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

BackgroundGlucocorticoids are the mainstay of immunosuppression for active moderate–severe Graves' orbitopathy (GO).AimTo 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.MethodsWe 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.ResultsIn 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.ConclusionsMost 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.

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Is Clinical Activity Score (CAS) a sufficient indicator of the response to therapy with i.v. methylprednisolone (MP) and external radiotherapy (RT) for Graves orbitopathy?

Endocrine Abstracts ◽

10.1530/endoabs.35.p1023 ◽

2014 ◽

Author(s):

Iwona Palyga ◽

Aldona Kowalska ◽

Janusz Mysliwiec ◽

Grazyna Gajos ◽

Robert Palyga ◽

...

Keyword(s):

Response To Therapy ◽

Activity Score ◽

Clinical Activity ◽

External Radiotherapy ◽

Clinical Activity Score ◽

Graves Orbitopathy ◽

Cas A

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TLR4 gene polymorphisms in Egyptian vitiligo patients: insights into emerging association with clinical activity, family history, and response to therapy

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00218-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Maha Abdelsalam ◽

Sherihan H. Allam ◽

Marwa Zohdy ◽

Hend Magdy ◽

Maged Mostafa

Keyword(s):

Family History ◽

Clinical Data ◽

Gene Polymorphisms ◽

Demographic Data ◽

Age Groups ◽

Response To Therapy ◽

Molecular Structures ◽

Control Group ◽

Clinical Activity ◽

Tlr4 Gene

Abstract Background Vitiligo is a common pigmentary disorder in which autoimmunity has been suggested to play an important role. Toll-like receptor (TLR) family are recognized different molecular structures expressed on immune cells and have been implicated in a number of autoimmune diseases (AIDs) such as vitiligo. The purpose of this study was to investigate the possible association between TLR4 gene polymorphisms: rs11536858, rs1927911, rs1927914 in Egyptian vitiligo patients and their clinical data, their response to therapy. Using PCR-RFLP for TLR4 gene polymorphisms (rs11536858, rs1927911, and rs1927914), both alleles and genotypes were determined after extraction of DNA in a case-control study of 100 vitiligo Egyptian patients and 100 matched age and sex controls. Results The distribution of the protective CT genotype of rs1927914 was higher in the control group. After dividing both patients and controls into 2 age groups (below 18 and above 18 years), no significant associations between the genotypes of the selected TLR4 SNPs and the demographic and clinical data of the vitiligo patients in group 1 (below 18 years) were observed. For group 2 (above 18 years), also no significant associations were found except for the association between the CC genotype of rs1927914 and psychiatric trauma, from one side, and between the CT genotype of rs1927911 and alopecia, from the other side. The association between combined genotypes and the risk of vitiligo showed either higher frequency in patients (risky), or controls (protective), and some equal frequencies (non-significant). The association between haplotypes and risk of vitiligo in patients’ group revealed the highest frequency for the risky ATT and the least frequency for ATC haplotypes. In control group, the protective GCT haplotype showed the highest frequency while the GTC and GCC showed the least frequency. No significant correlations of haplotypes with clinical and demographic data of selected patients’ group were observed apart from that between ACC haplotype and family history of AIDs and between ATT haplotype and remission after phototherapy. Conclusions The significant relationship between TLR4 gene polymorphisms and vitiligo patients charcteristics clarify the role of innate immunity in pathogensis of vitiligo and its effect on the used therapies.

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Phase II Study of Flavopiridol in Relapsed Chronic Lymphocytic Leukemia Demonstrating High Response Rates in Genetically High-Risk Disease

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.6944 ◽

2009 ◽

Vol 27 (35) ◽

pp. 6012-6018 ◽

Cited By ~ 160

Author(s):

Thomas S. Lin ◽

Amy S. Ruppert ◽

Amy J. Johnson ◽

Beth Fischer ◽

Nyla A. Heerema ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Dose Escalation ◽

Single Agent ◽

Tumor Lysis Syndrome ◽

Response To Therapy ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Treatment Schedule ◽

