potential association between prolactin and psoriasis (93) support the postulation that these seronegative spondyloarthropathies would also respond to bromocriptine administration. In Reiter’s syndrome, 4 patients with infectious gastroenteritis and chronic Reiter’s syndrome with arthritis and enthesopathy refractory to NSAIDs and sulfasalazine were treated with bromocriptine at doses of 2.5 to 5 mg/d. Serum prolactin concentrations were 3 to 10 ng/dL before treatment and were suppressed to 1.5 to 4.7 ng/dL with treatment. Bromocriptine-induced prolactin suppression was associated with a dramatic improvement within 1 to 4 days as documented by decreases in numbers of swollen joints, decreased visual analog pain scale, and decreased erythrocyte sedimentation rate. Sustained remission persisted for 4 months. Upon discontinuation of bromocriptine in 1 patient, the arthritis recurred (85). Certainly additional trials are warranted, but in recalcitrant Reiter’s disease there is a reported precedent for intervention with bromocriptine. Case reports document resolution of psoriatic arthritis and psoriasis induced by bromocriptine administration (86-93). Controlled trials are absent, but these clinical observations suggest that bromocriptine may be a therapeutic alternative or adjunct in recalcitrant enthesopathic disease. In the largest study, which was open-label, 35 patients suffering from psoriatic arthritis recalcitrant to other rheumatic therapies were systematically treated with bromocriptine at increasing doses, starting at 2.5 mg up to 30 mg per day. In 77% of patients, significant benefit was observed: 34% showed total remission and 43% had approximately 50% improvement of the articular symptoms. Similar subjective results were seen in case reports (87-92). Obviously objective, controlled studies are required to determine the reproducibility of these observations and support the use of bromocriptine in psoriasis; however, in recalcitrant disease, bromocriptine may be a viable alternative. BROMOCRIPTINE IN UVEITIS

In a disorder occasionally associated with the seronegative spondyloarthropathies, uveitis, bromocriptine also has been shown to be efficacious. Initial animal studies suggested a possible thera-

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peutic role for bromocriptine. Bromocriptine suppressed the development of experimental autoimmune uveitis with bromocriptine alone or in combination with cyclosporine (94). Extension of these studies to humans have not been as dramatic but still show significant suppression of uveal tract inflammation alone or in combination with cyclosporine (95-102). Bromocriptine administration reduced the severity of iridocyclitis (although objective measurements were not clearly documented) and facilitated the tapering or discontinuation of ophthalmic or systemic corticosteroids in most studies. However, a beneficial effect was not seen in one small, blinded study (99) prompted by these case reports. In a double-blind, placebo-controlled study (95), bromocriptine treatment was examined in 13 patients with chronic recurrent anterior uveitis who had experienced 3 or more recurrences during the previous year. Bromocriptine was started gradually during the symptom-free interval and continued for 1 year with 2.5 mg twice daily. Two recurrences or relevant side effects led to discontinuation of therapy. In the bromocriptine group, 2 of 7 patients had no recurrences during the study period. Two patients had to stop because of 2 recurrences but, in contrast to earlier recurrences, they responded to local corticosteroid treatment within a few days. The remaining 3 patients (1 with one recurrence, 2 without) had to stop because of side effects (arterial hypotension and arthritic complaints). In 5 of 6 patients in the placebo group, treatment was discontinued because of recurrences; in 1 patient it was stopped because she believed she was experiencing a side effect from bromocriptine (breast atrophy). In summary, bromocriptine seems to have a prophylactic effect on anterior uveitis. Side effects were frequent but mild compared with other immunosuppressives. This study (95) suggested that abnormalities of dopamine metabolism might occur in uveitis and these abnormalities are required for a therapeutic response to bromocriptine. Although it has not achieved widespread use, bromocriptine may be a reasonable nonstandard therapy for the treatment of uveitis, particularly in the presence of a spondyloarthropathy. BROMOCRIPTINE IN MS

Clinical and experimental observations have suggested that prolactin has a pathophysiologic role in MS (103-106). Its predominance in women

