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Arthritis Care & Research Apr 2022An unmet need exists for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet's syndrome. The Outcome Measures in...
OBJECTIVE
An unmet need exists for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet's syndrome. The Outcome Measures in Rheumatology (OMERACT) Behçet's Syndrome Working Group, a large, multidisciplinary group of experts in Behçet's syndrome and patients with Behçet's syndrome, had an objective of developing a core set of data-driven outcome measures for use in all clinical trials of Behçet's syndrome.
METHODS
The core domain set was developed through a comprehensive, iterative, multistage project that included a systematic review, a focus group meeting and qualitative patient interviews, a survey among experts in Behçet's syndrome, a Delphi exercise involving both patients and physician experts in Behçet's syndrome, and use of the data, insight, and feedback generated by these processes to develop a final core domain set.
RESULTS
All steps were completed and domains were delineated across the organ systems involved in this disease. Since trials in Behçet's syndrome often focus on specific manifestations and not on the disease in its entirety, the final proposed core set includes 5 domains mandatory for study in all trials in Behçet's syndrome (disease activity, new organ involvement, quality of life, adverse events, and death) with additional subdomains mandatory for study of specific organ-systems. The final core set was endorsed at the 2018 OMERACT meeting.
CONCLUSION
The core set of domains in Behçet's syndrome provides the foundation through which the international research community, including clinical investigators, patients, the biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective therapies.
Topics: Behcet Syndrome; Focus Groups; Humans; Outcome Assessment, Health Care; Quality of Life; Rheumatology
PubMed: 33202101
DOI: 10.1002/acr.24511 -
Scientific Reports Feb 2016The relationships between polymorphisms of the trans-membrane(TM) region located in the major histocompatibility complex (MHC) class I chain-related gene A (MICA) and... (Meta-Analysis)
Meta-Analysis
The relationships between polymorphisms of the trans-membrane(TM) region located in the major histocompatibility complex (MHC) class I chain-related gene A (MICA) and Behcet's disease (BD) have been discussed previously, however, the results were contradictory. In this study, we thoroughly assess whether MICA-TM gene variants are associated with BD by means of a systematic review and meta-analysis. Our study focused on the effects of polymorphisms of MICA-A4, A5, A5.1, A6, and A9 from the included articles. Sixteen previous original publications representing 1,555 BD patients and 2,086 unrelated healthy controls analyzed the association of BD with MICA-TM gene polymorphisms. For the five alleles, MICA-A6 showed a strongly positive correlation with BD patients and could be viewed as an increased risk factor of BD (OR = 2.34, 95%CI: 2.02-2.70). Furthermore, MICA-A4, A5, A5.1, and A9 exhibited negative associations with BD (OR = 0.71, 95%CI: 0.58-0.86; OR = 0.75, 95%CI: 0.63-0.90; OR = 0.63, 95%CI: 0.44-0.91; OR = 0.70, 95%CI: 0.58-0.84, respectively). Our meta-analysis confirmed MICA-A6 could be responsible for BD in three ethnic regions and should probably be treated as a risk factor for BD. MICA-A4, A5, A5.1, and A9 could be regarded as protective factors, especially in the Middle East and East Asia.
Topics: Alleles; Behcet Syndrome; Ethnicity; Genetic Association Studies; Genetic Predisposition to Disease; Histocompatibility Antigens Class I; Humans; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 26875668
DOI: 10.1038/srep21033 -
Medicina Clinica Sep 2020To generate recommendations on the use of immunomodulators in patients with non-infectious, non-neoplastic intermediate uveitis (IU), posterior uveitis (PU) and...
OBJECTIVE
To generate recommendations on the use of immunomodulators in patients with non-infectious, non-neoplastic intermediate uveitis (IU), posterior uveitis (PU) and panuveitis (PanU) based on best evidence and experience.
