Impact of hyperprolactinemia in a patient with polyautoimmunity

Key Clinical Message Hyperprolactinemia has been proposed as a triggering factor for autoimmune diseases. The increased levels of prolactin could induce an abnormal immune response. Herein, we present a patient with hyperprolactinemia who developed polyautoimmunity. Patient's symptoms were associated with slightly raised levels of prolactin (20‐40 ng/mL) and administration of dopaminergic agonists.

present at the moment of diagnosis. After 2 years with bromocriptine, PRL levels decreased at 72 ng/mL, but at the same time, she developed morning stiffness and arthralgia. Due to symptoms recurrence, she decided to withdraw bromocriptine for 3 years with paradoxical improvement of her musculoskeletal symptoms. In 2007, amenorrhea recurred due to high levels of PRL; therefore, bromocriptine was restarted ( Figure 1).
After 5 years of treatment, high levels of PRL persisted despite bromocriptine prescription. A magnetic resonance image was performed, disclosing a pituitary microadenoma. Consequently, bromocriptine was changed for cabergoline 0.5 mg twice per week. This treatment showed an evident decrease in PRL concentration. Interestingly, after treatment adjustment, arthralgia, fatigue, and malar rash returned. In 2015, when lower PRL levels were reached, new Specific autoimmune diseases are in colors. The pedigree discloses both polyautoimmunity (ie, two or more autoimmune diseases in a single patient) and familial autoimmunity (ie, diverse autoimmune diseases in a nuclear family). One patient's cousin suffers from prolactinoma and SLE onset of Raynaud's phenomenon, sicca symptoms, alopecia, and unintentional weight loss were identified (Figure 1). At that time, mild leuko-lymphopenia (leukocytes: 4.000/mm 3 , lymphocytes 1.400/mm 3 ) was observed, and serological tests for infectious diseases (including syphilis, toxoplasmosis, rubella, and HIV) were negative. Renal and hormonal function tests, including thyroid and hypothalamic-pituitary-gonadal axis, were normal.
A diagnosis of PolyA characterized by the presence of SLE and Sjögren's syndrome (SS) was made. Treatment with hydroxychloroquine (200 mg/d), deflazacort (6 mg/d), and acetylsalicylic acid (100 mg/d) was started. Cabergoline was continued (0.5 mg twice per week). One year after follow-up, signs and symptoms improved, including malar rash, arthralgia, and Raynaud's phenomenon associated with levels of PRL below 20 ng/mL.