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and flares during menstrual cyclicity (reviewed in 105) support possible hormonal immunomodulatory effects related to sex hormones. In experimental autoimmune encephalomyelitis, bromocriptine suppressed autoimmune demyelination, supporting a pathophysiologic role for prolactin and potential efficacy of bromocriptine in MS (106,107). A case report described control of paroxysmal flares of disease activity by bromocriptine (108); however, an open-label pilot study did not show therapeutic effects on MS activity (109). At the current time, the therapeutic efficacy of bromocriptine in MS is not established and requires further investigation. BROMOCRIPTINE IN MISCELLANEOUS RHEUMATIC DISEASE COMORBID CONDITIONS

Prolactin levels appear to be elevated in Sjogren’s syndrome (110) and scleroderma (111113), providing a compelling but understudied area of pathophysiologic and therapeutic possibilities. This potential relationship is further extended by the observed reduction of prolactin by captopril (114), the preferred treatment of scleroderma renal crisis (115). However, there are no recent studies that evaluate the therapeutic efficacy of bromocriptine in scleroderma. Bromocriptine, because of its dopaminergic activity, has been used successfully in a wide variety of miscellaneous diseases that may be seen in association with rheumatic syndromes. For example, in restless legs syndrome, bromocriptine significantly reduced periodic movement and improved total sleep time (116). Bromocriptine also has been used successfully in treatment of fatigue (117), migraine headache (118), premenstrual syndrome (119), and depression (78-81). Preliminary studies have suggested increased serum prolactin concentrations in association with fibromyalgia (120) and potential therapeutic efficacy for bro-

mocriptine in some patients with fibromyalgia (R. McMurray, unpublished data). Although the apparent widespread beneficial actions of bromocriptine seem extraordinary, its effects may be explained either by inhibition of the complex endocrinological, psychological, and immunological actions of prolactin; the broad effects of bromocriptine’s dopaminergic agonism in different tissues; or both. DISCUSSION

Although hampered by the lack of placebocontrolled, double-blind studies, bromocriptine has a panoply of neurohormonal and immune effects and has shown therapeutic efficacy that warrants further evaluation as an antirheumatic agent. The broad, yet superficial, therapeutic spectrum of bromocriptine actions suggests a deeper question beyond bromocriptine’s immunosuppressive qualities: Does dopamine or its receptors have a role in the pathogenesis of rheumatic or autoimmune disease and their frequent associated comorbidities? This is further exemplified by reports of effects of bromocriptine on the onset and severity of diabetes mellitus, in which prolactin manipulation and dopamine agonism by bromocriptine reduces metabolic abnormalities and frequency of diabetes in an experimental model (121) and reduces hyperglycemia and fat stores in humans (122). Moreover, bromocriptine, as an adjuvant immunosuppressive, exhibited significant effects in heart transplant patients and reduced the number of complicating infections (123). Although bromocriptine is not a panacea, evidence of its therapeutic properties, in the setting of its reasonable safety profile, support its use as an adjunctive or primary treatment in difficult-to-treat rheumatic disease. Furthermore, incisive investigation of its therapeutic properties also may reveal significant pathophysiologic relationships.

REFERENCES 1. Jara LJ, Lavalle C, Fraga A, Gomez-Sanchez C, Silveira LH, Martinez-Osuna P, et al. Prolactin, immunoregulation, and autoimmune diseases. Semin Arthritis Rheum 1991;20:273-84. 2. Buskila D, Sukenik S, Shoenfeld Y. The possible role of prolactin in autoimmunity. Am J Reprod Immunol 1991;26: 118-23. 3. Walker SE. Prolactin: an immune-stimulating peptide that regulates other immune-modulating hormones. Lupus 1993;2: 67-9.

