| BACKGROUNDThyroid associated ophthalmopathy (TAO), also known as Graves’orbitopathy and thyroid eye disease, is a common organ specific autoimmune disorder and closely linked with thyroid disease. About50%patients of Graves’ disease have apparent clinical eye involvement, such as proptosis, eyelid contracture, extraocular muscle dysfunction and other symptoms. Approximately3%to5%of patients experience severe disease including dysthyroid optic neuropathy, corneal ulceration, and profound impairment of their quality of life.The pathogenesis of TAO is not yet completely understood. According to a leading pathogenetic hypothesis, it is extremely complex, involving autoreactive T lymphocytes, B-lymphocytes, the thyroid stimulating hormone receptor, the insulin-like growth factors receptor, and secretion of a number of cytokines which maintain the reactions occurring in the orbit. These cytokines are able to stimulate the secretion of glycosaminoglycans from orbital fibroblasts, leading to the accumulation of a large quantity of hydrophilic glycosaminoglycans. Moreover, they cause fibroblasts to differentiate into adipocytes, resulting in excessive orbital fat deposition. The increase in orbital content therefore can explain many of the clinical manifestations of TAO.A study designed to assess the quality of life in patients with TAO has shown that mild to moderately severe TAO has a profound influence on quality of life. Treatment of TAO, using for example, glucocorticoids, orbital radiotherapy or orbital decompression, is therefore quite important. However, no clear treatment strategy has been developed to date. A questionnaire survey on the management of TAO in Europe demonstrated that inappropriate treatments are still prevalent.Glucocorticoids are a widely used to treat TAO. It can decrease inflammation and suppress immune responses by interfering with the functions of T and B lymphocytes, reducing the recruitment of monocytes and macrophages, inhibiting the function of immunocompetent cells, inhibiting the release of inflammatory mediators, and decreasing glycosaminoglycan synthesis and secretion by activated orbital fibroblasts. But they are ineffective for20～25%of patients with glucocorticoids. On another hand, side effects of glucocorticoids include Cushing syndrome, hypertension, high glucose levels, depression, osteoporosis, and other conditions. A major advantage of oral glucocorticoids (ORGC) is the full compliance of patients with this protocol. However, ORGC therapy requires the use of high doses of the drug for prolonged periods of time and therefore more side effects. Reports of the efficacy and safety of intravenous glucocorticoids (IVGC) therapy seem to suggest an improvement over ORGC; however, the different studies carried out to date have given inconsistent results. It has been widely used for nearly20years, especially in Europe. The protocol is usually use high-dose methylprednisolone pulse therapy. The treatments of moderate to severe TAO are still a big challenge. Randomized controlled trials are infrequent in this field and require developing treatment protocols based on evidence-based medicine, in order to improve the efficacy and prognosis of TAO patients. Dr. Stiebel-Kalish and his colleagues conducted a meta-analysis including four randomized controlled trials comparing IVGC with ORGC; they found that IVGC may be more effective and safer than ORGC. However, the only measure of outcome used was clinical activity score and the trials included were not comprehensive, so the quality of this evaluation is limited.Considering the difficulties of carrying out clinical trials and the need to review the current best evidence, our study is guided in the Cochrane systematic review, developed strict inclusion criteria, included randomized controlled trials that met the inclusion criteria and made a rigorous assessment of the trials’ quality. To assess the efficacy and safety of IVGC, we conduct quantitative and qualitative analysis based on the characteristics of the data. It can help us to make a further understanding of the treatment of TAO and provide a scientific basis for further application in practice.Chapter I Comparison of treatments with intravenous and oral glucocorticoids in patients with TAOObjectiveTo evaluate the quality of included trials comparing intravenous glucocorticoids with oral glucocorticoids and conduct quantitative or qualitative analysis, and further assess the efficacy and safety of intravenous glucocorticoids compared with oral glucocorticoids.MethodsInclusion criteria (1) Patients were diagnosed meet for the diagnostic criteria for TAO proposed by Bartley GB, with moderate to severe and active TAO defined according to the EUGOGO consensus statement;(2) Patients received IVGC in experiment group, and ORGC in the control, with or without other therapy just as orbital radiotherapy; the duration of follow up was at least3months;(3) The primary outcomes of treatment were the incidence of appearance, disappearance or changes in the degree of diplopia and changes in the clinical activity scores (CAS); the secondary outcomes were variations in proptosis, variations in lid width, self-assessment evaluation and the incidence of side effects;(4) Randomized controlled trials;(5) There was no language restriction for the search. Search strategyWe searched Medline, Embase, the Cochrane Central Register of Controlled Trials, Chinese Biological Medicine, National Knowledge Infrastructure, and Wang Fang Data databases till December31th,2012using the terms "thyroid associated ophthalmopathy" and "glucocortcoid". Furthermore, we reviewed the reference lists of the retrieved articles to search for additional relevant studies. Selection and quality assessmentTwo reviewers (Li and Chen) independently assessed trial eligibility and trial bias risk and extracted data. The bias risk of trials was assessed using the components