METHODS
A multidisciplinary panel of 5 experts was established, who defined the scope, users, and sections of the document. A systematic literature review (SLR) was performed to assess the efficacy and safety of immunomodulatory drugs in patients with non-infectious, non-neoplastic, non-anterior uveitis. The results of the SLR were presented and discussed during an expert meeting in which 34 recommendations were generated. The level of agreement with the recommendations was also tested in 25 additional experts following a Delphi process. Recommendations were voted from 1 (total disagreement) to 10 (total agreement). We defined agreement if at least 70% of the experts voted ≥7. The level of evidence and grade or recommendation were assessed using the Oxford Centre for Evidence-based Medicine Levels of Evidence.
RESULTS
The SLR included 33 articles. The 34 recommendations were accepted after 2 Delphi rounds (3 of them were modified after the first round). They include specific recommendations on patients with non-infectious, non-neoplastic, PU and PanU, as well as different treatment guidelines.
CONCLUSIONS
In patients with non-infectious, non-neoplastic, non-anterior uveitis these recommendations might help treatment decision making, due to the lack of robust evidence or other globally accepted algorithms.
Topics: Evidence-Based Medicine; Humans; Immunosuppressive Agents; Panuveitis; Uveitis; Uveitis, Anterior
PubMed: 32199631
DOI: 10.1016/j.medcli.2019.10.023 -
The Cochrane Database of Systematic... Oct 2022Non-infectious intermediate, posterior, and panuveitis (NIIPPU) represent a heterogenous collection of autoimmune and inflammatory disorders isolated to or concentrated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Non-infectious intermediate, posterior, and panuveitis (NIIPPU) represent a heterogenous collection of autoimmune and inflammatory disorders isolated to or concentrated in the posterior structures of the eye. Because NIIPPU is typically a chronic condition, people with NIIPPU frequently require treatment with steroid-sparing immunosuppressive therapy. Methotrexate, mycophenolate, cyclosporine, azathioprine, and tacrolimus are non-biologic, disease-modifying antirheumatic drugs (DMARDs) which have been used to treat people with NIIPPU.
OBJECTIVES
To compare the effectiveness and safety of selected DMARDs (methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, and azathioprine) in the treatment of NIIPPU in adults.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE, Embase, the Latin American and Caribbean Health Sciences database, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, most recently on 16 April 2021.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) comparing selected DMARDs (methotrexate, mycophenolate, tacrolimus, cyclosporine, and azathioprine) with placebo, standard of care (topical steroids, with or without oral steroids), or with each other.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 11 RCTs with a total of 601 participants in this review. DMARDs versus control Two studies compared an experimental DMARD (cyclosporine A or enteric-coated mycophenolate [EC-MPS]) plus oral steroid with steroid monotherapy. We did not pool these results into a meta-analysis because the dose of cyclosporine used was much higher than that used in current clinical practice. The evidence is very uncertain about whether EC-MPS plus low-dose oral steroid results in a higher proportion of participants achieving control of inflammation over steroid monotherapy (risk ratio [RR] 2.81, 95% confidence interval [CI] 1.10 to 7.17; 1 study, 41 participants; very low-certainty evidence). The change in best-corrected visual acuity (BCVA) was reported separately for right and left eyes. The evidence for improvement (lower logarithm of the minimum angle of resolution (logMAR) indicates better vision) between the groups is very uncertain (mean difference [MD] -0.03 and -0.10, 95% CI -0.96 to 0.90 and -0.27 to 0.07 for right and left, respectively; 1 study, 82 eyes; very low-certainty evidence). No data were available for the following outcomes: proportion of participants achieving a 2-line improvement in visual acuity, with confirmed macular edema, or achieving steroid-sparing control. The evidence for the proportion of participants requiring cessation of medication in the DMARD versus control group is very uncertain (RR 2.61, 95% CI 0.11 to 60.51; 1 study, 41 participants; very low-certainty evidence). Methotrexate versus mycophenolate We were able to combine two studies into a meta-analysis comparing