4. Reber PM. Prolactin and immunomodulation. Am J Med 1993;95:637-44. 5. Gutierez MA, Anaya JM, Cabrera GE, Vindrola O, Espinoza LR. Prolactin, a link between the neuroendocrine and immune systems. Role in the pathogenesis of rheumatic diseases [in French]. Rev Rheum Ed Fr 1994;61: 278-85 6. Buskila D, Shoenfeld Y. Prolactin, bromocriptine, and autoimmune diseases. Isr J Med Sci. 1996;32:23-7 7. Compan-Gonzalez DA, Martinez-Aguilar NE, Vargas-

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Camano ME, Guido-Bayardo R. Hyperprolactinemia and autoimmunity. Rev Allerg Mex 1996;43:128-32. 8. Leanos Miranda A, Quintal Alvarez MG, Cervera Castillo H, Blanco Favela F. Prolactin as an immunomodulator. Rev Allerg Mex 1997;44:116-23. 9. McMurray RW. Estrogen, prolactin, and autoimmunity. Int J Immunopharmacol (in press). 10. Frantz AG. Prolactin. N Engl J Med 1978;298:201-6. 11. Franks S. Regulation of prolactin secretion by oestrogens: physiological and pathological significance. Clin Sci 1983;65:457-62. 12. Matera L. Action of pituitary and lymphocyte prolactin. Neuroimmunomodulation 1997;4:171-80. 13. Sabharwal P, Glaser R, Lafuse W, et al. Prolactin synthesized and secreted by human peripheral blood mononuclear cells: an autocrine growth factor for lymphoproliferation. Proc Natl Acad Sci U S A 1992;89:7713-6. 14. Wilson JD, Foster DW, Eds. Williams Textbook of Endocrinology (8th ed), Philadelphia, Saunders, 1992:733-98. 15. Batrinos ML, Panitsa-Faflia C, Tsiganou E, Laipi C. Incidence and characteristics of microprolactinomas (3-5 mm) in 4199 women assayed for prolactin. Horm Metab Res 1992; 24:384-91. 16. Ambrosi B, Faglia G. Multicenter Pituitary Tumor Study Group, Lombardia Region. Epidemiology of pituitary tumors. In: Pituitary Adenomas: New Trends in Basic and Clinical Research, Faglia G, Beck-Peccoz P, Ambrosi P, Travaglini P, Spada A., eds. Amsterdam: Elsevier 1991;159-68. 17. Klareskog L, Forsum U, Peterson PA. Hormonal regulation of the expression of Ia antigens on mammary gland epithelium. Eur J Immunol 1980;10:958-63. 18. Weisz-Carrington P, Roux ME, McWilliams M, PhillipsQuagliata J, Lamm ME. Hormonal induction of the secretory immune system in the mammary gland. Proc Natl Acad Sci U S A 1975;75:2928-32. 19. Kelly PA, Djiane J, Edery M. Different forms of the prolactin receptor. Insights into the mechanism of prolactin action. Trends Endocrinol Metab 1992;3:54-9. 20. Yu-Lee L-Y, Stevens AM, Hrachovy JA, Schwarz LA. Prolactin-mediated regulation of gene transcription in lymphocytes. Ann NY Acad Sci 1990;594:146-55. 21. Yu-Lee LY. Molecular actions of prolactin in the immune system. Proc Soc Exp Biol Med 1997;215:35-52. 22. Thoreau E, Petridou B, Kelly PA, Djiane J, Mormon JP. Structural symmetry of the extracellular domain of the cytokine/growth hormone/prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis. FEBS Lett 1991;282:26-31. 23. Bazan JF. Structural design and molecular evolution of a cytokine receptor super-family. Proc Natl Acad Sci U S A 1990;87:6934-8. 24. Russell DH, Kibler R, Matrisian L, Larson DF, Poulos B, Magun BE. Prolactin receptors on human T and B lymphocytes: antagonism of prolactin binding by cyclosporine. J Immunol 1985;134:3027-31. 25. Parkes D. Bromocriptine. N Engl J Med 1979;301:873-8. 26. Ascoli M, Segaloff DL. Adenohypophyseal hormones and their hypothalamic releasing factors. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics (9th ed), Harmon JG, Limband LF, eds. New York, McGraw-Hill 1996; 1371-2.

