Corneal involvement in Graves' orbitopathy : an in vivo confocal study

PURPOSE: To study the clinical involvement of the ocular surface and the in vivo morphology of corneal cells and nerves, in patients affected by active and inactive Graves' orbitopathy (GO). METHODS: The study included 26 consecutive GO patients and 20 age- and sex-matched healthy control subjects. GO was diagnosed on the basis of the criteria of the European Group on Graves' Orbitopathy, and disease activity was evaluated by the Clinical Activity Score (CAS). Each participant underwent a full eye examination, including an evaluation of symptoms (Ocular Surface Disease Index score), tear break-up time, fluorescein and lissamine green staining, corneal apex sensitivity, and Schirmer's test. The corneal apex was examined by means of confocal microscopy to investigate the number and morphology of epithelial and stromal corneal cells and subbasal nerves. RESULTS: Eleven (43%) of the 26 patients had active GO. One-way ANOVA with the least-significant difference (LSD) post hoc test revealed statistically significant differences between patients and controls in all the evaluated parameters, except corneal sensitivity and nerve reflectivity. Among the GO patients, the only significant difference observed in active compared with inactive disease was in the number of hyperreflective (activated) keratocytes (P<0.001, LSD). Corneal sensitivity correlated inversely with proptosis (P<0.001, Spearman's test). CONCLUSIONS: GO patients show clinical and confocal corneal alterations and signs and symptoms partially related to dry eye disease. The ocular surface inflammation in GO seems to be due to both the dry eye and the autoimmune orbitopathy

New immunomodulators in the treatment of Graves' ophthalmopathy

Steroids have been used in the therapy of the moderate to severe forms of Graves' ophthalmopathy (GO) and other autoimmune diseases as they act only as general immunosuppressants. Previous work has shown that blocking the CD-20 receptor on B lymphocytes has significantly affected the clinical course of GO, by rapidly reducing inflammation and the degree of proptosis. We have studied nine patients with Graves' disease, of whom seven had active GO and two, with newly diagnosed hyperthyroidism, only mild lid signs. We also studied a group of 20 consecutive patients, treated with intravenous glucocorticoids (IVGC) according to a standard protocol. Patients treated with RTX (1000 mg i.v. twice at two-week interval) and those treated with IVGC (500 mg i.v. for 16 weeks) were studied monthly up to 12 months after the first drug infusion. By ophthalmological examination, GO was assessed by the clinical activity score (CAS) and by the NOSPECS score. Thyroid function and lymphocyte count were measured by standardized methods. RTX was well-tolerated and only minor side-effects were reported in 30% of patients during the first infusion. All patients attained peripheral B-cell depletion with the first RTX infusion. All but one patients showed both CD20+ cells and CD19+ cells depletion, while one had persistent 3-5% CD19+ cells in the periphery, mostly CD19 + 5+. Thyroid function was not affected by RTX therapy. Titers of antithyroglobulin (TgAb), antithyroperoxidase and anti-TSH receptor antibodies (TRAb) did not change significantly (P = NS) and did not correlate to CD20+ depletion (P = NS). CAS values decreased significantly (P < 0.0001). Proptosis decreased significantly after RTX in both patients with active GO (ANOVA; P < 0.0001) and in those with Graves' hyperthyroidism and lid signs (ANOVA; P < 0.003). The degree of inflammation (NOSPECS class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). In patients treated with IVGC, mean CAS value decreased significantly less than in those treated with RTX (P < 0.05). Adverse effects were more frequent after IVGC (45% of patients). Seventy-five percent of patients responded to IVGC and 10% showed relapse of active GO six to eight weeks after withdrawal. The results of this study on RTX in GO suggest that the drug is effective in modifying the disease course and that the improvement of the clinical activity of GO after RTX was more significant than after IVGC. We did not observe relapse of active GO, even after B-cell return in peripheral blood. This might be related to the persistence of a significant degree of B-cell depletion after RTX observed in the peripheral blood as late as two years of follow-up. RTX therapy was also effective in improving proptosis and soft tissue inflammation. The mechanism by which RTX affects GO is unknown. It may act as a true immunosuppressor by switching off reactions inducing the active phase of TAO, perhaps by influencing the cytokine production in the orbit or by inducing depletion of antigen presenting B-cells

