Patrizio Caturegli

Thyroid and other organ-specific autoantibodies in healthy ceritenarians

To investigate the prevalence of thyroid autoantibodies in very old subjects, we assayed sera from 34 healthy centenarians (7 men, 27 women; age range 100-108 years) for these antibodies. There was a clear age-dependent increase in prevalence of thyroid autoantibodies in sera from 549 control subjects aged 7-85 years, prevalence in 40 subjects aged 70-85 being significantly greater (p less than 0.001, chi 2) than that in 436 subjects aged less than 50. By contrast, prevalence of thyroid autoantibodies in centenarians was not significantly different from that in controls aged less than 50. Cytofluorimetric analysis of peripheral blood lymphocytes showed a striking age-dependent decrease in total and CD5+B cells (without changes in their ratio), which reached its nadir in centenarians. The age-dependent increase in prevalence of thyroid autoantibodies in the elderly is not seen after the ninth decade of life. What relation this characteristic has to derangement of circulating B cells is unknown.

Hashimoto thyroiditis: Clinical and diagnostic criteria

Hashimoto thyroiditis (HT), now considered the most common autoimmune disease, was described over a century ago as a pronounced lymphoid goiter affecting predominantly women. In addition to this classic form, several other clinico-pathologic entities are now included under the term HT: fibrous variant, IgG4-related variant, juvenile form, Hashitoxicosis, and painless thyroiditis (sporadic or post-partum). All forms are characterized pathologically by the infiltration of hematopoietic mononuclear cells, mainly lymphocytes, in the interstitium among the thyroid follicles, although specific features can be recognized in each variant. Thyroid cells undergo atrophy or transform into a bolder type of follicular cell rich in mitochondria called Hürthle cell. Most HT forms ultimately evolve into hypothyroidism, although at presentation patients can be euthyroid or even hyperthyroid. The diagnosis of HT relies on the demonstration of circulating antibodies to thyroid antigens (mainly thyroperoxidase and thyroglobulin) and reduced echogenicity on thyroid sonogram in a patient with proper clinical features. The treatment remains symptomatic and based on the administration of synthetic thyroid hormones to correct the hypothyroidism as needed. Surgery is performed when the goiter is large enough to cause significant compression of the surrounding cervical structures, or when some areas of the thyroid gland mimic the features of a nodule whose cytology cannot be ascertained as benign. HT remains a complex and ever expanding disease of unknown pathogenesis that awaits prevention or novel forms of treatment.

Pituitary Expression of CTLA-4 Mediates Hypophysitis Secondary to Administration of CTLA-4 Blocking Antibody

CTLA-4 blocking antibody induces secondary hypophysitis by binding to CTLA-4 antigen and initiating a type II hypersensitivity reaction. Inflammation Is the Pits Ipilimumab—an antibody that blocks the immune cell inhibitory receptor CTLA-4—has been used successfully as a form of cancer immunotherapy. However, some patients treated with ipilimumab develop secondary hypophysitis—inflammation of the pituitary gland. Iwama et al. now report that this side effect may be an on-target effect on CTLA-4–expressing cells in the pituitary gland. The authors noticed that advanced cancer patients treated with ipilimumab expressed autoantibodies to the pituitary gland. What’s more, pituitary cells expressed CTLA-4. Therefore, they developed a murine model of secondary hypophysitis by repetitive injections of antibodies to CTLA-4. They found that injection of the CTLA-4 antibody resulted in complement deposition on hormone-secreting cells in the pituitary, and suggest a direct effect of ipilimumab in secondary hypophysitis. Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone–, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed “ectopically” on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.

