Acneiform cADRs typically develop weeks to months after initiating a new medication and, similar to acne vulgaris, predominantly appear in areas rich in sebaceous glands, including the face, upper trunk, and scalp. However, they may extend to non-seborrheic areas and involve atypical sites such as palms and soles. Notably, different agents can induce distinct clinical patterns of acneiform cADRs with nuanced differences (Table 1). Common symptoms include seborrhoea, burning sensations, pruritus, sometimes flushing and xerosis. Xerosis on the other hand may also be secondary in response to treatment approaches. Normally, there are neither laboratory abnormalities nor systemic involvement. EGFR-inhibitors may actually induce a range of symptoms involving skin, mucosa and adnexa apart from folliculotropic papulopustules, particularly paronychia, regulatory abnormalities of hair growth, itching and dryness, which is summarized under the acronym PRIDE (8).

It is very important to distinguish acneiform cADRs from more severe cutaneous drug reactions (SCARs). With an estimated incidence of 1 to 5 cases per million people per year, acute generalized exanthematous pustulosis (AGEP) is a rarer event. It is characterized by the abrupt onset of erythema with sterile, non-follicular pustules, typically appearing within 24–72 h after starting a new medication (90% of the cases), mostly beta-lactam antibiotics, and resolving by pin-point desquamation within 8 days once the agent is discontinued. Systemic symptoms like fever, neutrophilia, and eosinophilia are frequent (9). AGEP usually appears on the trunk and intertriginous regions (armpits, neck and groin), unlike acneiform reactions that characteristically affect areas rich in sebaceous glands. Notably, a localized variant (ALEP) usually involves the face and may be mistaken for acne by non-dermatologists.

Acne vulgaris is the most important differential diagnosis to acneiform ADRs. It typically presents with polymorphic lesions including comedones, papules, pustules, and nodules, with a predilection for seborrheic areas originally coining the term “acneiform distribution.” Acne vulgaris is one of the most common skin diseases worldwide. The highest prevalence is seen in adolescence with up to 85% of people between 13 and 25 years of age affected. Yet, it can persist or develop de-novo in adulthood as acne tarda, most often at ≥25 years of age. Flares of acne may occur in temporal relation to a new drug which may lead to confusion with cADRs and the best management. Standardized, questionnaire-based tools may help to determine the likelihood of drug-reaction, among others, the Naranjo Scale developed in 1981 or decision tree tools such as the Liverpool Adverse Drug Reaction Causality Assessment Tool (LCAT) (10, 11).

Another important differential diagnosis, especially in adulthood, is rosacea, which is characterized by persistent central facial erythema, telangiectasia, papules, and pustules, but lacks comedones. Demodex mite overgrowth is a central driver in the pathogenesis of rosacea, whereas in acne pathophysiology, cutibacterium acnes is of greatest importance, although demodex may contribute to the development of folliculitis (12). Diagnostic challenges arise in darker skin types due to the subtle nature of erythema; vascular and nociceptive symptoms may be more useful for making a definitive diagnosis of rosacea in these instances. However, as stated above, cADRs may also encompass burning or stinging sensations. Apart from that, perioral dermatitis needs mentioning, which presents as grouped erythematous papules and pustules around the mouth, sparing the vermillion border. It is more common in girls and young women. Comedones are usually absent. Acne excoriée des jeunes filles is defined by excoriated papules and postinflammatory changes due to habitual skin picking. It appears usually in young women, with evidence of manipulation and psychological distress (13). It should be borne in mind as differential diagnosis in atypical cases irresponsive to adequate treatment. Another pustular dermatosis potentially mimicking acneiform cADRs is eosinophilic folliculitis characterized by pruritic, grouped follicular papules and pustules, often on the face and upper trunk. It is more common in immunocompromised individuals and potentially associated to human immunodeficiency virus infection (14). Moreover, cutaneous lupus erythematosus (CLE) may rarely mimic acneiform eruptions, especially acute CLE with malar rash. Chronic discoid CLE typically presents with erythematous plaques, follicular plugging, and scarring, rarely papules may be folliculocentric. Cutaneous sarcoidosis presents with remarkable clinical heterogeneity as papules, nodules, or plaques, often with orange-yellowish areas and linear branching vessels on dermoscopy. It lacks follicular and comedonal features but may involve the central face (e.g., lupus pernio). The list of potential differential diagnoses is inexhaustive and we refer to common dermatology textbooks for other folliculocentric dermatoses. As drug history may be misleading, it is important to closely pay attention to clinical features to allow confident distinction. Still, histopathology will be needed in many instances.

