Thyroid Diseases: Currò N

Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas G, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. · Department of Clinical Medicine, University of Insubria, Varese, Italy. · Thyroid. · Pubmed #18341379 No free full text.

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Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. · Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore IRCCS, Milan, Italy. · Eur J Endocrinol. · Pubmed #17218723 links to  free full text

Abstract: 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 IVGC (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 methimazole. 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.

Salvi M, Vannucchi G, Campi I, Currò N, Simonetta S, Covelli D, Pignataro L, Guastella C, Rossi S, Bonara P, Dazzi D, Ratiglia R, Beck-Peccoz P. · Department of Medical Sciences (Padiglione Granelli), University of Milan, Fondazione Ospedale Maggiore, IRCCS Via Sforza, Milan, Italy. · Clin Immunol. · Pubmed #19195932 No free full text.

Abstract: 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.

Salvi M, Vannucchi G, Campi I, Currò N, Beck-Peccoz P. · Department of Medical Sciences, Endocrinology Unit, University of Milan, 20100 Milan, Italy. · Ann Endocrinol (Paris). · Pubmed #18417090 No free full text.

Abstract: 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 (1000mg i.v. twice at two-week interval) and those treated with IVGC (500mg 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.

Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM, Anonymous00022. · Department of Clinical Medicine, University of Insubria, 21100 Varese, Italy. · Eur J Endocrinol. · Pubmed #18299459 links to  free full text

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