Doxycycline-associated hyperpigmentation: A rare adverse drug reaction

Dear Editor,

Doxycycline is a semisynthetic antibiotic within the tetracycline class that exerts its effect by reversibly binding to the 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis. It is frequently utilized for short-term management of acute bacterial infections, including those caused by methicillin-resistant Staphylococcus aureus, as well as for prolonged therapy in conditions such as acne vulgaris.^[1] Cutaneous hyperpigmentation is a recognized adverse effect most commonly associated with minocycline and, less frequently, with other tetracyclines.^[2] Reports of doxycycline-induced pigmentation are rare, with isolated cases describing progressive, symmetrical blue-grey periocular discoloration following extended therapeutic use.^[3] Herein, we describe a patient undergoing doxycycline therapy for acne who developed extensive hyperpigmentation involving previously unaffected skin. The temporal relationship and clinical features suggest a probable association with doxycycline administration. A 15-year-old previously healthy female presented for evaluation of acne vulgaris. Dermatologic examination revealed inflammatory papules localized to the forehead and bilateral malar regions. The clinical presentation was consistent with moderate inflammatory acne, and initial management included oral doxycycline monohydrate 100 mg administered twice daily. Adjunctive topical therapy consisted of once-daily benzoyl peroxide 5% gel in combination with clindamycin phosphate 1% solution. At 6-week follow-up, the patient reported complete resolution of acneiform lesions within 3 weeks of initiating therapy. However, she also described the onset of progressive cutaneous hyperpigmentation involving the face and hands, beginning ~2 weeks after treatment initiation, without any reported history of sun exposure. Physical examination demonstrated symmetric hyperpigmentation over the bilateral malar regions extending to the mandibular area, as well as involvement of the palmar aspects of both hands [Figures 1 and 2]. There was no evidence of mucosal, subungual, or nail pigmentation. According to the World Health Organization, the assessment of causality for hyperpigmentation induced by doxycycline was categorized as “probable.” According to the Hartwig and Siegel criteria, the severity of adverse drug reaction is classified as “Level 3.” Management included prompt discontinuation of doxycycline. To sustain acne remission, oral azithromycin 250 mg twice daily was initiated. The patient was advised to continue topical benzoyl peroxide 5% gel and clindamycin phosphate 1% solution once daily.

Close

Figure 1: (a and b) Cutaneous hyperpigmentation induced by doxycycline over malar area.

Export to PPT

Close

Figure 2: Doxycycline-associated skin pigmentation on palmar aspect of hands.

Export to PPT

Doxycycline is associated with a spectrum of adverse effects, including systemic manifestations such as headache, pseudotumor cerebri, and tremors.^[4] A rare but well-documented complication of prolonged tetracycline exposure is hyperpigmentation involving the skin, nails, thyroid gland, oral mucosa, teeth, and bone.^[5] Although a definitive duration of therapy required for the development of hyperpigmentation has not been established, the risk appears to correlate with cumulative exposure and prolonged use.^[6] The onset of hyperpigmentation is variable, occurring within days in some patients, whereas in others, it may take several years to become clinically apparent. Notably, pigmentary changes may persist even after discontinuation of the offending agent.^[7] In a study, two pediatric patients, aged 11 and 17 years, were given doxycycline at a 200 mg dose. Both developed hyperpigmentation after starting the medication, appearing on days 15 and 20 of treatment. The discoloration affected the nails in both cases, and one patient also showed pigmentation on the thumb. In both individuals, the condition resolved within one month after stopping doxycycline.^[7] These results correspond with those observed in our case report. Similarly, Wilson et al.^[8] also reported a case of a man who had been taking 100 mg of minocycline twice daily for >30 years and developed similar conjunctival and macular changes, along with hyperpigmentation of the sclera and nail beds. Their findings also showed nodular deposits of retinal pigment epithelium located between Bruch’s membrane and the retinal pigment layer [Table 1].

In a case reported in 2022 by Roy et al.,^[9] an 11-year-old patient developed Type I onycholysis 3 weeks after initiation of therapy at a dose of 100 mg twice daily. Partial clinical recovery was observed after 1 month of follow-up. Baran et al.^[10] reported a case of onycholysis in a 10-year-old patient receiving 200 mg of the drug. The onset of nail changes occurred within a few days of treatment initiation. However, details regarding the type of onycholysis, concomitant medications, and clinical outcome were not reported. A case series published by Lareb^[11] described 12 patients aged between 8–71 years who developed hyperpigmentation following administration of doses ranging from 100–500 mg. The latency period varied from 1 to 12 weeks. Clinical outcomes included complete recovery in three patients, partial recovery in two patients, and absence of recovery in two patients. However, Pazzaglia et al.^[12] reported a pediatric case of photo-onycholysis occurring after the use of doxycycline at a dose as low as 20 mg, highlighting the importance of photoprotection even at lower dosages. Similarly, Elmas et al.^[13] reported a case involving a 16-year-old patient receiving 200 mg twice daily who developed Type I onycholysis. No concomitant medications were documented. The time to onset was not specified, and the patient was subsequently lost to follow-up [Table 2]. In light of these considerations, the duration of tetracycline therapy should be carefully limited, and patients should be monitored for early signs of cutaneous or mucosal pigmentation. Minocycline-induced cutaneous hyperpigmentation is classified into three subtypes: Type I (blue-black discoloration in scarred or inflamed areas), Type II (blue-gray pigmentation on normal skin), and Type III (muddy-brown discoloration on photo-exposed sites).^[14] In the present case, the patient demonstrated hyperpigmentation not only confined to post-acne scar sites but also involving the palmar aspects of the hands, indicating a more widespread distribution. The literature describes four principal mechanisms involved in the pathogenesis of drug-induced pigmentation: enhanced deposition of melanin, tissue accumulation of the offending pharmacologic agent, biosynthesis of specialized pigmented compounds, and iron deposition.^[15]

The palmar aspect of the patient’s hands demonstrated distinct hyperpigmentation [Figure 2], suggesting that the observed pigmentation is unlikely to represent deposition of doxycycline itself. Previous histopathological analysis of doxycycline-associated hyperpigmentation has shown increased melanization within the basal layer of epidermal keratinocytes,^[14,16] supporting the hypothesis of melanocyte activation either directly induced by tetracycline derivatives or mediated through an additional co-stimulatory factor. Moreover, existing evidence suggests that doxycycline, potentially in the form of chelated complexes with iron and/or calcium, may be directly deposited within lesional cutaneous tissue.^[14]

Cutaneous hyperpigmentation represents a potential adverse effect of doxycycline, even when administered within the therapeutic dosing range. Given its extensive use in both short-term and prolonged treatment regimens, it is clinically important to recognise this generally reversible or partially reversible complication to facilitate timely discontinuation of therapy when indicated.