IgG4-Related Hypophysitis: A New Addition to the Hypophysitis Spectrum

CONTEXT Hypophysitis is a chronic inflammation of the pituitary gland that comprises an increasingly complex clinicopathological spectrum. Within this spectrum, lymphocytic and granulomatous hypophysitis are the most common forms, but newer variants have recently been reported. OBJECTIVE The aims of the study were to describe a new patient with IgG4-related hypophysitis, review the published literature, and provide diagnostic criteria. SETTING A 75-yr-old man presented with a 1-yr history of frontal headache. Initial studies revealed panhypopituitarism and a mass in both the sella turcica and the sphenoidal sinus. The patient underwent transphenoidal surgery, initiated high-dose prednisone followed by hormone replacement therapy, and was closely monitored for 3 yr. RESULTS Symptoms improved after prednisone, along with shrinkage of the pituitary and sphenoidal masses, but recurred when prednisone dose was lowered. Histopathology showed a marked mononuclear infiltrate in both the pituitary and sphenoidal specimens, mainly characterized by increased numbers of plasma cells. Many of the infiltrating plasma cells (>10 per high-power field) were IgG4-positive. Review of the literature identified 11 cases of IgG4-related hypophysitis (two diagnosed based on pituitary histopathology). CONCLUSIONS We describe the first Caucasian patient with biopsy-proven IgG4-related hypophysitis and provide classification criteria for this disease.

Pituitary autoimmunity: 30 years later

Pituitary autoimmunity encompasses a spectrum of conditions ranging from histologically proven forms of lymphocytic hypophysitis to the presence of pituitary antibodies in apparently healthy subjects. Hypophysitis is a rare but increasingly recognized disorder that typically presents as a mass in the sella turcica. It mimics clinically and radiologically other non-functioning sellar masses, such as the more common pituitary adenoma. Hypophysitis shows a striking temporal association with pregnancy, and it has been recently described during immunotherapies that block CTLA-4. Several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool. This review summarizes the advances made in the field since the publication of the first review on pituitary autoimmunity, and the challenges that await clarification.

Sjögren syndrome: Advances in the pathogenesis from animal models

Sjögren syndrome is an autoimmune disease characterized by hyposecretion of the lacrimal and salivary glands, resulting in dryness of the eyes and mouth. Individuals may experience primary Sjögren syndrome or a secondary form accompanying another rheumatic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The pathogenic mechanisms of Sjögren syndrome remain largely unknown, in part a consequence of the heterogeneity of the disease. Animal models have shed light on the connections between specific pathways and symptoms, but an ideal system is wanting. Improved disease models will enable a better understanding of Sjögren syndrome, including how immune tolerance is lost and potential therapeutic interventions. Most importantly, an optimal model will enable detection of disease biomarkers, since injury to the salivary glands may precede lymphocytic infiltration. This review aims to characterize available mice models of Sjögren syndrome, including advantages and disadvantages, from the researchers perspective.

A Radiologic Score to Distinguish Autoimmune Hypophysitis from Nonsecreting Pituitary Adenoma Preoperatively

BACKGROUND AND PURPOSE: Autoimmune hypophysitis (AH) mimics the more common nonsecreting pituitary adenomas and can be diagnosed with certainty only histologically. Approximately 40% of patients with AH are still misdiagnosed as having pituitary macroadenoma and undergo unnecessary surgery. MR imaging is currently the best noninvasive diagnostic tool to differentiate AH from nonsecreting adenomas, though no single radiologic sign is diagnostically accurate. The purpose of this study was to develop a scoring system that summarizes numerous MR imaging signs to increase the probability of diagnosing AH before surgery. MATERIALS AND METHODS: This was a case-control study of 402 patients, which compared the presurgical pituitary MR imaging features of patients with nonsecreting pituitary adenoma and controls with AH. MR images were compared on the basis of 16 morphologic features besides sex, age, and relation to pregnancy. RESULTS: Only 2 of the 19 proposed features tested lacked prognostic value. When the other 17 predictors were analyzed jointly in a multiple logistic regression model, 8 (relation to pregnancy, pituitary mass volume and symmetry, signal intensity and signal intensity homogeneity after gadolinium administration, posterior pituitary bright spot presence, stalk size, and mucosal swelling) remained significant predictors of a correct classification. The diagnostic score had a global performance of 0.9917 and correctly classified 97% of the patients, with a sensitivity of 92%, a specificity of 99%, a positive predictive value of 97%, and a negative predictive value of 97% for the diagnosis of AH. CONCLUSIONS: This new radiologic score could be integrated into the management of patients with AH, who derive greater benefit from medical as opposed to surgical treatment.

