title: 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.
abstract: BACKGROUND
  Glucocorticoids are the mainstay of immunosuppression for active moderate-severe Graves' orbitopathy (GO).
  
  
  OBJECTIVE
  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.
authors.affiliation: Endocrine Unit, Department of Clinical Sciences and Community Health, Graves' Orbitopathy Center, Endocrinology.
authors.forename: Guia
authors.initials: G
authors.lastname: Vannucchi
authors.forename: Danila
authors.initials: D
authors.lastname: Covelli
authors.forename: Irene
authors.initials: I
authors.lastname: Campi
authors.forename: Daniele
authors.initials: D
authors.lastname: Origo
authors.forename: Nicola
authors.initials: N
authors.lastname: Currò
authors.forename: Valentina
authors.initials: V
authors.lastname: Cirello
authors.forename: Davide
authors.initials: D
authors.lastname: Dazzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Mario
authors.initials: M
authors.lastname: Salvi
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004172:Diplopia / Q000209:etiology / Q000517:prevention & control; D004351:Drug Resistance; D005094:Exophthalmos / Q000209:etiology / Q000517:prevention & control; D005260:Female; D056726:Genetic Association Studies; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D049970:Graves Ophthalmopathy / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007558:Italy; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D008775:Methylprednisolone