A systematic review of tumor necrosis factor-α blockers, anti-interleukins, and small molecule inhibitors for dissecting cellulitis of the scalp treatment

Abstract

Background

Dissecting cellulitis of the scalp (DCS) is a type of neutrophilic scarring alopecia identified by the development of folliculitis with clusters of perifollicular pustules and then progresses to abscesses and intercommunicating sinus formation. In the absence of evidence-based guidelines, the treatment of DCS remains a therapeutic challenge. Our study aimed to assess the safety and efficacy of biologics, including tumor necrosis factor-α (TNF-α) blockers, anti-interleukins (ILs), and small molecule inhibitors, including Janus kinase (JAK) inhibitors and phosphodiesterase inhibitors in treating DCS.

Methods

PubMed/Medline, Scopus, and Ovid Embase databases were systematically searched until February 4th, 2024. Study selection was restricted to case reports, case series, cohort studies, and clinical trials published in English-language. NIH and Murad et al.’s quality assessment tools were utilized for critical appraisal.

Results

A total of 34 articles involving 81 patients met the inclusion criteria. The immunomodulators studied for the treatment of DCS include adalimumab, infliximab, certolizumab pegol, ustekinumab, secukinumab, guselkumab, risankizumab, tildrakizumab, apremilast, upadacitinib, and baricitinib. Our findings implied that TNF-α blockers and IL inhibitors were associated with clinical improvement in most individuals with moderate-to-severe DCS, especially in those who had failed earlier treatments. Moreover, certolizumab pegol could be a safe option for DCS in pregnancy. In addition, the prescription of small molecule inhibitors, including JAK inhibitors and apremilast in DCS patients, demonstrated a significant amelioration in DCS symptoms with a desirable safety profile. Nevertheless, the available data was limited, warranting further investigation. Besides, all aforementioned immunomodulators are still debated for their effectiveness on hair regrowth and reversing the scarring process.

Conclusions

The application of immunomodulators in treating DCS was associated with satisfactory outcomes, although there is still a need to assess the long-term safety and effectiveness of these therapeutic agents in preventing disease progression and new flare-ups.

Highlights

• Dissecting cellulitis of the scalp (DCS) is a rare, refractory skin disease that manifests with a widespread infiltrate of neutrophils and lymphocytes, which turn into papules, pustules, and abscesses, interconnecting sinuses, and fistulas, and eventually, develops scarring alopecia.

• A combination of antibiotics, corticosteroids, retinoids, and surgical interventions have been utilized to alleviate DCS symptoms.

• Similar to hidradenitis suppurativa, DCS pathogenesis is triggered by inflammatory cascades supported by cytokines such as interleukin (IL)-1b, IL-17, IL-23, IL-10, tumor factor necrosis alpha (TNF-α), and the JAK/STAT signaling pathway.

• Immunomodulatory agents, including JAK inhibitors, TNF-α antagonists, IL inhibitors, and phosphodiesterase inhibitors, represent a therapeutic potential for individuals afflicted with DCS due to their notable efficacy and limited adverse events.

Background

Dissecting cellulitis of the scalp (DCS), known as perifolliculitis capitis abscedens et suffodiens or Hoffman’s disease, represents an orphan disease and uncommon form (1 up to 2%) of neutrophilic cicatricial alopecia [1, 2]. DCS primarily afflicts young males of African-American descent during their second to fourth decades of life [3]. The initial pathologic process involves pilar infundibulum blockade arising from hyperkeratosis, retention of obstructed follicular components following rupture, and inducing an extreme inflammatory response at the bulb of the hair follicle [4]. These sequences lead to the formation of pustules that evolve into interconnected tracts, eventually resulting in the development of keloid scar and patchy areas of alopecia [5]. Histopathological examination unveils early lesions identified by dense neutrophilic, lymphocytic, histiocytic, and plasma cell infiltration [6]. DCS exhibits a spectrum of involvement, ranging from isolated scalp area to the entire scalp, with a predominance of the posterior vertex and upper occiput [1, 5].

