Alemtuzumab-induced thyroid eye disease successfully treated with a single low dose of rituximab.

Introduction: Secondary thyroid autoimmunity, especially Graves' disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment. Case presentation: A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy. Conclusion: RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.

Increased Risk of Thyroid Eye Disease Following Covid-19 Vaccination.

CONTEXT: SARS-CoV-2 infection and Covid-19 vaccines have been associated with thyroid disorders. OBJECTIVE: We analyzed the risk of thyroid eye disease (TED) following Covid-19 vaccination. This was a self-controlled case series study at a tertiary referral center for TED. A total of 98 consecutive patients with newly developed (n = 92) or reactivated (n = 6) TED occurring between January 1, 2021, and August 31, 2022, were included. TED was assessed in patients undergoing Covid-19 vaccination. Person-days were defined as exposed if TED occurred 1 to 28 days after vaccination, and unexposed if occurring outside this time window. Conditional Poisson regression models were fitted to calculate incidence rate ratio (IRR) and 95% CI of exposed vs unexposed. Sensitivity analyses were conducted considering different exposed periods, and effect modification by potential TED risk factors. RESULTS: Covid-19 vaccines were administered in 81 people, 25 (31%) of whom developed TED in exposed and 56 (69%) in unexposed periods. The IRR for TED was 3.24 (95% CI 2.01-5.20) and 4.70 (95% CI 2.39-9.23) in patients below 50 years of age. Sex, smoking, and radioiodine treatment did not modify the association between TED and vaccination. TED risk was unrelated to the number of vaccine doses, and progressively decreased over time following vaccination (P trend = .03). CONCLUSION: The risk of TED was significantly increased after Covid-19 vaccination, especially in people below 50 years of age. Possible mechanisms include spike protein interaction with the angiotensin-converting enzyme II receptor, cross-reactivity with thyroid self-proteins, and immune reactions induced by adjuvants. We suggest monitoring of individuals undergoing Covid-19 vaccination, especially if young and at risk for autoimmunity.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Clinical and Visual Outcomes of Dysthyroid Optic Neuropathy After Surgical Orbital Decompression.

Background: Current guidelines suggest high-dose steroids as first-line treatment for dysthyroid optic neuropathy (DON). When steroids fail, decompressive surgery is mandatory. Methods: We conducted a single-center, retrospective cohort study in a tertiary care combined Thyroid-Eye clinic in Milan, Italy. We studied 88 orbits of 56 patients that were submitted to surgical orbital decompression to treat DON from 2005 to 2020. Of these, 33 orbits (37.5%) underwent surgery as first-line treatment for DON whereas the other 55 (62.5%) were decompressed after being unresponsive to very high-dose steroids. Previous orbital surgery, concurrent neurological or ophthalmologic diseases, or incomplete follow-up were considered as exclusion criteria from this study. Surgery was considered successful if no further decompression was needed to preserve vision. Pinhole best corrected visual acuity (p-BCVA), color sensitivity, automated visual field, pupil reflexes, optic disk and fundus appearance, exophtalmometry, and ocular motility were studied before and after surgery (1 week, 1, 3, 6, and 12 months). Activity of Graves' Orbitopathy (GO) was graded using a clinical activity score (CAS). Results: Surgery was successful in 77 orbits (87.5%). The remaining 11 orbits (12.5%) needed further surgery to treat DON definitively. All parameters of visual function improved significantly at follow-up and GO inactivated (CAS <3) within 1 month. At 3 months, all 77 responding orbits had p-BCVA >0.63 whereas all of the 11 non-responding orbits had p-BCVA ≤0.63. Visual field parameters and color sensitivity were not associated with response to surgery. High-dose steroid treatment before surgery was associated with a better response rate (96% vs. 73%; p = 0.004). Balanced decompression was associated with a higher response rate compared with medial wall decompression (96% vs. 80%; p = 0.04). A significant inverse correlation was observed between final p-BCVA and the patient's age (r = -0.42; p = 0.0003). Conclusions: Surgical decompression was found to be a very effective treatment for DON. In this study, all clinical parameters improved after surgery and further intervention was rarely needed.