methotrexate versus mycophenolate mofetil. Methotrexate probably results in a slight increase in the proportion of participants achieving control of inflammation, including steroid-sparing control, compared to mycophenolate at six months (RR 1.23, 95% CI 1.01 to 1.50; 2 studies, 261 participants; moderate-certainty evidence). Change in BCVA was reported per eye and the treatments likely result in little to no difference in change in vision (MD 0.01 logMAR higher [worse] for methotrexate versus mycophenolate; 2 studies, 490 eyes; moderate-certainty evidence). No data were available for the proportion of participants achieving a 2-line improvement in visual acuity. The evidence is very uncertain regarding the proportion of participants with confirmed macular edema between methotrexate versus mycophenolate (RR 0.49, 95% CI 0.19 to 1.30; 2 studies, 35 eyes; very low-certainty). Methotrexate versus mycophenolate may result in little to no difference in the proportion of participants requiring cessation of medication (RR 0.99, 95% CI 0.43 to 2.27; 2 studies, 296 participants; low-certainty evidence). Steroids with or without azathioprine versus cyclosporine A Four studies compared steroids with or without azathioprine (oral steroids, intravenous [IV] steroids, or azathioprine) to cyclosporine A. We excluded two studies from the meta-analysis because the participants were treated with 8 mg to 15 mg/kg/day of cyclosporine A, a significantly higher dose than is utilized today because of concerns for nephrotoxicity. The remaining two studies were conducted in all Vogt-Koyanagi-Harada disease (VKH) populations and compared cyclosporine A to azathioprine or IV pulse-dose steroids. The evidence is very uncertain for whether the steroids with or without azathioprine or cyclosporine A influenced the proportion of participants achieving control of inflammation (RR 0.84, 95% CI 0.70 to 1.02; 2 studies, 112 participants; very low-certainty evidence), achieving steroid-sparing control (RR 0.64, 95% CI 0.33 to 1.25; 1 study, 21 participants; very low-certainty evidence), or requiring cessation of medication (RR 0.85, 95% 0.21 to 3.45; 2 studies, 91 participants; very low-certainty evidence). The evidence is uncertain for improvement in BCVA (MD 0.04 logMAR lower [better] with the steroids with or without azathioprine versus cyclosporine A; 2 studies, 91 eyes; very low-certainty evidence). There were no data available (with current cyclosporine A dosing) for the proportion of participants achieving a 2-line improvement in visual acuity or with confirmed macular edema. Studies not included in synthesis We were unable to include three studies in any of the comparisons (in addition to the aforementioned studies excluded based on historic doses of cyclosporine A). One was a dose-response study comparing cyclosporine A to cyclosporine G, a formulation which was never licensed and is not clinically available. We excluded another study from meta-analysis because it compared cyclosporine A and tacrolimus, considered to be of the same class (calcineurin inhibitors). We were unable to combine the third study, which examined tacrolimus monotherapy versus tacrolimus plus oral steroid, with any group.
AUTHORS' CONCLUSIONS
There is a paucity of data regarding which DMARD is most effective or safe in NIIPPU. Studies in general were small, heterogenous in terms of their design and outcome measures, and often did not compare different classes of DMARD with each other. Methotrexate is probably slightly more efficacious than mycophenolate in achieving control of inflammation, including steroid-sparing control (moderate-certainty evidence), although there was insufficient evidence to prefer one medication over the other in the VKH subgroup (very low-certainty evidence). Methotrexate may result in little to no difference in safety outcomes compared to mycophenolate.
Topics: Adult; Humans; Macular Edema; Cyclosporine; Mycophenolic Acid; Tacrolimus; Azathioprine; Methotrexate; Steroids; Immunosuppressive Agents; Panuveitis; Inflammation; Antirheumatic Agents
PubMed: 36315029
DOI: 10.1002/14651858.CD014831.pub2 -
Rheumatology (Oxford, England) Jan 2015We investigated the effect of gender on the clinical Adamantiades-Behçet's disease (ABD) phenotype with data from the German ABD registry and a meta-analysis from a... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
We investigated the effect of gender on the clinical Adamantiades-Behçet's disease (ABD) phenotype with data from the German ABD registry and a meta-analysis from a systematic literature review.