DCS is recognized as a constituent of the follicular occlusion triad or tetrad (FOT), alongside hidradenitis suppurativa (HS), acne conglobata (AC), and pilonidal disease [5, 6]. DCS and HS can be explained as variant localizations of a similar disease as they share many genetics and environmental factors commonalities [7]. Both genetics and hormonal factors, as well as bacterial propagations, have claimed to possess a crucial role in the pathology of HS and DCS [8]. Additionally, Although the exact pathophysiological pathway of DCS is still unclear, there are several similarities between DCS and HS regarding probable pathogenesis and treatments [9]. HS lesions have exhibited elevated levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and various interleukins (ILs), representing novel potential targets for treatment [10]. It has been postulated that the primary pathogenic event leading to HS is infundibular hyperplasia that proceeds to intrinsic keratinocyte defect. Furthermore, cyst formation and rupture are distinguished by infiltration of neutrophils, macrophages, dendritic cells, and T and B cells. Additionally, the expression of cytokines such as IL-1β, IL-17, and TNF-α is also induced [11]. Moreover, several transcriptomic studies have depicted an upregulation in Janus kinases (JAKs) and subsequent induction of signal transducer and activator of transcription (STAT) activity [12, 13]. TNF-α is a cytokine involved in the pathogenesis of certain inflammatory and autoimmune conditions. Immunomodulator agents act as antagonists by inhibiting the interaction between TNF-α and its type 1 (TNFR1) and 2 (TNFR2) receptors. Additionally, ILs are cytokines first thought to be produced only by leukocytes but have been discovered to be produced by many other body cells [11]. ILs modulate a variety of actions during inflammatory and immune conditions, including growth, differentiation, and activation responses. The cathelicidin gene is responsible for the production of an antimicrobial protein, hCAP18, which is processed into various peptides, including LL-37. Cutaneous inflammation triggers LL-37 production. It has been observed that LL-37 production is amplified in the skin of HS patients. LL-37 is able to attract CD4 T cells and dendritic cells which in turn results in the release of TNF-α, IL-6, and IL-12, which leads to T helper (Th)1/Th17 phenotype, which is not dependent on antigen-presenting cells. HS severity is also directly related to increased cytokine production promoted by LL-37, including IL-17 and TNF-α.

Furthermore, histological findings of both disorders have indicated the accumulation of dense neutrophils, CD3 + T cells (CD4 + and CD8 +), histiocytes, and plasma cells in the early stages of lesion formation, and granulomas, scarring, and fibrosis appearing in later stages [7, 14]. Neutrophils and Th cells produce proinflammatory cytokines, such as TNF-α, IL-1, IL-23, and IL-17, which are of great importance in the pathogenesis of HS [7, 15]. Moreover, keratinocyte proliferation is caused by the linkage of IL-17 A to IL-17 receptor (IL-17R) A, IL-17RC, or IL-17RD [16]. In addition, there is evidence that the IL-23/IL-17 signaling pathway significantly impacts chronic inflammation in HS since IL-23 increases IL-17 production, a key cytokine associated with HS severity, by stimulating the development and differentiation of Th17 cells. Also, TNF-α raises the Th17/TREG ratio following Th17 polarization enhancement, which is a major contributor to disease development in lesion-involved tissues [17]. Likewise, elevated serum and lesional skin levels of TNF- α, IL1β, IL-10, and IL-17 in the HS subjects than healthy individuals propose these inflammatory markers as potential therapeutic targets as they affect different phases of HS pathology [18]. Notably, anti-TNF-α therapy correlated with a significant drop in Th17 cell number, confirming that TNF-α is critical in provoking IL-17 production in HS lesions [17]. Elevated TNF-a levels in serum and skin patients suffering from DCS along with the prevalent coexistence of DCS and HS as part of the FOT, support the relevance of TNF-a in the pathogenesis of DCS [5, 19]. These findings suggested that biologics can hold a promising effect on DCS management.

Moreover, the JAK/STAT pathways possess a crucial role in numerous inflammatory disorders [20]. Of note, JAKs are a kind of protein tyrosine kinases interacting with transmembrane type 1 and type 2 cytokine receptors to regulate cellular responses to different cytokines and growth factors, which plays a vital role in immune system function [21, 22]. Inhibiting the JAK-STAT pathway suppresses cytokine signaling, resulting in decreased serum inflammatory markers, such as C-reactive protein.