Efficacy Profile and Safety of Very Low-Dose Rituximab in Patients with Graves' Orbitopathy.

Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second-line therapy in patients unresponsive to intravenous steroids. We conducted an open-label prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose. Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone and eight with newly diagnosed GO, were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long-term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events. Results: Mean baseline CAS was 4.56 ± 0.96 and decreased to 1.25 ± 1.14 at 24 weeks (p = 0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome. Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time, and are extremely cost effective, compared with higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid ON.

Quantification of Global Ocular Motility Impairment in Graves' Orbitopathy by Measuring Eye Muscle Ductions.

Background: The overall changes of ocular motility in Graves' orbitopathy (GO) are not easily quantifiable with the methods currently available, especially in clinical studies. The aim of the present study was to calculate parameters that quantify the changes of ocular motility in GO in relation to the Gorman score for diplopia. Methods: We studied 100 GO patients (Group 1) and 100 controls (Group 2). We also included 30 patients treated with intravenous methylprednisolone (iv-MP), assessed at baseline and after 12 and 24 weeks (Group 3), and 66 patients submitted to squint surgery, assessed at baseline and after 12 weeks (Group 4). Ocular ductions were measured in four gaze directions by a perimeter arc and were used to calculate a total motility score (TMS) as the sum of ductions in each direction; a biocular TMS (b-TMS) as the sum of the TMS of two eyes; and an asymmetry ratio (AR) as the sum of the differences of the corresponding ductions between the two fellow eyes divided by the mean difference found in controls. Quality of life was accessed by a specific questionnaire (Graves' orbitopathy quality of life [GO-QoL] questionnaire). Results: TMS and b-TMS were lower, while AR was higher, in Group 1 compared with controls (p < 0.001). In Group 1, TMS and b-TMS were inversely correlated with the Gorman score (p < 0.001) and AR was higher in patients with constant diplopia compared with the others (p < 0.001). In Group 3, TMS and b-TMS increased after treatment in responders to iv-MP (p < 0.001). In Group 4, TMS and b-TMS improved in all patients after surgery (p < 0.01), while AR and GO-QoL score improved only in those without residual constant diplopia (p < 0.001). Conclusion: We describe a quantitative method to assess eye motility dysfunction in any stage of GO to be used as an outcome measure in clinical studies.

Therapy With Different Dose Regimens of Rituximab in Patients With Active Moderate-To-Severe Graves' Orbitopathy.

Background: Immunosuppressive therapy of Graves' orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC. Methods: of 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety. Results: Baseline CAS decreased significantly in all groups (P<0.0001), independently of GO duration or whether patients had newly occurring or relapsing GO after IVGC. Proptosis did not significantly change. There was an inverse correlation between the Gorman score for diplopia and RTX dose (P<0.01). The appearance score of the GO-QoL improved in Group 1 (P=0.015), and the visual function score, in Group 2 (P=0.04). A reduction of serum TRAb was observed in Group 1 (P=0.002) and Group 2 (P<0.0002), but not in Group 3. CD19+ cell decreased in all groups (P<0.01), independently of the dose. Conclusions: We studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients' quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.

Prevention of Orbitopathy by Oral or Intravenous Steroid Prophylaxis in Short Duration Graves' Disease Patients Undergoing Radioiodine Ablation: A Prospective Randomized Control Trial Study.

