mycophenolic-acid and Graves-Ophthalmopathy

The role of mycophenolate mofetil (MMF) in the treatment of Graves' orbitopathy (GO) has attracted much attention. This study is to evaluate the benefit and safety of MMF in moderate-to-severe GO. A meta-analysis of clinical control trials comparing MMF (with or without glucocorticoid (GC)) for the treatment of GO with GC was conducted. We searched the databases, including PubMed, EMBASE, the Cochrane Library, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI), for articles published up to 15 June 2022. The primary outcome is referred to the improvement in overall response, and secondary outcomes included the change in clinical activity score (CAS) and adverse events (AEs). Of the 289 articles initially searched, 6 studies were finally eligible for inclusion. The results showed that MMF (with or without GC) was superior to GC in the treatment of GO (OR 3.34, 95% CI 2.17-5.14;

Topics: China; Graves Ophthalmopathy; Humans; Mycophenolic Acid; Treatment Outcome

The dual antiproliferative mechanism of mycophenolate appears to be beneficial in Graves' orbitopathy (GO).. Safety data from the two published mycophenolate trials and the original database of the European Group on Graves' Orbitopathy (EUGOGO) trial were systematically analyzed. Treatment efficacy stratified by individual visual parameters of activity and severity were compared.. A total of 129 adverse events (AE) involving 50 patients (29.4%) were noted among all mycophenolate-treated patients. Mycophenolate sodium plus intravenous glucocorticoid (MPS + GC) group of the EUGOGO trial recorded significantly more AE (55.4% versus 4.6% of patients affected) and serious adverse events (SAE) (12.5% versus 0%) than mycophenolate mofetil (MMF) group of the Chinese trial. None of those SAE was side effect (SE). Most SE in MPS + GC group were mild. Gastrointestinal disorders, infection and liver dysfunction affected 8.8%, 7.1% and 1.2% of all mycophenolate-treated patients (versus 5.4%, 5.4% and 1.2% of all patients on GC monotherapy, respectively). MPS + GC did not significantly increase the risk of infection or liver dysfunction when compared to GC monotherapy. No cytopenia, serious infection or treatment-related mortality was reported. The much higher AE rates of mycophenolate trials in other autoimmune diseases or transplantations suggested that major mycophenolate toxicities were mostly dose- and duration dependent. Mycophenolate, either as monotherapy or as combination, achieved better overall response than GC monotherapy.. The risk-benefit ratio of low-dose mycophenolate treatment in active moderate-to-severe GO is highly favorable given its reassuring safety profile with low rate of mild-to-moderate SE and promising efficacy.

Topics: Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Gastrointestinal Diseases; Glucocorticoids; Graves Ophthalmopathy; Humans; Mycophenolic Acid; Randomized Controlled Trials as Topic

Various treatments have been investigated for Graves' ophthalmopathy (GO). We aimed to provide an overall profile of the efficacy and tolerability of various interventions for active and moderate to severe GO.. PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched on 6 July 2018. Randomised controlled trials (RCT) investigating GO treatments were included. Two researchers independently extracted data according to a predefined form. A random effects network meta-analysis was performed using a frequentist approach. The primary outcome was efficacy, and the secondary outcome was tolerability (side effect discontinuation).. Thirty-three studies with 1846 patients with GO were included. Orbital radiotherapy (ORT) plus intravenous glucocorticoids (IVGC) (OR 27.11; 95% CI 4.57 to 160.92), mycophenolate mofetil (MMF) (24.40, 95% CI 5.28 to 112.67), oral glucocorticoids (OGC) plus ciclosporin (20.22, 95% CI 1.60 to 255.20), IVGC plus MMF (12.08, 95% CI 2.96 to 49.35), teprotumumab (8.92, 95% CI 2.51 to 31.77), ORT plus OGC (4.88, 95% CI 1.25 to 19.06), rituximab (RTX) (4.85, 95% CI 1.18 to 19.86), somatostatin analogues (4.23, 95% CI 1.60 to 11.16), OGC plus azathioprine (AzA) (5.77, 95% CI 1.17 to 28.47) and IVGC (4.96, 95% CI 1.96 to 12.55) showed significantly better improvement than no treatment. ORT plus IVGC ranked first, followed by MMF. High heterogeneity and significant local inconsistency were observed in the RTX studies. The results of the sensitivity analyses were similar to those of the main analysis.. A robust recommendation regarding the best treatment cannot be made, because most evidence was rated as low or very low quality according to the Grading of Recommendations, Assessment, Development and Evaluations framework. Large RCTs and individual participant data meta-analyses are necessary to confirm these results and explore potential moderators.. CRD42018103029.

