Autoimmune Thyroid Dysfunction Research Articles

The influence of monoclonal antibodies for cancer treatment on the endocrine system

Summary Cancer is one of the main causes of mortality worldwide. Thanks to scientific research, new methods of cancer treatment, including molecularly targeted therapy, are being developed. Monoclonal antibodies are used to treat many diseases, including some types of cancer, and affect various systems of the human body. The presented article aims to present the adverse effects of molecularly targeted cancer therapy on the endocrine system based on the current literature data. Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 or its ligand PD-L1, can cause a variety of autoimmune adverse effects, among others, thyroid dys-function, hypophysitis, and diabetes mellitus. The authors also paid attention to monitoring selected diagnostic parameters to prevent endocrine adverse effects during a therapy with monoclonal antibodies. The development of adverse effects may sometimes progress atypically and rapidly, and may be a life-threatening condition. Clinicians should choose individual schemes of treatment for particular patients. The patient’s condition should also be monitored before, during and after the therapy. The decision about the continuation of treatment with monoclonal antibodies should be based especially on a risk connected with the cessation of treatment. Clinical trials should be continued to improve knowledge about the side effects of monoclonal antibodies.

Autoimmune Thyroid Disease, Thyroid Functions, and Thyroid Ultrasonography in Pediatric Celiac Disease

Objective: To compare thyroid function tests, autoantibodies and ultrasound findings in pediatric celiac patients following a gluten-free diet with the non-celiac control group.
 Material and Methods: The data of 64 celiac patients (median age 11 years) followed up with a gluten-free diet in the pediatric outpatient clinic and 143 control patients were retrospectively reviewed. The patient group consisted of 18 men, 46 women, and the control group 39 men and 103 women. The age range of the cases was 6-17 years. The duration of gluten-free diet was between three months and 15 years (median four years). The diagnosis of celiac disease was made according to the criteria of the European Society for Paediatric Gastroenterology, Association of Hepatology, and Nutrition. Free thyroxin, thyroid stimulating hormone (TSH), anti-thyroid peroxidase (anti-TPO), and antithyroglobulin (anti-Tg) levels were measured. In the thyroid ultrasound, gland volume, parenchymal structure, and thyroid nodules were evaluated. The positivity of thyroid autoantibodies and a heterogeneous appearance on ultrasound were assessed in favor of thyroiditis. The findings were compared between the celiac and control groups.
 Results: Autoimmune thyroid disease was seen in 12.5% of celiac patients and 4.2% of the controls (p<0.05). The rate of abnormalities in thyroid function tests was 9.3% in the celiac group and 2.8% in the control group (p=0.05). The mean thyroid volume was 3.58 ml in celiac patients and 3.95 ml in controls (p>0.05). The parenchymal heterogeneity was 12.5% in the celiac group and 2.1% in the control group (p<0.05), and the incidence of thyroid nodules was 25% and 4.2%, respectively (p<0.05).
 Conclusion: The autoimmune thyroiditis and thyroid dysfunction is more frequent in children with celiac disease. In addition, heterogeneous parenchyma and thyroid nodules are more common than the normal population on ultrasound. Celiac patients should be carefully evaluated for possible thyroid disease.

Integrative analysis of key candidate genes and signaling pathways in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy by bioinformatics