Background: Radioiodine (RAI) is a known risk factor for activation or de novo occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GCs) in patients with pre-existing GO. We have previously shown that Graves' disease duration (GDd) <5 years is a risk factor for RAI-induced GO. We studied the effect of prophylaxis with either oral GCs (OGCs) or intravenous GCs (IVGCs) on GO activation in patients with GDd. Methods: In total, 99 hyperthyroid patients without GO or with pre-existing inactive GO with GDd <5 years were randomized to receive IVGCs (N = 49) or OGCs (N = 50) before RAI; 22 patients with GDd >5 did not receive steroids and were studied as controls. All patients underwent ophthalmological assessment before and 45, 90, 180 days and for a 5-year follow-up after RAI. Serum thyrotropin (TSH) receptor antibodies (TRAbs), thyroid hormones, and thyroid volume (TV) were also measured in response to RAI therapy and steroid prophylaxis. Results: No patient on prophylaxis developed GO after RAI. One woman of the control group, without steroid prophylaxis, and who had a marked elevation of her TSH, showed transient reactivation of GO, which spontaneously improved after restoring euthyroidism. On follow-up at 12 and 20 months after RAI, two patients developed overt optic neuropathy. A smaller TV was associated with a higher prevalence of RAI-induced hypothyroidism. Serum TRAbs increased significantly after RAI (p < 0.0001) but less in patients receiving steroids than in those without prophylaxis at 45 days (p < 0.01). Conclusions: The risk of RAI-induced GO can be prevented in all patients with GDd <5 years by steroids. Such treatment may not be necessary in patients with GDd >5 years. The blunting of TRAb elevation after RAI may be related to the prophylactic effect of steroids.

Predictive score for the development or progression of Graves' orbitopathy in patients with newly diagnosed Graves' hyperthyroidism.

OBJECTIVE: To construct a predictive score for the development or progression of Graves' orbitopathy (GO) in Graves' hyperthyroidism (GH). DESIGN: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Mycophenolate plus methylprednisolone versus methylprednisolone alone in active, moderate-to-severe Graves' orbitopathy (MINGO): a randomised, observer-masked, multicentre trial.

BACKGROUND: European guidelines recommend intravenous methylprednisolone as first-line treatment for active and severe Graves' orbitopathy; however, it is common for patients to have no response or have relapse after discontinuation of treatment. We aimed to compare the efficacy and safety of add-on mycophenolate to methylprednisolone in comparison with methylprednisolone alone in patients with moderate-to-severe Graves' orbitopathy. METHODS: MINGO was an observer-masked, multicentre, block-randomised, centre-stratified trial done in two centres in Germany and two in Italy. Patients with active moderate-to-severe Graves' orbitopathy were randomly assigned to receive intravenous methylprednisolone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) either alone or with mycophenolate (one 360 mg tablet twice per day for 24 weeks). The prespecified primary endpoints were rate of response (reduction of at least two parameters of a composite ophthalmic index [eyelid swelling, clinical activity score, proptosis, lid width, diplopia, and eye muscle motility] without deterioration in any other parameter) at 12 weeks and rate of relapse (a worsening of symptoms that occurred after a response) at 24 and 36 weeks. Rates of response at week 24 and sustained response at week 36 were added as post-hoc outcomes. Prespecified primary outcomes and post-hoc outcomes were assessed in the modified intention-to-treat population (defined as all patients assigned to treatment who received at least one infusion of methylprednisolone, when outcome data were available), and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EUDRACT number 2008-002123-93. FINDINGS: 164 patients were enrolled and randomised between Nov 29, 2009, and July 31, 2015. 81 were randomly assigned to receive methylprednisolone alone and 83 to receive methylprednisolone with mycophenolate. In the intention-to-treat population at 12 weeks, responses were observed in 36 (49%) of 73 patients in the monotherapy group and 48 (63%) of 76 patients in the combination group, giving an odds ratio (OR) of 1·76 (95% CI 0·92-3·39, p=0·089). At week 24, 38 (53%) of 72 patients remaining in the monotherapy group and 53 (71%) of 75 patients remaining in the combination therapy group had responded to treatment (2·16, 1·09-4·25, p=0·026). At week 24, relapse occurred in four (11%) of 38 patients in the monotherapy group and four (8%) of 53 patients in the combination group (OR 0·71, 0·17-3·03, p=0·72). At week 36, relapse occurred in an additional three (8%) patients in the monotherapy group and two (4%) patients in the combination group (0·65, 0·12-3·44, p=0·61). At week 36, 31 (46%) of 68 patients in the monotherapy group and 49 (67%) of 73 patients in the combination group had a sustained response (OR 2·44, 1·23-4·82, p=0·011). 23 patients had 24 serious adverse events, with 11 events in ten patients in the combination group and 13 events in 13 patients in the monotherapy group. Mild and moderate (grade 1-2) drug-related adverse events occurred in 16 (20%) of 81 patients receiving monotherapy and 21 (25%) of 83 patients receiving combination therapy (p=0·48). INTERPRETATION: Although no significant difference was seen in the rate of response at 12 weeks or rate of relapse at 24 and 36 weeks, post-hoc analysis suggested that addition of mycophenolate to treatment with methylprednisolone improved rate of response to therapy by 24 weeks in patients with active and moderate-to-severe Graves' orbitopathy. FUNDING: Novartis, Germany.