Histologically, acneiform cADRs most commonly present as a superficial neutrophil-predominant suppurative folliculitis. The epidermis often shows spongiosis with occasional necrotic keratinocytes, while the dermis contains a perivascular and perifollicular mixed inflammatory infiltrate composed mainly of neutrophils and sometimes eosinophils, accompanied by mild papillary edema. The follicular apparatus typically reveals ectatic infundibula, focal rupture of the follicular epithelium, and dense neutrophilic infiltrates within and around the follicle (Supplementary Figure 1). Notably, comedones may be absent, helping to distinguish these reactions from classical acne vulgaris (15). In more severe cases, follicular rupture may lead to a granulomatous reaction with numerous histiocytes and multinuclear giant cells engulfing keratin material. AGEP as a relevant differential diagnosis is characterized by spongiform subcorneal and/or intraepidermal pustules filled with neutrophils. Key epidermal findings include necrotic keratinocytes, as well as spongiosis with neutrophilic exocytosis. In the dermis, prominent papillary edema is present together with mixed superficial, interstitial, and mid/deep-mixed infiltrates of neutrophils and eosinophils (16). Acne vulgaris, on the other hand, is defined histologically by more pronounced follicular hyperkeratinization, dilated follicles filled with keratin, sebum, and bacteria, and perifollicular lymphocytic and neutrophilic inflammation. Follicular rupture may lead to granulomatous inflammation and abscess formation. The presence of comedones remains a hallmark feature (17). Rosacea shows histopathologically no comedones, but follicular spongiosis and exocytosis of inflammatory cells, particularly lymphocytes, into hair follicles. The intensity of perifollicular inflammation and follicular inflammatory reactions are dependent on the severity of rosacea. The dermis reveals perivascular and perifollicular lymphohistiocytic infiltrates, sometimes accompanied by plasma cells. Vascular alterations such as telangiectasia and vascular proliferation are frequent, and Demodex mites may be present or abundant (18). Eosinophilic folliculitis is distinguished by a dense perifollicular and folliculotropic infiltrate of eosinophils and lymphocytes, with exocytosis of eosinophils into the follicular epithelium. The dermis often shows accompanying perivascular and periadnexal inflammation (14).

Acneiform cADRs are best described in the context of EGFR- and Mitogen-activated protein kinase (MEK)-inhibitors. Satoh et al. (19) identified the skin commensal Cutibacterium acnes as a key driver of IL-36γ production in follicular keratinocytes. Transcriptomic analyses of affected skin revealed upregulation of IL-36γ, which occurs predominantly from keratinocytes within the hair follicle. IL-36γ is a proinflammatory cytokine known to drive expression of the neutrophil chemoattractant IL-8 (20). Given that both acne vulgaris and EGFRi-induced eruptions preferentially occur in areas with dense pilosebaceous units, a synergistic interaction between EGFR inhibition and C. acnes, which activates NF-κB through TLR2 signaling, is proposed. Combined exposure of primary human keratinocytes to C. acnes and EGFR inhibition resulted in a strongly enhanced induction of IL-36γ, an effect abolished by TLR2 siRNA. A similar treatment of human skin explants induced IL-8 in an IL-36γ–dependent manner and triggered neutrophil recruitment into hair follicles, resulting in folliculocentric pustular eruptions typical of acneiform cADRs (19). Satoh et al. further demonstrated that IL-36γ induction is mediated by binding of both NF-κB and the transcription factor Krüppel-like factor 4 (KLF4) to the IL36G promoter. KLF4 accumulates when the EGFR/MEK/ERK pathway is inhibited, as ERK1/2 normally promotes its polyubiquitination and proteasomal degradation. These mechanisms also explain the pustular inflammatory phenotype observed in individuals with genetic EGFR defects (19). Notably, drug-induced acneiform eruption is associated with favorable outcomes (better disease control and overall response rate) in cancer patients treated with EGFR-inhibitors (21). This was reported for lung cancer, colorectal cancer, pancreatic cancer and head and neck cancer. It resembles a robust pharmacodynamic marker of effective inhibition of the pathway. Effective on-target tumor activity correlates with on-target toxicitiy in the skin (5).

