Endocrine sequelae of immune checkpoint inhibitors.

Cancer immunotherapy has introduced a novel class of drugs known as immune checkpoint inhibitors (ICIs). They enhance antitumour immunity by blocking negative regulators (checkpoints) of T cell function that exist on both immune and tumour cells. ICIs targeting CTLA-4 and PD-1/PDL-1 have dramatically changed the outcome of patients with several advanced-stage malignancies but they may lead to a variety of inflammatory toxicities and autoimmune consequences. The main endocrine immune-related adverse events (IRAEs) include hypophysitis, primary thyroid dysfunction, adrenalitis and type 1 diabetes mellitus. In general, the management of endocrine IRAEs requires assessment of their severity, in moderate or severe cases interruption of the checkpoint inhibitor and use of corticosteroid or alternative immunosuppression and appropriate hormone replacement or treatment when necessary.

Lymphocytic adrenal medullitis and lymphocytic thyroiditis in a laboratory beagle dog.

Lymphocytic adrenal medullitis characterized by inflammation and atrophy in the medulla of the bilateral adrenal glands was observed in an 18-month-old male laboratory beagle dog. It might be that the present lymphocytic adrenal medullitis is an autoimmune-mediated disease as the histological characteristics are consistent with an autoimmune pathogenesis. However, the actual cause remains unclear as the existence of serum autoantibodies against the adrenal medulla could not be confirmed. Although this dog also contracted lymphocytic thyroiditis along with serum thyroglobulin autoantibodies, indicating that the thyroiditis occurred with an autoimmune basis; the relation between the adrenal medullitis and thyroiditis is unknown.

Polymorphisms of the Toll-Like Receptor-3 Gene in Autoimmune Adrenal Failure and Type 1 Diabetes in Polish Patients.

Infectious agents are plausible environmental triggers for autoimmunity in genetically susceptible individuals. Polymorphic variants of genes implicated in innate immunity may affect immune responses and hence promote auto-aggressive reactions. Genes such as Toll-like receptor-3 (TLR3), which participate in recognizing conserved foreign molecules and mounting the first line of defence against viral infections, are promising functional candidates in autoimmune conditions. We investigated the association of the TLR3 variants, rs13126816 and rs3775291, with the autoimmune endocrine disorders, Addison's disease (AD) and type 1 diabetes (T1D) in the Polish population. The study comprised 168 AD patients, 524 individuals with T1D and 592 healthy controls. Genotyping was performed by real-time PCR. Distribution of the TLR3 genotypes and alleles did not reveal significant differences between patients and controls (p > 0.05). No effect on age at disease onset was found in affected cohorts. This analysis does not support an association between TLR3 variants and the risk for autoimmune destruction of the adrenal cortex and beta cells. However, innate immunity merits further studies in autoimmune endocrine conditions.

Ovarian autoimmune disease: clinical concepts and animal models.

The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.

Brief report: adrenal autoimmunity in primary Sjögren's syndrome.

OBJECTIVE: To evaluate the prevalence of antibodies to 21-hydroxylase (anti-21[OH]), a marker of autoimmune adrenal disease, in a cohort of patients with primary Sjögren's syndrome (SS) and to investigate whether the presence of anti-21(OH) correlates with clinical, serologic, and salivary gland features of the disease. METHODS: Sera from 63 consecutive patients with primary SS, 32 patients with autoimmune thyroid disease (AITD), and 20 healthy controls were obtained and anti-21(OH) levels were determined by radioimmunoassay. Clinical, serologic, and histopathologic features were recorded, and a short Synacthen test was used to assess adrenal function reserve. Seven available minor salivary gland (MSG) tissue specimens from patients in the primary SS cohort were also assessed for interferon-α (IFNα), BAFF, and interleukin-21 (IL-21) cytokine transcripts, which are all implicated in B cell activation. RESULTS: Anti-21(OH) positivity was detected in 17.5% and 28.1% of primary SS and AITD patients, respectively, and in none of the healthy controls. While no evidence of adrenal insufficiency was detected in any of the patients studied, a blunted rate of increase in cortisol levels was observed in patients with detectable serum autoantibodies against 21(OH), compared to their anti-21(OH)-negative counterparts. A strong correlation between the serum titer of anti-21(OH) antibodies and expression of IFNα, BAFF, and IL-21 messenger RNA in MSG tissues was also detected. CONCLUSION: Adrenal autoimmunity occurs in almost 20% of patients with primary SS in association with markers of B cell activation. Although the presence of adrenal autoantibodies was not associated with adrenal insufficiency in the present study, there was a blunted adrenal response, suggesting the need for further followup and monitoring of adrenal function in patients with primary SS who are positive for the autoantibodies.