METHODS
Using the German ABD registry data, we compared 36 clinical variables by gender (with women as the reference category) and investigated potential effect modification by HLA-B5 or ethnic background. The registry data were combined with those from a literature search to calculate pooled relative risks (RRs) for variables with data from ≥10 relevant datasets.
RESULTS
The German ABD registry provided information for 747 subjects (58.1% males) and the systematic literature review identified another 52 datasets informing on 16 variables. Both analyses consistently revealed the association of male gender with ocular involvement (RR 1.28 and 1.34 from the ABD registry and meta-analysis, respectively), folliculitis (RR 1.30 and 1.26), papulopustular lesions (RR 1.23 and 1.25), vascular involvement (RR 2.31 and 2.27), superficial (RR 2.96 and 1.63) and deep venous thromboses (RR 2.56 and 2.16) and female gender with genital ulcers (RR 0.78 and 0.92) and joint involvement (RR 0.79 and 0.89). The ABD registry data additionally showed male gender associated with heart involvement (RR 10.60), whereas the meta-analyses revealed male gender associated with the pathergy test (RR 1.14) and female gender associated with erythema nodosum (RR 0.86). HLA-B5 and Turkish or German origin did not affect the observed associations.
CONCLUSION
These analyses support gender-associated clinical variations in ABD and in particular a clinically meaningful risk of cardiovascular involvement for men.
Topics: Adolescent; Adult; Behcet Syndrome; Female; Folliculitis; Genital Diseases, Female; Germany; HLA-B Antigens; Humans; Incidence; Joint Diseases; Male; Phenotype; Registries; Risk Factors; Sex Factors; Venous Thrombosis; Young Adult
PubMed: 25118314
DOI: 10.1093/rheumatology/keu247 -
Ophthalmology Jul 2024Sympathetic ophthalmia (SO) is a rare bilateral granulomatous panuveitis that can present after trauma or intraocular surgery (IOS). The incidence of SO after IOS varies... (Meta-Analysis)
Meta-Analysis Review
TOPIC
Sympathetic ophthalmia (SO) is a rare bilateral granulomatous panuveitis that can present after trauma or intraocular surgery (IOS). The incidence of SO after IOS varies among studies. The purpose of this review was to determine the incidence proportion of SO after IOS.
CLINICAL RELEVANCE
The incidence proportion of SO after IOS can provide physicians and patients with information on the risk of SO during the consent process before surgery.
METHODS
In this systematic review and meta-analysis, MEDLINE, EMBASE, and Cochrane databases were searched from inception to January 1, 2023 for population-based studies of SO after IOS. Two reviewers independently screened the results. Random-effects meta-analyses calculated incidence proportion. Subgroup analysis assessed SO incidence based on IOS type and technological advancements. Study quality and bias were assessed using the Newcastle-Ottawa scale and the Grades of Recommendation, Assessment, Development, and Evaluation framework.
RESULTS
The final meta-analyses included 19 studies, with 118 cases of SO occurring after 505 178 inciting events. The estimated overall incidence proportion of SO after IOS was 0.061% (95% confidence interval [CI], 0.033%-0.111%; I = 83%), and the estimated incidence rate was 9.24 cases per 100 000 person-years (95% CI, 4.03-21.19; I = 88%). The average study duration across these studies was 10.8 years. Within the reviewed literature, SO after glaucoma and vitreoretinal IOS was studied most, with 9 and 6 studies, respectively. Observed differences in incidence between glaucoma (0.098%; 95% CI, 0.042%-0.232%; I = 40%) and vitreoretinal (0.043%; 95% CI, 0.022%-0.085%; I = 88%) IOS were not statistically significant (P = 0.14). Also, no significant difference was found in the incidence proportion before and after 1975, when modern intraocular surgical techniques emerged (0.060% vs. 0.058%; P = 0.98). The outcome measures showed low-certainty Grades of Recommendation, Assessment, Development, and Evaluation evidence.
