What are the causes of acneiform rash?

Causes of Acneiform Rash

Acneiform rash is primarily caused by EGFR inhibitors and other targeted cancer therapies (occurring in 45-100% of patients), drug-induced reactions from various medications including antipsychotics and high-dose vitamins, and less commonly by infectious agents or idiopathic inflammatory processes. 1, 2

Primary Causes: Targeted Cancer Therapies

EGFR Inhibitors

• EGFR inhibitors are the most common cause of acneiform rash in oncology patients, affecting 75-90% of patients (all grades) and 10-20% with grade 3-4 severity. 1, 2
• The rash typically develops within the first 2-4 weeks of treatment, presenting as macular, papular, or pustular lesions predominantly on the face, upper trunk, and areas rich in sebaceous glands. 1
• This is a class effect of EGFR inhibitors, occurring with both monoclonal antibodies and small molecule tyrosine kinase inhibitors, though monoclonal antibodies show slightly higher rates of severe reactions (grade 3/4: 0-17%). 1

MEK Inhibitors

• MEK inhibitors cause papulopustular eruption in 74-85% of patients (all grades) and 5-10% with grade 3-4 severity. 2

Other Tyrosine Kinase Inhibitors

• Bosutinib causes rash in 43% of patients (6% grade 3-4) in second-line use and 20% in first-line use for chronic myeloid leukemia. 2
• Patients who develop rash on imatinib typically do not experience recurrence when switched to dasatinib or other TKIs. 2

Pathophysiological Mechanism of Drug-Induced Acneiform Rash

EGFR Inhibitor Mechanism

• EGFR inhibition abolishes phosphorylated EGFR, triggering release of inflammatory cell chemoattractants (CXCLs and CCLs). 1
• This results in upregulation of growth inhibitory proteins (cyclin-dependent kinase inhibitor p27) while reducing phosphatidylinositol turnover, diacylglycerol formation, proliferation marker Ki67, and MAPK expression. 1
• The cascade causes abnormal skin maturation and differentiation, growth and migration arrest, increased apoptosis, and inflammatory response leading to tissue damage. 1
• Histologically, there is dense periadnexal leucohistiocytic inflammatory infiltrate with clustering of macrophages, Langerhans cells, T cells, mast cells, and neutrophils. 2
• EGFR inhibitors impair expression of skin antimicrobial peptides, resulting in impaired host defense and increased susceptibility to bacterial superinfections (occurring in up to 38% of cases). 1, 2
• The process damages the basal epidermis, sweat and sebaceous glands, and hair follicles. 1

Other Medication-Induced Causes

Antipsychotic Agents

• Aripiprazole can induce acneiform rash with papulopustular, nodular, or cystic lesions following a distribution pattern similar to acne vulgaris. 3

Isotretinoin (Vitamin A Derivative)

• Isotretinoin itself can cause rash, including facial erythema, seborrhea, eczema, pruritus, and various other dermatologic reactions as listed in FDA labeling. 4
• Many side effects of isotretinoin are similar to those from very high doses of vitamin A, including dryness of skin and mucous membranes. 4

High-Dose Vitamin Supplements

• Megadose vitamins B6 and B12 can precipitate acneiform eruptions resembling acne rosacea. 5

Infectious Causes

• Gram-negative folliculitis can produce eruptions superficially resembling acne vulgaris. 6
• Bacterial superinfection can complicate existing acneiform rash, particularly in patients on EGFR inhibitors. 1, 2

Idiopathic Inflammatory Causes

• Acne necrotica and acne aestivalis are acneiform conditions of unknown etiology. 6

Key Distinguishing Features from Acne Vulgaris

The acneiform rash from EGFR inhibitors is fundamentally different from acne vulgaris because it lacks comedones. 1

• Histopathology confirms a sterile eruption consisting of follicular papules and pustules in an acneiform distribution. 1
• The term "acneiform rash" should be used instead of "acne" or "acne-like rash" to describe EGFR-inhibitor-induced skin reactions. 1

Clinical Pitfalls to Avoid

• Do not confuse drug-induced acneiform rash with life-threatening conditions like Stevens-Johnson syndrome or toxic epidermal necrolysis, which require immediate hospitalization and discontinuation of all suspected agents. 2
• The initial lesion in acneiform dermatoses is inflammatory (papule or pustule), while comedones are later secondary lesions resulting from encapsulation and healing of the primary abscess—the opposite sequence from acne vulgaris. 6
• Important diagnostic clues for drug-induced acneiform eruptions include: sudden onset within days, widespread involvement, unusual locations (forearm, buttocks), occurrence beyond typical acne age, monomorphous lesions, and sometimes systemic drug toxicity with fever and malaise. 6

Prognostic Consideration

Paradoxically, the occurrence and severity of acneiform rash from EGFR inhibitors correlates positively with therapy response and improved survival, making appropriate management without treatment discontinuation clinically important. 2, 7