Genomic Features

PurposePatients with chronic lymphocytic leukemia (CLL) with high-risk genomic features achieve poor outcomes with traditional therapies. A phase I study of a pharmacokinetically derived schedule of flavopiridol suggested promising activity in CLL, irrespective of high-risk features. Given the relevance of these findings to treating genetically high-risk CLL, a prospective confirmatory study was initiated.Patients and MethodsPatients with relapsed CLL were treated with single-agent flavopiridol, with subsequent addition of dexamethasone to suppress cytokine release syndrome (CRS). High-risk genomic features were prospectively assessed for response to therapy.ResultsSixty-four patients were enrolled. Median age was 60 years, median number of prior therapies was four, and all patients had received prior purine analog therapy. If patients tolerated treatment during week 1, dose escalation occurred during week 2. Dose escalation did not occur in four patients, as a result of severe tumor lysis syndrome; three of these patients required hemodialysis. Thirty-four patients (53%) achieved response, including 30 partial responses (PRs; 47%), three nodular PRs (5%), and one complete response (1.6%). A majority of high-risk patients responded; 12 (57%) of 21 patients with del(17p13.1) and 14 (50%) of 28 patients with del(11q22.3) responded irrespective of lymph node size. Median progression-free survival among responders was 10 to 12 months across all cytogenetic risk groups. Reducing the number of weekly treatments per cycle from four to three and adding prophylactic dexamethasone, which abrogated interleukin-6 release and CRS (P ≤ .01), resulted in improved tolerability and treatment delivery.ConclusionFlavopiridol achieves significant clinical activity in patients with relapsed CLL, including those with high-risk genomic features and bulky lymphadenopathy. Subsequent clinical trials should use the amended treatment schedule developed herein and prophylactic corticosteroids.

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Different therapeutic outcomes in two cases with active moderate-to-severe Graves'orbitopathy treated with intravenous steroid therapy-case presentation

Endocrine Abstracts ◽

10.1530/endoabs.35.p1016 ◽

2014 ◽

Author(s):

Ioana Zosin ◽

Mihaela Vlad ◽

Melania Balas ◽

Carmen Bolintineanu

Keyword(s):

Steroid Therapy ◽

Case Presentation ◽

Intravenous Steroid ◽

Therapeutic Outcomes

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Steroid-Resistant Graves’ Orbitopathy Treated with Tocilizumab in Real-World Clinical Practice: A 9-Year Single-Center Experience

Journal of Clinical Medicine ◽

10.3390/jcm10040706 ◽

2021 ◽

Vol 10 (4) ◽

pp. 706

Author(s):

José V. Pérez-Moreiras ◽

María Varela-Agra ◽

M. Consuelo Prada-Sánchez ◽

Guillermo Prada-Ramallal

Keyword(s):

Adverse Drug Reactions ◽

Disease Recurrence ◽

Clinical Activity ◽

Eyelid Retraction ◽

Single Center ◽

Drug Reactions ◽

Steroid Resistant ◽

Single Center Experience ◽

Graves Orbitopathy ◽

The Absolute

This study aimed to assess the effectiveness and safety of tocilizumab use for the treatment of active steroid-resistant Graves’ orbitopathy (GO). A retrospective longitudinal study was conducted by reviewing the medical records at a single center between November 2009 and December 2018. A total of 114 patients with steroid-resistant Graves’ orbitopathy were examined and treated with tocilizumab, of which 54 adults met the inclusion criteria. No concomitant medication for the treatment of orbitopathy was used. The main primary outcomes included changes from baseline in the Clinical Activity Score (CAS) and thyrotropin receptor antibody (TRAb) levels throughout therapy with tocilizumab. The absolute responses to treatment were defined as the achievement of CAS ≤ 1 and TRAb ≤ 10 U/L. A composite ophthalmic score including CAS, proptosis, eyelid retraction, and diplopia was used to evaluate individual improvement in GO. Adverse drug reactions were also assessed. Analysis of the patient’s CAS and TRAb levels showed meaningful reductions during tocilizumab treatment. Differences between values at baseline and subsequent time points were statistically significant (p < 0.001 for all comparisons). The absolute CAS response (CAS = 0 or 1) was achieved in 74% (37/50) of patients after the fourth dose of tocilizumab (at week 16), with a TRAb response being achieved in 55% (23/42) of patients. The relative CAS response (reduction ≥ 2 points) was achieved in 90.9% of patients (40/44) after the first dose of tocilizumab (at week 4). Measurements of proptosis (reduction ≥ 2 mm in 78% of patients, 42/54) and eyelid retraction (reduction ≥ 2 mm in 75%, 33/44), and the prevalence of diplopia (improvement in 68%, 19/28) were significantly reduced after the last dose of tocilizumab (p < 0.001 for all comparisons). GO improved in 98% (53/54) of patients when at least two criteria of the composite evaluation were required. Four patients exhibited disease recurrence, defined as an increase in CAS of ≥2 points in the six months following the date of inactivation. Most adverse drug reactions were mild or moderate in severity. In conclusion, our data suggest that a course of at least 4 months (one monthly dose) of tocilizumab therapy provides a significant benefit to patients with active moderate-to-severe steroid-resistant GO.

