A Rare Case of Oral Isotretinoin–Induced Achilles Tendinitis

Oral isotretinoin (13-cis retinoic acid) is a vitamin A derivative used for the treatment of moderate to severe acne vulgaris. The generally recommended dosage of isotretinoin ranges between 0.5 and 2.0 mg/kg/day where therapy is typically initiated at 0.5 mg/kg/day, then increased as tolerated to 1 mg/kg/day for the duration of therapy, which lasts several months.¹
 
While isotretinoin has high success rates in the treatment of nodular acne, it is also known to have a large adverse effect profile. The most common side effect is cheilitis, with up to 98% of patients experiencing some level of this symptom.¹ Other common adverse effects include xerosis, mucocutaneous manifestations, myalgias and arthralgias. Since 1985, isotretinoin has been labeled with a black box warning detailing of severe birth defects if becoming pregnant while taking isotretinoin. Other less common adverse effects include depression, gastrointestinal symptoms, and tendinopathy. Retinoid levels return to baseline after 1 month of discontinuing oral isotretinoin, thus patients who experience these adverse effects usually have subsequent resolution of symptoms after decreasing or discontinuing the medication in this time period.¹
 
Drug-induced tendinopathy has been associated with several classes of drugs including statins, fluroquinolones, aromatase inhibitors and glucocorticoids. Less commonly, tendinopathy has been associated with amlodipine, anabolic steroids, antiretrovirals, renin-angiotensin II receptor antagonists, rituximab, sitagliptin, and in some cases, isotretinoin.²
 
The pathophysiology of the isotretinoin effect on tendons, and more specifically the Achilles tendon, is still unknown at this time, though studies have found that symptom onset after beginning oral therapy ranges from 2–6 weeks.³ In a 2018 study on rats Beytemür and colleagues “detected histopathological and biomechanical negative effect of isotretinoin on Achilles tendon. Therefore, isotretinoin use should be questioned in medical history of patients with tendinopathy.”⁴
 
In a 1991 series of 3 patients, Bottomley and colleagues discovered that symptoms of Achilles tendinitis correlated with the dosage of isotretinoin. Due to this, the authors concluded that isotretinoin could be continued at reduced dosages with increased duration while still providing resolution of patients’ acne and diminishing the side effect of Achilles tendinopathy.⁵

Case Presentation: Bilateral Achilles Pain in a Runner

A healthy 36-year-old woman presented to the podiatry clinic for pain to bilateral Achilles tendons for several weeks, worse in the left than the right. The patient reports that she is a long-distance runner but has not had increases to her activity level or experienced any trauma. She also reported she recently began taking isotretinoin for the treatment of acne vulgaris several weeks prior and has had many symptoms from the medication including myalgias and cheilitis.

Upon physical examination, the patient’s Achilles tendon was extremely tender to palpation at the insertion bilaterally. The physical exam was otherwise normal. An X-ray was negative for insertional calcifications, bony abnormalities, with a normal Toyger’s angle. The patient was instructed to decrease activity levels, wear supportive shoe gear, perform at home stretching exercises and prescribed ibuprofen 800mg and a 4mg oral methylprednisolone dose pack. The patient was also instructed to discuss her isotretinoin dosage with her dermatologist to decrease the adverse effect profile the medication had.
 
The patient returned 2 weeks later for further examination. She described that she had not had any alleviation of pain levels to the bilateral extremity after following the agreed-upon treatment plan. She also stated she took the methylprednisolone as instructed and has decreased her isotretinoin dosage in half after having a telehealth appointment with dermatology. Patient was given a controlled ankle motion (CAM) boot to offload the left lower extremity, given an order for physical therapy and instructed to return to clinic after physical therapy begins.

Six weeks after discontinuing the isotretinoin, the patient returned to the office for a 1-month follow-up at which she reported 80% relief. She was instructed to refrain from long distance running until she is pain free with activities of daily living, then she may incrementally increase her exercise back to her normal levels. Patient was instructed to return to clinic PRN.

Figure 1. Left foot MRI.

Figure 2. Left foot sagittal MRI.

Figure 3. Right foot MRI.

Figure 4. Right foot sagittal MRI.

In Conclusion

There are many known drug classes found to cause tendinopathy, though to the best of our knowledge, isotretinoin has not been mentioned in podiatric journals regarding this phenomenon. While a rare side effect, tendinopathy may be underreported due to the lack of studies on the topic. Oral isotretinoin is commonly prescribed and as such it is important to keep the side effect profile in mind when treating patients for foot and ankle pain.

Desiree Major, BS, is a fourth year podiatry student at Midwestern University College of Podiatric Medicine. She will be completing her residency at Carl T. Hayden Veteran Affairs Medical Center.

Chase Corley, DPM, is in private practice in Mesa, Scottsdale and Sun City, Arizona. Dr. Corley is adjunct faculty at Midwestern University College of Podiatric Medicine.

References
 
1. On SCJ, Zeichner J. Isotretinoin updates. Dermatol Ther. 2013;26(5):377-389.
 
2. Cohen PR. Cephalexin-associated Achilles tendonitis: case report and review of drug-induced tendinopathy. Curēus (Palo Alto, CA). 2018;10(12):e3783.
 
3. Kirchgesner T, Larbi A, Omoumi P, et al. Drug-induced tendinopathy: From physiology to clinical applications. Joint Bone Spine. 2014;81(6):485-492.
 
4. Beytemür O, Yüksel S, Tetikkurt ÜS, Genç E, Olcay E, Güleç A. Isotretinoin induced Achilles tendinopathy: Histopathological and biomechanical evaluation on rats. Acta Orthop Traumatol Turc. 2018;52(5):387-391.
 
5. Bottomley WW, Cunliffe WJ. Acute Achilles tendonitis following oral isotretinoin therapy for acne vulgaris. Clin Exp Dermatol. 1992;17(4):250-251.