SummaryCytotoxic T lymphocyte-associated antigen-4 (CTLA-4), the first immune checkpoint to be targeted clinically, has provided an effective treatment option for various malignancies. However, the clinical advantages associated with CTLA-4 inhibitors can be offset by the potentially severe immune-related adverse events (IRAEs), including autoimmune thyroid dysfunction. To investigate the candidate genes and signaling pathways involving in autoimmune thyroid dysfunction related to anti-CTLA-4 therapy, integrated differentially expressed genes (DEGs) were extracted from the intersection of genes from Gene Expression Omnibus (GEO) datasets and text mining. The functional enrichment was performed by gene ontology (GO) annotation and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Protein-protein interaction (PPI) network, module enrichment, and hub gene identification were constructed and visualized by the online Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. A total of 22 and 17 integrated human DEGs in hypothyroidism and hyperthyroidism group related to anti-CTLA-4 therapy were identified, respectively. Functional enrichment analysis revealed 24 GO terms and 1 KEGG pathways in the hypothyroid group and 21 GO terms and 2 KEGG pathways in the hyperthyroid group. After PPI network construction, the top five hub genes associated with hypothyroidism were extracted, including ALB, MAPK1, SPP1, PPARG, and MIF, whereas those associated with hyperthyroidism were ALB, FCGR2B, CD44, LCN2, and CD74. The identification of the candidate key genes and enriched signaling pathways provides potential biomarkers for autoimmune thyroid dysfunction related to anti-CTLA-4 therapy and might contribute to the future diagnosis and management of IRAEs for cancer patients.

Autoimmune and non-autoimmune thyroid dysfunction in HCV infected and HCV–HIV co-infected patients before and after interferon alpha therapy: A prospective study

IntroductionAutoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients’ monoinfected and coinfected HCV–HIV at baseline, during and after IFNα therapy. MethodsWe studied 790 HCV infected patients: G1 (monoinfected HCV: N=580) and G2 (HCV–HIV coinfected: N=210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy.If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. ResultsNo difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p=0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. ConclusionOur hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases’ applications.

Lupus erythematosus tumidus (LET) with autoimmune thyroid dysfunction (AITD) as the first presentation of systemic lupus erythematosus: A case report and review of the literature

IntroductionLupus erythematosus tumidus (LET) is a rare cutaneous manifestation especially as a first presentation of systemic lupus erythematosus (SLE). Autoimmune thyroid dysfunction (AITD) may be associated with SLE but rarely at initial presentation, and its diagnosis may be delayed. Case reportA 29 year old male presented to Tishreen Hospital in Damascus with a three-year history of recurrent cellulitis-like lesions on the face, and more recently, he developed similar lesions on the trunk and the chest, in addition to the development of peripheral and scrotal edema, constipation, xeroderma, hair loss, musculoskeletal pain and depression. Laboratory investigations revealed: leukopenia, anaemia, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Immunological tests identified the positive anti-nuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), anti Ro/SSA, anti La/SSB antibodies. Additionally, there was consumed complement C3, elevated thyroid stimulating hormone (TSH), thyroid hormones decreased free T3 and T4 and anti-thyroid peroxidase (anti-TPO) antibody was positive. Skin biopsy from the cheek plaque suggested the presence of LET and revealed slight hyperkeratosis; actinic elastosis, telangiectasia and edema of the papillary dermis; deep dermis perivascular and periadnexal inflammatory infiltrates with karyorrhexis of the lymphocytes and dermis edema between strands of collagen. The patient fulfilled the SLE classification criteria and consequently, methylprednisolone, azathioprine, hydroxychloroquine, levothyroxine were introduced with dramatic improvement. ConclusionLET is a rare cutaneous lupus-specific lesion that may be associated with SLE. AITD, hypothyroidism in particular, could be an initial presentation of SLE. Increased awareness and early diagnosis of such clinical presentations may improve patient outcomes.

