Anti-Thyroid Peroxidase and Anti-Thyroglobulin Autoantibodies in the Cerebrospinal Fluid of Patients with Unipolar Depression

Introduction: The risk of developing depression is increased in patients with autoimmune thyroiditis. Autoimmune Hashimoto thyroiditis is diagnosed using the serum markers anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies. In rare cases, patients with autoimmune thyroiditis can also suffer from the heterogeneous and ill-defined syndrome of Hashimoto encephalopathy. Biomarkers for Hashimoto encephalopathy or for any brain involvement of autoimmune thyroiditis are currently lacking. The aim of the present descriptive study was therefore to determine whether a subgroup of seropositive patients shows intrathecal anti-thyroid antibody synthesis in the cerebrospinal fluid (CSF). Participants and methods: Paired serum and CSF samples from 100 patients with unipolar depression were examined for anti-TPO and anti-TG antibodies using enzyme-linked immunosorbent assays. Antibody-specific indices (ASIs) were calculated for seropositive samples. These ASIs allow the differentiation between the brain-derived fraction of antibodies and antibodies which are passively diffused from the serum. ASIs >1.4 were assessed as positive for brain-derived antibodies. Additionally, for explorative evaluations, a stricter ASI limit of >2 was applied. Results: Anti-TPO antibodies were increased in the serum of 16 patients (16%); increased anti-TPO ASIs (>1.4) were detected in 11 of these patients (69%). Anti-TG antibodies in the serum were detected in three patients (3%), with two of them (67%) showing increased ASIs (>1.4). Overall, the authors found increased anti-thyroid antibodies in 17 of 100 patients (17%), with 13 out of 17 patients showing increased ASIs (76%; range 1.4–4.1). Choosing ASI levels of >2 led to positive findings in six out of 16 patients (38%) with anti-TPO antibodies in their serum but no increase in ASIs in three patients (0%) who were seropositive for anti-TG antibodies. The patients with elevated ASIs (N = 13) were younger than the ASI-negative patients (N = 87; p = 0.009); no differences were noted in the frequency of CSF, electroencephalography, and/or magnetic resonance imaging alterations. Discussion: A subgroup of seropositive patients showed intrathecal synthesis of anti-TPO and, more rarely, of anti-TG antibodies, which might be an indication of central autoimmunity in a subgroup of patients with unipolar depression. The confirmation of elevated ASIs as a biomarker for Hashimoto encephalopathy must await further studies. The relevance of the findings is limited by the study’s retrospective and uncontrolled design.

Prognostic Significance of Thyroglobulin Antibodies in Differentiated Thyroid Cancer

Objective. To investigate whether variations in thyroglobulin autoantibodies (TgAb) are related to the recurrence or persistence of differentiated thyroid carcinoma (DTC) and may therefore be useful as surrogate tumor markers. Design and Methods. We retrospectively studied 98 subjects (83 women, 47 ± 15 years old) from an initial cohort of 1017 patients treated for DTC in five hospitals, with positive TgAb at any time during the follow-up. Patients presented five different patterns of evolution of serum TgAb concentrations: (1) stable positive TgAb, (2) de novo appearance, (3) an increase of more than 50%, (4) TgAb levels from positive to negative, and (5) a decrease of more than 50%. Results. In the group of 11 patients with stable TgAb, four cases presented persistence of the disease with structural incomplete response. In the group of 22 patients with sustained increasing trend rising more than 50% or de novo detectable TgAb levels, three patients were diagnosed with structural incomplete response. There was no evidence of recurrence or persistence of the disease in any of the 65 patients who showed a significant decrease in (n = 35) or disappearance of (n = 30) TgAb. Conclusions. Our results suggest that not only the appearance of a significant increase in TgAb but also stable concentrations of TgAb should be regarded as a sufficient risk condition for an active search for recurrent or persistent disease. Conversely, a significant decrease in TgAb levels can represent a good prognostic sign.