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AB1027 EFFECTIVENESS OF SUBCUTANEOUS ANTI-INTERLEUCINE 6 TREATMENT IN PATIENTS WITH ACTIVE MODERATE-SEVERE GRAVES’ ORBITOPATHY REFRACTORY TO CONVENTIONAL THERAPY.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6201 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1806.2-1806

Author(s):

L. Fernández de la Fuente Bursón ◽

F. J. Toyos Sáenz de Miera ◽

D. Ruiz-Montesinos ◽

M. Gessa Sorroche ◽

M. C. Díaz Ruiz ◽

...

Keyword(s):

Demographic Data ◽

Case Series ◽

Multicenter Trial ◽

Smoking History ◽

Clinical Aspects ◽

Clinical Activity ◽

Nonsurgical Management ◽

Usual Clinical Practice ◽

Antithyroid Treatment ◽

Graves Orbitopathy

Background:Graves’ Orbitopathy (OG) is the main extrathyroid manifestation of Graves’ disease (GD). Up to 25% of patients have moderate-severe inflammatory activity with a risk of major sequelae. Intravenous (i.v.) glucocorticoids (GC) pulses are the standard therapy. In refractory cases, several classic and some biological immunosuppressantsare used, obtaining variable responses. Interleukin 6 (IL6) is involved in the pathogenesis of OG, which has justified the off-label treatment with Tocilizumab (TCZ)1, whose use by route i.v. has shown favorable results in published small case series and a single multicenter trial2.Objectives:To analyse the ocular effectiveness of anti-IL6 therapy used subcutaneously (s.c.) in patients with moderate-severe active refractory OG in usual clinical practice.Methods:Retrospective descriptive observational study of a series of cases of moderate-severe OG patients treated with anti-IL6 s.c. The patient medical records of those who had received at least 1 cycle of anti-IL6 treatment were reviewed (December 2013-December 2019). The primary effectiveness outcome was the change of the Clinical Activity Score (CAS). Favorable response was considered: reduction of CAS≥2 points together with obtaining inactivity (CAS <3). Demographic data, personal medical history, clinical aspects of GD, previous therapies and data on the use and safety of anti-IL6 were collected. The SPSS11 package was used for statistical analysis, using non-parametric tests for quantitative variables. The study was approved by the local Ethical Committee.Results:12 of the 15 patients (80%) were women with a mean of 50.27 years (21-72). 60% (n=9) had smoking history, 40% (n=6) active. 26.7% (n=4) were diabetic, all without retinopathy. 100% of patients received imidazole antithyroid treatment. 46.7% (n=7) required β-blockers and 20% (n=3) diuretics. 66.7% thyroidectomy (n=10) and 20% (n=3) decompressive eye surgery and/or blepharoplasty were performed. Thyroid and ocular radiotherapy were used in 2 patients. 3 patients received botox. 80% (n=12) of them had previously received GC. 93.3% (n=14) were naïve to biological therapy, only 1 patient previously used Rituximab. All except one patient who was treated with SRL received TCZ as IL6 therapy. A significant favorable response was obtained in 100% of the patients (p=0.008), decreasing CAS average from 4.9 (2-7) to 1.7 (0-2) at the end of the therapy [Figure 1]. The severity of the OG changed from being moderate in 72.7% of the patients to mild in 66.7% of the total. The median time to inactivity was 8 months (2-15). 73.3% (n=11) of the patients finished the treatment reaching inactive OG, the rest (although inactive) maintained therapy. After 6 months, 100% of those who completed the treatment remained inactive with average CAS of 1.3 (0-2). Smoking did not influence the response, nor any other variable collected. Adverse events appeared in 26.7% (n=4) of the cases, all of them mild and without widrawal.Conclusion:Treatment with anti-IL6 s.c. steadily decreases the clinical activity measured by CAS in patients with moderate-severe refractory OG, despite poor prognosis factors (such as smoking), with a good safety profile.References:[1]Taylor PN, Zhang L, Lee RWJ, Muller I, Ezra DG, Dayan CM, et al. New insights into the pathogenesis and nonsurgical management of Graves’ orbitopathy. Nat Rev Endocrinol. 2020 Feb;16(2):104-116.[2]Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodríguez Álvarez FM, et al. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Gravesˊ Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol. 2018;195:181–90.Disclosure of Interests:None declared

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