# Selective Complement Inhibition in Anti-p200 Pemphigoid: Immune Infiltrate Profiles and Therapeutic Implications Compared to Bullous Pemphigoid

## TL;DR

This study explores how complement inhibition could be a new treatment for anti-p200 pemphigoid, an autoimmune skin disease, by comparing its immune features to bullous pemphigoid.

## Contribution

The study identifies distinct immune infiltrate profiles in anti-p200 pemphigoid and demonstrates the potential of pathway-specific complement inhibition as a therapeutic strategy.

## Key findings

- Anti-p200 pemphigoid shows a neutrophil-predominant infiltrate, differing from the eosinophil-rich pattern in bullous pemphigoid.
- Complement inhibition drugs like sutimlimab and avacopan effectively block complement deposition in anti-p200 pemphigoid in vitro.
- Patients with anti-p200 pemphigoid can be stratified based on complement fixation levels, suggesting personalized treatment approaches.

## Abstract

Anti-p200 pemphigoid is an autoimmune blistering disease (AIBD) caused by autoantibodies against laminin β4 and/or γ1, and clinically resembles bullous pemphigoid (BP) as well as the inflammatory variant of epidermolysis bullosa acquisita (EBA). All three diseases show IgG and/or C3 deposition along the cutaneous basement membrane zone (BMZ). Although complement activation is central to BP and EBA pathogenesis, its role in anti-p200 pemphigoid remains unclear. To investigate this, we analyzed inflammatory infiltrates in lesional and perilesional skin from anti-p200 pemphigoid patients (n = 11), revealing a neutrophil-predominant pattern, with mixed neutrophil–eosinophil infiltrates in 81% of cases, which contrasted with the eosinophil-rich infiltrates typical of BP. Infiltrating neutrophils expressed C5aR1 and C5aR2. Complement fixation test (CFT) of patient sera demonstrated C3c deposition at the BMZ in 40% (20/50) of anti-p200 pemphigoid cases and 87% (13/15) of BP cases. Patients in both cohorts could be stratified into high, mild, and non-complement-fixating groups. Pharmacological inhibition of C1s (sutimlimab), C3 (compstatin), C5 (tesidolumab), or C5aR1 (avacopan) significantly blocked C3c or C5 deposition in vitro. These findings indicate that selective blockade of the classical, alternative, or terminal complement pathways effectively prevents BMZ complement deposition, highlighting pathway-specific complement inhibition as a potential therapeutic strategy for anti-p200 pemphigoid.