Kalot, Mohamad A

Background. The study aims is to use the fragility index (FI) to examine the strength of evidence of randomized controlled trials (RCTs) published in the last decade on kidney transplantation. Methods. We searched MEDLINE for studies on kidney transplantation. We included the RCTs that compared 2 groups with 1:1 randomization and reported significant P values (<0.05) for a dichotomous outcome and were published in the top 10 transplant journals. We calculated the FI; a calculation used to determine the minimum number of subjects needed to change from a nonevent to an event to make the study results nonsignificant (P ≥ 0.05). Results. Fifty-seven RCTs met our inclusion criteria. The median sample size was 100 participants in each arm, the median number of events was 16 (interquartile range, 8–30) in the intervention group. Among the included trials, 79% were industry-funded, 93% involved medications, and the majority were open label. The median FI was 3 (interquartile range, 1–11). In 43% of the trials, the number of patients reported lost to follow-up was higher than or equal to the FI. Only 4% of the RCTs imputed a value for the missing dichotomous outcome. Furthermore, the median number of subjects who discontinued the trial because of adverse effects was 21, which was greater than the FI in 60% of the RCTs. Conclusions. The arbitrary classification of results into “significant” and “nonsignificant” based on P value <0.05 should perhaps be interpreted with the help of other statistical parameters and FI is one of them.

This systematic review compares treatment options for patients with giant cell arteritis (GCA) and evaluates the test accuracy of studies used in diagnosing and monitoring GCA. These studies were used to inform evidence‐based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) vasculitis management guidelines. A systematic review and search of articles in English in Ovid Medline, PubMed, Embase, and the Cochrane Library was conducted. Articles were screened for suitability, and studies presenting the highest level of evidence were given preference. Three hundred ninety‐nine full‐text articles addressing GCA questions were reviewed to inform 27 Population, Intervention, Comparison, and Outcome questions. No benefit was found with intravenous glucocorticoids (GCs) compared with high‐dose oral GCs in patients with cranial ischemic symptoms (27.4% vs 12.3%; odds ratio [OR] 2.39 [95% confidence interval (CI) 0.75‐7.62], [very low certainty of evidence]). Weekly tocilizumab with a 26‐week GC taper was superior to a 52‐week GC taper in patients achieving remission (risk ratio 4.00 [95% CI 1.97‐8.12], [low certainty of evidence]). Non‐GC immunosuppressive therapies with GCs compared with GCs alone showed no statistically significant in relapse at 1 year (OR 0.87 [95% CI 0.73‐1.04], [moderate certainty of evidence]) or serious adverse events (OR 0.81 [95% CI 0.54‐1.20]; [moderate certainty of evidence]). Temporal artery biopsy has a sensitivity of 61% (95% CI 38%‐79%) and a specificity of 98% (95% CI 95%‐99%) in patients with a clinical diagnosis of suspected GCA. This comprehensive systematic review synthesizes and evaluates the benefits and harms of different treatment options and the accuracy of commonly used tests for the diagnosis and monitoring of GCA.

ObjectiveThe aim of this systemic review is to compare different treatments for patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) to inform evidence‐based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) Vasculitis Management Guidelines.MethodsA systemic review was conducted by searching articles in English using OVID Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing PICO questions, with studies presenting the highest level of evidence given preference.ResultsA total of 729 full‐text articles addressing GPA and MPA PICO questions were reviewed. For remission induction, rituximab was shown to be noninferior to cyclophosphamide (CYC) (odds ratio [OR]: 1.55, moderate certainty of evidence). The addition of plasma exchange to induction therapy in severe disease did not improve the composite end point of death or end stage renal disease (hazard ratio [HR]: 0.86 [95% confidence interval CI: 0.65, 1.13], moderate certainty of evidence). In nonsevere disease, methotrexate was noninferior to CYC for induction of remission (remission at 6 months of 90% vs. 94%). For maintenance of remission, methotrexate and azathioprine showed no difference in the risk of relapse over a mean follow‐up of 29 months (HR: 0.92, [95% CI: 0.52, 1.65]low certainty of evidence). As maintenance therapy, rituximab was superior to a tapering azathioprine strategy in major relapse‐free survival at 28 months (HR: 6.61, [95% CI: 1.56, 27.96], moderate certainty of evidence). In two randomized trials, longer‐term azathioprine maintenance therapy (>24 months) is associated with fewer relapses without an increase in adverse events.ConclusionThis comprehensive systematic review synthesizes and evaluates the benefits and toxicities of different treatment options for GPA and MPA.