DISCUSSION
Sympathetic ophthalmia after IOS is rare and might not have changed over the past 5 decades. The estimated incidence proportion of SO may be useful during the consent process before surgery. Also, no significant difference may exist in the incidence of SO between glaucoma and vitreoretinal IOS, based on low-certainty evidence.
FINANCIAL DISCLOSURE(S)
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Topics: Humans; Ophthalmia, Sympathetic; Incidence; Postoperative Complications; Ophthalmologic Surgical Procedures
PubMed: 38215990
DOI: 10.1016/j.ophtha.2024.01.014 -
Seminars in Arthritis and Rheumatism Dec 2020Non-infectious non-anterior uveitis (NINA) is a sight-threatening condition that often requires immunomodulatory drugs (IMDs) for its management.
Efficacy and safety of immunomodulatory drugs in patients with non-infectious intermediate and posterior uveitis, panuveitis and macular edema: A systematic literature review.
BACKGROUND
Non-infectious non-anterior uveitis (NINA) is a sight-threatening condition that often requires immunomodulatory drugs (IMDs) for its management.
OBJECTIVES
To evaluate the published evidence regarding the use of IMDs in adult patients with NINA uveitis including intermediate (IU) and posterior uveitis (PU), panuveitis (PanU) and macular edema (ME).
METHODS
We performed a systematic literature review. Search strategies were designed for Medline, Embase, and Cochrane Libraries for articles up to 2019 to evaluate the efficacy and safety of the IMDs. A quality assessment was performed using the Jadad Scale.
RESULTS
Nineteen randomized clinical trials were selected from the 1,103 articles retrieved. Characteristics of patients, treatment dosages and outcome measures were heterogeneous. The outcomes most frequently analyzed were visual acuity (VA), macular thickness and vitreous haze (VH). Different IMDs were used at their usual dosages. Methotrexate (MTX), micophenolate mofetil, cyclosporine A (CsA), tacrolimus, adalimumab and sarilumab were effective in NINA uveitis. Rituximab combined with MTX was effective in PU. Interferon-β was superior to MTX, albeit with more adverse events in IU with ME. CsA was similar to cyclophosphamide (Cyc) in Behçet uveitis. Tacrolimus was safer and similar to CsA. Cyc was effective in serpiginoid choroiditis, but when combined with azathioprine in PU, but did not improve VA. Secukinumab did not prevent NINA uveitis recurrences, although intravenously it showed a higher response rate than when used subcutaneously. Daclizumab did not show any benefits in Behçet NINA uveitis.
CONCLUSION
Several IMDs and their combinations can be useful in treating NINA uveitis. The available studies were heterogeneous regarding patient characteristics and outcomes.
Topics: Adult; Humans; Macular Edema; Panuveitis; Pharmaceutical Preparations; Treatment Outcome; Uveitis; Uveitis, Posterior
PubMed: 33065425
DOI: 10.1016/j.semarthrit.2020.08.010 -
International Journal of Molecular... Apr 2020In this both narrative and systematic review, we explore the role of TNF-α in the immunopathogenesis of Behçet's disease (BD) and the effect of treatment with TNF-α...
In this both narrative and systematic review, we explore the role of TNF-α in the immunopathogenesis of Behçet's disease (BD) and the effect of treatment with TNF-α blockers. BD is an auto-inflammatory disease, characterized by recurrent painful oral ulcerations. The pathogenesis of BD is not yet elucidated; it is assumed that TNF-α may play a key role. In the narrative review, we report an increased production of TNF-α, which may be stimulated via TLR-signaling, or triggered by increased levels of IL-1β and IFN-γ. The abundance of TNF-α is found in both serum and in sites of inflammation. This increased presence of TNF-α stimulates T-cell development toward pro-inflammatory subsets, such as Th17 and Th22 cells. Treatment directed against the surplus of TNF-α is investigated in the systematic review, performed according to the PRISMA guideline. We searched the Pubmed and Cochrane database, including comparative studies only. After including 11 studies, we report a beneficial effect of treatment with TNF-α blockers on the various manifestations of BD. In conclusion, the pivotal role of TNF-α in the immunopathogenesis of BD is reflected in both the evidence of their pro-inflammatory effects in BD and in the evidence of the positive effect of treatment on the course of disease in BD.
