Beate Quadbeck

Impact of smoking on the response to treatment of thyroid associated ophthalmopathy.

Background: In patients with Graves’ disease, smoking considerably increases the incidence and severity of thyroid associated ophthalmopathy (TAO). The authors sought to determine if smoking also influences the course of TAO during treatment, and the efficacy of therapy. Methods: 41 smokers and 19 non-smokers with moderate untreated TAO were included in this prospective study. All patients were treated with steroids and, 6 weeks after the beginning of drug therapy, with orbital irradiation. Follow up was performed 1.5, 4.5, 7.5, and 12 months after the beginning of the study. Proptosis, clinical activity score (CAS), and motility were evaluated. The extent of smoking was derived from the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV), a parameter of long term smoking. Results: There was no difference in the clinical manifestations of TAO between smokers and non-smokers at the beginning of treatment. However, CAS decreased (p<0.05) and motility improved (p<0.02) significantly faster and to a greater extent in non-smokers than smokers. Inverse correlations between the CAS decrease and the HEV levels observed 4.5 and 7.5 months after the beginning of treatment and between the improvement of motility and the HEV levels after 1.5, 4.5, and 7.5 months indicated a dose dependence. Mean HEV levels did not vary much during the follow up period and were significantly different in smokers (mean 5.4 (SD 2.7) μg/l) and non-smokers (mean 1.8 (1.3) μg/l; p<0.01). Conclusion: Smoking influences the course of TAO during treatment in a dose dependent manner. The response to treatment is delayed and considerably poorer in smokers.

Clinical results of anti-inflammatory therapy in Graves’ ophthalmopathy and association with thyroidal autoantibodies*

objective  Graves’ ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH‐receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti‐inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO.

The peroxisome proliferator activated receptor gamma Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome.

Background  Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation. The genetic background of the insulin resistance frequently associated with PCOS is unclear.

Thyroid associated ophthalmopathy: evidence for CD4+ γδ T cells; de novo differentiation of RFD7+ macrophages, but not of RFD1+ dendritic cells; and loss of γδ and αβ T cell receptor expression

Aim: To characterise periorbital immune cells (stages, kinetics) in active and inactive thyroid associated ophthalmopathy (A-TAO; I-TAO). Methods: In orbital tissue cryosections of patients with A-TAO (n = 15), I-TAO (n = 11), and healthy controls (n = 14), adipose and fibrovascular areas were evaluated for MHC II+ cells, CD45+ total leukocytes, myeloid cells (CD33+ monocytes; CD14+ macrophages; mature RFD7+ macrophages; RFD1+ dendritic cells (DCs)), and lymphoid cells (CD4+ T cells; αβ and γδ T cells; CD20+ B cells). Results are expressed as medians and 5% confidence intervals. Results: In fibrovascular septae, a surge of CD33+ immigrants clearly correlating with disease activity generated significantly increased (p<0.05) percentages of CD14+ and RFD7+ macrophages. Intriguingly, CD4+ cells were mostly γδ T cells, while αβ T helper cells were much less frequent. Successful treatment rendering TAO inactive apparently downregulates monocyte influx, macrophage differentiation, and T cell receptor expression. Similar trends were recorded for adipose tissue. Interestingly, RFD1+ DCs were completely absent from all conditions examined. Conclusion: A-TAO coincides with periorbital monocyte infiltration and de novo differentiation of macrophages, but not DCs. The authors discuss a novel potential role for inflammatory CD4+ γδ T cells in TAO. Successful treatment apparently downregulates orbital monocyte recruitment and effects functional T cell knockout.

[Role of TSH receptor autoantibodies for the diagnosis of Graves' disease and for the prediction of the course of hyperthyroidism and ophthalmopathy. Recommendations of the Thyroid Section of the German Society of Endocrinology].

