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Summary objective To investigate whether variations over time of TSH-receptor antibodies (TRAb) and antibodies against G2s (G2sAb) and extraocular muscles (EMAb) can predict worsening of ophthalmopathy in Graves’ patients treated with intravenous glucocorticoid (IVGC) therapy. patients Of 65 consecutive patients with treated Graves’ disease and severe and active ophthalmopathy (GO) chosen to undergo IVGC treatment, only 57 patients, persistently euthyroid under methimazole therapy, were studied longitudinally for ocular parameters, TRAb, G2sAb and EMAb before therapy, at the end of therapy and, subsequently, every month for 21 months. measurements TRAb was detected by radioimmunoassay (RIA), G2sAb by enzyme-linked immunosorbent assay (ELISA) and EMAb by indirect immunofluorescence. results Forty-three out of 57 patients (75·4%, group 1) responded positively to therapy [improvement in diplopia and decrease in proptosis and clinical activity score (CAS)] but 14 (24·6%) did not (group 2). During follow-up after IVGC therapy, 12 out of 43 patients in group 1 (28%) showed a worsening in GO (group 1a), while 31 (72%) had stable ocular conditions or further improvement (group 1b). At the start of the study, TRAb, G2sAb and EMAb were not significantly different among the three groups. At the end of IVGC therapy TRAb levels decreased significantly with respect to starting values in all three groups of patients, whereas G2sAb and EMAb decreased significantly in groups 1a and 1b but not in group 2. During the subsequent follow-up, 10 patients in group 1a one/two months before and all 12 patients at the time of GO worsening showed an increase in G2sAb and EMAb but not in TRAb, which were consistently absent or present at low titre in all patients in this group. In group 1b TRAb, G2sAb and EMAb further decreased or became negative during the follow-up period. In all patients, TRAb were positively correlated with both CAS and proptosis only at the start of the study; by contrast, a significant correlation between both G2sAb and EMAb and diplopia was observed in groups 1a and 1b at all the times during the study, except one/two months before the worsening of GO in group 1a. conclusions Our results indicate that TRAb, G2sAb and EMAb can be considered sensitive markers of Graves’ ophthalmopathy during the initial stages of ophthalmopathy, but that only G2sAb and EMAb seem to be good predictive markers of the outcome in patients after corticosteroid therapy. Thus, taking into account the cost/benefit ratio, a longitudinal evaluation of either EMAb or G2sAb could be useful in monitoring the intravenous glucocorticoid therapy in patients with severe and active ophthalmopathy to predict a possible worsening of Graves’ ophthalmopathy.

The role of antipituitary antibodies (APA) in autoimmune pituitary diseases still needs to be clarified. The aim of this study was 2-fold: first, to investigate the presence of APA in adults with idiopathic or acquired GH deficiency (GHD) and in adults with autoimmune endocrine diseases; and second, to evaluate whether in autoimmune endocrine patients APA titer is correlated to the pituitary function and particularly to GH secretion. We studied 12 adults with isolated and apparently idiopathic GHD who were treated with recombinant GH in childhood (group 1a), 14 patients with adult GHD secondary to surgery for pituitary and parasellar tumors (group 1b), and 180 patients with organ-specific autoimmune diseases (group 2). APA were evaluated by indirect immunofluorescence. In all APA-positive patients and in 20 APA-negative patients of group 2, GH secretion was investigated by testing its response to insulin-induced hypoglycemia (insulin tolerance test) and, when impaired, also to arginine. APA were found (at high titers) in 4 of 12 patients of group 1a (33.3%) but were absent in all patients in group 1b. APA were also found in 40 of 180 patients of group 2 (22.2%), 35 of them at low titers (group 2a) and 5 at high titers (group 2b). Twenty of the 140 autoimmune endocrine APA-negative patients studied (group 2c) and all APA-positive patients at low titers (group 2a) had normal pituitary function. Conversely, all APA-positive patients at high titers (groups 1a and 2b) had a severe isolated GHD. An inverse correlation between APA titers and GH peak serum response to insulin tolerance test in autoimmune endocrine patients was observed. Our results suggest that APA, when detected at high titers, may be considered a good diagnostic tool to highlight the possible occurrence of GHD in adults with autoimmune endocrine diseases. Moreover, they may indicate an autoimmune pituitary involvement in adults with apparently idiopathic GHD, suggesting that the prevalence of autoimmune GHD is much higher than that so far considered.