Topics: Antibodies, Monoclonal, Humanized; Azathioprine; Combined Modality Therapy; Cyclosporine; Glucocorticoids; Graves Ophthalmopathy; Humans; Mycophenolic Acid; Network Meta-Analysis; Radiotherapy; Rituximab; Somatostatin

Graves' orbitopathy is a debilitating disorder which occurs in patients with autoimmune thyroid disease, mainly Graves' disease, and adds layers of complexity to management of both conditions. We conducted a comprehensive review of literature for publications relating to established and new management options for Graves' orbitopathy and have summarized key articles in this review. Initial evaluation of patients with Graves' disease should also include clinical evaluation for orbitopathy. If eye disease is present, patients are best managed by a multi-specialty team including an endocrinologist and ophthalmologist. All patients with Graves' orbitopathy benefit from risk factor modification and normalization of thyroid function tests. Patients with active, mild disease generally benefit from local therapies and selenium, while patients with moderate-to-severe disease usually require the addition of intravenous glucocorticoid therapy. If there is an inadequate response to glucocorticoid therapy, several second-line therapies have been investigated for use, including orbital radiotherapy (with additional glucocorticoids), rituximab, cyclosporine, mycophenolate mofetil, and methotrexate. Use of new biologic agents, mainly teprotumumab and tocilizumab, have demonstrated impressive reductions in disease activity and severity. If these results are confirmed, the treatment paradigm is likely to change in the future. Finally, there are several novel immunotherapies being investigated for Graves' disease, which may have treatment implications for Graves' orbitopathy as well. Overall, there are many encouraging advances in the therapy of Graves' orbitopathy that are making the future more promising for patients suffering from this disease.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cyclosporine; Glucocorticoids; Graves Ophthalmopathy; Humans; Immunotherapy; Methotrexate; Mycophenolic Acid; Rituximab; Selenium; Severity of Illness Index

To offer an update on advances and controversies in the assessment, investigation and treatment of thyroid eye disease (TED), a disfiguring orbital autoimmune disease, which can manifest with diplopia and threaten not only sight - but also life.. Developments in biomarkers and imaging are helping to tailor the management of patients. Emerging therapies target different pathways in the disease and are informed by studies into TED pathogenesis: the last 2 years has, for example, seen the culmination of a two-decade long bench-to-bedside story in which an original focus on the IGF1 receptor has translated into an effective treatment for proptosis in thyroid eye disease. Whether this will result in a real-world reduction in TED-related morbidity will depend on access; commercial pricing decisions may preclude widespread adoption of novel therapies.. Thyroid eye disease research is enjoying a renaissance with advances in both monitoring and treatment coupled with a renewed emphasis on a holisitic approach, which includes aesthetic care for patients; this is perhaps the most exciting time to be part of the international thyroid eye disease community in decades - for physicians, surgeons and patients. The commercial window for break-through drugs are narrowing with an array of new therapeutic agents in the pipeline over the coming decade.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Decompression, Surgical; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Sirolimus

Graves' ophthalmopathy (GO) is a complicated autoimmune disease. Various therapies have been used to manage GO; however the optimum therapy is not clear. Glucocorticoids (GCs) therapy is the mainstay of treatment especially for active moderate to severe patients, which needs evidence-based support.. We searched all the randomized controlled trials (RCTs) involving corticosteroid treatment for patients diagnosed with GO from EMBASE, Medline, and the Cochrane library and then conducted a system review and meta-analysis. The electronic search covered the period from April 1966 to March 2018.. Our meta-analysis confirmed the effects of GCs in the management of GO and intravenous GCs are proved to be better than oral GCs as ever reported. Combination of radiotherapy and GCs did not enhance the effects of GCs. However, if proptosis is the main issue, combination of

Topics: Adrenal Cortex Hormones; Cyclosporine; Graves Ophthalmopathy; Humans; Mycophenolic Acid; Randomized Controlled Trials as Topic

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.. 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.. 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).. 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.. Novartis, Germany.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Double-Blind Method; Drug Therapy, Combination; Female; Graves Ophthalmopathy; Humans; Italy; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Severity of Illness Index; Treatment Outcome; Young Adult