A variety of treatment modalities have been utilized in the management of DCS, including antibiotics, zinc sulfate, isotretinoin, corticosteroids, antiandrogens, laser therapy, aminolevulinic acid-photodynamic therapy, and different types of surgery [1]. There are, however, many prevailing issues associated with these therapies, including recurrence, relapses, limited effectiveness, and complications. Therefore, immunomodulators that suppress different parts of the inflammatory cascade in the HS can also be a potential treatment choice for DCS patients, given several similarities between the aforementioned disorders [5, 9]. Prior investigations indicated that TNF-α and IL inhibitors showed effectiveness in treating HS patients [23–26]. Additionally, previous evidence has demonstrated the potential efficacy of JAK inhibitors as novel options in the treatment of individuals with HS [27, 28]. Further, apremilast is a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4), which reduces the serum level of inflammatory cytokines, such as TNF-α and different ILs [29]. Apremilast administration for HS patients has been associated with satisfactory results in HS cases [30]. A deeper understanding of the efficacy and safety of such immunomodulators in DCS holds great promise for patients who fail conventional therapies [31,32,33,34,35]. This systematic review aims to assess biologics’ clinical effectiveness and safety profile, including anti-ILs, TNF-α, blockers, and small molecule inhibitors, including JAK inhibitors and apremilast, in treating DCS.

Methods

This systematic review was conducted based on Preferred Reporting Item for Systematic Reviews and Meta-Analysis (PRISMA) checklists [37]. These checklists are included in the S1 and S2 Tables.

Search strategy

A systematic search was conducted through PubMed/Medline, Scopus, and Ovid Embase up to February 4 th, 2024. The S3 Table contains the complete list of search terms, including keywords and MeSH terms, and final systematic search results.

Eligibility criteria and study selection

This systematic review included clinical trials, observational studies, case series, and case reports, with an available English full text. The eligible source populations were patients with no age limits who suffered from DCS and received TNF blockers, anti-ILs, PDE4 inhibitors, or JAK inhibitors. Non-English studies, review articles, guidelines, and experimental studies were excluded.

Data extraction

Each study was extracted by two independent reviewers (RG and MF) through a data extraction sheet based on the following information: (I) Study Characteristics (author, year, design, sample size), (II) patients’ characteristics (mean age, gender distribution, past medical history and comorbidities, disease condition and duration, and previous treatments), and (III) outcomes (treatment efficacy, safety, and adverse events, follow-up).

Risk of bias assessment

Two independent investigators (RG and MF) evaluated the articles’ methodological quality and bias risk by using the National Institutes of Health’s Quality Assessment Tool for Cohort and Cross-Sectional Studies [37] and Methodological quality and synthesis of case series and case reports Murad et al. [38] for case reports and case. S4 and S5 Tables illustrated the bias assessment results.

Results

Search results

The systematic literature search achieved 116 related studies, including 22 from PubMed, 57 from Embase, and 37 from Scopus, in the search up to February 4 th, 2024. A total of 64 articles were further screened based on title and abstract after removing the duplicates. After excluding further studies based on title and abstract screening, two independent investigators (NH and YG) evaluated the full texts of 40 articles, given the inclusion and exclusion criteria. In the ultimate evaluation, 31 articles were selected. Moreover, a citation search was conducted, and three studies were included. A total of 34 studies were included for data extraction. Figure 1 demonstrates the PRISMA flowchart of this systematic review.

Fig. 1

PRISMA 2020 flow diagram for new systematic reviews, which included searches of databases, registers, and other sources

Characteristics of eligible studies

A total of 34 articles involving 81 patients with DCS who were treated with anti-TNF-α agents, IL blockers, and small molecule inhibitors, including JAK inhibitors and apremilast were included in the systematic review. The selected studies were as follows: four cohort studies, six case series, and 24 case reports. Although the gender of patients was not mentioned in two articles [39, 40], only three out of 73 patients (4.1%) were women based on the studies in which gender had been reported. Biologics studied for the treatment of DCS include adalimumab, infliximab, secukinumab, guselkumab, risankizumab, ustekinumab, cetulizumab pegol, and tildrakizumab. Moreover, small molecule inhibitors utilized for DCS patients include apremilast, upadacitinib, and baricitinib. All characteristics of eligible studies are summarized in Table 1.