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27. Morikawa K, Oseko F, Morikawa S. Immunosuppressive activity of bromocriptine on human T lymphocyte function in vitro. Clin Exp Immunol 1994;95:514-8. 28. Morikawa K, Oseko F, Morikawa S. Immunosuppressive property of bromocriptine on human B lymphocyte function in vitro. Clin Exp Immunol 1993;93:200-5. 29. Degli Esposti E, Sturani A, Santoro A, Zuccala A, Chiarini C, Zucchelli P. Effect of bromocriptine treatment on prolactin, noradrenaline and blood pressure in hypertensive haemodialysis patients. Clin Sci 1985;69:51-6. 30. Nilsson A, Hokfelt B. Effect of the dopamine agonist bromocriptine on blood pressure, catecholamines and renin activity in acromegalics at rest, following exercise and during insulin induced hypoglycemia. Acta Endocrinol Suppl (Copenh) 1978;216:83-96. 31. Turkalj I, Braun P, Krupp P. Surveillance of bromocriptine in pregnancy. JAMA 1982;247:1589-91. 32. Nagy E, Berczi I. Immunodeficiency in hypophysectomized rats. Acta Endocrinol 1978;89:530-7. 33. Murphy WJ, Durum SK, Longo DL. Differential effects of growth hormone and prolactin on murine T cell development and function. J Exp Med 1993;178:231-6. 34. Nagy E, Berczi I, Wren GE, Asa SL, Kovacs K. Immunomodulation by bromocriptine. Immunopharmacology 1983; 6:231-43. 35. Ijaz MK, Dent D, Babiuk LA. Neuroimmunomodulation of in vivo anti-rotavirus humoral immune response. J Neuroimmunol 1990;26:159-71. 36. Cross RJ, Cambell JL, Roszman TL. Potentiation of antibody responsiveness after the transplantation of syngeneic pituitary gland. J Neuroimmunol 1989;25:29-35. 37. Schwarz LA, Stevens AM, Hrachovy JA, Yu-Lee L. Interferon regulatory factor-1 is inducible by prolactin, interleukin-2 and concanavalin A in T cells. Mol Cell Endocrinol. 1992;86(1-2):103-10. 38. Hooghe R, Delhase M, Vergani P, Malur A, HooghePeters EL. Growth hormone and prolactin are paracrine growth and differentiation factors in the haemopoietic system. Immunol Today 1993;14:212-4. 39. Kooijman R, Hooghe-Peters EL, Hooghe R. Prolactin, growth hormone, and insulin-like growth factor-I in the immune system. Adv Immunol 1996;63:377-454. 40. Clevenger CV, Russell DH, Appasamy PM, Prystowsky MB. Regulation of interleukin 2-driven T-lymphocyte proliferation by prolactin. Proc Natl Acad Sci U S A 1990;87:6460-4. 41. Hartmann DP, Holaday JW, Bernton EW. Inhibition of lymphocyte proliferation by antibodies to prolactin. FASEB J 1989;3:2194-202. 42. McMurray RW, Hoffman RW, Walker SE. In vivo prolactin manipulation alters in vitro IL-2, IL-4, and IFN-␥ mRNA levels in female B/W mice (abstr). Clin Res 1991;39: 734A. 43. Elbourne KB, Keisler D, McMurray RW. Differential effects of estrogen and prolactin on autoimmune disease in the NZB/NZW F1 mouse model of systemic lupus erythematosus. Lupus 1998;7:420-7. 44. McMurray RW, Keisler D, Kanuckel K, Izui S, Walker S. Prolactin influences autoimmune disease activity in the female B/W mouse. J Immunol 1991;147:3780-7. 45. Neidhart M. Bromocriptine has little direct effect on murine lymphocytes, the immunomodulatory effect being me-