ObjectiveTakayasu’s arteritis (TAK) is a granulomatous large‐vessel vasculitis primarily affecting the aorta and its proximal branches. TAK can be a difficult disease to diagnose and manage given the rarity of the disease as well as current limitations in biomarkers, imperfect imaging modalities, and few randomized controlled trials.MethodsIn developing the American College of Rheumatology/Vasculitis Foundation guideline for the management of TAK, we performed an extensive systematic literature review to guide our recommendations. We included RCTs first. When RCTs were not available, we included observational studies that reported on patient‐important outcomes for the intervention and comparison. When studies with comparative data were not available, we included case series that present patient‐important outcomes for either the intervention or the comparison.ResultsThree hundred forty‐seven articles were included for full review to answer 27 population, intervention, comparison, and outcome questions related to TAK. Ten studies were evaluated that addressed the use of glucocorticoids (GCs), non‐GC nonbiologic therapies, as well as biologics in treating TAK. A total of 33 studies, including 8 comparative studies, were included to determine the test accuracy of commonly available diagnostic tests for TAK.ConclusionThis comprehensive systematic review synthesizes and evaluates the benefits and harms of different treatment options and the accuracy of commonly used tests for the management of TAK.

ObjectiveThe object of this study was to analyze the benefits and harms of different treatment options and to analyze test accuracy used in the evaluation of patients with primary systemic polyarteritis nodosa (PAN).MethodsA systematic search of published English‐language literature was performed in Ovid Medline, PubMed, Embase, and the Cochrane Library from the inception of each database through August 2019. Articles were screened for suitability in addressing patient, intervention, comparison, and outcome questions, with studies presenting the highest level of evidence given preference.ResultsOf 137 articles selected for data abstraction, we analyzed 21 observational studies and seven randomized controlled trials (RCTs). The results showed indirect evidence that a deep skin biopsy provides good diagnostic accuracy. A combined nerve and muscle biopsy should be obtained for patients with PAN with peripheral neuropathy. Cyclophosphamide with high‐dose glucocorticoids (GCs) is effective as an induction treatment for newly diagnosed active and severe PAN. GC monotherapy is adequate in the majority of patients with nonsevere PAN, although it has a high relapse rate with GC taper. There was insufficient data in determining the optimal duration of non‐GC and GC maintenance therapy. Tumor necrosis factor inhibitors are effective treatment for patients with deficiency of adenosine deaminase 2 (DADA2) with stroke and vasculitis manifestations.ConclusionThis comprehensive systematic review synthesizes and evaluates the harms and benefits of different treatment options and the accuracy of commonly used tests for the diagnosis of systemic PAN. Data for diagnosis and management of PAN and DADA2 are mostly limited to observational studies. More high‐quality RCTs are needed.

ObjectiveEosinophilic granulomatosis with polyangiitis (EGPA) is part of a group of vasculitides commonly referred to as antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), in addition to granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal‐limited vasculitis. Patients with EGPA characteristically have asthma and marked peripheral eosinophilia with only approximately 30% to 35% of patients being myeloperoxidase (MPO)‐ANCA positive, distinguishing it from other forms of AAV (1,2). The aim of this systematic review is to support the development of the American College of Rheumatology/Vasculitis Foundation guideline for the management of EGPA.MethodsA systematic review was conducted of the literature for seven forms of primary systemic vasculitis (GPA, MPA, EGPA, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, and Takayasu arteritis). The search was done for articles in English using Ovid Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing population/patients, intervention, comparator, and outcomes (PICO) questions, with studies presenting the highest level of evidence given preference. Two independent reviewers conducted a title/abstract screen and full‐text review for each eligible study.ResultsThe initial search, conducted in August 2019, included 13 800 articles, of which 2596 full‐text articles were reviewed. There were 190 articles (addressing 34 PICO questions) reporting on the diagnosis and management of EGPA.ConclusionThis comprehensive systematic review synthesizes and evaluates the accuracy of commonly used tests for EGPA as well as benefits and toxicities of different treatment options.

Background. Participant withdrawal from clinical trials occurs for various reasons, predominantly adverse effects or intervention inefficacy. Because these missing participant data can have implications for the validity, reproducibility, and generalizability of study results, when conducting a systematic review, it is important to collect and appropriately analyze missing data information to assess its effects on the robustness of the study results. Methods. In this methodologic survey of missing participant data reporting and handling in systematic reviews, we included meta-analyses that provided pooled estimates of at least 1 dichotomous intervention outcome of a randomized controlled trial performed in adult kidney transplant subjects. Results. Eighty-three systematic reviews (17 Cochrane and 66 non-Cochrane reviews) met the inclusion criteria. The most common intervention was drugs (80%), with the majority involving immunosuppressant drugs 55% (n = 46), followed by surgery in 14% (n = 12). The median follow-up duration was 12 months (maximum, 240 mo). Intention-to-treat or modified intention-to-treat analysis was reported in 24% (n = 20) of the reviews (76% of Cochrane and 10% of non-Cochrane). Overall, the majority of systematic reviews did not quantify (90% [n = 60] non-Cochrane and 29% [n = 5] Cochrane) or include the reasons for missing participant data (88% [n = 58] non-Cochrane and 24% [n = 4] Cochrane). Eleven percent (n = 9) handled missing participant data, 5% (n = 4) justified the analytical method(s) used to handle it, and 2% (n = 2) performed a sensitivity analysis for it. Conclusions. Systematic reviews of kidney transplantation provide inadequate information on missing participant data and usually do not handle or discuss the associated risk of bias with it.