B Cell Activating Factor (BAFF) and BAFF Receptor Expression in Autoimmune and Nonautoimmune Thyroid Diseases.

BACKGROUND: The B cell activating factor (BAFF) is a member of the tumor necrosis factor family, which controls the survival/proliferation of B cells and is involved in the pathogenesis of a number of autoimmune diseases. The objective of the present study was to investigate the expression of BAFF and BAFF receptor (BAFF-R) in the thyroid tissue of patients affected with autoimmune thyroid disorders (AITD) or multinodular goiter (MNG) compared with those with normal thyroids. METHODS: Immunohistochemistry was performed using a panel of antibodies against BAFF, BAFF-R, CD3, CD4, CD8, CD20, CD34, CD79a, CD1a, CD68, and CD163 on the thyroid sections of 27 patients affected with Graves' disease (GD), 23 with Hashimoto's thyroiditis (HT), 16 with nontoxic nodular goiter (NTG), and 15 with toxic nodular goiter (TG), submitted to total thyroidectomy between 2000 and 2011. RESULTS: The overall BAFF-R expression in thyrocytes was weak and not different in AITD and MNG. Conversely, a stronger BAFF expression was observed in MNG compared with AITD. BAFF and BAFF-R expression in the infiltrating lymphocytes was higher in AITD compared with MNG. Interestingly, in lymphocytes of follicular-like structures observed in HT, BAFF and BAFF-R were localized in the germinal center or in the mantle, respectively. CONCLUSIONS: This study shows that BAFF and BAFF-R are expressed in the thyrocytes derived from patients with either AITD or MNG, in addition to the expected expression of BAFF and its receptor in the infiltrating immune cells of GD and HT. These findings suggest a possible involvement of BAFF and its receptors in the pathophysiology of AITD.

PREGO (presentation of Graves' orbitopathy) study: changes in referral patterns to European Group On Graves' Orbitopathy (EUGOGO) centres over the period from 2000 to 2012.

BACKGROUND/AIMS: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time. METHODS: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000. RESULTS: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01). CONCLUSIONS: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

Statins may increase the risk of liver dysfunction in patients treated with steroids for active graves' orbitopathy.

CONTEXT: Intravenous glucocorticoids (IVGC) administered at high doses for the treatment of active moderate-severe Graves' orbitopathy (GO) may induce liver toxicity. Cumulative doses should not exceed 8 g and strict monitoring of liver function is recommended to avoid potentially life-threatening side effects. The 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, also known as statins, are employed to prevent major cardiovascular events. Patients with active GO, requiring immunosuppression with IVGC, are often treated with statins also. OBJECTIVE: We studied a 64-year-old man and a 58-year-old woman who developed significant liver toxicity after moderate doses of IVGC (methylprednisolone 2.3 g and 5 g in patients 1 and 2, respectively) and concomitant administration of statins. DESIGN AND INTERVENTION: Liver function tests were monitored every two weeks. Hepatitis virus markers and serology for autoimmune hepatitis were negative. At the occurrence of liver dysfunction (5-fold increase of serum aspartate aminotransferase/alanine aminotransferase concentrations), in patient 1 we stopped simvastatin indefinitely and discontinued IVGC for 2 weeks, whereas in patient 2, ongoing treatment with rosuvastatin was discontinued 3 weeks after IVGC therapy. RESULTS: In patient 1, off simvastatin, liver function remained normal after resuming IVGC. In patient 2, a further increase of the aminotransferase values was observed 3 weeks after IVGC discontinuation, with a progressive normalization only after statin withdrawal. CONCLUSIONS: Our study shows that statins, when concomitantly employed with methylprednisolone, may be a cause of liver dysfunction during IVGC in active GO. An accurate pharmacological history of all patients who are candidates for IVGC treatment is suggested to identify subjects at risk for hepatotoxicity.

Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study.

BACKGROUND: Preliminary studies have shown that rituximab (RTX) is effective in the treatment of active Graves' orbitopathy (GO). METHODS: We conducted a double-blind, randomized trial (European Clinical Trials Database [EudraCT] 2007-003910-33) to compare RTX with iv methylprednisolone (ivMP) in patients with active moderate to severe GO. Thirty-two patients were randomized to receive either ivMP (7.5 g) or RTX (2000 or 500 mg). The primary end point was the decrease of the clinical activity score of 2 points or to less than 3 at week 24. Changes of proptosis, lid fissure, diplopia and eye muscle motility, and quality of life score were secondary end points. The number of therapeutic responses, disease reactivation, and surgical procedures required during follow-up and the patients' quality of life were also assessed. RESULTS: The clinical activity score decreased with both treatments but more after RTX at 16, 20, and 24 weeks (P < .04, P < .02, P < .006, respectively), whether 1000 mg RTX twice or 500 mg RTX once was used (P = NS). At 24 weeks 100% of RTX patients improved compared with 69% after ivMP (P < .001). Disease reactivation was never observed in RTX patients but was observed in five after ivMP. Patients treated with RTX scored better motility at 52 weeks in both the right (P = .014) and the left eye (P = .026). Overall rehabilitative surgical procedures carried out during follow-up (at 76 wk) were 12 in 16 ivMP patients and 5 in 15 RTX patients (P = .049). CONCLUSIONS: The results of this trial confirm preliminary reports on a better therapeutic outcome of RTX in active moderate to severe GO, when compared with ivMP, even after a lower RTX dose. The better eye motility outcome, visual functioning of the quality of life assessment, and the reduced number of surgical procedures in patients after RTX seem to suggest a disease-modifying effect of the drug.

Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy.

BACKGROUND: While pulsed intravenous methylprednisolone (iv-MP) has been shown to be effective and well tolerated in moderate to severe Graves' orbitopathy (GO), limited data are available on dysthyroid optic neuropathy (DON). The objective of this retrospective study was to investigate the efficacy of iv-MP in the treatment of DON and to seek parameters predictive of response. METHODS: Twenty-four DON patients (40 eyes) treated with iv-MP from 2007 to 2012 were included in the study. Concurrent neurological or ophthalmologic diseases or signs of corneal exposure were considered as exclusion criteria. Iv-MP was administered daily for three consecutive days and repeated the following week. At six months, eyes not requiring surgery to preserve visual function were considered as responsive to treatment. Visual acuity, color sensitivity, visual field, and optic discs were analyzed at two and four weeks, and at 3, 6, and 12 months after treatment. Activity of GO was graded using a clinical activity score (CAS). Visual and clinical characteristics of the eyes responsive to iv-MP were studied by comparison to those of nonresponsive eyes. RESULTS: At six months, 17 of 40 (42.5%) eyes had complete visual recovery and were spared from surgical decompression. At two weeks, visual acuity, color sensitivity, and visual field improved significantly in almost all eyes, but GO inactivated (CAS<4) only in the eyes that permanently responded to iv-MP (p<0.01). The CAS at two weeks was a good predictor of response (cutoff ≥4; 66.7% sensitivity, 76.9% specificity). Optic disc swelling at diagnosis was highly predictive for unresponsiveness to iv-MP (34% sensitivity, 100% specificity). At baseline, high CAS (cutoff >5; 40.2% sensitivity, 94.1% specificity) and severely altered visual field mean defect (cutoff ≤6.31 dB; 73.9% sensitivity, 58.8% specificity) were associated with unresponsiveness to steroids. No major side effects were observed. CONCLUSIONS: High-dose iv-MP was effective in permanently restoring visual function in about 40% of the eyes treated. When successful, it generally induced inactivation of the orbital disease within two weeks and normalization of visual function within one month. The presence of optic disc swelling at diagnosis and persistent active disease at two weeks were good predictors of unresponsiveness to steroids.