Histopathologic findings of autoimmunity in thyroid, pituitary, and adrenal diseases in chronic hepatitis C postmortem cases.

OBJECTIVE: To assess the histologic prevalence of immune-mediated thyroid, pituitary, and adrenal diseases in postmortem cases with hepatitis C. METHODS: We reviewed 108 consecutive cases of chronic hepatitis C in patients in whom a complete postmortem examination was performed. All microscopic and histologic slides of the thyroid, pituitary, and adrenal reports were reviewed and assessed for evidence of autoimmune diseases. These were compared with a control group of 100 postmortem cases without hepatitis C. RESULTS: In chronic hepatitis C infection, there is a heightened immune response resulting in many autoimmune diseases. The commonest endocrinopathy in association with this chronic infection is thyroid disease, a finding confirmed in our current study. Among the 108 postmortem cases of hepatitis C, there were 14 cases (13%) with evidence of thyroiditis. No cases of pituitary or adrenal disease were found. The mean age of the patients was 52 years (range, 29 to 68). This frequency compared with 7 cases of thyroid disease (7%) in the control group (no significant difference between the 2 groups). CONCLUSION: On the basis of our postmortem data, thyroid disease was the only major endocrinopathy associated with hepatitis C infection, with a prevalence of 13%. This was comparable with other serologic and nonhistologic antemortem findings. There was no evidence of pituitary or adrenal involvement.

[Immunoendocrine associations in adrenal glands]. / Imunoendokrinní vztahy u nadledvin.

Immune and endocrine systems are basic regulatory mechanisms of organism and, including the nervous system, maintain the organism's homeostasis. The main immune system representatives are mononuclear cells, T- and B-cells and their products, in the endocrine system the main representatives are cells of the glands with inner secretion and their products. One of the most important glands for maintaining homeostasis are adrenal glands. It has been proven that either cells of the immune system, either endocrine cells can, although in trace amounts, produce mutually mediators of both systems (hormones, cytokines). Disorders in one system can lead to pathological symptoms in the other system. Also here represent adrenals an important model.

Rheumatic manifestations of endocrine diseases.

PURPOSE OF REVIEW: Musculoskeletal complaints accompanying or as a result of endocrine disorders are common and have been well described. This review re-examines these associations in light of newer information on biology and genetics. RECENT FINDINGS: In this article, we describe the recent studies on pathophysiology of the muscular skeletal complaints in endocrine disease. In addition we report on population as well as genetic studies, which address the relationship between endocrine and rheumatologic disease, both of which are autoimmune. SUMMARY: Very often, the presentation of rheumatic manifestations is the initial presentation of endocrine disease. Being aware of the presentation as well as the unique physiology of these complaints will help alert the clinician to an early diagnosis of endocrine disease. In addition understanding whether certain endocrine disease occurs more often in rheumatologic illness will enable the clinician to investigate their occurrence early, leading to earlier intervention and resulting in decreased morbidity from these concomitant illnesses.

Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening.

CONTEXT: Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur together in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndrome I, autoimmune polyendocrine syndrome II, and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. EVIDENCE ACQUISITION: Review of the medical literature was performed with particular attention to the natural history, genetic factors, and syndromes associated with T1D, AIT, CD, and AD. EVIDENCE SYNTHESIS: Genetic risk for these diseases overlaps and includes genes within the major histocompatibility complex (MHC) such as the human leukocyte antigens (HLA) DR and DQ alleles and the MHC I-related gene A (MIC-A). Other genes outside of the MHC have been associated with these autoimmune diseases, including the gene encoding the lymphoid tyrosine phosphatase (PTPN22) and the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene. CONCLUSION: Genetic risk for T1D overlaps with AIT, CD, and AD. Disease risk is associated with organ-specific autoantibodies, which can be used to screen subjects with T1D.

Growth hormone deficiency in autoimmune polyglandular syndrome.

We describe a boy with autoimmune adrenal failure and compensated hypothyroidism, associated with isolated growth hormone deficiency (GHD). We suggest an autoimmune mechanism as the underlying etiology for the GHD in this case.

