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

Am J Dermatopathol. 2021 Oct 1;43(10):689-699. doi: 10.1097/DAD.0000000000001817.


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 I2 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.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Autoimmune Diseases / diagnosis*
  • Complement C3d / analysis*
  • Complement C4b / analysis*
  • Dermatitis Herpetiformis / diagnosis
  • Humans
  • Immunoglobulin A / analysis
  • Immunoglobulin G / analysis*
  • Immunoglobulin M / analysis
  • Immunohistochemistry
  • Paraffin Embedding
  • Pemphigoid, Bullous / diagnosis
  • Pemphigus / diagnosis
  • Peptide Fragments / analysis*
  • Skin Diseases, Vesiculobullous / diagnosis*


  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin M
  • Peptide Fragments
  • Complement C3d
  • Complement C4b
  • complement C4d