MON-495 Influence of Lymphocytic Thyroiditis at Histology and Serum Thyroglobulin Autoantibodies on the Course of Papillary Thyroid Carcinoma

PURPOSE Papillary thyroid carcinoma (PTC) is frequently associated with diffuse lymphocytic thyoiditis (LT) at histology and serum autoantibodies to thyroglobulin (TgAb) and to thyroperoxidase (TPOAb). The influence of LT and thyroid autoantibodies on the prognosis of PTC is debated. We evaluated the clinical course of a large group of PTC patients according to the presence or absence of LT (LT+ and LT-) and thyroid autoantibodies. METHODS We evaluated 194 consecutive and non-selected PTC patients treated with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009, followed for 7.2 years (mean). 72 patients had follicular variant of PTC, 97 classic, 16 tall cells and the remaining 9 others variants (solid or oxyphilic cells). LT was diagnosed in presence of >10 lymphocytes/field (40x). At the time of ablation, all patients underwent measurement of Tg, TgAb and TPOAb, neck ultrasound and whole body scan. After ablation, patients underwent Tg (Beckman Coulter), TgAb and TPOAb (Tosoh) measurement and neck ultrasound (associated with other imaging if required) every 6-12 months. PTC was considered in remission according to the following criteria: un-stimulated Tg <0.2 ng/mL or stimulated Tg <1 ng/mL with TgAb <8 IU/mL and no evidence of structural disease. PTC was considered as persistent when un-stimulated Tg was ≥0.2 ng/mL or stimulated Tg was ≥1 ng/mL, or when TgAb were ≥8 IU/mL, or there was evidence of structural disease. RESULTS LT was found in 47% of patients, with a F/M ratio of 6.6/1, and was associated with a hypoechoic pattern at thyroid ultrasound (p = 0.05). At the end of follow-up 44/194 (22.7%) had persistent disease. Among them, 17/72 (23.6%) were follicular, 19/97 (19.6%) classic, 6/16 (37.5%) tall cells and 2/9 (22.2%) other variants. The time to remission was longer in the LT+ compared to the LT- patients (19.5 vs 7.5 months) (median) (p <0.001), in TgAb positive compared to TgAb negative patients (28.5 vs 7.5 months) (p <0.001) and in TPOAb positive compared to TPOAb negative patients (28.0 vs 8.0 months) (p = 0.005). At multivariate analysis TgAb were the only independent factor influencing the time to remission (0.54; 0.35-0.83; HR and confidence interval) (p = 0.001). However, evaluating only the 111 TgAb negative patients, the time to remission (undetectable un-stimulated or stimulated Tg and no evidence of structural disease) was similar in the LT+ and LT- groups (8.0 months for both). At variance, in 83 TgAb positive patients the time to remission was longer in LT+ than in LT- patients (29.3 vs 13.0 months) (p=0.01). CONCLUSIONS The time to remission is longer in LT+ compared to LT- PTC patients treated with total thyroidectomy plus ¹³¹I ablation. This is due to the frequent association of LT with TgAb, because undetectable TgAb is required to define the remission of PTC. Indeed, coexistent LT does not influence the time to remission when the analysis is restricted to TgAb negative patients.

A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves’ Hyperthyroidism – A Proof-Of-Concept Trial

Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD Design Open label, phase II proof-of-concept study Setting Multicenter Patients Fifteen with GD Intervention Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P<0.001) and TSH-R-Ab levels normalized in four (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P<0.001). Twelve (80.0%) patients reported at least one adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of Iscalimab should be further tested.

A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves Hyperthyroidism—A Proof-of-Concept Trial

Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. Objective Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. Design Open-label, phase II proof-of-concept study. Setting Multicenter. Patients Fifteen with GD. Intervention Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P &lt; 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P &lt; 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested.

A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves’ Hyperthyroidism – A Proof-Of-Concept Trial

Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD Design Open label, phase II proof-of-concept study Setting Multicenter Patients Fifteen with GD Intervention Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P<0.001) and TSH-R-Ab levels normalized in four (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P<0.001). Twelve (80.0%) patients reported at least one adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of Iscalimab should be further tested.