ZusammenfassungDie Autoimmunhyperthyreose (Synonym Morbus Basedow) ist eine antikörpervermittelte Autoimmunerkrankung, bei der es zu einer Stimulation der Schilddrüse, aber auch anderer Zielgewebe kommt. Neben der Hyperthyreose können extrathyreoidale Manifestationen wie die endokrine Orbitopathie (EO) auftreten.Zur Diagnosesicherung des Morbus Basedow sollten die TSH-Rezeptor-Autoantikörper (TRAK) bestimmt werden. Aufgrund der deutlich höheren Sensitivität und Spezifität sollten anstelle überholter TRAK-Assays der ersten Generation (Einheiten in U/l) Assays der zweiten Generation (Einheiten in IU/l) verwendet werden. Für einen Teil der Patienten ist eine Prognoseabschätzung des Morbus Basedow mit hoher Wahrscheinlichkeit durch eine Bestimmung der TRAK im Verlauf der Erkrankung möglich, so dass eine Operation bzw. Radiojodtherapie mit hohen TRAK-Werten schon vor Ablauf des 1. Jahres (frühestens nach 6 Monaten bei einem TRAK-Wert von > 10 IU/l) einer thyreostatischen Therapie empfohlen werden kann. Für Patienten mit niedrigeren TRAK-Werten kann keine sichere Vorhersage getroffen werden.Mittels der TRAK-Bestimmung auf der Basis eines Assays der zweiten Generation kann auch der Verlauf der EO abgeschätzt werden, womit Therapieentscheidungen beeinflusst werden können.AbstractGraves’ disease (GD) is the only autoimmune disease where autoantibodies stimulate the target organs. Among the most common clinical manifestations are hyperthyroidism and orbitopathy (GO).To ensure the diagnosis of autoimmune hyperthyroidism, activity of TSH receptor autoantibodies (TRAb) should be determined. Because of their significantly improved sensitivity and equal specificity, second-generation TRAb assays (activity given in IU/l) should be preferred over first-generation assays (activity given in U/l). During follow-up of antithyroid drug therapy it is possible to predict outcome for some patients with high chances if TRAb levels are high. On this basis, thyreoablative treatment (operation or radioiodine) can already be indicated before the 1st year of antithyroid drug treatment has passed. If TRAb antibody titers are > 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs.TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration.

Dysregulation of TNF/TNFR Superfamily Members: A Systemic Link Between Intra- and Extrathyroidal Manifestations in Graves’ Disease

Graves’ disease (GD) coincides with the occurrence of disease‐associated intrathyroidal dendritic cells (DC) and intraorbital inflammatory macrophages (Mφ). Physiologically, tumour necrosis factor‐α (TNF‐α) strongly affects the differentiation of DC and Mφ from monocytic precursors; we thus hypothesized that dysregulation of the TNF/TNFR superfamilies may provide a systemic pathogenic link in GD. In patients without eye symptoms, percentages of TNF‐α‐stimulated blood monocytes were highly significantly (P < 0.001) elevated, corresponding to both intrathyroidal DC maturation as well as increases in mature blood DC (MHC‐IIhi/CD40+/RFD1hi) and B cells (CD20hi/CD40+). GD patients also displaying eye symptoms revealed a striking reduction in blood monocytes, yet significantly (P < 0.05) increased CD40hi and TNF‐αhi leucocytes. These findings suggest for GD that excess TNF‐α induces monocytes to differentiate into hyperactivated thyroidal DC that, once emigrated, initiate systemic humoral autoimmunity associated with CD40/TNF‐α upregulation. Such overexpression may instigate differentiation of periorbital inflammatory Mφ from CD14hi/CD16+ monocytes as a likely precursor subset. These results indicate that dysregulation of TNF/TNFR superfamily members provides a systemic pathogenic link in GD in that hyperactivated circulating monocytic precursors give rise to locally restricted, disease‐associated DC and Mφ. Monocytes, therefore, may serve as a suitable target to therapeutically address the common precursor of key promoters of GD.

Bedeutung der TSH-Rezeptor-Antikörper für die Diagnose des Morbus Basedow sowie die Prognoseabschätzung der Schilddrüsenüberfunktion und der endokrinen Orbitopathie

