Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review

To the Editor,

Primary neutrophilic cicatricial alopecias (PNCAs) are conditions marked by neutrophilic inflammation preceding scarring hair loss. ¹ This group includes folliculitis decalvans (FD) and dissecting cellulitis of the scalp (DCS). First-line therapy currently involves retinoids (DCS) and antibiotics (FD), however, the novel use of biologics and small molecules has been recently reported. ¹ This systematic review summarizes evidence surrounding these treatments for PNCAs.

We registered a protocol to PROSPERO (ID: 404616) and followed PRISMA guidelines to search Embase and MEDLINE databases using variations of specific keywords (Supplemental Table 1). Quality of evidence was assessed using Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. After independent screening by two reviewers, 36 articles (publication date: 2007-2023) reflecting 107 patients and 120 treatments were included (Supplemental Figure 1; Supplemental Table 2). The mean age was 33.2 years (range: 15-67 years) with 88 males (82.2%), 15 females (14%), and unreported sex in 4 patients (3.7%). PNCAs refractory to systemic or topical therapy was reported in 99% (106/107) of patients.

There were 55% (66/120) and 45% (54/120) of treatments involving DCS and FD respectively (Supplemental Table 3). Mean treatment duration was 231.4 days (117/120). Concurrent medication use was described in 14% (15/107) of patients with frequent use of systemic/topical corticosteroids (73%, 11/15) (Supplemental Table 2). The biologic or small molecule classes most commonly reported were: tumor necrosis factor-α inhibitors (TNF-αi) (78.3%, 94/120), Janus kinase inhibitors (JAKi) (7.5%, 9/120), interleukin-23 inhibitors (IL-23i) (4.2%, 5/120), immunoglobulins (3.3%, 4/120), IL-17i (2.5%, 3/120), and phosphodiesterase-4 inhibitors (2.5%, 3/120) (Supplemental Table 4). Overall, TNF-αi (86.2%, 81/94) resulted in the greatest mean resolution (complete or partial). In DCS, IL-17/23i (100%, 4/4) demonstrated high resolution rates whereas in FD, favorable outcomes were observed with JAKi (77.9%, 7/9) and immunoglobulins (100%, 4/4). Twenty (16.7%, 20/120) separate adverse events occurred including 7/120 discontinuations due to upper respiratory tract infection, candidal intertrigo, and condyloma accuminata (Supplemental Table 2).

The pathogenesis of FD and DCS remains unclear with limited available literature on the involvement of immune dysregulation. Nonetheless, a recent study demonstrated that IL-8 may play a prominent role in the early neutrophilic stage of FD development with moderate contribution by TNF-α, IL-4, and IL-1. ² Furthermore, late colonization by Staphylococcus aureus with superantigens may trigger a TNF-α-mediated cytokine cascade. ^{2 -4} Although no current studies have evaluated the cytokine profile of DCS, shared follicular hyperkeratosis and clinical features in hidradenitis suppurativa (HS) have indicated DCS and HS may be variants of a single entity. ⁵ It has been found that HS patients have elevated lesional TNF-α along with increased expression of Th17-related cytokines. ⁵ These findings may explain the overall efficacy of TNF-αi for PNCAs in this review along with the benefit seen with pan-cytokine inhibition through JAKi and IL-23/17i in FD and DCS respectively.

Study limitations include: identified articles restricted to observational studies, small sample sizes, and the lack of standardized outcome measures for DCS/FD. Meta-analysis was not performed due to heterogeneity. Regardless, we highlight evidence on biologic and small molecule therapy for PNCAs, supporting the indication for larger-scale studies.

Supplemental Material

Table S1 - Supplemental material for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review

Supplemental material, Table S1, for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review by Siddhartha Sood, Aswen Sriranganathan, Martin Heung, Jorge R. Georgakopoulos, Asfandyar Mufti and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Table S2 - Supplemental material for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review

Supplemental material, Table S2, for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review by Siddhartha Sood, Aswen Sriranganathan, Martin Heung, Jorge R. Georgakopoulos, Asfandyar Mufti and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Table S3 - Supplemental material for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review

Supplemental material, Table S3, for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review by Siddhartha Sood, Aswen Sriranganathan, Martin Heung, Jorge R. Georgakopoulos, Asfandyar Mufti and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Table S4 - Supplemental material for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review

Supplemental material, Table S4, for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review by Siddhartha Sood, Aswen Sriranganathan, Martin Heung, Jorge R. Georgakopoulos, Asfandyar Mufti and Jensen Yeung in Journal of Cutaneous Medicine and Surgery

Supplemental Material

Figure S1 - Supplemental material for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review

Supplemental material, Figure S1, for Biologic and Small Molecule Treatments for Primary Neutrophilic Cicatricial Alopecias: An Evidence-Based Review by Siddhartha Sood, Aswen Sriranganathan, Martin Heung, Jorge R. Georgakopoulos, Asfandyar Mufti and Jensen Yeung in Journal of Cutaneous Medicine and Surgery