Summary Objective In order to investigate whether somatotrophs are the target of antipituitary antibodies (APA) in adult patients with growth hormone deficiency (GHD), we studied the sera of 37 APA positive patients. Patients Patients were grouped as follows: nine patients with APA at high titre (> 1 : 8) affected by apparently idiopathic GHD; four of them (group 1a) with isolated GHD diagnosed during childhood and five with GHD diagnosed during adulthood associated with autoimmune endocrine diseases (group 1b), and 28 patients with autoimmune endocrine diseases without pituitary impairment, previously found positive for APA at low titre (1 : 8, group 2). Measurements APA were evaluated by a four-layer double indirect immunofluorescence technique. Results In group 1a patients, APA immunostained exclusively GH-producing cells. In group 1b patients, APA were directed not only to GH- but also to other pituitary hormone-producing cells. In group 2 patients, APA were directed selectively to PRL-producing cells and rarely to some GH-producing cells. Conclusions In the present study, we demonstrated that GH-secreting cells are the target of the autoimmune reaction in autoimmune GHD and that the immunostaining of only the somatotrophs is typical of isolated GHD. In contrast, the finding of diffuse staining of APA indicates the need to search for other autoimmune diseases. Finally, the presence of APA at low titre directed against PRL-secreting cells in patients with autoimmune endocrine diseases in the absence of pituitary impairment, seems to be only a nonspecific marker of pituitary autoimmunity. A longitudinal study would be useful to clarify the relationship between the different pituitary cell involvement and the natural history of pituitary dysfunction in autoimmune hypophysitis.

Summary objective The aim of this study was twofold: first to investigate the presence of extraocular muscle antibodies (EMAb) in sera of Graves’ patients with ophthalmopathy characterized by clinical extraocular muscle (EM) involvement; second to evaluate in Graves’ patients without ophthalmopathy whether longitudinal variations of EMAb have a predictive role for the development of eye disease. patients We evaluated sera of Graves’ patients previously tested for G2sAb and FpAb; in particular, sera of 32 patients with moderate or severe ophthalmopathy and EM involvement: 18 with active disease (group 1), 14 with inactive disease (group 2). Moreover, we evaluated longitudinally sera of 19 Graves’ patients without ophthalmopathy previously tested for anti-GS2 (G2sAb) and antiflavoprotein antibodies (FpAb; group 3). During the 18-month follow-up, four of them did not develop ophthalmopathy (group 3a), and 15 did: seven developed eye disease (group 3b) with clinical EM involvement. In particular, moderate disease and clinical activity score (CAS) ≥ 4 in four of them, severe ophthalmopathy and CAS ≤ 1 in three were observed. The remaining eight patients showed moderate ophthalmopathy and CAS ≥ 4 without EM involvement (group 3c). measurements EMAb were evaluated in all samples by indirect immunofluorescence method. results EMAb were detected in 13 out of 18 patients (72·2%) in group 1 (titre 1/32–1/128) and in five out of 14 patients (35·7%) in group 2 (titre 1/2–1/8). As regards to group 3, at the start of the study EMAb were detected in 13 out of 19 patients (72%) at titres 1/2–1/8; during the follow-up they became or persisted negative in all patients in group 3a, while they increased at titres ranging from 1/64 to 1/128 in all patients in group 3b before the onset of ophthalmopathy. Finally, in group 3c, four patients showed a mild increase (1/8–1/16) of EMAb before the onset of eye disease, while four patients were negative during the entire follow-up. conclusions Our results indicate that EMAb are a good marker of ophthalmopathy with EM involvement and their titre is higher in patients with active than in those with inactive disease. Thus, even if our results must be confirmed on a larger cohort of patients, the increase of EMAb in patients with Graves’ disease could be considered as a risk factor for the development of ophthalmopathy with subclinical/clinical EM impairment. In this connection we propose the evaluation of EMAb, in Graves’ patients with subclinical and clinical ophthalmopathy, as a simple and sensitive marker of the EM inflammatory process.