Table 1 Characteristics of clinical studies on Tumor necrosis factor-α blockers, anti-interleukins, and small molecule inhibitors in the treatment of dissecting cellulitis of the scalp

Biologics

Tumor necrosis factor-α blockers (TNF-α blockers)

Anti-TNF-α agents, including adalimumab, infliximab, and certolizumab pegol, were administered to 71 subjects suffering from DCS in four cohort studies, four case series, and 18 case reports. Adalimumab was the most immunomodulator drug studied, with the dose ranging from 40 to 160 mg every 1–2 weeks. The infliximab dosing interval was 5 mg/kg every 4–8 weeks. Moreover, HS and AC were reported as a comorbidity in 22.3% (15/67) and 11.94% (8/67) of subjects. However, in two cohort studies that evaluated the efficacy of various treatments in DCS, the association of HS with anti-TNF-treated HS and AC patients was not mentioned [41, 42].

A retrospective study conducted by Gamissans et al. [42] investigated adalimumab and infliximab as two potential agents for treating cases resistant to conventional therapies, such as isotretinoin, dapsone, and surgery. Based on this study, 14 DCS patients, including 11 patients with DCS stage II and III, were investigated. Of 14 patients, only three received anti-TNF-α: two were treated with adalimumab, and infliximab was administered to one patient. As a result, a complete response was observed in two patients, and one patient experienced a partial response. Nonetheless, treatment withdrawal following infusion reaction was reported in one patient.

Another retrospective cohort study designed by Alzahrani et al. [43] studied 26 patients who were ineffectively treated by systemic antibiotics (92%), isotretinoin (65%), and oral corticosteroids (11%). In 24 cases, TNF-α blockers were started as the third-line treatment. Adalimumab and infliximab were administered in five and 21 patients, respectively. After 19 months, a remarkable decrease in the median number of inflammatory nodules and abscesses, physician’s global assessment (PGA), dermatology life quality index (DLQI), and severity of pain were observed. Furthermore, the median patient satisfaction index was claimed to be seven out of ten. In this study, however, anti-TNFs were discontinued in eight patients for several reasons. Two of these cases developed severe adverse events, including optic neuritis and hepatic cytolysis. Among the individuals who discontinued the treatment, two were in remission, three showed moderate efficacy, and one was lost to follow-up.

Badaoui et al. [41] investigated 51 DCS patients in a retrospective study, one of whom received infliximab. The patient did not show any significant improvement in 11.2 months of follow-up. Moreover, two subjects with DCS were assessed in a cohort study conducted by Sand et al. [44] that aimed to use the off-label TNF-α inhibitors in multiple dermatological conditions. After the failure of isotretinoin, dapsone, and triamcinolone, patients decided to receive adalimumab. Within three months of treatment, one patient achieved a complete clearance of the disease, while the other one did not demonstrate a considerable response despite six months of therapy. During the treatment period, these patients reported no adverse events.

In a case series employed by Frechet et al. [45], adalimumab and infliximab were given to 9 patients who were unresponsive to several treatments. Following the treatment, a notable reduction in PGA and DLQI was detected, as well as the number of inflammatory nodules and abscesses. Additionally, the mean treatment satisfaction index was found to be 6.6 ± 1.6 out of ten. Regarding adverse events, retrobulbar optic neuritis occurred in a patient receiving infliximab, leading to treatment discontinuation. Furthermore, Navarini et al. [46] assessed the efficacy of adalimumab in three DCS patients who had been treated with antibiotics and isotretinoin unsuccessfully. Ultimately, the patients reached a prominent improvement in clinical symptoms within eight weeks and a significant reduction in subjective symptoms after three months. An episode of relapse was observed in one patient after stopping the medication. Moreover, adalimumab administration led to a remarkable reduction in clinical inflammation and burden of disease in seven cases with DCS and severe HS [39]. In addition, Lim et al. [47] assessed five patients with spondylitis and Achilles tendonitis in another case series. Only one patient received adalimumab for his concurrent DCS and obtained sustained improvement in DCS and stabilization of the co-existing diseases without any complication. Moreover, Sanchez-Diaz et al. [48] utilized adalimumab and infliximab to treat two patients with DCS. In both cases, a marked clinical response for hidradenitis suppurativa clinical response was achieved, along with a significant reduction in disease indicators such as nodulocystic acne pain, pruritis, suppuration, Hurley stage of disease, International hidradenitis suppurativa severity, and abscesses and nodules count. Moreover, this favorable response persisted for up to 24 weeks of follow-up in the patient treated with infliximab and extended to 32 weeks of follow-up in the patient treated with adalimumab.