Alterations in sebum composition, triggered by corticosteroids, androgens, targeted therapies, and other drugs, lead to microbial imbalance and consecutive abnormal keratinocyte proliferation and differentiation. This contributes to follicular plugging and formation of inflammatory lesions. Overall increases in sebum production and shifts in lipid quality, such as enhanced squalene oxidation and changes in fatty acid profiles, create a lipid-rich and pro-inflammatory environment. This milieu promotes the overgrowth of pathogenic C. acnes phylotypes and reduces microbial diversity (22). The loss of C. acnes phylotype diversity and the overrepresentation of virulent IA1 strains directly contributes to Th17-mediated inflammation (23). IA1 strains are more efficient in stimulating early inflammatory responses, including the release of IL-1, IL-6, IL-8, and IL-17, thereby activating the Th17 pathway and driving neutrophil recruitment and pustule formation via IL17 and IL-22 (23) (Supplementary Figure 2).

Although the precise contribution of JAK-signaling to acne vulgaris remains uncertain, previous work has shown that JAK1 and JAK3 are overexpressed in acne lesions (24). JAK1-inhibitor-associated acneiform cADR seems to be dose-dependent and more severe in individuals with a prior history of acne vulgaris. A systematic review indicates that the incidence of drug-acne (“JAKne”) is highest with JAK1-selective agents, followed by JAK1/2 inhibitors, and lowest with TYK2 inhibitors (25). TYK2 inhibition, through attenuation of Th1 and Th17 pathways, may permit overproliferation of commensal microorganisms and subsequently induce inflammation of the pilosebaceous unit (26). Accordingly, selective TYK2 inhibition, e.g., by deucravacitinib, may divert inflammatory signaling toward alternative JAK pathways, particularly JAK1 and JAK3, thereby contributing to acneiform eruptions. Notably, both pan-JAK inhibitors and JAK1-selective inhibitors have been employed in the management of rosacea (27), raising the possibility that more than one mechanistic subtype of januskinase-associated acneiform eruption exists.

Oil-based or occlusive topicals are known to cause acne comedonica by promoting follicular hyperkeratinization and plugging. This process is independent of systemic drug exposure and might be thought of as an exogenous acneiform reaction rather than an actual cADR (30, 31). To retain brevity, we do not further elude on this topic, as it is out of scope of this mini-review.

Drugs such as corticosteroids, androgens, lithium, anticonvulsants and anti-infectives induce acneiform lesions through several mechanisms, including increased sebum production, changes in neutrophil migration or shifts in inflammatory cytokines like IL-8 or TNF-α (4, 30, 31). The timing of onset varies considerably, often appearing weeks or even months after therapy initiation. Lesions are usually monomorphic and may include comedones in lithium- or androgen-associated eruptions. The distribution is mainly seborrheic, though lithium and halogens can involve non-seborrheic sites as well. Most of these reactions respond to standard acne treatments, including tetracyclines, although clinical improvement sometimes requires reducing or discontinuing the trigger, particularly in corticosteroid- or lithium-associated cases (1).

Acneiform reactions to targeted systemic agents typically appear soon after treatment initiation, often within one to 3 weeks (19). They interfere with epidermal growth factor receptor signaling, disturb keratinocyte differentiation and weaken barrier and innate immune function, which facilitates IL-36γ- and IL-8-mediated recruitment of neutrophils (32, 33). The resulting papulopustular lesions are highly inflammatory, tender and characteristically lack comedones. They are most often located on the face, scalp and upper trunk, although some patients also develop palmoplantar involvement. Her2-inhibitors exert similar downstream inflammatory effects (34), and CFTR-modulators can lead to crystalline folliculitis (35). Immune checkpoint inhibitors seldom cause acneiform eruptions, and in those cases, nonspecific T-cell activation is assumed to play a role (36, 37).

Agents that inhibit intracellular signaling, including JAK-, TYK2-, Bruton’s tyrosine kinase (BTK-) and multikinase tyrosine kinase inhibitors (TKIs), can lead to acneiform inflammation through modulation of the JAK–STAT axis or off-target inhibition of kinases such as EGFR, SRC or ITK (38). The time to onset generally lies between two and 12 weeks, although BTK inhibitors may deviate from this pattern. The eruptions are monomorphic and neutrophil-rich and often appear on the face or scalp; TKIs can show a more variable distribution of lesions (39). JAK1-selective agents and TYK2 inhibitors have shown the highest incidence in clinical studies (40–42). Treatment usually follows protocols for acne vulgaris even though some authors consider JAK-induced acneiform ADRs to resemble rosacea. JAK- or TYK2-associated eruptions are often mild, whereas reactions to BTK inhibitors or certain TKIs may require more intensive therapy, including isotretinoin.