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diated by the suppression of prolactin secretion. Biomed Pharmacother 1997;51:118-25. 46. Schaaf L, Zierhut M, Baur EM, Geissler W, Thiel HJ, Seif FJ, et al. Bromocriptine in patients with chronic autoimmune-associated disorders. Klin Wochenschr 1991;69:943-51. 47. Lopez-Karpovitch X, Larrea F, Cardenas R, Valencia X, Piedras J, Diaz-Sanchez V, et al. Cellular and humoral immune parameters in women with pathological hyperprolactinemia before and during treatment with bromocriptine. Am J Reprod Immunol 1994;31:32-9. 48. McMurray RW, Weidensaul D, Allen SH, Walker SE. Efficacy of bromocriptine in an open label therapeutic trial for systemic lupus erythematosus. J Rheumatol 1995;22:2084-91. 49. Blank M, Palestine A, Nussenblatt R, Shoenfeld Y. Down-regulation of autoantibody levels of cyclosporine and bromocriptine treatment in patients with uveitis. Clin Immunol Immunopathol 1990;54:87-97. 50. Whyte A, Williams RO. Bromocriptine suppresses postpartum exacerbation of collagen-induced arthritis. Arthritis Rheum 1988;31:927-8. 51. Berczi I, Nagy E, Asa SL, Kovacs K The influence of pituitary hormones on adjuvant arthritis. Arthritis Rheum 1984; 27:682-8. 52. Mattsson R, Mattsson A, Holmdahl R, Whyte A, Rook GA. Maintained pregnancy levels of oestrogen afford complete protection from post-partum exacerbation of collagen-induced arthritis. Clin Exp Immunol 1991;85:41-7. 53. Neidhart M, Gay RE, Gay S. Prolactin and prolactin-like polypeptides in rheumatoid arthritis. Biomed Pharmacother 1999;53:218-22. 54. Mateo L, Nolla JM, Bonnin MR, Navarro MA, RoigEscofet D. High serum prolactin levels in men with rheumatoid arthritis. J Rheumatol 1998;25:2077-82. 55. Jorgensen C, Maziad H, Bologna C, Sany J. Kinetics of prolactin release in rheumatoid arthritis. Clin Exp Rheumatol 1995;13:705-9. 56. Barrett JH, Brennan P, Fiddler M, Silman A. Breastfeeding and postpartum relapse in women with rheumatoid and inflammatory arthritis. Arthritis Rheum 2000;43:1010-5. 57. Nagafuchi H, Suzuki N, Kaneko A, Asai T, Sakane T. Prolactin locally produced by synovium infiltrating T lymphocytes induces excessive synovial cell functions in patients with rheumatoid arthritis. J Rheumatol 1999;26:1890-900. 58. Dougados M, Duchesne L, Amor B. Bromocriptine and cyclosporine. A combination therapy in rheumatoid arthritis. Arthritis Rheum 1988;31:1333-4. 59. Figueroa F, Carrion F, Martinez ME, Rivero S, Mamani I, Gonzalez G. Effects of bromocriptine in patients with active rheumatoid arthritis. Rev Med Chil 1998;126:33-41. 60. Figueroa FE, Carrion F, Martinez ME, Rivero S, Mamani I. Bromocriptine induces immunological changes related to disease parameters in rheumatoid arthritis. Br J Rheumatol 1997;36:1022-3. 61. Mader R. Bromocriptine for refractory rheumatoid arthritis. Harefuah 1997;133:527-9,591. 62. Jara LJ, Gomez-Sanchez C, Silveira LH, MartinezOsuna P, Vasey FB, Espinoza LR. Hyperprolactinemia in systemic lupus erythematosus: association with disease activity. Am J Med Sci 1992;303:222-6. 63. Pauzner R, Urowitz MB, Gladman DD, Gough JM.