Significance of Prediagnostic Thyroid Antibodies in Women with Autoimmune Thyroid Disease

INTRODUCTION Antibodies to thyroglobulin (Tg), thyroperoxidase (TPO), and TSH receptor (TSH-R) are prevalent in autoimmune thyroid diseases. We aimed to assess whether females with Graves disease or Hashimoto thyroiditis are more likely than age-matched controls to have thyroid antibodies before clinical diagnosis and to measure the timing of antibody seroconversion. METHODS This was a nested case-control study using the Department of Defense Serum Repository and the Defense Medical Surveillance System, 1998-2007. We assessed thyroid antibodies in the serum of 522 female, active-duty, military personnel including: 87 Graves disease cases, 87 Hashimoto thyroiditis cases, and 348 age matched controls. One serum sample was available at the time of the clinical diagnosis (±6 months); three additional samples were retrieved from the repository up to 7 yr before the clinical diagnosis, for a total of 2088 samples. RESULTS In Hashimoto thyroiditis, TPO antibodies were found in about 66% of the cases at all time points. Tg antibodies showed a similar stationary trend, at a lower prevalence of about 53%at all time points. No TSH-R antibodies were found. In Graves disease, TPO antibodies gradually increased from 31% at 5-7 yr prior to diagnosis to 57% at diagnosis and Tg antibodies from 18 to 47%. TSH-R antibodies were present before diagnosis and showed an increasing prevalence from 2, 7, 20, to 55%. CONCLUSIONS Antibodies to Tg, TPO, and TSH-R precede by years the development of the diagnostic autoimmune thyroid diseases phenotype. Overall, the presence of thyroid antibodies in apparently healthy individuals should not be neglected.

Novel autoantigens in autoimmune hypophysitis

Background  Pituitary autoantibodies are found in autoimmune hypophysitis and other conditions. They are a marker of pituitary autoimmunity but currently have limited clinical value. The methods used for their detection lack adequate sensitivity and specificity, mainly because the pathogenic pituitary autoantigen(s) are not known and therefore antigen‐based immunoassays have not been developed.

Hashimoto's Thyroiditis: Celebrating the Centennial Through the Lens of the Johns Hopkins Hospital Surgical Pathology Records

Hashimotos thyroiditis is now considered the most prevalent autoimmune disease, as well as the most common endocrine disorder. It was initially described in 1912, but only rarely reported until the early 1950s. To celebrate this centennial, we reviewed the surgical pathology archives of the Johns Hopkins hospital for cases of Hashimotos thyroiditis, spanning the period from May 1889 to October 2012. Approximately 15,000 thyroidectomies were performed at this hospital over 124 years. The first surgical case was reported in 1942, 30 years after the original description. Then, 867 cases of Hashimotos thyroiditis were seen from 1942 to 2012, representing 6% of all thyroidectomies. Hashimotos thyroiditis was the sole pathological finding in 462 cases; it accompanied other thyroid pathologies in the remaining 405 cases. The most commonly associated pathology was papillary thyroid cancer, an association that increased significantly during the last two decades. The most common indication for thyroidectomy was a thyroid nodule that was cytologically suspicious for malignancy. Hashimotos thyroiditis remains a widespread, intriguing, and multifaceted disease of unknown etiology one century after its description. Advances in the understanding of its pathogenesis and preoperative diagnosis will improve recognition and treatment of this disorder, and may one day lead to its prevention.