Serum Metabolomic Patterns in Patients with Autoimmune Thyroid Disease

Objective: Autoimmune thyroid disease, including Graves disease (GD) and Hashimoto thyroiditis (HT), is one of the most common endocrine diseases. GD and HT are the main etiologies for hyperthyroidism and hypothyroidism, respectively. This study aimed to provide a metabolomic analysis of GD patients with hyperthyroidism and HT patients with hypothyroidism. Methods: This study investigated serum metabolomics in 43 GD patients with hyperthyroidism, 45 HT patients with hypothyroidism, and 52 age- and sex-matched healthy controls. The metabolomic data were analyzed by performing multivariate statistical analysis. Results: The 186 metabolites including amino acids, bile acids, free fatty acids, and lipids were identified in all participants. Multivariate models indicated systematic differences in the hyperthyroidism, hypothyroidism, and control groups. Compared to healthy controls, the 22 metabolites in the hyperthyroidism group and the 17 metabolites in the hypothyroidism group were significantly changed. Pathway analysis showed that hyperthyroidism had a significant impact on arginine and proline metabolism and aminoacyl-transfer ribonucleic acid biosynthesis, while hypothyroidism had a significant impact on alanine, aspartate, and glutamate metabolism. Conclusion: The serum metabolomic pattern changes in patients with autoimmune thyroid dysfunction. Abbreviations: BMI = body mass index; CA = cholic acid; CDCA = chenodeoxycholic acid; DCA = deoxycholic acid; FBG = fasting plasma glucose; FINS = fasting plasma insulin; FT3 = free triiodothyronine; FT4 = free thyroxine; GD = Graves disease; GDCA = glycodeoxycholic acid; HDL-C = high-density lipoprotein cholesterol; HOMA-IR = homeostasis model assessment of insulin resistance; HT = Hashimoto thyroiditis; LDL-C = low-density lipoprotein cholesterol; PC = phosphatidylcholine; PCA = principal component analysis; PLS-DA = partial least squares discriminant analysis; SM = sphingomyelin; TBA = total bile acid; TC = total cholesterol; TG = triglyceride; TSH = thyrotropin; VIP = variable influences on projection.

Development of auto-immune thyroid dysfunction in multiple sclerosis patients receiving Alemtuzumab is associated with improved response to treatment

Development of auto-immune thyroid dysfunction in multiple sclerosis patients receiving Alemtuzumab is associated with improved response to treatment

Prevalence of thyroid autoimmunity in first-degree relatives of patients with celiac disease.

Patients with celiac disease (CeD) are prone to develop other autoimmune diseases such as autoimmune thyroid disease and type 1 diabetes. While 7.5% of first-degree relatives (FDRs) of patients with CeD develop CeD, it is not clear whether FDRs of patients with CeD are at higher risk of developing autoimmune thyroid disease. In this prospective case-control study, we recruited 194 FDRs (males 53.1%) of 91 patients with CeD and 140 age-matched healthy controls (males 76.4%). They were screened for CeD using anti-tissue transglutaminase antibodies (anti-tTG Ab) and thyroid disease using a symptom questionnaire, anti-thyroid peroxidase antibodies (anti-TPO) and serum thyroid-stimulating hormone (TSH). Subjects having positive anti-TPO but a normal TSH were classified as having thyroid autoimmunity and those with elevated TSH with or without positive anti-TPO Ab were classified as having autoimmune thyroid dysfunction. The prevalence of thyroid autoimmunity and autoimmune thyroid dysfunction in FDRs was significantly higher than that in healthy controls (17.5% vs. 5.0%, p < 0.01; 11.8% vs. 3.5%, p < 0.01), respectively. A significantly higher number of FDRs had a positive anti-tTG Ab in comparison with controls (13.9% vs. 2.2%, p < 0.001). Amongst FDRs having thyroid autoimmunity, 44.1%, 47.0% and 8.8% were siblings, parents and children of patients with CeD, respectively. Familial clustering was seen only in 1 family. FDRs of patients with CeD have 3-fold higher risk of developing autoimmune thyroid disorders and associated thyroid dysfunction. Therefore, it is advisable for early screening of FDRs for CeD and associated thyroid autoimmune through screening measures.