ROBERT W. McMURRAY

Prolactin in systemic lupus erythematosus. J Rheumatol 1994; 21:2064-7. 64. Ostendorf B, Fischer R, Santen R, Schmitz-Linneweber B, Specker C, Schneider M. Hyperprolactinemia in systemic lupus erythematosus? Scand J Rheumatol 1996;25:97-102. 65. Buskila D, Lorber M, Neumann L, Flusser D, Shoenfeld Y. No correlation between prolactin levels and clinical activity in patients with systemic lupus erythematosus. J Rheumatol 1996;23:629-32. 66. Neidhart M. Elevated serum prolactin or elevated prolactin/cortisol ratio are associated with autoimmune processes in systemic lupus erythematosus and other connective tissue diseases. J Rheumatol 1996;23:476-81. 67. Huang CM, Chou CT. Hyperprolactinemia in systemic lupus erythematosus. Chung Hua I Hsueh Tsa Chih (Taipei) 1997;59:37-41. 68. Jimena P, Aguirre MA, Lopez-Curbelo A, de Andres M, Garcia-Courtay C, Cuadrado MJ. Prolactin levels in patients with systemic lupus erythematosus: a case controlled study. Lupus 1998;7:383-6. 69. Blanco-Favela F, Quintal-Alvarez G, Leanos-Miranda A. Association between prolactin and disease activity in systemic lupus erythematosus. Influence of statistical power. J Rheumatol 1999;26:55-9. 70. Blank M, Krause I, Buskila D, Teitelbaum D, Kopolovic J, Afek A, et al. Bromocriptine immunomodulation of experimental SLE and primary antiphospholipid syndrome via induction of nonspecific T suppressor cells. Cell Immunol 1995;162: 114-22. 71. Shoenfeld Y. Immunosuppression of experimental systemic lupus erythematosus and antiphospholipid syndrome. Transplant Proc 1994;26:3211-3. 72. Rabinovich CE, Schanberg LE, Kredich DW. Intravenous immunoglobulin and bromocriptine in the treatment of refractory neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1990;33(suppl):R22. 73. McMurray RW, Allen SH, Braun AL, Rodriguez F, Walker SE. Longstanding hyperprolactinemia associated with systemic lupus erythematosus: possible hormonal stimulation of an autoimmune disease. J Rheumatol 1994;21:843-50. 74. Funauchi M, Ikoma S, Enomoto H, Sugiyama M, Ohno M, Hamada K, et al. Prolactin modulates the disease activity of systemic lupus erythematosus accompanied by prolactinoma. Clin Exp Rheumatol 1998;16:479-82. 75. McMurray RW, Weidensaul D, Allen SH, Walker SE. Efficacy of bromocriptine in an open label therapeutic trial for systemic lupus erythematosus. J Rheumatol 1995;22:2084-91. 76. Walker SE, Allen SH, Hoffman RW, McMurray RW. Prolactin: a stimulator of disease activity in systemic lupus erythematosus. Lupus 1995;4:3-9. 77. Walker SE, Smarr KL, Parker JC, Weidensaul DN, Nelson W, McMurray RW. Mood states and disease activity in patients with systemic lupus erythematosus treated with bromocriptine. Lupus 2000;9:527-33. 78. Theohar C, Fiacher-Cronelssen K, Brosch H, Fiacher EK, Petrovic D. A comparative multicenter trial between bromocriptine and amitryptiline in the treatment of endogenous depression. Arzneimittelforschung 1982;32:783-7. 79. Sitland-Marken PA, Wells BG, Froemming JH, Chu CC, Brown CS. Psychiatric applications of bromocriptine therapy. J Clin Psychiatry 1990;51:68-82.