The therapeutic outcome to intravenous steroid therapy for active Graves' orbitopathy is influenced by the time of response but not polymorphisms of the glucocorticoid receptor.

BACKGROUND: Glucocorticoids are the mainstay of immunosuppression for active moderate-severe Graves' orbitopathy (GO). AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A quantitative method for assessing the degree of axial proptosis in relation to orbital tissue involvement in Graves' orbitopathy.

PURPOSE: To define a method of quantifying axial proptosis in patients with Graves' orbitopathy (GO) and to validate a score that correlates with the orbital involvement and helps determine the degree of proptosis correction for elective orbital decompression. DESIGN: Retrospective, case series. PARTICIPANTS: The study included 50 patients (group A) and 29 control subjects who underwent orbital computed tomography (CT). The method was then validated in another group of 21 patients with GO (group B). METHODS: The orbital area (OA) was measured manually on the central axial section of the CT scan at a level where the lens is visualized. The OA intersects the projection of the globe and delimitates the chord of an arch (globe chord [OC]). The area of the circular sector under the chord (CA) represents the portion of the globe within the orbit. MAIN OUTCOME MEASURES: A CA-to-OA ratio was calculated to reduce the error due to variability of the measurements and to perform correlations with some of the clinical parameters of GO. RESULTS: Measurement error was low (<2%). We did not observe significant differences in the mean OA of patients with GO (783.6 ± 12.1 mm(2)) and controls (758.5 ± 20.4 mm(2); P = not significant). The OC value in patients with GO was 130.2 ± 11.5 mm(2), significantly lower than in controls (281.8 ± 9.7 mm(2); P<0.0001). The CA-to-OA ratio also was lower in patients with GO than in controls (0.16 ± 0.01 vs. 0.38 ± 0.01; P<0.0001). A significant correlation was found in patients with GO between the CA-to-OA ratio and proptosis (P<0.001), lid fissure (P = 0.004), and intraocular pressure (P<0.001). In group B, the CA-to-OA ratio was 0.18 ± 0.02, significantly different from that of controls (P<0.0001) and inversely correlated with proptosis (P<0.0001) and lid fissure (P<0.045). CONCLUSIONS: By measuring the CA-to-OA ratio, we were able to quantify the degree of axial proptosis in patients with GO. The significant correlation of CA/OA with some orbital parameters confirms that this parameter also may be used as a measure of orbital involvement in GO. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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

INTRODUCTION: 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 syndrome. OBJECTIVE: We have measured serum BAFF concentrations in patients with Graves' disease (GD) with or without Graves' orbitopathy (GO) and in active GO in relation to immunosuppressive treatment. METHODS: Forty-two patients and nine normal controls were studied. Thirty-four patients had GO, which was active in 23. Of these, nine were treated with rituximab (RTX) and 14 with i.v. methylprednisolone (MP). Serum BAFF concentrations were measured at baseline in all patients, at peripheral B cell depletion and repopulation after RTX, and after therapy with MP. RESULTS: Serum basal BAFF concentrations in GD patients were significantly higher when compared with normal controls (P = 0.0001), and no difference was observed in those with active or inactive GO. Serum BAFF concentrations were also significantly correlated with serum antithyroglobulin antibodies (P = 0.04) but not with sex, age, smoking habits, therapy for thyroid disease, and serum antithyroperoxidase antibodies and TSH receptor antibodies. After RTX, there was an increase of serum BAFF concentrations at the time of B cell depletion (P = 0.02) but also at B cell repopulation (P = 0.04). In patients treated with MP, serum BAFF concentrations decreased significantly after therapy (P < 0.01). CONCLUSIONS: We report that serum BAFF concentrations are elevated in patients with GD, in whom hyperthyroidism is known to be based on a B-cell-driven pathophysiological mechanism. In active GO, BAFF further increases after therapy with RTX as a consequence of the B cell depletion per se. The decrease of serum BAFF after iv steroids suggests that MP may exert an immunosuppressive effect by modifying B-cell-derived immune reactions.