3.1 Controlled Clinical Trials with Biologicals in Moderate to Severe Acne

According to the current body of knowledge, TNFα, IL-1α, IL-1β, IL-6, IL-8, IL-17, and IL-36 are the most significant cytokines that characterize the immune milieu in acne pathogenesis. Given the elevated levels in acne lesions, the targeting of these cytokines has emerged as a promising therapeutic strategy for acne management. However, to date, only three clinical trials have explored the efficacy of cytokine inhibitors in the treatment of acne, targeting IL-1, IL-17, and IL-36. These trials have been designed to target the factors that are particularly significant contributors to the development of acne.

3.1.1 Targeting Interleukin (IL)-1β

The IL-1β antibody gevokizumab, which neutralizes IL-1β by competing with its binding to its receptor IL-1R [38], was evaluated in a double-blind, randomized, phase 2 trial for acne vulgaris (registered on ClinicalTrials.gov, NCT01498874) [39]. In this study, patients received subcutaneous injections of gevokizumab at doses of 0.2 mg/kg or 0.6 mg/kg, or placebo, once monthly for 3 months. Interim results from up to 92 participants were reported. The 0.2-mg/kg dose group showed no clinically or statistically significant improvement in inflammatory lesion count compared to placebo at any time point. In contrast, the 0.6-mg/kg dose group demonstrated both clinically and statistically significant improvements at day 84, with a 31% responder rate compared to 5% in the placebo group [40]. Although the difference was statistically significant, the overall response rate was low, and thus far, there is no evidence in the literature of gevokizumab progressing to phase 3 trials for acne vulgaris. Moreover, the drug also failed to demonstrate therapeutic efficacy in the treatment of pyoderma gangrenosum [41].

3.1.2 Targeting IL-36 Receptor

IL-36 belongs to the IL-1 cytokine family, and has been shown to be elevated in acne lesions [19]. An anti-IL-36 receptor (IL-36R) monoclonal antibody, imsidolimab (ANB019) has been evaluated for treating patients with acne vulgaris (ClinicalTrials.gov, NCT04856917) [42]. In this phase 2 clinical trial, a total of 123 moderate-to-severe acne patients were enrolled. Patients received either a 400-mg subcutaneous induction dose of imsidolimab at day 1, followed by monthly 200-mg subcutaneous doses at weeks 4 and 8 (high-dose group), or a 200-mg subcutaneous induction dose and monthly 100-mg subcutaneous doses (low-dose group). Imsidolimab did not demonstrate efficacy over placebo in moderate-to-severe acne patients; therefore, imsidolimab is not further considered for treating acne. However, there are ongoing, promising studies with imsidolimab for the treatment of palmo-plantar pustular psoriasis and palmoplantar pustulosis.

3.1.3 Targeting IL-17A

A prospective, randomized, placebo-controlled study by Thiboutot et al. was the first to evaluate the clinical utility of an IL-17A inhibitor in moderate-to-severe acne. CJM112, a potent anti-IL-17A monoclonal antibody with proven efficacy in psoriasis, was tested for its effect on moderate to severe acne in a randomized, placebo-controlled, double-blind study (ClinicalTrials.gov, NCT02998671) [43]. Participants received subcutaneous injections of CJM112 at doses of 300 mg or 75 mg, or a placebo, during the treatment phase. Due to the lack of efficacy observed in interim analysis, only 52 of the planned 75 patients were enrolled. At week 12, no significant differences were observed in the reduction of total inflammatory facial lesion counts between the CJM112-treated groups and the placebo group. Consequently, the study was terminated [44].

Despite the well-established inflammatory nature of acne and the presence of elevated cytokines such as IL-1β, IL36, and IL-17 in acne lesions, biologics targeting these cytokines have not yet demonstrated efficacy in controlled clinical trials. Although various antibodies targeting these cytokines or their receptors are used to treat immune-mediated diseases, no other clinical trials have been done in acne, and currently there are no registered clinical trials using biologics in acne. The failure of these clinical trials might be due to inadequate patient selection, lack of early treatment, and suboptimal dosing regimens. Moreover, acne may not be driven by a single dominant cytokine pathway in all patients, which raises the possibility that monotherapy with a single biologic agent may be insufficient. It is conceivable that a combined approach targeting both microbial and immune pathways along with targeting sebum production may yield better outcomes.