A total of 18 case reports evaluated the efficacy of adalimumab, infliximab, and certolizumab pegol in 16 peers with DCS. Thirteen cases received adalimumab for their condition [5, 20, 32, 49–58]. Signs and symptoms completely resolved after adalimumab administration in 13 patients. Only one patient did not respond to the treatment properly and underwent surgical management [50]. Nevertheless, two patients exhibited adverse events, such as an elevation in triglyceride and total cholesterol serum levels and a tender lump and panniculitis lesions located on the lower limb [49, 50].

Infliximab was administrated in four patients due to an unsuccessful treatment by conventional medications [55, 59–61]. All patients achieved favorable outcomes following infliximab. However, one patient developed a psoriasiform exanthema as a side effect [59].

Among all cases, only one patient was treated with certolizumab pegol [62]. Certolizumab pegol, in conjunction with cephalexin, was given to a female patient at week 12 of her pregnancy. After four months, the patient experienced a reduction in purulent discharge, tenderness, and erythema. Also, certolizumab pegol was safe and tolerable during pregnancy, as no adverse reaction was observed.

Anti-interleukins (Anti-ILs)

Anti-ILs had been administered in a total of seven DCS patients in five case reports [33, 40, 63–66]. These biologics include risankizumab, which targets IL-23 A; tildrakizumab, which is designed to block IL-23; secukinumab, an anti-IL-17 A; guselkumab, a monoclonal antibody against IL-23, and ustekinumab that acts against both IL-12 and IL-23. 28.5% (2/7) of subjects suffered from concomitant HS and AC [64, 66]. The dose range of IL inhibitors was as follows: risankizumab: 150 mg every 12 weeks; secukinumab: an anti-IL-17 A; and guselkumab: 100 mg every four weeks for the first two doses and then every eight weeks. The dose range of tildrakizumab was not reported [64].

In a study performed by Phillips et al. [40], ustekinumab did not lead to a favorable response in a DCS patient suffering from inflammatory bowel disease. In contrast to ustekinumab, other anti-ILs demonstrated a significant improvement in signs and symptoms of patients with other comorbidities who were resistant to previous therapeutic options. Muzumdar et al. [66] reported the use of guselkumab in a patient suffering from DCS, HS, folliculitis, AC, and pyoderma gangrenosum who was refractory to all conventional therapies and adalimumab. In this patient, switching adalimumab to guselkumab led to near‑complete healing of the scalp lesions and resolution of all symptoms. Furthermore, administration of tildrakizumab in an individual with a history of concurrent DCS, HS, and AC resulted in hair regrowth as well as a significant reduction in scalp tenderness and the number and severity of pustules [64]. Risankizumab also demonstrated a desirable efficacy and safety profile in three subjects with DCS [33, 63]. In addition, treatment with secukinumab resulted in complete cessation of drainage and pain and regression of nodules in a patient with DCS [65]. Despite eczematous reactions and treatment discontinuation due to lack of insurance coverage, the subject remained in remission at a one-year follow-up. However, it is important to note that while the effectiveness of these treatments in managing DCS has been documented, no data is available on the evolution of concurrent Pyoderma Gangrenosum, HS, and AC in these cases.

Small molecule inhibitors

Janus kinase inhibitors (JAK inhibitors)

JAK inhibitors, including upadacitinib (JAK1 inhibitor) and baricitinib (JAK1/2 inhibitor), have been applied in two DCS patients [34, 51]. Upadaticinib administration in a 26 year-old male with DCS who failed previous treatment resulted in significant improvement in the pain, pustular draining, and bleeding with no major side effects [34]. Yu et al. [51] described a case where a combination of the JAK inhibitor baricitinib and the TNF blocker adalimumab was used to treat a 15 year-old patient with DCS. This treatment regimen led to improvements in scalp condition, control of inflammation, disappearance of alopecic patches, and hair regrowth. Notably, while the patient did not experience any adverse reactions directly related to baricitinib, an increase in triglyceride and cholesterol levels was reported. It is important to note that dyslipidemia can be associated with both adalimumab and baricitinib, and attributing it solely to adalimumab may not fully reflect the contributions of baricitinib. As there are limited number of patients reported and the nature of the available literature (primarily case reports), further studies with larger patient populations and controlled settings are needed to better understand the effectiveness and safety profile of JAK inhibitors for this condition.