BROMOCRIPTINE THERAPY

80. Inoue T, Tsuchiya K, Miura J, Sakakibara S, Denda K, Kasahara T, et al. Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression. Biol Psychiatry. 1996;40:151-3. 81. Buckman NT, Kellner R. Reduction of distress in hyperprolactinemia with bromocriptine. Am J Psychiatry 1985;142: 242-4. 82. Alvarez-Nemegyei J, Cobarrubias-Cobos A, EscalanteTriay F, Sosa-Munoz J, Miranda JM, Jara LJ. Bromocriptine in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled study. Lupus 1998;7:414-9. 83. Walker SE, Reddy GH, Miller D, Yangco D, Kalanje S, Abdou NI, et al. Treatment of active systemic lupus erythematosus (SLE) with the prolactin lowering drug bromocriptine: comparison with hydroxychloroquine in a randomized, blinded one-year study. Arthritis Rheum 1999;42:S282. 84. Lavalle C, Graef A, Baca V, Ramirez-Lacayo M, Blanco-Favela F, Ortiz O. Prolactin and gonadal hormones: a key relationship that may have clinical, monitoring and therapeutic implications in systemic lupus erythematosus. Lupus 1993;2:71-5. 85. Bravo G, Zazueta B, Lavalle C. An acute remission of Reiter’s syndrome in male patients treated with bromocriptine. J Rheumatol 1992;19:747-50. 86. Weber G, Frey H. Treatment of psoriasis arthropathica with bromocriptine. Z Hautkr 1986;61:1456-66. 87. Eulry F, Bauduceau B, Mayaudon H, Lechevalier D, Ducorps M, Magnin J. Therapeutic efficacy of bromocriptine in psoriatic arthritis (two case-reports). Rev Rheum Engl Ed 1995; 62:607-8. 88. Buskila D, Sukenik S, Holcberg G, Horowitz J. Improvement of psoriatic arthritis in a patient treated with bromocriptine for hyperprolactinemia. J Rheumatol 1991;18:611-2. 89. Weber G, Frey H. Treatment of psoriatic arthritis with bromocriptine. J Am Acad Dermatol 1987;16:388-9. 90. Eulry F, Mayaudon H, Bauduceau B, Lechevalier D, Crozes P, Magnin J, et al. Blood prolactin under the effect of protirelin in spondylarthropathies. Treatment trial of 4 cases of reactive arthritis and 2 cases of psoriatic arthritis with bromocriptine. Ann Med Interne (Paris) 1996;147:15-9. 91. Eulry F, Mayaudon H, Lechevalier D, Bauduceau B, Ariche L, Ouakil H, et al. Treatment of rheumatoid psoriasis with bromocriptine. Presse Med 1995;24:1642-4. 92. Eulry F, Bauduceau B, Bouee S, Crozes P, Magnin J, Mayaudon H, et al. Prolactin response to protirelin in reactive arthritis and ankylosing spondyloarthritis. Failure of treatment of 4 reactive arthritis with bromocriptine. Rev Rheum Ed Fr 1994;61:863-4. 93. Giasuddin AS, El-Sherif AI, El-Ojali SI. Prolactin: does it have a role in the pathogenesis of psoriasis? Dermatology 1998;197:119-22. 94. Palestine AG, Muellenberg-Coulombre CG, Kim MK, Gelato MC, Nussenblatt RB. Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat. J Clin Invest 1987;79:1078-81. 95. Zierhut M, Thiel HJ, Pleyer U, Waetjen R, Weidle EG. Bromocriptine in therapy of chronic recurrent anterior uveitis. Fortschr Ophthalmol 1991;88:161-4. 96. Nussenblatt RB. Basic and clinical immunology in uveitis. Jpn J Ophthalmol 1987;31:368-74. 97. Hedner LP, Bynke G. Endogenous iridocyclitis relieved

