PRIDE without prejudice

By Warren R. Heymann, MD, FAAD
July 30, 2025
Vol. 7, No. 30

As the years march on, I am bemused by having witnessed once-novel findings become mainstream affairs. I recall my excitement describing the development of paronychia in a 76-year-old woman with metastatic colon carcinoma who was participating in a study of the anti-epidermal growth factor receptor antibody, cetuximab. (1) Two decades later, epidermal growth factor receptor inhibitors (EGFRIs) are routinely used to treat advanced malignancies with definite improvement in survival and quality of life. (2)

EGFRIs are used to treat many cancers located in head and neck, lung, large bowel, prostate, breast, ovary, stomach, and pancreas. EGFRIs can comprise monoclonal antibodies against EGFR (cetuximab and panitumumab), EGFR-specific small molecule tyrosine kinase inhibitors (erlotinib and gefitinib), dual EGFR and HER2 kinase inhibitors (lapatinib, neratinib, and afatinib), and other less specific multikinase inhibitors (vandetanib).

According to Recuero et al., “The exact mechanism leading to skin toxicity during treatment with an EGFRi is not well known, but it is undoubtedly the result of genetic modifications of the signals associated with its activation. It is known to interfere with the RAS/RAF/MEK/ERK pathway, which affects cell cycle regulation, including epidermal cell proliferation and differentiation.” (3) Because EGFR is located in the basal layer of the epidermis, sebocytes, outer root sheath of hair follicles, nail matrix, dermal smooth muscle cells, and endothelial cells (4), having adverse effects of the skin and its appendages makes sense.

The constellation of common cutaneous reactions due to EGFRIs is known by the acronym PRIDE syndrome — Papulopustular rash and/or Paronychia, Regulatory changes in hair, Itching, and Dryness caused by EGFRIs. The papulopustular eruption (PPE) is the most frequent manifestation — this will be discussed in greater detail below. Paronychia and other nail changes may present as nail discoloration, pitting, periungual pyogenic granuloma, cracked and swollen nail folds and cuticles, ingrown nails, and partial or complete loss of nails. These appear 1 to 2 months after treatment initiation and occur in 10% to 15% of patients. Hair may grow slowly, becoming finer, brittle, or curled. Alopecia may appear several months into therapy. Usually this is non-cicatricial, but cicatricial alopecia has been reported in 5% of patients treated with cetuximab, possibly due to secondary bacterial infection of the scalp. Paradoxically, hypertrichosis, facial hirsutism, and trichomegaly of the eyebrow and eyelashes may also occur for reasons yet to be determined. Most patients can be reassured that these hair changes are temporary; normal growth should begin within a month after cessation of medication. Itchiness (pruritus) affects half of EFGRI patients and xerosis in approximately a third. Xerosis results from abnormal keratinocyte differentiation, with a decrease in epidermal loricrin affecting the stratum corneum causing a reduction in moisture retention. Mucous membrane complications such as mucositis or conjunctivitis are infrequent. (3,5)

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The PPE is observed in 50-100% of patients on EGFRIs, usually appearing 2-3 weeks after treatment initiation (2), most commonly on the scalp, face, chest, and back. Although referred to as “acneiform” it is distinguished from acne by the lack of comedones and cysts. Compared with other drug-induced acneiform eruptions (e.g., seen after systemic corticosteroid use), the PPE lesions in the PRIDE-complex are more pruritic, erythematous, and inflammatory. (6) Histopathologic features of PPE demonstrate a superficial inflammatory cell infiltrate surrounding hyperkeratotic follicular infundibula or a florid neutrophilic suppurative folliculitis with a rupture of the epithelial lining. (5)

Recent literature expands our understanding of the PRIDE complex. Lapatinib is a member of a newer generation of EGF (ErbB)-targeting drugs. Compared to conventional EGFRIs, reports of cutaneous adverse reactions due to lapatinib are extremely rare. Sil et al. reported the case of a 52-year-old woman with metastatic breast cancer who developed the PRIDE syndrome (PPE, paronychia, and pruritus) with the administration of capecitabine and lapatinib. (7) Chaudhary et al. reported the case of a 53-year-old man with a squamous cell carcinoma of right gingivobuccal sulcus who developed PRIDE syndrome (PPE, paronychia) and pemphigus vulgaris induced by gefitinib. (8) Behera et al. detailed the case of a 63-year-old man with chronic myeloid leukemia who developed the PRIDE complex (follicular PPE and xerosis) from imatinib. Histopathology from the follicle-based pustule showed a subcorneal abscess comprising neutrophils, eosinophils, lymphocytes, and multiple acantholytic cells. Direct immunofluorescence was negative.

Clinicians can easily be subject to anchoring bias when confronting PPE in a patient on an EGFRI — however, we should not be prejudicial. The clinical differential diagnosis of the PPE component of PRIDE syndrome includes bacterial folliculitis, Candida folliculitis, disseminated herpes, atypical varicella infection, Grover disease, other follicular drug eruptions, and acute generalized exanthematous pustulosis (AGEP). (9) Histopathology and appropriate cultures may rule out these disorders.

The PRIDE complex can typically be managed symptomatically without discontinuing the EFGRI regimen. (7) The mainstay of treating the PPE component of PRIDE is with topical antibiotics (clindamycin, erythromycin) or systemic antibiotics (doxycycline, minocycline). Isotretinoin may be utilized in recalcitrant cases. (5) Benzoyl peroxide agents and topical retinoids are usually avoided because of irritancy. (3,5)

“Oh! Mr. Bennet, you are wanted immediately; we are all in an uproar. You must come and make Lizzy marry Mr. Collins, for she vows she will not have him, and if you do not make haste he will change his mind and not have her.”