| DISCUSSION
PRL receptor belongs to the family of cytokine receptors associated with interleukin IL-2, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and leptine. 3 These receptors are linked to secondary messengers such as JAK/ STAT and MAPK, which act through NF-κB, enhancing proliferative response to antigens, increasing production of cytokines and autoantibodies. 4 Thus, the Th1 (cellular immunity) or Th2 (humoral immunity) cell responses are induced in presence of PRL. 5 Our patient illustrates the paradoxical effect of PRL levels on the development of autoimmunity, as was observed by Jacobi et al 2 who described that in peripheral mononuclear cells from patients with SLE, concentrations of PRL at 20 ng/ mL induced a higher IgG production than concentrations of 100 ng/mL. Our patient presented lupus flares with PRL levels between 20 and 40 ng/mL and had remission of symptoms with PRL concentrations above 100 ng/mL (Figure 1). On the other hand, a confounder effect of dopamine agonists is unlikely, although thank to treatment the levels of PRL decreased. Nevertheless, as we discuss below, dopamine agonists may induce Raynaud's phenomenon, but neither the plethora of other symptoms nor the development of SLE and SS observed in our patient.
On the other hand, it has been described that individuals with hyperprolactinemia may exhibit PolyA phenomena (ie, more than one AD in a single patient). 6 Some reports have shown the association of PRL with several ADs, such as SS, SLE, vasculitis. 6,7 This is in line with our patient since she developed PolyA (ie, SLE and SS), thus suggesting a possible role of PRL in this phenomenon. Although the mechanism is not clear, it was described that HLA-DRB1 alleles (*04:01,*03:01) and microsatellite marker alleles close to the PRL gene (D6S422 and D6S285 in chromosome 6) in women with RA and SLE were associated through linkage disequilibrium with ADs. 8 This differs from our patient who carried HLA-DRB1*10:01. Nevertheless, some polymorphisms, such as HLA-DRB1*10:01 in RA, 9 HLA-DRB1*15:01 in multiple sclerosis (MS), 10 and HLA-DRB1*15:03 in SLE, 11 were found in this patient, thus suggesting that PRL in subjects with genetic predisposition may trigger the development of autoimmunity. Further analysis is warranted to clarify the role of novel HLA alleles, which in association with hyperprolactinemia may induce the development of ADs.
In addition, as shown in the pedigree, the patient exhibited a high genetic burden, set by the existence of ADs in first relatives. This phenomenon is known as "familial autoimmunity", 12 which has been previously associated with the development of PolyA. 13 SLE, RA, and SS were previously diagnosed in her first-degree relatives ( Figure  2), which could be associated with a higher risk of developing PolyA. Interestingly, a relative also developed microadenoma in association with ADs. Lauruche et al 14 found that patients with functioning and non-functioning pituitary adenomas showed a high frequency of ADs, including autoimmune thyroid disease, Addison's disease, MS, and SS. Although the mechanisms associated with this phenomena are not clear, some families exhibit a high frequency of pituitary adenomas, and more recently, the presence of familial prolactinoma was associated with genes, such as the aryl hydrocarbon receptor interacting protein (AIP) gene, 15 which in turn is related to inflammatory conditions. 16 These data advocate for the key role of genetics in the development of pituitary adenomas, and the association between PRL and PolyA based on genetic background. Treatment effects with dopamine agonists are wide and variable. 17 As of 2 April 2018, seven cases of Raynaud's phenomenon during cabergoline treatment were reported to the Food and Drug Administration; interestingly, all the reports were within 5 to 10 years of cabergoline use (Cabergoline and Raynaud's phenomenon -from FDA reports-https:// www.ehealthme.com/ds/cabergoline/raynaud-s-phenomenon/-accessed 2 April 2018). Further, some studies suggested that activation of dopamine receptors (type 1 and type 2) could increase production of IL-6 and IL-17. 18,19 These cytokines are strongly associated with the development of ADs, including RA, SLE, and SS. [20][21][22][23] Nevertheless, an Iranian pilot randomized double-blind clinical trial assessed the effect of cabergoline in RA patients, showing improvement in tender and swollen joint count, and patients pain assessment. The authors suggest that these findings support the utility of dopamine agonist in RA management. 24 These results differ from our patient, since she developed musculoskeletal symptoms after PRL levels decreased associated with the treatment with cabergoline. We hypothesize that administration of dopamine agonists in patients with a permissive genetic background may act as adjuvants triggering autoimmunity.
Finally, pituitary gland size frequently decreases after treatment with dopamine agonists. 25 Size reduction is expected to be symmetric 26 ; however, asymmetry of pituitary gland in STNMR following cabergoline treatment was observed in this patient ( Figure 3B). This phenomenon was previously reported, 27 and it may be associated with treatment effectiveness. Although there was not a prior comparative NMR, we consider that the presence of this pituitary asymmetry was associated with imagenological response to treatment.

| CONCLUSION
In conclusion, PRL levels showed relationship with autoimmunity and could be associated with PolyA development in susceptible individuals. It appears to act as a disease activity biomarker for ADs in patients with PolyA, especially at levels between 20 and 40 ng/mL. Patients with ADs, especially with PolyA, should be tested for hyperprolactinemia, and additional studies aiming to clarify the influence of slightly raised levels of PRL in activity and severity of disease are warranted.