Apremilast (Phosphodiesterase-4 inhibitor)

To date, apremilast has been investigated in one patient with long-standing refractory DCS [35]. Apremilast prescription with the dose of 30 mg twice daily, in this case, resulted in a decrease in the disease flares along with dramatic improvement in clinical manifestations with no adverse events.

Safety

Biologic and small molecule inhibitors are relatively safe and effective. The adverse events with these agents in DCS patients in our study were as follows: elevated triglycerides and cholesterol levels (1/81), optic neuritis (2/81), infusion reaction (1/81), hepatic cytolysis (1/81), and psoriasiform exanthema (1/81) with TNF-α inhibitor, and eczematous reaction with secukinumab (1/81).

Discussion

DCS is a chronic, inflammatory, suppurative disease of the scalp, with relapse and remission periods. This disease clinically initiates with folliculitis, with clusters of perifollicular pustules, and then progresses to abscesses and intercommunicating sinus formation, ultimately leading to the development of neutrophilic scarring (cicatricial) alopecia [67, 68]. Apart from the increased risk of bacterial growth, considerable pain, psychological issues, discomfort, and cosmetic problems arising from DCS, squamous cell carcinoma may develop over time from long-standing lesions [67]. Moreover, the refractory nature of the disease, despite various treatments, makes this disease challenging for specialists to manage. Thus, timely diagnosis has a crucial role in effectively managing this therapeutically challenging disease and optimizing patients’ outcomes.

DCS is identified as a part of FOT along with HS, AC, and pilonidal cysts [69]. While DCS is the least prevalent disease of the FOT, it can occur concomitantly with HS and AC, suggesting a similar pathogenic pathway between the diseases [15]. Regardless of the different parts of the body affected by the mentioned diseases, all FOT diseases arise from keratin retention in the follicles of the apocrine gland, leading to pore dilation, bacterial infection, and sinus tract formation [67]. Follicular occlusion can be stimulated by external triggers such as obesity, smoking, and mechanical friction, as well as endogenous factors such as genetic mutations that result in dysregulating keratinocyte differentiation and proliferation [8].

In the absence of evidence-based guidelines, treating DCS is still a therapeutic challenge for dermatologists. Different treatment methods have been utilized alone or in combination to improve the DCS over time, including topical treatment, systemic medication, and invasive modalities [70]. Medical treatments consist of antibiotics, retinoids, steroids, dapsone, and biological therapies [9]. Despite antibiotics and retinoids being the usual treatment protocol for DCS, they are not efficacious enough and have demonstrated a high recurrence rate after treatment cessation [51]. Moreover, invasive modalities, including surgical excision with or without graft, modern external beam radiation therapy, x-ray treatment, and ablative laser therapy of the scalp, were associated with negative sequelae due to their aggressive approach [6, 61]. Concerning previous treatment strategy challenges, immunomodulators are novel treatment agents acting by downregulating the immune system and decreasing inflammatory mediators such as TNF-α, IL-17, and IL-23, which are crucial factors for developing follicular disorders like DCS [9]. Immunomodulatory treatments utilized for managing DCS involve TNF-α blockers, IL inhibitors, JAK inhibitors, and phosphodiesterase inhibitors.