Mr. Bennet raised his eyes from his book as she entered, and fixed them on her face with a calm unconcern which was not in the least altered by her communication.

“I have not the pleasure of understanding you,” said he, when she had finished her speech. “Of what are you talking?” – Jane Austen, Pride and Prejudice

Our understanding of the pathophysiology underlying the manifestations of the PRIDE complex is incomplete. More research is necessary to fully understand what we are talking about.

Point to Remember: As the use of epidermal growth factor inhibitors expands, dermatologists should be familiar with all aspects of the PRIDE syndrome.

Our expert’s viewpoint

David A. Wetter, MD, FAAD
Professor of Dermatology
Mayo Clinic
Rochester, Minnesota

Our dermatology hospital practice frequently receives consultations regarding patients with suspected drug eruptions from their anti-cancer treatments. The spectrum of both the causative medications and the cutaneous morphologies continues to expand at a rapid rate. Dermatologists are ideally situated to be the experts in describing the known and emerging eruptions from anti-cancer treatments (as well as recognizing when skin eruptions are unrelated to treatment), including their delineation, classification, and dissemination to the greater medical community. The value of hospital dermatology has been increasingly recognized (11, 12) and the presence of supportive oncodermatology practices has blossomed across both the inpatient and outpatient dermatologic landscape. (13) Dermatologists are well versed in topical and systemic (including anti-inflammatory and immunomodulatory) treatments that can be safely used in the setting of an active malignancy, and which can effectively treat the cutaneous adverse effects while allowing patients to remain on their potentially life-saving anti-cancer treatments whenever possible. Dr. Heymann’s insightful commentary illuminates the salient diagnostic and therapeutic role of dermatologists in the multidisciplinary care of oncologic patients who are receiving targeted treatments for their cancer.

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References

1. Boucher KW, Davidson K, Mirakhur B, Goldberg J, Heymann WR. Paronychia induced by cetuximab, an antiepidermal growth factor receptor antibody. J Am Acad Dermatol. 2002 Oct;47(4):632-3. doi: 10.1067/mjd.2002.124621. PMID: 12271317.

2. Bhanja DB, Sil A, Punithakumar EJ, Panigrahi A, Das A, Biswas SK. PRIDE syndrome. Postgrad Med J. 2021 Aug;97(1150):489-490. doi: 10.1136/postgradmedj-2020-137939. Epub 2020 Jun 29. PMID: 32601257.

3. Recuero JK, Fitz JR, Pereira AA, Bonamigo RR. EGFR inhibitors: clinical aspects, risk factors and biomarkers for acneiform eruptions and other mucosal and cutaneous adverse effects. An Bras Dermatol. 2023 Jul-Aug;98(4):429-439. doi: 10.1016/j.abd.2022.10.004. Epub 2023 Mar 27. PMID: 36990917; PMCID: PMC10334360.

4. Behera B, Nayak AK, Dash S, Sethy M, Ayyanar P. Acantholytic PRIDE syndrome. J Cutan Pathol. 2025 Jan;52(1):5-8. doi: 10.1111/cup.14684. Epub 2024 Jul 10. PMID: 38987224.

5. Reyes-Habito CM, Roh EK. Cutaneous reactions to chemotherapeutic drugs and targeted therapy for cancer: Part II. Targeted therapy. J Am Acad Dermatol. 2014 Aug;71(2):217.e1-217.e11; quiz 227-8. doi: 10.1016/j.jaad.2014.04.013. PMID: 25037801.

6. Singh B, Rajput A, Tripathi M, Mahajan R. PRIDE complex-like skin rash associated with bevacizumab. BMJ Case Rep. 2022 Jul 22;15(7):e249844. doi: 10.1136/bcr-2022-249844. PMID: 35868802; PMCID: PMC9316022.

7. Sil A, Sikder B, Biswas SK, Chandra A. Lapatinib-induced PRIDE complex: a new kid on the block. Postgrad Med J. 2023 Sep 21;99(1176):1128-1129. doi: 10.1093/postmj/qgad064. PMID: 37535871.

8. Kumar Chaudhary R, Bhandari R, Doshi B, Karoli SS, Spoorthi Marripalli S, Ganachari MS. Gefitinib induced Pemphigus Vulgaris with PRIDE complex. J Oncol Pharm Pract. 2022 Sep;28(6):1465-1473. doi: 10.1177/10781552221076755. Epub 2022 Feb 1. PMID: 35102778.

9. Behera B, Nayak AK, Dash S, Sethy M, Ayyanar P. Acantholytic PRIDE syndrome. J Cutan Pathol. 2025 Jan;52(1):5-8. doi: 10.1111/cup.14684. Epub 2024 Jul 10. PMID: 38987224.

10. http://becomingjane.blogspot.com/2009/07/jane-austen-quote-of-week-week-63.html

11. Sokumbi O, el-Azhary RA, Bruce AJ, et al. Missed opportunities in resident education: The role of hospital dermatology. J Am Acad Dermatol. 2013;68:677-8.

12. El-Azhary RA, Weenig RH, Gibson LE. The dermatology hospitalist: Creating value by rapid clinical pathologic correlation in a patient-centered care model. Int J Dermatol. 2012;51:1461-6.

13. Freites-Martinez A, Apalla Z, Fattore D, et al. Supportive oncodermatology practices in Europe and the USA. J Eur Acad Dermatol Venereol. 2024;38:e440-443.

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