[Anticardiolipin antibodies, cerebral ischemia and adrenal hemorrhage in a newborn infant]. / Anticorps anticardiolipine, ischémie cérébrale et hémorragie surrénalienne chez un nouveau-né.

BACKGROUND: Anticardiolipin antibodies, usually associated with vascular thrombosis in systemic lupus erythematosus, have been recently found associated with strokes in childhood, and acute adrenal hemorrhage in the adult. CASE REPORT: A 3 day-old fullterm newborn suffering from cerebrovascular ischemia and bilateral massive hemorrhage was found to have anticardiolipin antibodies detected during the neonatal period and 7 months later. There was no evidence of pathology in the mother or perinatal asphyxia. However, anticardiolipin antibodies were present in the mother 5 and 15 weeks after delivery. CONCLUSION: Association of anticardiolipin antibodies and vascular thrombosis has never been reported in the neonate. Persistence of such antibodies favor the hypothesis that they are not transmitted by the mother; they could represent an early manifestation of primary antiphospholipid syndrome.

Immunoprecipitation assay for autoantibodies to steroid 21-hydroxylase in autoimmune adrenal diseases.

Adrenal autoantibodies characteristic of autoimmune Addison disease are directed towards steroid 21-hydroxylase (21-OH; EC 1.14.99.10). We describe a new assay to measure 21-OH autoantibodies (21-OH Abs), based on immunoprecipitation by the antibodies of 35S-labeled human 21-OH. Using this immunoprecipitation assay (IPA), we detected 21-OH Abs in 42 of 64 (66%) patients with Addison disease and in 14 of 19 (74%) patients with autoimmune polyendocrine syndromes type I and type II. No 21-OH Abs were detected by the IPA in any patients with Addison disease attributable to tuberculosis (n = 9) or adrenoleukodystrophy (n = 9) or in patients with autoimmune thyroid disease (n = 28), systemic lupus erythematosus (n = 10), myasthenia gravis (n = 10), rheumatoid arthritis (n = 10), or insulin-dependent diabetes mellitus (n = 12). None of the 26 sera from healthy normal blood donors was positive for 21-OH Abs by the assay. We found good agreement between 21-OH Abs measured by IPA and by Western blotting (r = 0.83, n = 123, P < 0.001). The inter- and intraassay CVs for IPA were well < 10% at high, medium, and low concentrations of 21-OH Abs. Overall, our studies indicate that the IPA provides a specific, sensitive, and convenient system for measuring 21-OH Abs.

[HLA antigens in persons with a predisposition to frequent sympathetic-adrenal paroxysms]. / Antigeny HLA u lits so sklonnost'iu k chastym simpatiko-adrenalovym paroksizmam.

Comparison of the rate of HLA antigens I in 81 patients with frequently occurring sympathoadrenal paroxysms (SAP) associated with vegetovascular dystonia and 113 healthy subjects revealed the increase of the number of antigen B12 carriers among the patients as compared to the healthy subjects' group. The number of antigens A9, B35 in SAP patients was elevated whereas that of B18, B38 and B40 decreased. SAP related to age-associated hormonal rearrangements were marked by antigens Cw4 and A1, the grave SAP patterns by B12, SAP without nocturnal paroxysms and the early disease onset by the lack of antigen A19. The dominant gene that determines the onset of SAP is localizes in the HLA area. It may be associated with a hypothetical gene analogous to the locus implicated in the determination of the threshold of neuromuscular excitability of rats. It is not excluded that such a relationship is mediated via the blood content of Mg2+.

Antiphospholipid antibodies and adrenal hemorrhage.

We recently encountered two cases of massive bilateral adrenal hemorrhage in patients with antiphospholipid antibodies. A search of the records of this institution covering the past 15 years revealed two additional patients with massive adrenal hemorrhage associated with evidence of antiphospholipid antibodies. Three of these four patients were receiving anticoagulant drug therapy. The presence of the antiphospholipid antibodies may increase the risk of massive adrenal hemorrhage, particularly in patients who receive anticoagulant drugs.

Postoperative primary adrenal failure in a patient with anticardiolipin antibodies.

A 50-year-old woman with no history of thrombosis or recurrent abortions developed pulmonary thromboembolism and bilateral hemorrhagic adrenal infarction with adrenal failure after hysterectomy for uterine fibroids. Anticardiolipin antibodies (aCL) were detected in high titer and have persisted. She remains well, without further thromboses, taking steroid replacement and warfarin anticoagulation. The initial presentation of aCL related disease can be as thrombotic postoperative complications in middle-age.