Central diabetes insipidus (CDI) is a rare hypothalamus-pituitary disease due to the deficiency of arginine vasopressin (AVP) synthesis from the hypothalamus and/or secretion from the neurohypophysis. The etiology of CDI is unknown in over one third of cases, classified as idiopathic CDI. The aim of this study was 2-fold: 1) to evaluate the occurrence of circulating autoantibodies to AVP-secreting cells (AVPcAb), and 2) to correlate it to clinical (sex, age of disease onset, disease duration, and degree), immunological (clinical history of autoimmune diseases and presence of related organ-specific autoantibodies), and radiological features (neurohypophyseal bright spot, pituitary stalk thickening, and empty sella) in a large cohort of patients with apparently idiopathic CDI or CDI of known etiology. To this purpose, 150 patients with CDI were studied: 64 idiopathic, 6 familial, 12 associated to granulomatous diseases, and 68 secondary to cranial trauma, tumor, or surgery. AVPcAb were measured by an indirect immunofluorescence method. AVPcAb were found in 23.3% of CDI patients: 21 idiopathic (32.8%) and 14 nonidiopathic (16.3%; chi(2) = 13.1; P < 0.001). AVPcAb were independently associated with age less than 30 yr at disease onset (P = 0.001) in patients with idiopathic CDI and with history of autoimmune diseases (P = 0.006 and P = 0.02, respectively) and radiological evidence of pituitary stalk thickening (P = 0.02 and P = 0.003, respectively) in both idiopathic and nonidiopathic CDI. The likelihood of autoimmunity in one patient with apparently idiopathic CDI with age of disease onset less than 30 yr was 53%, it increased to 91% when history of autoimmune diseases was associated and to 99% when pituitary stalk thickening was further associated. In conclusion, autoimmunity is associated with one third of patients with apparently idiopathic CDI, which should therefore be classified as autoimmune CDI. Autoimmune CDI is highly likely in young patients with a clinical history of autoimmune diseases and radiological evidence of pituitary stalk thickening. Conversely, autoimmunity probably represents an epiphenomenon in patients with nonidiopathic CDI.

Objective: To determine the prevalence of steroid-cell autoantibodies, 3β-hydroxysteroid dehydrogenase (3β-HSD) antibodies, 17α-hydroxylase (17α-OH) antibodies, and P450 side-chain cleavage antibodies in premature ovarian failure. Design: Cross-sectional, observational study. Setting: Academic research hospitals. Patient(s): Eighty-one women with premature ovarian failure, 20 women with Addison disease not associated with premature ovarian failure, 42 women with type 1 diabetes mellitus, and 90 healthy women. Main Outcome Measure(s): Serum levels of steroid-cell autoantibodies, 17α-OH antibodies, P450 side-chain cleavage antibodies, and 3β-HSD antibodies. Result(s): Steroid-cell autoantibodies were present in none of 57 women with isolated premature ovarian failure or premature ovarian failure plus nonadrenal autoimmune disease and in 21 of 24 (87%) women with Addison disease-related premature ovarian failure. 17α-Hydroxylase antibodies and P450 side-chain cleavage antibodies were significantly more frequent in women positive for adrenal autoantibodies than in those negative for adrenal autoantibodies (50% vs. 0% and 71% vs. 2%, respectively). The presence of 17α-OH antibodies or P450 side-chain cleavage antibodies was strongly associated with presence of steroid-cell autoantibodies. Two of 24 (8%) women with Addison disease-related premature ovarian failure and 1 of 57 (2%) women with isolated premature ovarian failure or premature ovarian failure plus nonadrenal autoimmune disease were positive for 3β-HSD antibodies. None of 20 adult women with autoimmune Addison disease and none of 42 adult women with type 1 diabetes mellitus not associated with premature ovarian failure was positive for 3β-HSD antibodies. Conclusion(s): Markers of steroid-cell autoimmunity are found only rarely in idiopathic premature ovarian failure not associated with Addison disease. Most women with Addison disease-related premature ovarian failure were positive for steroid-cell autoantibodies, 17α-OH antibodies, or P450 side-chain cleavage antibodies. 3β-Hydroxysteroid dehydrogenase antibodies do not appear to be a major marker of steroid-cell autoimmunity.