Graves' orbitopathy (GO) is a potentially sight-threatening disease for which currently available medical therapy is not reliably successful. Mycophenolate mofetil (MMF) is a selective immunosuppressant used widely in many autoimmune diseases. Preliminary studies have shown that MMF is effective in the treatment of active GO.. To evaluate the efficacy and safety of MMF in patients with active moderate-to-severe GO.. One hundred and 74 patients with active moderate-to-severe GO were randomized to receive either MMF or glucocorticoids (GC).. The primary outcome was overall response at the 12th and 24th weeks; the outcome assessments included clinical activity score (CAS), soft tissue involvement, pain, visual acuity, proptosis, diplopia and reduction in eye movements. The secondary outcome was changes in those individual parameters. Adverse effects were recorded at each visit.. A greater overall response rate was found in the MMF group compared with the GC group at the 24th week (91·3% vs 67·9%, P = 0·000). MMF therapy showed a better CAS response than GC (92·5% vs 70·5% improved, P < 0·05). Patients treated with MMF showed a significantly improved rate of diplopia and proptosis than patients treated with GC at the 24th week (90·4% and 68·8% improved, respectively). Disease reactivation was not observed in the patients treated with MMF but was observed in five patients after GC therapy. Adverse events occurred in 4 of 80 patients treated with MMF (5%), all of which were mild to moderate. A severe adverse event was only observed in one patient treated with GC but not at all in patients treated with MMF.. Compared with GC treatment, MMF therapy is more effective and safer for patients with active moderate-to-severe GO.

Topics: Adolescent; Adult; Aged; Glucocorticoids; Graves Ophthalmopathy; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Remission Induction; Treatment Outcome; Young Adult

Topics: Diplopia; Drug Therapy, Combination; Graft Rejection; Graves Ophthalmopathy; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mycophenolic Acid; Prospective Studies; Sirolimus

Graves' orbitopathy (GO) is the primary cause of exophthalmos in adults. It appears in 30 to 50% of patients with Graves' disease. About 5% are moderate-to-severe cases that might be see-threatening or lead to long term disabling sequelae. Recommendations have been established in 2016 by the European thyroid association (ETA) and the European group on Grave's orbitopathy (EUGOGO), suggesting a wide use of corticosteroids in moderate to severe forms. However, disappointing results have been reported in 20 to 30% of cases. Improved understanding of pathophysiological mechanisms has allowed the use of non-specific immunomodulatory agents, currently under evaluation, and which place in the therapeutic strategy remains to be determined. Very recently, new promising therapeutic advances have emerged with the identification of new therapeutic targets, such as the TSH receptor and IGF-1 receptor complex.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Graves Ophthalmopathy; Humans; Mycophenolic Acid; Radiotherapy; Receptors, Thyrotropin; Rituximab

The antiproliferative mechanism of mycophenolate acid (MPA) suggests a beneficial effect in patients with Graves' orbitopathy (GO).. To systematically analyze for the first time adverse events (AEs) during MPA treatment in GO.. Prospective longitudinal study.. Academic tertiary referral center with a joint thyroid-eye clinic.. Fifty-three consecutive, unselected patients with clinically active and moderate-to-severe GO.. MPA 0.720 g was given once daily for 24-weeks in GO patients. AEs were documented and coded according to the standardized medical dictionary for regulatory activities (MedDRA). AE were followed up and seriousness as defined by ICH-guideline E6 was documented. All AEs were analyzed regarding a possible underlying cause and if not, graded as side effect (SE).. Fifty GO patients (93 %) had Graves' disease, 37 (70 %) and 29 (54.7 %) were female and smoker, respectively. Thirty-six patients (68 %) reported at least one AE. A total of 88 AEs were documented, most frequent AEs were insomnia (N = 6), fatigue (N = 5) and optic neuropathy (N = 5), while other AEs occurred in up to three patients (5.6 %), only. In 12 (23 %) patients, at least one SE occurred. All 17 reported SE, i.e. mild infections and gastrointestinal intolerance were within the known safety profile of MPA. No patient dropped MPA medication because of drug-induced SE. Most AEs showed a recovered (76 %) or recovering (16 %) outcome. Seven (13 %) patients were hospitalized, five (62 %) due to optic neuropathy, none of these events was graded as SE.. MedDRA-coded data documented the good tolerance of a moderate MPA dose in GO patients.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Female; Graves Ophthalmopathy; Humans; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Patient Safety; Prospective Studies; Tertiary Care Centers; Young Adult