Various TNF-α blockers, including adalimumab, infliximab, golimumab, etanercept, and certolizumab, have been approved for clinical practice in different inflammatory diseases [71]. Adalimumab and infliximab are the most commonly prescribed TNF-α blockers for ameliorating DCS. Adalimumab is the first Food and Drug Administration (FDA)-approved biologic administered as the first-line therapy for moderate-to-severe HS [72]. Off-label treatment of FOT, which carries a similar pathogenesis as DCS, with TNF-α blockers, provided a considerable influence on patients’ outcomes, according to a retrospective study [44]. Also, there have been reported complete responses in two patients and decreased inflammatory symptoms in another patient suffering from DCS after administering TNF-α inhibitors, based on Gamissans et al. investigation [42]. Notably, TNF-α inhibitors were associated with minimized secretion, diminished inflammation, alleviated pain, and improved disease severity scores in most cases suffering from moderate-to-severe DCS who failed on antibiotics and retinoids as well as the patients who developed concomitant HS [5, 32, 39, 43, 45–49, 52–61]. It is imperative to mention that the remaining pathologic residual tissues, such as the interconnecting sinus tract, augment the chance of recurrence in DCS cases receiving conventional options [46]. This was uncommon with TNF-α inhibitor therapy, indicating the lower rates of flare-ups and relapses in treatment with these biologics. Nevertheless, TNF-α inhibitors cannot entirely cure hair loss following DCS, but partial hair regrowth has been documented in some cases [5, 32, 53, 58]. Further, TNF-α inhibitor therapy before surgical excision limited the spread of HS and DCS lesions and provided the basis for faster recovery following surgery [59]. Additionally, adalimumab therapy in a DCS case reduced the serum level of TNF-α and cytokines, such as IL-1RA, IL-1b, and IL-8 [20]. Overall, adalimumab and infliximab were associated with promising outcomes in moderate-to-severe DCS; however, their effectiveness on hair regrowth is still in doubt.

Certolizumab pegol is a novel humanized monoclonal TNF-α inhibitor acting similarly to infliximab and adalimumab [73]. The unique aspect of certolizumab pegol is the absence of fragment crystallizable (Fc) region due to pegylation, which limits antibody-mediated cytotoxicity and passes through the placenta. These findings suggest that certolizumab pegol is a safe choice for pregnant patients suffering from an inflammatory skin condition like HS [74]. In line with previous findings, the application of certolizumab pegol significantly improved the clinical condition of a pregnant patient with DCS without experiencing any adverse effects [62]. However, the data about certolizumab pegol is limited, and further investigations are warranted.

Aside from TNF-α blockers, there have been five reports of the application of IL inhibitors in DCS subjects as the role of IL-17/IL-23 has been established in the pathogenesis of FOT diseases [65, 75]. IL-17 inhibitors, including secukinumab, brodalumab, and ixekizumab, exert a beneficial impact on two-thirds of patients suffering from HS [26, 75, 76]. Administering secukinumab, which contains approval for moderate-to-severe HS, in a patient with DCS ameliorated clinical manifestations [65]. Nonetheless, no data is available regarding other IL-17 inhibitors. Likewise, IL-23 blockers, including guselkumab, tildrakizumab, and risankizumab, all demonstrated favorable outcomes in DCS patients along with improvement of concomitant HS and AC in two patients [63, 64, 66]. These findings were in line with the findings from investigations that evaluated the efficacy of the aforementioned agents in HS patients [77]. Contrariwise, ustekinumab, an IL12/23 blocker, was not correlated with clinical improvement of DCS despite showing desirable results in HS patients [40, 78].

Based on the available evidence, JAK/STATs are critical signaling cascades in a variety of inflammatory diseases [51]. Over 50 soluble factors, such as IL-2, IL-3, IL-4, IL-5, IL-6, and IL-12, as well as interferons, function through a particular composition of JAKs [79]. It has been found that JAK inhibitors selectively disable the ATP-binding site of JAKs, thereby suppressing downstream signaling pathways, which can modulate immune responses under a variety of pathological conditions [80]. Moreover, JAK inhibitors interrupt TNF-α/interferon-γ (IFN-γ) synergy, which induces an inflammatory feedback loop via STAT to minimize hyper-inflammation [81]. Furthermore, a growing body of evidence supports that JAK inhibition influences hair follicle activation and stimulates human dermal papilla cells [82]. This was confirmed by the rapid onset of anagen followed by hair growth in mouse and human skin after administering selective and reversible inhibitors of JAK1 and JAK2 an FDA-approved treatment option for the management of moderate-to-severe alopecia areata, autoimmune non-scarring alopecia [82, 83]. Subsequently, the efficacy and safety findings of JAK inhibitors in HS have depicted a promising prospect of these immunomodulators in treating inflammatory diseases [28, 84, 85]. Recently, utilizing baricitinib in combination with adalimumab in a patient with severe DCS led to obtaining satisfactory outcomes [51]. Further, upadacitinib therapy in another patient with DCS led to dramatic resolution of pustular draining, and bleeding and remarkable improvement in quality of life [34]. Considering the fact that both alopecia areata and DCS are caused by an inflammatory process, it is conceivable that baricitinib may have an impact on DCS’s underlying inflammatory pathway and prevent further scarring [51, 86]. However, it is noteworthy that there is no strong evidence about the impact of JAK inhibitors in reversing the scarring process and inducing hair regrowth, even in other types of CA [86]. Thus, further investigations are recommended to evaluate the efficacy, safety, and mechanism of JAK inhibitors in treating DCS.