Subclinical Addison's disease is characterized by the presence of adrenal autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21OHAb) with or without adrenal function failure. In our previous longitudinal study some patients with high titers of ACA and at stage 2 of subclinical adrenocortical failure showed disappearance of ACA with recovery of normal adrenocortical function after corticosteroid treatment for Graves' ophthalmopathy. To investigate whether corticosteroid-induced modification of the adrenal autoimmune markers can also involve 21OHAb and to evaluate whether the remission of subclinical adrenocortical failure can persist over a long period of time, we followed-up for 100 months the levels of 21OHAb and ACA as well as the metabolic markers of adrenal function in one patient with Graves' ophthalmopathy and at stage 2 of subclinical adrenocortical failure before and after corticosteroid therapy. A 34-yr-old woman with Graves' disease and active ophthalmopathy who was found to be positive for ACA and to have high PRA, low aldosterone levels, and normal basal ACTH and cortisol levels, but impaired cortisol response to ACTH was studied. The patient was treated with oral corticosteroid therapy for 6 months. After corticosteroid therapy, 21OHAb, initially positive, became negative in concomitance with the disappearance of ACA and the restoration of normal adrenal function. The disappearance of both 21OHAb and ACA and their prolonged absence during the follow-up suggest that corticosteroid treatment can induce long-term remission of subclinical adrenal insufficiency and prevent the onset of the clinical phase of the disease. Our pilot study may pave the way to future trials aimed at preventing the onset of the clinical signs of Addison's disease in ACA/21OHAb-positive patients.

Cytoplasmic autoantibodies to vasopressin-cells (AVPcAb) have been detected not only in patients with overt central diabetes insipidus (CDI), but also in patients with endocrine autoimmune diseases without CDI. This suggests that complete CDI can be preceded by a preclinical stage. Among 878 patients with endocrine autoimmune diseases without CDI, 9 patients found to be AVPcAb positive and 139 AVPcAb-negative controls were enrolled in this open prospective study. They were evaluated for AVPcAb and posterior pituitary function at least yearly for about 4 yr (range, 37‐ 48 months); during this span, magnetic resonance imaging (MRI) of posterior pituitary and stalk was performed only in the AVPcAb-positive patients. Five of the 9 AVPcAb-positive patients had normal posterior pituitary function at study entry. They were AVPcAb positive throughout the follow-up period. At later stages of the study, 3 of them developed partial CDI, and 1 developed complete CDI. The remaining 4 patients showed impaired response to the water deprivation test at study entry and were diagnosed as having partial CDI. Two of them agreed to receive desmopressin replacement for 1 yr. After this treatment, the patients became negative for AVPcAb and displayed normal posterior pituitary function until the end of the follow-up. Conversely, the 2 untreated patients with partial CDI remained AVPcAb positive. One of them developed overt CDI. None of the controls became AVPcAb positive or developed CDI. The normal hyperintense MRI signal of the posterior pituitary, present at study entry, persisted subsequently in all 9 AVPcAb-positive patients, including those developing overt CDI, only disappearing in the late phase of complete CDI. In asymptomatic subjects, the monitoring of AVPcAb, but not MRI, seems to be useful to predict a progression toward partial/overt CDI. Early desmopressin therapy in patients with partial CDI could interrupt or delay the autoimmune damage and the progression toward clinically overt CDI. (J Clin Endocrinol Metab 84: 3047‐3051, 1999)