Onychocryptosis and asymptomatic external urethritis as complications of oral isotretinoin therapy

Abstract

This case report presents a patient who, while undergoing oral isotretinoin therapy for acne vulgaris, developed onychocryptosis and asymptomatic external urethritis. These uncommon adverse events are not well-documented in medical literature. While his urethritis spontaneously resolved, his onychocryptosis symptoms necessitated surgical intervention. This report illustrates both cosmetic and functional adverse effects of isotretinoin and provides insight into the progression of these reactions over time.

Background

Isotretinoin was approved by the Food and Drug Administration in 1982 and has since become the most effective treatment for severe acne vulgaris.^{1 2} It is also the only therapy available for acne that offers the potential for remission or even permanent cure.^{3 4} Common side effects of isotretinoin are related to cutaneous dryness and include cheilitis, xerosis, conjunctivitis, and epistaxis.^{1 4} It is also a well-known teratogen.⁵ Rarely, patients taking isotretinoin experience onychocryptosis⁶ and external urethritis,^{7 8} but the true incidence of these reactions remains unclear. Herein we report the case of a single patient who experienced both onychocryptosis and external urethritis while on isotretinoin therapy for acne vulgaris. Similar to previously documented cases,^6–8 his asymptomatic external urethritis spontaneously resolved on completion of his isotretinoin regimen, but his onychocryptosis required surgical intervention. His story helps shed light on a potential treatment paradigm for these uncommon adverse events.

Case presentation

The patient was an 18-year-old Caucasian male with a medical history significant for diffuse, inflammatory acne vulgaris who had complete resolution of his acne symptoms after 6 months of daily oral isotretinoin. However, during his fourth month of therapy, he experienced new onset onychocryptosis of the bilateral halluces, followed by involvement of his left third toe one month later. Although he was an avid runner, he had no history of toenail pathology prior to initiating his isotretinoin regimen. His onychocryptosis episodes eventually necessitated surgical intervention with nail excisions and matrixectomies. Additionally, during his fifth month of therapy in late Fall, he noticed a new erythematous lesion of his external urethra.

He presented to his primary care clinic during his sixth month of isotretinoin therapy for evaluation of his onychocryptosis and external urethritis. He reported mild residual pain in his bilateral halluces (status post partial nail excisions and matrixectomies) and left third toe. He also noted asymptomatic, persistent redness on the inside of his urethral tip for the past month that was not associated with any discharge, pruritus, flank pain or dysuria. He denied any history of risky sexual behaviours or pertinent family history of similar dermatological changes.

Physical examination in the clinic revealed normal vital signs. His dermatological examination was notable for mild erythema of the lips and facial region with scant scaling, but without cheilitis, comedones, or inflammatory papules. There was trace erythema, mild tenderness to palpation, and postsurgical evidence of the bilateral halluces without evidence of purulence or oedema. The bilateral nail fold regions of his left third toe were painful to palpation. Otherwise, his extremities and torso were without cutaneous lesions. Genitourinary examination revealed an erythematous external urethra without discharge. Transition of the inflamed external urethra to normal internal urethral epithelium was visualised on examination.

Investigations

Regular evaluation of the patient’s complete blood counts, aspartate transaminase, alanine transaminase, cholesterol, and triglyceride levels were obtained throughout his treatment with isotretinoin. These were consistently unremarkable.

Given the significant improvement in his pain after surgical intervention and lack of alarming symptoms or physical examination findings, no further investigation was conducted with regards to his onychocryptosis. Workup of his asymptomatic external urethritis included nucleic acid amplification testing for gonorrhoea/chlamydia, blood testing for the HIV-1 p24 antigen and HIV-1/HIV-2 antibody, and non-treponemal blood analysis with the rapid plasma reagin test. All results were negative.

Differential diagnosis

Prior to surgical intervention, the patient’s symptoms included pain on ambulation, bleeding, and swelling of the affected toes. Physical examination findings of nail plates invading the medial and lateral nail folds of the affected digits made onychocryptosis the most likely diagnosis. Activity in rigorous weight-bearing sports and improper nail-care techniques are among the most common causes of onychocryptosis and may have contributed in this case, but his symptoms were refractory to 1 month of conservative management geared towards resolving these risk factors. Additionally, while onychocryptosis classically affects the halluces, the patient had involvement of his left third digit suggesting a more complex aetiology. In the setting of his acne vulgaris treatment, isotretinoin was postulated to be the instigating variable. This was further supported by the lack of onychocryptosis recurrence after completion of his isotretinoin course. While his history of being an avid runner likely contributed to his onychocryptosis onset, he continued to run after completing his isotretinoin regimen without recurrence of toenail pathology.