Apremilast is another small molecule inhibitor acting through increasing intracellular cyclic adenosine monophosphate by inhibiting PDE4 [87]. Elevated levels of cyclic adenosine monophosphate eventually suppress the secretion of proinflammatory mediators such as TNF-α, IFN-γ, and IL-2 while stimulating the production of the anti-inflammatory cytokine IL-10. Prior evidence illustrated that apremilast can be used as a potential therapeutic option for psoriasis and HS [31, 88]. Similarly, apremilast application in a refractory DCS patient was correlated with notable resolution of disease symptoms and diminution of exacerbations with no adverse events [35].

Regarding safety, our findings indicated that these biologics and small molecule inhibitors were safe with minimized unexpected adverse reactions. The frequency of each adverse event was found to be lower than 2.5% in our study. In a study evaluating adverse reactions following the use of TNF-α inhibitors in VigiAccess of the World Health Organization (WHO), the most reported adverse events of these drugs were infections and infestations (23.0%), musculoskeletal and connective tissue disorders (28.6%), gastrointestinal disorders (15.3%), skin and subcutaneous tissue disorders (13.5%), and nervous system disorders (11.0%) [89]. Besides, the most common adverse reactions of IL-17 inhibitors in psoriasis and psoriatic arthritis patients were as follows: Infection (33.16%), nasopharyngitis (13.74%), and injection site reactions (8.28%) [90]. Our study also showed that the application of small-molecule inhibitors did not result in the occurrence of any adverse events in DCS patients. In line with our findings, the rate of most adverse events did not differ between patients receiving immunomodulators and placebo groups, according to meta-analyses [91–93]. Furthermore, the most prevalent adverse events with IL-17/23 inhibitors and TNF-α blockers in meta-analyses, including injection site reaction, infections, nasopharyngitis, and headache, were not reported in DCS subjects in our study [94, 95]. It is noteworthy that the low frequency or absence of adverse reactions is due to the low prevalence of DCS and limited number of patients in our review.

It is imperative to mention that this study relies on the findings of case reports and cohort studies, which makes it prone to hidden biases. Accordingly, the lack of original studies, the low number of patients due to the disease’s low frequency, and the difficulties of evaluating DCS (relapses versus. remission, inflammation versus. scarring) are limitations that can influence the results. Besides, no study has compared different immunomodulators to gradual treatment protocols for efficacy and safety. Therefore, further research with minimized bias, enhanced power, and a larger scale is needed to verify these results and provide a standardized treatment protocol for DCS. Although many studies have examined different therapeutic options and prepared helpful data for specialists to choose the most effective treatment approach, this study is the only one focusing on immunomodulators due to their potential therapeutic role in candidates suffering from DCS. Furthermore, it is hard to evaluate different components of DCS (relapses vs remission, inflammation vs scarring), which is a common problem in autoinflammatory diseases. Despite the limitations, our study provides valuable information on DCS treatment. Along with all the advantages of immunomodulators, specialists should be aware of the patient’s characteristics and cautious about the increased risk of unwanted adverse events arising from combination therapy to select the most appropriate treatment method for individuals.

Conclusions

DCS is a chronic, devastating, autoimmune-driven skin disease with no definitive treatment, leading to scar formation. Our systematic review revealed that immunomodulatory drugs are potentially effective for improving DCS lesions in patients suffering from moderate-to-severe DCS, especially in the ones who did not respond to previous treatments. However, achieving a satisfactory treatment response to hair regrowth needs further assessment. Moreover, our study’s reliance on limited data highlights the need for extensive investigations to verify these findings and evaluate the broader landscape of effective treatment options and their adverse events to determine the most effective practice for DCS.