Anti-programmed cell death protein 1 (anti-PD1) immunotherapy induced autoimmune polyendocrine syndrome type II (APS-2): a case report and review of the literature

BackgroundAutoimmune polyendocrine syndrome type II (APS-2) is a rare constellation of autoimmune hypoadrenalism, thyroid dysfunction and/or type 1 diabetes (T1DM), usually occurring in the 3rd or 4th decades and associated with a human leukocyte antigen (HLA) DR3 or DR4 serotype. We detail the first report of an elderly woman developing the full triad of APS-2 shortly after commencing anti-programmed cell death protein 1 (anti-PD1) immune checkpoint inhibition for unresectable melanoma and review the literature for similar presentations secondary to anti-PD1 axis therapy.CaseA 78-year-old female with advanced unresectable BRAF wild-type melanoma was treated with pembrolizumab (2 mg/kg 3-weekly). Three weeks following the first dose she developed fulminant autoimmune diabetes, with an initially low C-peptide denoting rapid destruction of ß-islet cells. Following stabilisation of her diabetes, two further doses of pembrolizumab was administered. She then represented with symptomatic hypoadrenalism and hypothyroidism, consistent with APS-2. Her HLA class II genotype was HLA-DRB1*04.16 (DR4 serotype), a recognised association with this syndrome. Her melanoma responded rapidly to anti-PD1 therapy, and a complete response (CR) was attained after four doses of pembrolizumab. Treatment was discontinued and her CR is ongoing.ConclusionThis is the first report of the full triad of APS-2 developing in a genetically susceptible individual at the age of 78 after treatment with an anti-PD1 agent. Although scarcely reported, a literature review of similar reports seems to indicate a predilection for this syndrome in patients with HLA-DR4 serotypes. HLA Class II typing is not routinely recommended, but may provide useful predictive information for patients at risk of poly-endocrinopathy even in patients without a relevant personal or family history. Additional studies are required to determine if such testing would be useful and/or cost effective.

Autoimmune and non-autoimmune thyroid dysfunction in HCV infected and HCV–HIV co-infected patients before and after interferon alpha therapy: A prospective study

IntroductionAutoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients’ monoinfected and coinfected HCV–HIV at baseline, during and after IFNα therapy. MethodsWe studied 790 HCV infected patients: G1 (monoinfected HCV: N=580) and G2 (HCV–HIV coinfected: N=210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy.If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. ResultsNo difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p=0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. ConclusionOur hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases’ applications.

A cross-sectional study of thyroid autoimmunity in women with type 2 diabetes: case for routine thyroid dysfunction screening

Introduction: Subjects with diabetes have a higher prevalence of thyroid disorders compared to the general population. The reported prevalence of thyroid disorders is 10-24% in subjects with diabetes and 6 - 13% in subjects without diabetes. Auto immunity is held responsible for the increased prevalence of thyroid dysfunction in diabetes. Studies have proven the higher rates of autoimmune thyroid dysfunction in type 1 diabetes, but there is very little information regarding thyroid autoimmunity in type 2 diabetes. Objective: To estimate the prevalence of thyroid dysfunction and thyroid autoimmunity in women with type 2diabetes. Material and Methods: Samples for thyroid function test including free thyroxin (fT4), thyroid stimulating hormone (TSH) and thyroid peroxidase antibodies (anti -TPO) were obtained from 100 women with type 2 diabetes, attending the outpatient department of Karnataka Institute of Endocrinology and Research, Bangalore. Results: Thyroid dysfunction was found in 42% subjects, where 36% had subclinical hypothyroidism and 6% had overt hypothyroidism. Anti - TPO positivity was seen in 30% of the subjects. Anti-TPO positivity was found in 24.1% euthyroid subjects, 33.3% subclinical hypothyroid subjects and 66.7% overt hypothyroid subjects. Significant positive correlation was observed between anti-TPO and TSH (p value <0.001*). No statistically significant association was found between thyroid dysfunction and age, BMI, Hba1c, and diabetes duration. Conclusions: The prevalence of thyroid dysfunction is significantly high in women with type 2 diabetes. The most common abnormality is subclinical hypothyroidism and autoimmunity is the cause of thyroid dysfunction in large proportion of these subjects.