The differential diagnosis for his urethral symptom included urethritis and iatrogenic effect. The most commonly identified causes of urethritis are Neisseria gonorrhoeae and Chlamydia trachomatis. Urethritis is often suspected in patients complaining of dysuria, urethral pruritus, or urethral discharge, but the patient was experiencing external urethritis in the absence of any other symptoms. Additionally, sexually transmitted infection screening was negative. Mucocutaneous side effects are common in individuals taking isotretinoin, although these are not typically described as affecting the mucosal surface of the urethra. However, his asymptomatic external urethral erythema persisted during the last 2 months of his isotretinoin regimen and resolved soon after he completed his therapy, suggesting that isotretinoin was the aetiology of his symptom.

Treatment

The patient was treated for inflammatory acne vulgaris with oral isotretinoin for 6 months at a dosing weight of 72.7 kg for a total cumulative dose of 243 mg/kg. His onychocryptosis symptoms began after 4 months of therapy. Initially, he was managed with epsom salt soaks and given recommendations on appropriate nail trimming technique and reduction of strenuous physical activity. His onychocryptosis was complicated by paronychia two times (figure 1) and when this occurred, he was managed with oral cephalexin 500 mg, two times a day for ten days. Ultimately, his onychocryptosis symptoms were noted to be refractory to both conservative and medical therapy. He underwent multiple procedures including partial nail/nail root excision of the medial left hallux, partial nail excisions of the medial and lateral right hallux with matrixectomies and total nail avulsion of the left third toe. These procedures resolved both his pain and paronychia. He had no newly affected digits or recurrence of symptoms after completing his isotretinoin course.

Figure 1.

Onychocryptosis with paronychia of the patient’s medial left hallux (left) and lateral right hallux (right) after 4 months of isotretinoin treatment.

His asymptomatic external urethritis emerged during his fifth month of therapy in late Fall. He was informed that his lack of associated symptoms and negative STI screening were reassuring. He was advised to apply vaseline petroleum jelly to the tip of his urethra with the thought being that the relatively cool and dry climate of the season could be contributing to his presentation, but he reported no cosmetic improvement with this intervention. Notably, his symptom resolved soon after the completion of his isotretinoin regimen.

Outcome and follow-up

We followed up with the patient 3 months after his final dose of isotretinoin and learned that his symptoms of inflammatory acne, onychocryptosis, and external urethritis had resolved with no recurrence. His bilateral halluces and left third toe healed well after their respective surgeries with no complications (figure 2).

Figure 2.

Significant resolution of onychocryptosis and appropriate healing of surgical nail interventions 3 months after the patient’s final dose of isotretinoin.

Discussion

Acne vulgaris is believed to be the result of abnormal keratinisation, increased sebum production, Propionibacterium acnes proliferation, and host inflammation.⁹ The beneficial effects of isotretinoin have been described to be regulation of keratinisation¹⁰ and reduction of sebum production,¹¹ P. acnes proliferation and inflammation.¹² Despite these benefits, isotretinoin also has multiple potential adverse effects with mucocutaneous reactions such as xerosis and cheilitis being the most common.^{7 13} These effects have been shown to be dose-dependent and often improve with dose modification or symptomatic therapies.^{14 15} Historically, the typical dosing range for oral isotretinoin in the management of acne vulgaris was 0.5 to 1.0 mg/kg daily over 4 to 5 months for a cumulative dose between 120 mg/kg to 150 mg/kg.¹ These recommendations were based on observations of reduced relapse with a minimum cumulative dose of 120 mg/kg¹⁶ and a lack of further therapeutic gain beyond 150 mg/kg.¹⁷ However, research over the past decade has explored alternative dosing regimens^{18 19} with one study reporting that lower dosing to a mean cumulative dose of 81 mg/kg in the treatment of mild-to-moderate acne induced both clearance and long-term remission of acne symptoms.³ Meanwhile, Blasiak et al more recently reported that patients receiving a cumulative dose of more than 220 mg/kg had a significantly decreased risk for acne vulgaris relapse but increased risk of retinoid dermatitis compared with those receiving less than 220 mg/kg.⁴ Therefore, while reducing the patient’s cumulative isotretinoin exposure may have diminished his adverse event burden, this may have also increased his chances for future recurrence of his acne vulgaris.