Graves' orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis

Context: The reactivation of Graves' orbitopathy (GO) after radioiodine (RAI) for Graves' disease (GD) is a known effect, and its clinical relevance is controversial. Prevention of RAI-induced GO activation is possible in at-risk patients with oral glucocorticoids (OGC). Objectives: The aim of the study was to analyze the effects of RAI on GO with or without prophylactic steroids based on known risk factors and to compare the effectiveness of prophylaxis with iv glucocorticoids (IVGC) and OGC. Design: We conducted a retrospective study in which patients were assessed before and 1-12 months after RAI. Patients and Setting: A total of 113 patients were included in the study; 83 underwent RAI without prophylactic steroids for the absence of risk of activation, and 30 were treated with either OGC (n = 21) or IVGC (n = 9). Main Outcome Measures: We analyzed the prevalence of GO activation with or without steroid prophylaxis and the difference in the prevalence of GO activation after OGC or IVGC. Results: GO activation was observed in 7.2% of patients without and 33.3% of patients with steroid prophylaxis (P < 0.0001), for an overall prevalence of 14.6%. GO activation occurred in 47.6% of patients treated with OGC but in none of the nine patients treated with IVGC (P < 0.0001). Disease activation was more prevalent in males (P < 0.02) and in older patients (P < 0.04) with a shorter duration of GD (P < 0.01) and time from GO onset (P < 0.01). Conclusions: GO may occur after RAI in approximately 15% of patients also in the absence of signs of active GO. Prophylactic OGC did not prevent GO activation in a large proportion of patients, compared to IVGC. Copyrigh

New records of leatherback sea turtle, Dermochelys coriacea (Vandelli, 1761) (Testudines: Dermochelyidae) in the Strait of Sicily

We report three new records of leatherback sea turtle, Dermochelys coriacea (Vandelli, 1761) recovered in February 2011 and in spring-summer 2016 in the Strait of Sicily. The individuals were handed over dead to the IZS of Palermo for necropsy. The first specimen measured 139 and 91 cm of CCL and CCW respectively and was found beached and alive but died a few hours later for septicemia. The second measured 110 cm of CCL and 83 cm of CCW and showed a deep wound on its head probably due to contact with a boat propeller. The third individual measured 134 cm of CCL and 96 cm of CCW and had plastic bags, a piece of fishing net and debris of various nature in the stomach. For the second individual it was not possible to determine the sex because of the advanced state of decomposition, while the other two specimens were females and showed a typical picture of an immature ovary. These new records increase the knowledge on the presence of this species in the Mediterranean Sea and in particular along the Sicilian coast and are also useful for preparing strategic conservation plans

The 894G > T (Glu298Asp) variant in the endothelial NOS gene and MTHFR polymorphisms influence homocysteine levels in patients with cognitive decline

The presence and severity of cerebrovascular pathological findings have been shown to increase the risk and stage of cognitive decline observed in Alzheimer's disease and vascular dementia. Thus, the modification of vascular risk factors seems useful to reduce the risk of dementia regardless of type. Hyperhomocysteinemia has long been known as a major independent risk factor for vascular dysfunction. In this study, we evaluated the relationships between plasma homocysteine levels and genetic risk factors for hyperhomocysteinemia, i.e., the presence of gene variants for methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase (eNOS) in patients with cognitive impairment. Genotyping for MTHFR C677T and eNOS 894G&nbsp;&gt;&nbsp;T polymorphisms was carried out in 69 patients with probable diagnosis of AD and anamnestic mild cognitive impairment, matched for age and gender with 69 healthy volunteers. Patients with MTHFR TT677 genotype showed higher plasma Hcy levels than controls, even after adjustment for folate levels (P&nbsp;&lt;&nbsp;0.05). Moreover, Hcy plasma levels were higher in cases than controls for any given eNOS genotype. In particular, the presence of eNOS TT894 genotype in patients with cognitive decline resulted significantly associated with increased plasma Hcy levels when compared with controls having the same genotype or patients having other eNOS genotypes (P&nbsp;=&nbsp;0.02). These data suggest that both MTHFR C677T and eNOS G894T variants should be regarded as genetic risk factors for hyperhomocysteinemia in patients with cognitive decline

Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab : an open study

Introduction: Hyperthyroid Graves' disease (GD) is a B-cell-mediated condition caused by TSH receptor antibodies (TRAb), which decline when GD remits. Anti-CD20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophthalmopathy (TAO). Methods: Nine patients with GD, (seven with active TAO, two with mild lid signs) were studied. The trial was only approved as an open pilot study; thus we compared the effect of RTX therapy to that of i.v. glucocorticoids (IVGC) in 20 consecutive patients. Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with lVGC (500 mg i.v. for 16 weeks). TAO was assessed by the clinical activity score (CAS) and severity was classified using NOSPECS (No signs or symptoms; Only signs (lid): Soft tissue involvement; Proptosis, Extraocular muscle involvement; Corneal involvement; Sight loss). Thyroid function and lymphocyte count were measured by standardized methods. Results: All patients attained peripheral B-cell depletion with the first RTX infusion. Minor side effects were reported in three patients. Thyroid function was not affected by RTX therapy and hyperthyroid patients required therapy with methimazoic. After RTX, the changes in the levels of thyroglobulin antibodies, thyroperoxidase antibodies and TRAb were neither significant nor correlated with CD20+ depletion (P = NS). CAS values before RTX were 4.7 +/- 0.5 and decreased to 1.8 +/- 0.8 at the end of follow-up (P < 0.0001) and more significantly compared with IVGC (P < 0.05). Proptosis decreased significantly after RTX both in patients with active TAO (ANOVA; P < 0.0001) and those with lid signs (ANOVA; P < 0.003). The degree of inflammation (class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). Relapse of active TAO was not observed in patients treated with RTX but occurred in 10%, of those treated with IVGC, who also experienced adverse effects more frequently (45 vs 33% of patients). Conclusions: RTX positively affects the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TRAb. If our findings are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO

Serum BAFF concentrations in patients with Graves' disease and orbitopathy before and after immunosuppressive therapy

B cells are known to play a key role in the pathogenesis of autoimmune disease. B lymphocyte activating factor (BAFF), a member of TNF family, promotes autoantibody production by increasing B cell survival and proliferation. Serum BAFF concentrations have been found to be increased in systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrom

Rituximab treatment in a patient with severe thyroid-associated ophthalmopathy : effects on orbital lymphocytic infiltrates

Rituximab (RTX) has been shown in previous work to improve thyroid-associated ophthalmopathy (TAO), but very little data is available on the effects of RTX in the target tissues. We studied the effects of RTX on peripheral lymphocytes and on the intra-orbital infiltrates in one patient with severe TAO who was treated with two cycles of therapy. Intra-orbital tissues derived at decompression from 3 patients with moderate-severe and 1 with severe TAO, treated with standard immunosuppression, were studied as controls. Peripheral blood lymphocytes were analyzed throughout the study period, while intra-orbital tissue lymphocytes at decompression. In the patient treated with RTX visual field and acuity improved in response to peripheral CD 20+ cell depletion, although there was a proportion of persisting CD 19+ cells. After RTX re-treatment the patient's optic nerve function improved only transiently. The number of CD 20+ cells was lower in orbital tissues (0-1%) than in the peripheral blood (3%). A greater percentage of CD 19+ was observed in the orbits compared to the periphery, most of which were CD 19+5+ (80%). By immunohistochemistry, orbital tissues from all control patients showed CD 20+ and CD 3+ cells, independently of the duration of TAO and of the treatment with either steroids or radiotherapy. This is the first report on the therapeutic effect of RTX in active, severe TAO associated to the depletion of intra-orbital CD 20+ lymphocytes. After RTX, CD 19+5+ lymphocytes were shown to be 2-3 times more prevalent in the orbital infiltrates, compared to CD 20+ cells. Persistence of autoreactive cells is believed to be related to TAO relapse