Raised incidence of autoimmune thyroiditis among females in 2nd, 3rd and 4th decades: a randomized study

Background: Autoimmune thyroid disease (AITD), a mutual organ specific autoimmune disorder is seen mostly in women between 30-50 years of age. The rationale behind the study is to determine increased incidences of auto immune thyroiditis. The objective of the present study was to evaluate the incidence of autoimmune thyroiditis and thyroid dysfunction in healthy females with no previously known thyroid disease, in an urban area.Methods: The study was conducted on female volunteers with no known thyroid disease. 370 subjects among the hospital’s medical and administration personnel were recruited. All underwent thyroid ultrasound (US) and thyroid anti-peroxidase (TPOAb) and anti-thyroglobulin (TgAb) antibodies were measured. Hypoechogenicity and thyroid volume were determined by sonography.Results: the incidence of autoimmune thyroiditis was 23.2% and 20-30 years were most commonly affected (P = 0.008); when including cases of atrophic thyroid, the frequency decreased to 14.7%.Conclusions: The frequency of autoimmune thyroiditis is clearly elevated in the studied population. Further studies are necessary in order to define the increased incidence of autoimmune thyroid disease.

Thyroid Dysfunction in Type 1 Diabetes Mellitus in an Iranian Elderly Woman

Objective: Type 1 Diabetes mellitus (T1DM) and thyroid dysfunction consider as main metabolic and endocrine disorders. In previous studies, individuals with T1DM were susceptible to Thyroid disorders. The prevalence of clinical and subclinical Thyroid dysfunction have noticeable importance especially regarding women and their related stigma. Methods: The presented survey, a case-control study evaluated the thyroid dysfunction among T1DM elderly women referred to diabetes clinic of Tohid Hospital in Sanandaj city. The whole blood samples were attained from all individuals and then the following tests were done: fasting blood-sugar (FBS), Serum TSH, anti-Thyroperoxidase (Anti-TPO) and Free T4.Results: The prevalence of Thyroid disorder in examined patients was 17 percent and autoimmune Thyroid dysfunction disorder, that examined by positive test-result of Anti-TPO showed up in 10.2 percent of patients. Prevalence of sub-clinical Hypothyroidism was 13.2 percent; the clinical Hypothyroidism were 7.3 percent. Based on our data 2.9 percent of T1DM have subclinical Hyperthyroidism and 1.4 percent have clinical Hyperthyroidism. In our study, increased TSH level and existence of Anti-TPO in TIDM patients might be regarded as an additional TIDM problem in studied disease.Conclusion: This study confirmed the association between autoimmune Thyroid dysfunction (based on positive Serum-test of Anti-TPO) and T1DM.

The Roles of Thyroid and Thyroid Hormone in Pancreas: Physiology and Pathology.

It is widely accepted that thyroid hormones (THs), secreted from the thyroid, play important roles in energy metabolism. It is also known that THs also alter the functioning of other endocrine glands; however, their effects on pancreatic function have not yet been reviewed. One of the main functions of the pancreas is insulin secretion, which is altered in diabetes. Diabetes, therefore, could be related to thyroid dysfunction. Earlier research on this subject focused on TH regulation of pancreas function (such as insulin secretion) or on insulin function through TH-mediated increase of energy metabolism. Afterwards, epidemiological investigations and animal test research found a link between autoimmune diseases, thyroid dysfunction, and pancreas pathology; however, the underlying mechanisms remain unknown. Furthermore, recent studies have shown that THs also play important roles in pancreas development and on islet pathology, both in diabetes and in pancreatic cancer. Therefore, an overview of the effects of thyroid and THs on pancreas physiology and pathology is presented. The topics contained in this review include a summary of the relationship between autoimmune thyroid dysfunction and autoimmune pancreas lesions and the effects of THs on pancreas development and pancreas pathology (diabetes and pancreatic cancer).

Transient Hypothyroidism and Autoimmune Thyroiditis in Children With Chronic Hepatitis C Treated With Pegylated-interferon-α-2b and Ribavirin.