3.2 Case Reports with Biologicals in Acne: Rethinking the Diagnosis

Despite the absence of clear evidence from systematic clinical trials demonstrating the efficacy of biologicals in treating acne, a number of publications are known in the scientific literature offering contradictory findings. Case reports highlight the successful use of TNFα inhibitors (etanercept, infliximab, and adalimumab) and an IL-17 inhibitor (secukinumab) in severe, treatment-resistant cases of acne.

One case report described a 22-year-old man who presented with painful, inflamed nodular lesions, sinus tracts, pustules, and comedones on the face, neck, and trunk. The patient had failed conservative acne treatments, including topical agents, systemic antibiotics, and isotretinoin. Therefore, etanercept was initiated at a dosage of 25 mg twice weekly, leading to a complete regression of lesions within 24 weeks [45].

Another case report detailed a 22-year-old man with a 6-year history of severe nodular inflammatory acne involving the neck, chest, and posterior shoulders, notably without facial involvement, pustules, or comedones. The patient also had a history of ulcerative colitis. Previous treatments, including oral antibiotics (doxycycline), potent topical corticosteroids (clobetasol propionate 0.05%), intralesional corticosteroids, and isotretinoin (up to 80 mg daily), were ineffective. Infliximab was initiated at a dosage of 5 mg/kg administered intravenously every 8 weeks. Substantial improvement was observed after the first infusion, with no new lesions or reactivation of old lesions after three doses [46].

Shirakawa et al. reported a 64-year-old man with a three-month history of large, painful draining cysts. On examination, the patient also suffered from fluctuant nodules, pustules, and fibrotic scars on the anterior and posterior trunk, buttocks, and proximal areas of the arms and thighs. After 14 weeks of isotretinoin treatment (40 mg twice daily), the patient developed three draining lesions on the buttocks and trunk. Infliximab (3 mg/kg or 300 mg) dramatically reduced the size and number of cystic lesions, along with significant pain relief [47].

An 18-year-old patient presented with a 4-year history of multiple painful inflammatory nodular lesions and sinus tracts on the face. The patient had failed previous treatments, including doxycycline, isotretinoin, prednisolone, and dapsone. Adalimumab monotherapy was initiated with an 80-mg loading dose followed by 40 mg every 2 weeks. Within 4 weeks, a marked reduction in lesion size and inflammation was observed, and after 12 weeks, all nodular lesions had resolved [48].

Schettini et al. described a 24-year-old patient with a follicular occlusion triad encompassing dissecting cellulitis of the scalp (DCS), hidradenitis suppurativa (HS) involving the axillary, inguinal, and pubic areas, and conglobate acne. Previous treatments with isotretinoin, antibiotics, and adalimumab were largely ineffective. Off-label treatment with secukinumab resulted in a gradual clinical improvement, with a reduction in HS lesions and near-complete resolution of the inflammatory manifestations of DCS [49].

We assume that a notable proportion of severe acne cases reported to respond well to biologics may actually represent the conglobate form of HS and not acne. This is supported by the fact that most of the presented cases had some peculiar clinical symptoms that are not characteristic of conglobate acne. Van der Zee et al. proposed six phenotypes of HS: regular type, frictional furuncle type, scarring folliculitis type, conglobata type, syndromic type, and ectopic type [50].

The clinical characteristics of the published case reports on the efficacy of biologics on “acne” described above fit well with the clinical symptoms of conglobate-type HS. Therefore, it is not surprising that these patients did not respond to conventional acne treatments, including isotretinoin, as it is well known that HS does not respond well to isotretinoin but to TNF inhibitors. Misdiagnosis often arises due to overlapping clinical characteristics of acne and HS. Poor response to standard acne treatments, older patient age at onset, and atypical lesion locations, such as the back, face, or ears may suggest that what is often identified as acne conglobata could, in some cases, be a rare phenotype of HS.

3.3 Is “Acne” in Autoinflammatory Syndromes Truly Acne—or a Conglobate Form of HS?

Autoinflammatory syndromes often include acneiform lesions, referred to as “acne” in the acronyms. Several case reports show that biological treatments improve the different clinical manifestations, including acne, in these patients [51]. However, it is extremely difficult to evaluate the efficacy of these treatments on “acne,” as acneiform lesions are not well described in these case reports. Although conglobate acne is a cardinal component of the different autoinflammatory syndromes, in these autoinflammatory diseases, acne differs clinically (age, localization, lack of comedos) from the isolated acne, and also does not respond well to conventional acne treatments, including to isotretinoin. Therefore, we propose that the acne observed in autoinflammatory diseases is probably a different disease, maybe a conglobate type of HS. Therefore, the biological treatment efficacy of these syndromic acne forms should be carefully interpreted when treating isolated severe acne.