ZusammenfassungDie Autoimmunhyperthyreose (Synonym Morbus Basedow) ist eine antikörpervermittelte Autoimmunerkrankung, bei der es zu einer Stimulation der Schilddrüse, aber auch anderer Zielgewebe kommt. Neben der Hyperthyreose können extrathyreoidale Manifestationen wie die endokrine Orbitopathie (EO) auftreten.Zur Diagnosesicherung des Morbus Basedow sollten die TSH-Rezeptor-Autoantikörper (TRAK) bestimmt werden. Aufgrund der deutlich höheren Sensitivität und Spezifität sollten anstelle überholter TRAK-Assays der ersten Generation (Einheiten in U/l) Assays der zweiten Generation (Einheiten in IU/l) verwendet werden. Für einen Teil der Patienten ist eine Prognoseabschätzung des Morbus Basedow mit hoher Wahrscheinlichkeit durch eine Bestimmung der TRAK im Verlauf der Erkrankung möglich, so dass eine Operation bzw. Radiojodtherapie mit hohen TRAK-Werten schon vor Ablauf des 1. Jahres (frühestens nach 6 Monaten bei einem TRAK-Wert von > 10 IU/l) einer thyreostatischen Therapie empfohlen werden kann. Für Patienten mit niedrigeren TRAK-Werten kann keine sichere Vorhersage getroffen werden.Mittels der TRAK-Bestimmung auf der Basis eines Assays der zweiten Generation kann auch der Verlauf der EO abgeschätzt werden, womit Therapieentscheidungen beeinflusst werden können.AbstractGraves’ disease (GD) is the only autoimmune disease where autoantibodies stimulate the target organs. Among the most common clinical manifestations are hyperthyroidism and orbitopathy (GO).To ensure the diagnosis of autoimmune hyperthyroidism, activity of TSH receptor autoantibodies (TRAb) should be determined. Because of their significantly improved sensitivity and equal specificity, second-generation TRAb assays (activity given in IU/l) should be preferred over first-generation assays (activity given in U/l). During follow-up of antithyroid drug therapy it is possible to predict outcome for some patients with high chances if TRAb levels are high. On this basis, thyreoablative treatment (operation or radioiodine) can already be indicated before the 1st year of antithyroid drug treatment has passed. If TRAb antibody titers are > 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs.TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration.

Bedeutung der TSH-Rezeptor-Antikörper für die Diagnose des Morbus Basedow sowie die Prognoseabschätzung der Schilddrüsenüberfunktion und der endokrinen Orbitopathie@@@Role of TSH Receptor Autoantibodies for the Diagnosis of Graves’ Disease and for the Prediction of the Course of Hyperthyroidism and Ophthalmopathy. Recommendations of the Thyroid Section of the German Society of Endocrinology: Stellungnahme der Sektion Schilddrüse der DGE

ZusammenfassungDie Autoimmunhyperthyreose (Synonym Morbus Basedow) ist eine antikörpervermittelte Autoimmunerkrankung, bei der es zu einer Stimulation der Schilddrüse, aber auch anderer Zielgewebe kommt. Neben der Hyperthyreose können extrathyreoidale Manifestationen wie die endokrine Orbitopathie (EO) auftreten.Zur Diagnosesicherung des Morbus Basedow sollten die TSH-Rezeptor-Autoantikörper (TRAK) bestimmt werden. Aufgrund der deutlich höheren Sensitivität und Spezifität sollten anstelle überholter TRAK-Assays der ersten Generation (Einheiten in U/l) Assays der zweiten Generation (Einheiten in IU/l) verwendet werden. Für einen Teil der Patienten ist eine Prognoseabschätzung des Morbus Basedow mit hoher Wahrscheinlichkeit durch eine Bestimmung der TRAK im Verlauf der Erkrankung möglich, so dass eine Operation bzw. Radiojodtherapie mit hohen TRAK-Werten schon vor Ablauf des 1. Jahres (frühestens nach 6 Monaten bei einem TRAK-Wert von > 10 IU/l) einer thyreostatischen Therapie empfohlen werden kann. Für Patienten mit niedrigeren TRAK-Werten kann keine sichere Vorhersage getroffen werden.Mittels der TRAK-Bestimmung auf der Basis eines Assays der zweiten Generation kann auch der Verlauf der EO abgeschätzt werden, womit Therapieentscheidungen beeinflusst werden können.AbstractGraves’ disease (GD) is the only autoimmune disease where autoantibodies stimulate the target organs. Among the most common clinical manifestations are hyperthyroidism and orbitopathy (GO).To ensure the diagnosis of autoimmune hyperthyroidism, activity of TSH receptor autoantibodies (TRAb) should be determined. Because of their significantly improved sensitivity and equal specificity, second-generation TRAb assays (activity given in IU/l) should be preferred over first-generation assays (activity given in U/l). During follow-up of antithyroid drug therapy it is possible to predict outcome for some patients with high chances if TRAb levels are high. On this basis, thyreoablative treatment (operation or radioiodine) can already be indicated before the 1st year of antithyroid drug treatment has passed. If TRAb antibody titers are > 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs.TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration.