Rituximab (RTX) use in open-label series has been associated with very encouraging responses in patients with active and moderate-to-severe Graves’ orbitopathy (GO). Recently, randomized controlled trials of RTX have been performed in such patients to answer the question of clinical efficacy and the safety profile of this agent. That data, reported separately, focused on Clinical Activity Score (CAS) and indicated in one trial a strong benefit of RTX in comparison with IV glucocorticoids, whereas the other trial noted the absence of a benefit by comparison with placebo. The outcome was reanalyzed post hoc here, using EUGOGO criteria, and the results were not significantly different. The authors comment further on the differences between the two trials regarding populations treated, methodology, analysis of outcomes and the adverse effect profile of RTX. The populations treated appear different with younger patients, lower TRAb and shorter duration of disease prevalent in the Italian trial, all elements favoring a better response. Smoking, usually diminishing a response, was also more prevalent in some patients. The combined outcome proposed by EUGOGO revealed similar results with CAS regarding RTX efficacy; yet, it might be a more comprehensive outcome. The adverse events of concern relate mainly to the risk of DON, which seems to be increased by the use of RTX in a certain subset of patients. Based on available data, a multicenter trial using the EUGOGO-proposed outcomes might be the next best step to define the role of RTX in GO therapy.
Marius N Stan and Mario Salvi
Irene Campi, Guia Vannucchi and Mario Salvi
Management of Graves’ orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO.
In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20–30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials.
As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients’ personal needs.
Guia Vannucchi, Danila Covelli, Irene Campi, Daniele Origo, Nicola Currò, Valentina Cirello, Davide Dazzi, Paolo Beck-Peccoz and Mario Salvi
Glucocorticoids are the mainstay of immunosuppression for active moderate–severe Graves' orbitopathy (GO).
To analyze the response to therapy and the contribution of glucocorticoid receptor (GR) gene polymorphisms to the therapeutic outcome of intravenous glucocorticoids (IVGC) in active moderate–severe GO.
We have studied 58 patients treated with 7.5 g i.v. methylprednisolone (cumulative dose). Ophthalmological assessment was performed at baseline and at 6–8, 12–16, and 24–30 weeks after the first infusion. Three GR gene polymorphisms, ER22/23EK, N363S, and BCL1, which have been associated to variable sensitivity to steroids, were studied in 43/58 patients. The therapeutic outcomes defined as: i) reduction of the clinical activity score (CAS) ≥2 points or ii) reduction of proptosis ≥2 mm or iii) improvement of diplopia according to the Gorman score were also studied in relation to treatment schedule, age, gender, duration of thyroid or GO, smoking habits, and serum TSH-receptor autoantibodies levels.
In total, 70% of patients responded and had GO inactivation (CAS <4) as early as 6–8 weeks. At 12–16 weeks, the proportion of patients who became inactive increased by another 10% up to a total of 80%. ER22/23EK and N363S polymorphisms were present only in about 7%, while the Bcl1 variant was present in 30% of patients; no significant association of any of the GR polymorphisms with either the therapeutic response or the occurrence of side effects was observed.
Most patients with active GO respond to IVGC as early as 6–8 weeks of therapy and the analyzed GR polymorphisms do not influence the therapeutic effect of steroids. Questions arise about the need of continuing therapy up to 12 weeks in nonresponders. We suggest that these patients may be switched to other treatments alone or in combination with steroids.
Elio Roti, Luigi Bartalena, Roberta Minelli, Mario Salvi, Eliana Gardini, Antonio Pistolesi, Enio Martino and Lewis E Braverman
Roti E, Bartalena L, Minelli R, Salvi M, Gardini E, Pistolesi A, Martino E, Braverman LE. Circadian thyrotropin variations are preserved in normal pregnant women. Eur J Endocrinol 1995;133:71–4. ISSN 0804–4643
Serum thyrotropin (TSH) concentration circadian rhythm is abolished in many endocrine and nonendocrine diseases. In the present study we have measured serum TSH concentration over 24 h every 2 h in second and third trimester pregnant women. During the 24-h period, serum free thyroxine and free triiodothyronine concentrations did not change significantly. In contrast, serum TSH concentrations demonstrated significant circadian variations both in the second and third trimester pregnant women (p<0.02 and p <0.005, respectively). In summary, second and third trimester pregnancy is associated with a normal circadian TSH rhythm.
Elio Roti, Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, University of Parma, via Gramsci 14, 1-43100 Parma, Italy
Elio Roti, Giuseppe Robuschi, Alessandro Alboni, Rossella Emanuele, Lorenzo d' Amato, Eliana Gardini, Mario Salvi, Elisabetta Dall' Aglio, Angelo Gnudi and Lewis E. Braverman
Abstract. Somatostatin (SRIF) was infused (500 μg over 30 min) into 68 pregnant women during labour. As a control, saline was infused into 26 pregnant women. Maternal blood was obtained prior to the infusion and at delivery and cord blood was obtained at delivery. The subjects were divided into 4 groups based upon the interval of time from the termination of SRIF infusion and delivery. There was a marked decrease in cord blood thyrotrophin (TSH) from 0 to 180 min and in cord blood growth hormone (GH) from 0 to 120 min following SRIF infusion. SRIF infusion did not affect cord blood iodothyronine and thyroglobulin concentrations. SRIF administration induced a small but significant (P < 0.05) decrease in serum GH concentration but had no other effect on maternal hormone values. These studies strongly suggest that SRIF crosses the human placenta and transiently suppresses foetal anterior pituitary TSH and GH secretion.
Mario Salvi, Guia Vannucchi, Irene Campi, Stefania Rossi, Paola Bonara, Francesco Sbrozzi, Claudio Guastella, Sabrina Avignone, Giacinta Pirola, Roberto Ratiglia and Paolo Beck-Peccoz
One patient with Graves’ hyperthyroidism and ophthalmopathy in its active phase and unresponsive to steroid, was treated with the anti-CD20 monoclonal antibody, rituximab (RTX), as part of an open study. The effect of RTX in the thyroid and the orbital tissues was studied. The ophthalmopathy responded to RTX therapy by ameliorating the eye signs with a decrease in the clinical activity score from 5 to 2 in 3 months, while the patient had peripheral B-cell depletion. Hyperthyroidism did not improve during the 6 months of B-cell depletion and serum TSH-receptor antibodies (TRAb) levels did not significantly change after RTX therapy. Therefore, the patient underwent total thyroidectomy and few B-cells were found in the thyroid tissue specimens. While the patient eye disease remained stable (clinical activity score = 2), we performed corrective orbital decompression and we found absence of lymphocytes in the orbital tissue specimens. We believe that RTX treatment in Graves’ disease may cause amelioration of ophthalmopathy by depleting total lymphocytes population in the orbit. The persistence of Graves’ hyperthyroidism suggests that a single cycle of RTX does not result in complete lymphocyte depletion in thyroid tissue and thus no decline in serum TRAb was observed.
Mario Salvi, Flavia De Chiara, Eliana Gardini, Roberta Minelli, Lina Bianconi, Alberto Alinovi, Roberto Ricci, Fabrizio Neri, Claudio Tosi and Elio Roti
Salvi M, De Chiara F, Gardini E, Minelli R, Bianconi L, Alinovi A, Ricci R, Neri F, Tosi C, Roti E. Echographic diagnosis of pretibial myxedema in patients with autoimmune thyroid disease. Eur J Endocrinol 1994;131:113–19. ISSN 0804–4643
In the present study we have evaluated the use of pretibial ultrasound for the diagnosis of pretibial myxedema (PTM). We studied 76 patients, 58 with Graves' disease, 13 with Hashimoto's thyroiditis and five with idiopathic hypothyroidism. Thirty-two normal subjects were also studied as controls. Sixty-four patients had associated ophthalmopathy. The ultrasound scanner was equipped with 10-and 13-MHz probes. Punch biopsies were carried out in 11 patients and tissue sections examined on a light microscope. On clinical examination 21 patients (28%) had suspected PTM. By ultrasound, we measured the thickness of dermis and subcutaneous tissue (Dl) and that including only deeper dermis (D2) in normal subjects to define the echographic parameters of normal pretibial skin. We then found increased skin thickness in 25 patients (33%), with mean Dl and D2 values significantly higher than those measured in controls (p < 0.00001). The echographic study was positive in 20 patients with ophthalmopathy (31%). Ultrasound showed increased skin thickness in 16 of 21 patients (76%) with clinically suspected PTM. Histopathological findings confirmed the presence of PTM in all the patients who underwent pretibial skin biopsy. We believe that the measurement of pretibial skin thickness by ultrasound may be useful for revealing the presence of PTM.
Mario Salvi, Cattedra di Endocrinologia, Università di Parma, Via Gramsci 14-43100 Parma, Italy
Mario Salvi, Guia Vannucchi, Irene Campi, Nicola Currò, Davide Dazzi, Simona Simonetta, Paola Bonara, Stefania Rossi, Clara Sina, Claudio Guastella, Roberto Ratiglia and Paolo Beck-Peccoz
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.
Elio Roti, Giuseppe Robuschi, Alessandro Alboni, Lorenzo d'Amato, Mara Montermini, Eliana Gardini, Mario Salvi, Elisabetta Borciani, Elisabetta Dall'Aglio, Sandra Bisi, Giuseppe Zammarchi, Remo Lasagni, Angelo Gnudi and Lewis E. Braverman
Abstract. In the adult, dopamine inhibits prolactin (Prl) secretion and less so thyrotropin (TSH) release. Little information is available concerning the role of dopaminergic stimuli in the regulation of TSH and Prl secretion in the term human foetus. The dopamine agonist, bromocriptine (5 mg), or placebo were randomly administered orally to 120 pregnant women during labour. Maternal and foetal cord blood was obtained at parturition and analyzed for Prl, TSH, T4, T3 and rT3 concentrations. Since the time of parturition is unpredictable, maternal and cord blood hormone values were grouped at intervals of time from the time of bromocriptine or placebo administration to delivery. Hormone values were compared between the bromocriptine and placebo groups by two-way analysis of variance (ANOVA). Bromocriptine markedly inhibited maternal serum Prl conentrations compared to values in the placebo treated women (P < 0.001) and this decrease was more marked as the time interval between bromocriptine administration and delivery increased (P < 0.001, regression analysis). Cord blood Prl was also significantly lower in newborns whose mothers received bromocriptine (P < 0.001). Bromocriptine significantly inhibited maternal serum TSH concentrations as compared to values in women treated with placebo (P < 0.006). In contrast, bromocriptine administration did not affect cord blood TSH concentrations. These findings suggest that bromocriptine crosses the term human placenta and suppresses foetal Prl secretion. In contrast to the small inhibition of TSH secretion in pregnant women, bromocriptine does not affect foetal TSH secretion suggesting that regulation of TSH secretion in the term foetus may not be under dopaminergic control.
Wilmar Wiersinga, Miloš Žarković, Luigi Bartalena, Simone Donati, Petros Perros, Onyebuchi Okosieme, Daniel Morris, Nicole Fichter, Jurg Lareida, Georg von Arx, Chantal Daumerie, Maria-Christina Burlacu, George Kahaly, Susanne Pitz, Biljana Beleslin, Jasmina Ćirić, Goksun Ayvaz, Onur Konuk, Füsun Balos̜ Törüner, Mario Salvi, Danila Covelli, Nicola Curro, Laszlo Hegedüs, Thomas Brix and EUGOGO (European Group on Graves’ Orbitopathy)
To construct a predictive score for the development or progression of Graves’ orbitopathy (GO) in Graves’ hyperthyroidism (GH).
Prospective observational study in patients with newly diagnosed GH, treated with antithyroid drugs (ATD) for 18 months at ten participating centers from EUGOGO in 8 European countries.
348 patients were included with untreated GH but without obvious GO. Mixed effects logistic regression was used to determine the best predictors. A predictive score (called PREDIGO) was constructed.
GO occurred in 15% (mild in 13% and moderate to severe in 2%), predominantly at 6–12 months after start of ATD. Independent baseline determinants for the development of GO were clinical activity score (assigned 5 points if score > 0), TSH-binding inhibitory immunoglobulins (2 points if TBII 2–10 U/L, 5 points if TBII > 10 U/L), duration of hyperthyroid symptoms (1 point if 1–4 months, 3 points if >4 months) and smoking (2 points if current smoker). Based on the odds ratio of each of these four determinants, a quantitative predictive score (called PREDIGO) was constructed ranging from 0 to 15 with higher scores denoting higher risk; positive and negative predictive values were 0.28 (95% CI 0.20–0.37) and 0.91 (95% CI 0.87–0.94) respectively.
In patients without GO at diagnosis, 15% will develop GO (13% mild, 2% moderate to severe) during subsequent treatment with ATD for 18 months. A predictive score called PREDIGO composed of four baseline determinants was better in predicting those patients who will not develop obvious GO than who will.