This case represents one of the few documented instances of external urethritis in the setting of isotretinoin therapy. Some reports note that similar presentations in other patients resolved after the conclusion of isotretinoin treatment or dose-reduction measures.^{7 8 20} One case report also noted that in two patients receiving a second course of isotretinoin, recurrence of urethritis was well-managed with triple tetracycline (Deteclo) therapy.²⁰ However, a different report did not find Deteclo to be helpful in resolving their cases of isotretinoin-associated urethritis.²¹ The patient in this case was asymptomatic and did not require intervention, but the pathogenesis of his symptom remains unclear. One study has suggested that isotretinoin has keratolytic effects which leads to epidermal barrier impairments and consequent mucocutaneous adverse reactions.²² It is possible that these effects may extend to the urethral mucosal epithelium in select patients. Another possibility stems from the finding that isotretinoin induces apoptosis in sebocytes.²³ While this is beneficial in the treatment of acne vulgaris, sebocyte apoptosis may proliferate the mucocutaneous adverse effects of isotretinoin including urethral irritation. The presence and severity of these effects may even be intensified during dry seasons, as was the case in this patient. With regards to management, this case illustrates an instance of spontaneous resolution of asymptomatic urethritis after isotretinoin regimen completion.

Onychocryptosis is a rarely documented complication of isotretinoin that has significant implications for the patient with regards to both painful symptoms and invasive surgical interventions. In this case, the patient experienced two months of pain and was required to undergo multiple nail excisions and matrixectomies. Blasiak et al recently reported paronychia in 7.8% of patients treated with isotretinoin.⁴ Notably, the patient had two instances of associated paronychia, both of which resolved after surgical intervention of his onychocryptosis. Figueiras et al recently described a patient who developed paronychia, onychocryptosis, and granulation tissue on his toes during his sixth month of isotretinoin at a dose of 40 mg/day. While his paronychia and granulation tissue resolved after completing his isotretinoin regimen, onychocryptosis in his hallux persisted and required matrixectomy for complete resolution. Excessive development of granulation tissue was suggested to be a mechanism for his symptoms.⁶ One theory suggests that excess retinoids may disrupt the nail matrix at the epithelial level generating local dermatitis with accumulation of scales in the nail folds. These scales may act as foreign bodies leading to inflammation and subsequent granulation tissue formation, eventually leading to onychocryptosis.²⁴ Other studies have also noted the development of granulation tissue after treatment with retinoids.^25–27 Management guidelines for the development of onychocryptosis on isotretinoin therapy remain unclear. We believe that surgical approach is necessary after conservative and medical measures such as drying soaks, behavioural modification, and antibiotics fail to alleviate symptoms of onychocryptosis. However, the advantages and disadvantages of isotretinoin dose adjustment or discontinuation should also be considered and investigated.

This case depicts an instance of both onychocryptosis and asymptomatic external urethritis as reactions to isotretinoin therapy. Future analysis is warranted to determine the incidence of these adverse effects, identify patients at risk, and develop evidence-based management guidelines.

Patient’s perspective.

I decided to undergo therapy with isotretinoin because I saw the positive results that it had on my friends. Additionally, all the other treatments I had tried in the past didn’t work very well. I was nervous about starting the therapy because I knew that my acne symptoms would be difficult to treat. However, prior to starting the treatment I had no idea about the side effects which I eventually experienced.

In particular, the ordeal with my ingrown toenails was extremely frustrating because of both the multiple physician encounters and nail procedures that came with it. There seemed to be no way to treat my symptoms other than getting my toenails removed, and I was in constant pain. Prior to starting isotretinoin I had played sports my entire life including varsity football, rugby, and recreational running, with no nail issues. After my first ingrown toenail I had to decrease my physical activity. After each of my nail procedures I had to completely stop being active for a few weeks at a time. Towards the end of my regimen I had one toe that I was certain was going to become ingrown, but as soon as I got off the medication it straightened out. I am relieved that ever since I finished my acne treatment I have been able to continue running and working out without any new nail issues.

If given the option to start isotretinoin again, I would not do so. That being said, with respect to my acne, I am happy with the results.

Learning points.

• Asymptomatic external urethritis and onychocryptosis are rare but significant complications of oral isotretinoin treatment for acne vulgaris. The incidence of these complications is unknown.

• In this case, the patient’s asymptomatic external urethritis resolved spontaneously following the completion of his isotretinoin therapy.

• The patient’s onychocryptosis required multiple nail excisions and matrixectomies for complete symptom resolution. Evidence-based management guidelines for this complication remain unclear.

• Further investigation is warranted to determine if these adverse reactions are dose-dependent and if their presentation warrants isotretinoin dose adjustments, conservative management, or discontinuation of therapy.