recommended by the Cochrane Collaboration:(1) sequence generation of allocation;(2) allocation concealment;(3) blinding of participants, personnel, and outcome assessors;(4) incomplete outcome data and so on. Data extraction and managementTwo reviewers (Li and Chen) independently extracted data from included studies, including basic informations, methods, participants, interventions, measurements and confounders, and then entry the relevant data in Review Manager (RevMan5.2). Statistical analysisStatistical analysis were conducted with RevMan5.2. Heterogeneity significance was accepted at a value of P<0.10. When P>0.10we used a fixed effects model, subgroup analysis, sensitivity analysis or random effects model were analyzed when P≤0.10. We used relative risk (RR) or odds ratio (OR) in categorical variables and mean difference (MD) in numeric variables. Test for overall effect is statistically significant if P≤0.05.ResultStudy selection and characteristics of the trialsWe identified3063potentially relevant articles through electronic and hand searches, of which a total of five randomized controlled trials fulfilled the inclusion criteria and were chosen for this analysis. The five randomized controlled trials enrolled288participants, including72male and216female. Of the five trials, only one trial compared intravenous glucocorticoids combined orbital radiotherapy with oral glucocorticoids combined orbital radiotherapy. Comparison of intravenous glucocorticoids therapy and, oral glucocorticoids therapy are conducted in the other trial and the treatment protocols are different.Assessment of risk of biasOf the five trials, one trial used computer software to generate random numbers, two trials specified randomized protocol using envelopes. Outcome examination was performed by the same person who was blind to the treatment given to the patients both before and the end-point in three trials. All trials were carried out intention to treat analysis.Meta analysisImprovement of CAS:three trials described the improvement of CAS after treatment. Heterogeneity existed between trials (P=0.0005) and performed a subgroup analysis, test for heterogeneity P=1.00, MD=0.80, the difference of improvement of CAS between IVGC group and ORGC group was statistically significant (P<0.01).Improvement of diplopia:three trials described the improvement of diplopia after treatment. Test for heterogeneity P=0.31and performed fixed effects model, RR=1.11, improvement of diplopia between IVGC group and ORGC group was no significantly different (P=0.61).Improvement of exophthalmos:three trials described the improvement of exophthalmos after treatment. Heterogeneity existed between trials (P<0.01) and performed a subgroup analysis, test for heterogeneity P=0.37, MD=0.51, the difference of improvement of exophthalmos between IVGC group and ORGC group was statistically significant (P=0.0009).Change of lid width:two trials described the improvement of lid width after treatment. Test for heterogeneity P<0.01and performed randomed effects model, MD=1.30, improvement of lid width between IVGC group and ORGC group was no significantly different (P=0.06).Improvement of quality of life:three trials described the improvement of quality of life after treatment. Test for heterogeneity P=0.52and performed fixed effects model, RR=1.22, improvement of quality of life in IVGC group is better than in ORGC group (P=0.01).Incidence of hyperglucose:three trials described the incidence of hyperglucose after treatment. Test for heterogeneity P=0.16and performed fixed effects model, OR=0.93, incidence of hyperglucose between IVGC and ORGC group was no significantly difference (P=0.87).Incidence of hypertension:four trials described the incidence of hypertension after treatment. Test for heterogeneity P=0.70and performed fixed effects model, OR=0.16, incidence of hypertension in IVGC group is0.16times in ORGC group (P=0.008).Incidence of Cushing syndrome:two trials described the incidence of Cushing syndrome after treatment. Test for heterogeneity P=0.29and performed fixed effects model, RR=0.16, incidence of Cushing syndrome in IVGC group is0.16times in ORGC group (P<0.01).Incidence of weight gain:three trials described the incidence of weight gain after treatment. Test for heterogeneity P=0.60and performed fixed effects model, OR=0.20, incidence of weight gain in IVGC group is0.2times in ORGC group (P=0.002).Incidence of gastrointestinal:three trials described the incidence of gastrointestinal after treatment. Test for heterogeneity P=0.28and performed fixed effects model, RR=0.57, incidence of gastrointestinal between IVGC and ORGC group was no significantly different (P=0.25).Incidence of total adverse events:three trials described the incidence of total adverse events after treatment. Test for heterogeneity P=0.16and performed fixed effects model, OR=0.16, incidence of total adverse events in IVGC group is0.16times in ORGC group (P<0.01).ConclusionCompared with oral glucocorticoids, intravenous glucocorticoids in treatment of TAO has advantage of improving the quality of life in patients with TAO. The improvement of CAS and exophthalmos may be superior to oral glucocorticoids. Howeverthere are no obvious advantages in improvement of diplopia and lid width of intravenous glucocorticoids. Intravenous glucocorticoids are safer. The incidence of hypertension, Cushing syndrome, weight gain and total adverse events are lower in intravenous group than oral group. Chapter II Comparison of intravenous glucocorticoids with other methods in treatment of TAOObjectiveTo evaluate the quality of included trials compared intravenous glucocorticoids with other methods except oral glucocorticoids, and conduct quantitative or qualitative analysis, and then further assess the efficacy and safety of intravenous glucocorticoids compared with other methods.MethodsInclusion criteria(1) Patients were diagnosed met