Immunoglobulin and Complement Immunohistochemistry on Paraffin Sections in Autoimmune Bullous Diseases: A Systematic Review and Meta-analysis

Abstract

Immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tissue has been proposed as a potential tool in the diagnosis of autoimmune bullous diseases (AIBDs) in lieu of standard direct immunofluorescence (DIF) microscopy. To comprehensively determine the diagnostic accuracy of immunoglobulin and complement IHC for diagnosis of AIBDs, we conducted a systematic review and multivariate Bayesian model-based meta-analysis of the literature. Quality and heterogeneity assessment of studies was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist and the I 2 index, respectively. Electronic searches using PubMed from April 1964 to July 2020 identified 14 articles meeting predetermined inclusion and exclusion criteria. Median sensitivities with 95% credible intervals in pemphigus and pemphigoid were 0.24 (0.01-0.89) and 0.22 (0.02-0.77) with immunoglobulin G (IgG), 0.77 (0.39-0.95) and 0.25 (0.02-0.85) with IgG4, 0.11 (0.02-0.32) and 0.86 (0.56-0.98) with C3d, and 0.84 (0.56-0.97) and 0.75 (0.37-0.94) with C4d, respectively. Specificities were 1.00 (0.00-1.00) with IgG, 0.98 (0.89-1.00) with IgG4, 0.99 (0.97-1.00) with C3d, and 0.99 (0.97-1.00) with C4d. The risk of bias and heterogeneity among studies was a serious problem, decreasing the level of evidence. Our work suggests that, in selected cases, paraffin-based IHC may be a helpful procedure to screen for AIBDs, especially when specialized laboratories and/or biopsy specimens for DIF do not exist. Nevertheless, more studies with a refined quality design are needed to explore the true usefulness of this diagnostic method in AIBDs.

Impact of adding an IgG4 conjugate to routine direct immunofluorescence testing for subepithelial and intraepithelial autoimmune blistering disorders

“…Prior studies have reported relatively high sensitivity and specificity of IgG4 immunohistochemistry on fixed specimens for pemphigus and high specificity (although not sensitivity) for pemphigoid. 14 This study did not evaluate IgG4 immunohistochemistry on fixed specimens and believe larger validation trials are necessary before incorporating this diagnostic modality into routine clinical care.…”

Applications of Model-Based Meta-Analysis in Drug Development

“…Additional collaborations are also possible with the health economics and outcomes research (HEOR) function, with which outputs from the MBMA could be integrated into other, non-clinically focused models, such as cost-effectiveness models or financial forecasting models, potentially leading to improved commercial and financial strategies [45]. Therefore, continued education and communication among project stakeholders, team collaborators, and [19,[107][108][109][110] Correlation between early and late endpoints Allow the use of a biomarker or an early clinical efficacy time point to detect a signal of the treatment effect [38,42,63,111] Pharmacokinetic and pharmacodynamic relationship Establishing the relationship between exposure and an efficacy or safety biomarker, possibly a less frequently reported one and would need data from a large population to be detected [41,[112][113][114][115][116][117] Simulation of established MBMA models Simulate various scenarios using established MBMA models to optimize clinical trial design [62,118] Pharmacoeconomics Incorporate cost-effectiveness into a MBMA model [119] other pharmacometric specialty experts regarding MBMA and MIDD approaches in general are warranted [1]. Another important ally of MIDD approaches is from statistics.…”

State-of-the-art diagnosis of autoimmune blistering diseases

“…However, this method is hampered by its low sensitivity and specificity, most likely due to the lesional biopsy that favors unspecific labeling along the degraded BMZ and the degradation of immunoreactants by activated tissue proteases. As such, this method is only suitable in individual cases when no direct IFM and serology are available ( 147 ).…”

“…IgG reactivity along the blister floor of salt-split human skin, which can be seen in anti-laminin 332 mucous membrane pemphigoid, epidermolysis bullosa acquisita, and anti-p200 pemphigoid (F). As such, this method is only suitable in individual cases when no direct IFM and serology are available (147). In summary, lesional histopathology is still recommended in every patient with suspicion of an AIBD (19,20,25,29,65,68,148).…”