Autoimmune thyroid disease and thyroid dysfunction are common in adults receiving interferon (IFN)-based treatment for chronic hepatitis C (CHC). Few data are available in children with CHC. This study is aimed to evaluate the appearance and timing of thyroid dysfunction and antithyroid autoimmunity in children with CHC treated with pegylated IFN-α-2b and ribavirin (RBV). Sixty-one otherwise healthy children with CHC, 3-17 years of age, infected perinatally and treatment naïve, receiving therapy with pegylated IFN-α-2b and RBV and 183 age- and sex-matched controls were included in a multicenter, prospective, case-control study. Thyroid-stimulating hormone, free thyroxine, antithyroglobulin antibodies and antithyroid peroxidase antibodies were assessed before, during and 24 weeks after the end of treatment. From baseline to the end of treatment, subclinical hypothyroidism and autoimmune thyroiditis were diagnosed in 17 of 61 (27.94%) and in 4 of 61 (6.6%) of the children treated, respectively, and in 5 of 183 (2.7%) and in none of the controls (P < 0.0001, relative risk: 10.2, 95% confidence interval: 3.9-26.5; P = 0.03, relative risk: 26.8, 95% confidence interval: 1.5-489.1, respectively). Twenty-four weeks after the end of treatment, subclinical hypothyroidism persisted in only 4 of 61 (6.6%). Autoimmune thyroiditis persisted in 3 of 4 (75%) of the cases. Subclinical hypothyroidism is common in children with CHC receiving treatment with pegylated IFN-α-2b and RBV, but in most cases is transient. Autoimmune thyroiditis, which is less common, generally persists after treatment completion. Thyroid function should be carefully monitored in patients presenting with antithyroid autoantibodies and thyroid dysfunction during and after pegylated IFN-α-based treatment.

High Prevalence of Hypothyroidism In Systemic Lupus Erythematosus Patients Without an Increase in Circulating Anti-Thyroid Antibodies

Because routine investigations are necessary for the early detection of thyroid disease, this study aimed to assess the prevalence of autoimmune thyroid disease (ATD) and thyroid dysfunction (TD) in patients with systemic lupus erythematosus (SLE). Seventy-nine SLE patients (American College of Rheumatology criteria) and 159 control patients with no diagnosis of autoimmune diseases (except for ATD) were consecutively evaluated regarding changes in laboratory assessments of thyroid function and the presence of ATD. ATD was detected in 11.4% of the SLE patients and 13.8% of the control patients (P = .747), whereas TD was detected in 25.3 and 9.4% (P = .002), hypothyroidism was detected in 21.5 and 6.9% (P = .002), and hyperthyroidism was detected in 3.8 and 2.5% (P = .426) of the SLE and control patients, respectively. The mean duration of SLE was longer in patients with TD (P = .036). Mild hypothyroidism was more frequent in the SLE patients with anti-Smith antibodies (P = .029). Because hypothyroidism was more frequent in SLE patients and the frequency of ATD was high in both groups, the authors suggest that TSH and anti-thyroid antibody levels be assessed in SLE patients. ACA = anti-cardiolipin antibodies; ANF = anti-nuclear factor; anti-CCP = anti-cyclic citrullinated peptide; anti-dsDNA = anti-double-stranded DNA; anti-RNP = anti-ribonucleoprotein; anti-Scl70 = anti-topoisomerase I antibodies; anti-SM = anti-Smith antigen antibodies; anti-SS-A/Ro = anti-Sjögren syndrome-related antigen A (Ro); anti-SS-B/La = anti-Sjögren syndrome-related antigen B (La); anti-Tg = anti-thyroglobulin; anti-TPO = anti-thyroid peroxidase; ATD = autoimmune thyroid disease; ENA = extractable nuclear antigen; fT4 = free thyroxine; OR = odds ratio; RF = rheumatoid factor; SLE = systemic lupus erythematosus; SLEDAI = SLE Disease Activity Index; TD = thyroid dysfunction; TSH = thyroid-stimulating hormone; TT3 = total triiodothyronine.

Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution.

Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. 52 patients (30 F; age 61±13years) with advanced melanoma treated with ipilimumab (3mg/kg i.v./3weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3mg/kg i.v./2weeks) or pembrolizumab (2mg/kg i.v./3weeks). Thyroid function and autoimmunity were assessed before, after 6weeks, at the end of ipilimumab, as well as before and every 3months during nivolumab/pembrolizumab treatment. During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36±28months. Thyroid disorders occurred 45.1±20.8 and 151±67days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.

Variable Effects of Dietary Selenium in Mice That Spontaneously Develop a Spectrum of Thyroid Autoantibodies.

Selenium (Se) is a critical element in thyroid function, and variable dietary Se intake influences immunity. Consequently, dietary Se could influence development of thyroid autoimmunity and provide an adjunct to treat autoimmune thyroid dysfunction. Nonobese diabetic (NOD).H2h4 mice spontaneously develop autoantibodies to thyroglobulin (Tg) and thyroid peroxidase (TPO). This mouse strain expressing a human thyroid-stimulating hormone receptor (TSHR) A-subunit transgene in the thyroid also develops pathogenic TSHR autoantibodies. In this report, we investigated whether dietary Se influences these immune processes. Male and female wild-type and transgenic NOD.H2h4 mice were maintained on normal-, low-, or high-Se (0.1, 0, or 1.0 mg/kg) rodent diets. After 4 months, Se serum levels were extremely low or significantly increased on 0 or 1.0 mg/kg Se, respectively. Varying Se intake affected Tg antibody (TgAb) levels after 2 (but not 4) months; conversely, TPO antibody (TPOAb) levels were altered by dietary Se after 4 (but not 2) months. These data correspond to the earlier development of TgAb than TPOAb in NOD.H2h4 mice. In males, TgAb levels were enhanced by high Se and in females by low Se intake. Se intake had no effect on pathogenic TSHR autoantibodies in TSHR transgenic NOD.H2h4 females. In conclusion, in susceptible NOD.H2h4 mice, we found no evidence that a higher dietary Se intake ameliorates thyroid autoimmunity by reducing autoantibodies to Tg, TPO, or the TSHR. Instead, our finding that low dietary Se potentiates the development of autoantibodies to Tg and TPO in females is consistent with reports in humans of an increased prevalence of autoimmune thyroiditis in low-Se regions.

Thyroid peroxidase antibodies during early gestation and the subsequent risk of first-onset postpartum depression: A prospective cohort study

BackgroundDuring the postpartum period, women are at risk for the new onset of both auto-immune thyroid disorders and depression. The presence of thyroid peroxidase antibodies (TPO-ab) during early gestation is predictive for postpartum auto-immune thyroid dysfunction. The aim of this study was to investigate the association between TPO-ab status during early gestation and first-onset postpartum depression. MethodsProspective cohort study (n = 1075) with follow-up during pregnancy up to one year postpartum. Thyroid function and TPO-ab status were measured during early gestation. Depressive symptomatology was assessed during each trimester and at four time points postpartum with the Edinburgh Depression Scale (EDS). Women with antenatal depression were not eligible for inclusion. Self-reported postpartum depression was defined with an EDS cut-off of ≥ 13. ResultsThe cumulative incidence of self-reported first-onset depression in the first postpartum year was 6.3%. A positive TPO-ab status was associated with an increased risk for self-reported first-onset depression at four months postpartum (adjusted OR 3.8; 95% CI 1.3–11.6), but not at other postpartum time points. Prevalence rates of self-reported postpartum depression declined after four months postpartum in the TPO-ab positive group, but remained constant in the TPO-ab negative group. LimitationsDepression was defined with a self-rating questionnaire (EDS). ConclusionsWomen with an increased TPO-ab titer during early gestation are at increased risk for self-reported first-onset depression. The longitudinal pattern of self-reported postpartum depression in the TPO-ab positive group was similar to the typical course of postpartum TPO-ab titers changes. This suggests overlap in the etiology of first-onset postpartum depression and auto-immune thyroid dysfunction. Thyroid function should be evaluated in women with first-onset postpartum depression.

Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer

Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.