the diagnostic criteria for TAO proposed by Bartley GB, with moderate to severe and active TAO defined according to the EUGOGO consensus statement;(2) Patients received IVGC in experiment group, and other methods except ORGC, placebo or different doses of intravenous glucocorticoids in the control group, with or without other therapy at the same time; the duration of follow up was at least3months;(3) The primary outcomes of treatment were the incidence of appearance, disappearance or changes in the degree of diplopia and changes in the clinical activity scores (CAS); the secondary outcomes were variations in proptosis, variations in lid width, self-assessment evaluation and the incidence of side effects;(4) Randomized controlled trials;(5) There was no language restriction for the search.Search strategy, selection and quality assessment, data extraction and analysis were just the same as those of the Chapter I.Result Study selection and characteristics of the trialsWe identified3063potentially relevant articles through electronic and hand searches, of which a total of three randomized controlled trials fulfilled the inclusion criteria and were chosen for this analysis. The three randomized controlled trials enrolled189participants, including54male and135female. Of the three trials, one trial enrolled patients with very active TAO and optic neuropathy to compare intravenous pulse therapy with methylprednisolone and decompressive surgery. Another trial is a prospective, randomized, placebo-controlled study to compare the effect of methylprednisolone pulse therapy with the effect of placebo in previously untreated patients with moderately severe TAO. The third trial is a multicenter, double-blind, randomized clinical trial comparing three different cumulative doses of intravenous methylprednisolone in159patients with moderate to severe and active TAO.Assessment of risk of biasOf the three trials, two trials were randomized by external offices by the means of randomization lists, two trials specified randomized protocol using envelopes, two trials were blinded to participants and outcomes surveyors. All trials were carried out intention to treat analysis.Data analysis The three included trials were lack of sufficient outcome data precluded the ability to combine the results for meta-analysis. Thence, we performed qualitative analysis.Improvement of CAS:one trial showed the CAS decreased significantly in two groups (P<0.01). Another study described that the CAS fell in all patients in IVGC group and three patients in placebo group; a decrease of three points or more in four patients in IVGC group and one patient in placebo group, both two patients in groups had a decrease of two points. The third trial showed CAS improved in58%of the low dose patients,83%of the middle dose patients and81%of the high dose patients.Improvement of diplopia:two trials described the improvement of diplopia after treatment. One trial showed diplopia improved in two out of four of IVGC patients with diplopia at the time of inclusion and in none of five placebo patients; conversely, in the placebo group one patient showed worsening from no diplopia to diplopia in extremes of gaze. The other trial suggested changes in diplopia did not differ in the three groups.Improvement of exophthalmos:one trial showed the exophthalmos decreased significantly in two groups. Another study showed proptosis improved both two patients in two groups, worsening (≥2mm increase) of proptosis was seen in four placebo patients, of which one did not show proptosis at inclusion. The third study showed exophthalmos decreased significantly in a minority of patients, with no differences between the groups.Change of lid width:two trials described the improvement of lid width after treatment. One trial suggested aperture improved in four IVGC patients compared to five placebo patients, but increased in1placebo patient. The other trial showed palpebral aperture decreased significantly in a minority of patients, with no differences between the groups.Improvement of quality of life:there are two trials described the improvement of quality of life after treatment. One trial showed changes in quality of life were as follows, in IVGC group:four better, one equal and one worse; in the placebo group: four better, one equal and four worse. The other trial showed an improvement in the quality of life occurred in51%low dose patients,48%middle dose patients and67%high dose patients.Incidence of adverse events:two trials described incidence of adverse events after treatment. One trial reported three patients in IVGC group had Cushingoid symptoms; stomach ache occurred in two patients in IVGC group and1in the placebo group; only two patients in each group had weight gain exceeding1%. The other trial reported major adverse events occurred in ten patients (two in the low dose group, three in the middle group and five in the high dose group), and one patient in the high dose group had two major adverse events; in the low dose group, one patient had diabetes mellitus requiring therapy and the other patient dead due to myocardial infarction; in the middle group, one patients had major depression, one patients had occurrence of diabetes mellitus requiring therapy and one had profound muscle weakness; in the high dose group, one patient had occurrence of diabetes mellitus requiring therapy and severe infection requiring hospitalization, one patient had diabetes mellitus requiring therapy, the third patient had psychosis, and the last two patients had major depression.ConclusionIntravenous glucocorticoids in patients with TAO improve CAS, diplopia, exophthalmos and lid width, different doses of intravenous glucocorticoids therapy decrease the occurrence of adverse events in varying degree, but there was no sufficient outcome data to combine the results for meta-analysis. |
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