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during treatment with bromocriptine. Am J Ophthalmol 1985; 100:618-9. 98. Blank M, Palestine A, Nussenblatt R, Shoenfeld Y. Down-regulation of autoantibody levels of cyclosporine and bromocriptine treatment in patients with uveitis. Clin Immunol Immunopathol 1990;54:87-97. 99. Palestine AG, Nussenblatt RB. The effect of bromocriptine on anterior uveitis. Am J Ophthalmol 1988;106:488-9. 100. Nussenblatt R. The expanding use of immunosuppression in the treatment of non-infectious ocular disease. J Autoimmun 1992;5(suppl A):247-57. 101. Palestine AG, Nussenblatt RB, Gelato M. Therapy for human autoimmune uveitis with low-dose cyclosporine plus bromocriptine. Transplant Proc 1988;20(suppl 4):131-5. 102. Zierhut M, Pleyer U, Waetjen R, Thiel HJ, Weidle EG. Bromocriptine: a new therapy concept in the treatment of chronic recurrent uveitis? Klin Monatsbl Augenheilkd. 1989; 195:221-5. 103. Tanaka M, Suzuki T, Endo K, Harayama H. A case of multiple sclerosis with galactorrhea-amenorrhea syndrome. Rinsho Shinkeigaku 1997;37:483-6. 104. Azar ST, Yamout B. Prolactin secretion is increased in patients with multiple sclerosis. Endocr Res 1999;25:207-14. 105. Confavreux C, Hutchinson M, Hours MM, CortinovisTourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group [see comments]. N Engl J Med 1998;339:285-91. 106. Dijkstra CD, van der Voort ER, De Groot CJ, Huitinga I, Uitdehaag BM, Polman CH, et al. Therapeutic effect of the D2-dopamine agonist bromocriptine on acute and relapsing experimental allergic encephalomyelitis. Psychoneuroendocrinology 1994;19:135-42. 107. Riskind PN, Massacesi L, Doolittle TH, Hauser SL. The role of prolactin in autoimmune demyelination: suppression of experimental allergic encephalomyelitis by bromocriptine. Ann Neurol 1991;29:542-7. 108. Khan OA, Olek MJ. Treatment of paroxysmal symptoms in multiple sclerosis with bromocriptine. J Neurol Neurosurg Psychiatry 1995;58:253. 109. Bissay V, De Klippel N, Herroelen L, Schmedding E, Buisseret T, Ebinger G, et al. Bromocriptine therapy in multiple sclerosis: an open label pilot study. Clin Neuropharmacol 1994; 17:473-6. 110. Haga HJ, Rygh T. The prevalence of hyperprolactinemia in patients with primary Sjogren’s syndrome. J Rheumatol 1999;26:1291-5. 111. Alekperov RT, Nasonov EL, Masenko VP, Guseva NG. Prolactin levels in patients with systemic scleroderma. Klin Med (Mosk) 1998;76:25-9. 112. Straub RH, Zeuner M, Lock G, Scholmerich J, Lang B. High prolactin and low dehydroepiandrosterone sulphate serum levels in patients with severe systemic sclerosis. Br J Rheumatol 1997;36:426-32. 113. Kucharz EJ, Jarczyk R, Jonderko G, Rubisz-Brezezinska J, Brzezinska-Wcislo L . High serum level of prolactin in patients with systemic sclerosis. Clin Rheumatol 1996;15:314. 114. Saito I, Takeshita E, Hayashi S, Takenaka T, Murakami M, Saruta T, et al. Effect of captopril on plasma prolactin in patients with essential hypertension. Angiology 1990;41:37781.

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115. Thurm RH; Alexander JC. Captopril in the treatment of scleroderma renal crisis. Arch Intern Med 1984;144:733-5. 116. Walters AS, Hening WA, Kavey N, Chokroverty S, Gidro-Frank S. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol 1988;24:455-8. 117. Bruno RL, Zimmerman JR, Creange SJ, Lewis T, Molzen T, Frick NM. Bromocriptine in the treatment of postpolio fatigue: a pilot study with implications for the pathophysiology of fatigue. Am J Phys Med Rehabil 1997;75:340-7. 118. Herzog AG. Continuous bromocriptine therapy in menstrual migraine. Neurology 1997;48:101-2. 119. Bancroft J, Backstrom T. Review: premenstrual syndrome. Clin Endocrinol 1985;22:313-36.

ROBERT W. McMURRAY

120. Kotter I, Matter F, Durk H. Prolactin levels in primary fibromyalgia. Arthritis Rheum 1994;37(suppl):S350. 121. Liang Y, Jetton TL, Lubkin M, Meier AH, Cincotta AH. Bromocriptine/SKF38393 ameliorates islet dysfunction in the diabetic (db/db) mouse. Cell Mol Life Sci 1998;54: 703-11. 122. Meier AH, Cincotta AH, Lovell WC. Timed bromocriptine administration reduces body fat stores in obese subjects and hyperglycemia in type II diabetics. Experientia 1992;48:248-53. 123. Carrier M, Wild J, Pelletier LC, Copeland JG. Bromocriptine as an adjuvant to cyclosporine immunosuppression after heart transplantation. Ann Thorac Surg 1990;49: 129-32.