Commentary on “Localized pigmentation disorder after subcutaneous pegylated interferon beta 1a injection” by Coghe et al.

In the early 1990s, the arrival of beta interferon therapies revolutionized multiple sclerosis (MS) care across the globe. As first-line treatment options, these drugs have proven to be effective; however, adherence rates have proved challenging, ¹ side effects are common, ² and frequency of injections reported as a barrier to adherence as patient’s report forgetting to take doses. ³

PLEGRIDY (peginterferon beta 1a) is a “pegylated” form of interferon beta 1-A (IFNβ-1a). In the Efficacy and Safety Study of Peginterferon Beta-1a in Participants With Relapsing Multiple Sclerosis (ADVANCE) study, a 2-year phase III trial of 1500 people with relapsing MS, PLEGRIDY was shown after 1 year to reduce the relapse rate significantly more than placebo. ⁴

As a “pegylated” form of IFNβ-1a (which means that a polyethylene glycol has been attached to the interferon molecules), PLEGRIDY can maintain a longer biologic effect than IFNβ-1a alone. In practice, this means less frequent dosing is required reducing the number of times the individual needs to self-inject. PLEGRIDY is licensed as a subcutaneous injection administered once every 2 weeks. The individual may be prescribed a Single-Dose Prefilled PLEGRIDY Pen or a PLEGRIDY Single-Dose Prefilled Syringe. The pre-filled syringe or pre-filled pen contain up to 125 µg of peginterferon beta-1a. After an initial titration with 63 and 94 µg/ml solutions, the maintenance dose is 125 µg to be administered subcutaneously every other week. The pen and the syringe contain identical pharmacological compositions suspended in a pH solution of approximately 4.8. ⁵

In common with other subcutaneous interferon beta injection site reactions, PLEGRIDY is associated with injection site side effects. The side effects of erythema, pain, pruritus, or edema were reported by 66% of patients in the ADVANCE trial. ⁴ The exact cause of subcutaneous skin reactions associated with IFNβ-1a is unknown but may include cellular skin infiltration by at least three different pathways triggering inflammatory skin reactions through local chemokine induction followed by rapid immune cell extravasation. ⁶

In this issue of Multiple Sclerosis Journal, Coghe et al. report the first case of a localized pigmentation disorder due to subcutaneous PLEGRIDY in a 42-year-old Caucasian female patient who developed peculiar skin lesions. The patient had no comorbidities, was not using any other medication, and did not have personal or family history of eczematous dermatitis or allergy. The patient had previously been treated with Rebif subcutaneous IFN-beta 1a 22 µg three times/week for 7 years without skin site reactions.

In the first 3 months using PLEGRIDY, the patient experienced classical inflammatory post-injection reactions including pain, erythema, and pruritus. At 6-month follow-up, the injection site lesions were identified. The lesions manifested as hypopigmented macular lesions on the injection sites of both thighs and grayish diffuse hyperpigmentation irregular macules with central hypopigmentation on the abdomen. Investigations ruled out fungal infection pityriasis alba and vitiligo. Serum IgE levels were normal. The patient refused a skin biopsy. Treatment included a natural heparinoid and lenitive as a preventive measure and instructions to avoid injecting into the thigh. At 6-month follow-up, the lesions had worsened suggesting a direct effect of the drug.

Studies have reported injection site reactions as a common side effect of injectable interferon beta. ⁷ Self-injection delivery options include autoinjectors, prefilled syringes, and syringes and vials.

Devices such RebiSmart, an electronic autoinjector, include the ability to customize injection settings by adjusting the needle insertion speed, needle depth, injection speed, and injection time. ⁸ It is not known if Coghe’s patient used the RebiSmart device or an autoinjector when injecting Rebif or the PLEGRIDY PEN or PREFILLED SYRINGE when switched to PLEGRIDY. The injection device choice and patient self-injection technique may be implicated in development of skin site reactions as poor technique may result in subdermal rather than subcutaneous drug release. ⁹

Interferon therapies have been associated with cytostatic action upon melanoma cells ¹⁰ and vitiligo has been reported in patients with Hepatitis C treated with interferon alpha. ¹¹ Vitiligo has also been reported in a single case of a 33-year-old female with MS treated with Rebif 22 μg s.c. three times weekly, who developed depigmented maculae on the dorsal aspects of her hands when she had been on treatment for 2 years, 22 months after the appearance of the first skin lesions, new depigmented patches occurred around the mouth and chin. ¹² Unlike Coghe’s case study, these vitiligo lesions significantly improved 3 months after cessation of Rebif and remained stable on follow-up. The authors suggest that the pegylated molecule in PLEGRIDY may be responsible for prolonged levels of inflammation and subsequent damage to subcutaneous tissue.

It should be remembered that cosmetic disfigurement caused by skin disease can disrupt the lives of patients and add to emotional distress.^13,14 Those who cope well with disfigurement have high self-esteem and those that cope poorly include those with low self-esteem, young people, and those in the lower socioeconomic groups. ¹⁴ Psychological distress is present in MS patients with minimal to no neurologic disability patients within the first 3 years after diagnosis. ¹⁵

It is common for many young people to start treatment with injectable therapies in the first three years after diagnosis so clinicians should be vigilant for added distress that a seemingly inconsequential skin disease may cause should one occur.

This case provides a warning about the risk of local consequences of subcutaneous PLEGRIDY and reminds clinicians not to make assumptions that an individual’s response to a past therapy will apply to a new product. Individuals switching to, or starting PLEGRIDY as their first disease-modifying therapy, should be made aware that hypopigmentation has been reported, however it is considered a rare adverse event. Clinicians should remain vigilant in detection of adverse skin reactions such as hypopigmentation in real-world settings.