Topics: Animals; Behcet Syndrome; Disease Management; Disease Susceptibility; Humans; Molecular Targeted Therapy; Tumor Necrosis Factor-alpha
PubMed: 32349254
DOI: 10.3390/ijms21093072 -
Journal of Digestive Diseases Feb 2021Behçet's disease (BD) is a chronic inflammatory disease characterized by recurrent oral aphthous ulcers, intestinal lesions, genital ulcers, uveitis, and skin lesions.... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Behçet's disease (BD) is a chronic inflammatory disease characterized by recurrent oral aphthous ulcers, intestinal lesions, genital ulcers, uveitis, and skin lesions. Evidence regarding mucosal healing for the prognosis of intestinal BD is scarce. The aim of this systematic review and meta-analysis was to determine the association between mucosal healing and long-term outcomes of patients with intestinal BD.
METHODS
Relevant studies were identified in a comprehensive search of PubMed, Cochrane Library, and EMBASE databases. Studies reporting long-term outcomes of mucosal healing in patients with intestinal BD were included. Pooled risk ratio (RR) and 95% confidence interval (CI) for disease recurrence and surgery were calculated using the Mantel-Haenszel random-effects models. Heterogeneity among the eligible studies was evaluated using the Q test and I statistics.
RESULTS
Of the 4785 studies initially identified, 8 were finally included. The pooled RR for the association between mucosal healing and disease recurrence was 0.41 (95% CI 0.30-0.57, P < 0.001). For the association between mucosal healing and the risk of surgery, the pooled RR was 0.33 (95% CI 0.17-0.63, P < 0.001). Confounding factors were adjusted in one study, whereas other studies only reported a crude association between mucosal healing and long-term outcomes without adjustment.
CONCLUSIONS
Mucosal healing is associated with a decreased risk of recurrence and surgery in intestinal BD. However, more studies are required given a small number of currently eligible studies and insufficient adjustment for confounding factors.
Topics: Behcet Syndrome; Humans; Intestinal Diseases; Intestines; Prognosis; Stomatitis, Aphthous
PubMed: 33314672
DOI: 10.1111/1751-2980.12965 -
European Journal of Clinical... Aug 2022Behçet disease (BD) is a systemic vasculitis. In addition to the mucocutaneous lesions, the vascular injury of pathophysiology in BD is theoretically correlated with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Behçet disease (BD) is a systemic vasculitis. In addition to the mucocutaneous lesions, the vascular injury of pathophysiology in BD is theoretically correlated with cardiovascular diseases. This study aimed to elucidate the association of BD with ischaemic heart diseases (IHDs) and stroke.
METHODS
A systematic search of PubMed, Embase, Web of Science and Cochrane Library databases was performed for all relevant observational studies from database inception until 10 July 2021. No language restriction was applied. A random-effects model was used for meta-analysis.
RESULTS
A total of six observational studies consisting of three cohort studies, two cross-sectional studies and one study with both study designs were adopted in the meta-analysis. The numbers of patients with BD and healthy controls were 9,813 and 41,802, respectively. The pooled analysis demonstrated no significant association between BD and IHD. By contrast, we found that patients with BD had a significantly higher risk of stroke (adjusted hazard ratio, 2.083; 95% confidence interval, 1.339-3.240; p = 0.001) than healthy controls. We observed substantial heterogeneity across studies in few meta-analyses, but no significant publication bias was detected in any of the meta-analyses.
CONCLUSIONS
BD was significantly associated with stroke but not IHD. Physicians should be aware of possible vascular and neurological complications during care of patients with BD.
Topics: Behcet Syndrome; Cross-Sectional Studies; Humans; Myocardial Ischemia; Risk Factors; Stroke
PubMed: 35342952
DOI: 10.1111/eci.13778