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Clinical Surveillance Remains Necessary Among Cladribine-Treated Patients With RRMS


A prospective bicentric cohort study among individuals with relapsing-remitting multiple sclerosis (RRMS) showed that 32% developed at least 1 skin-related adverse reaction following cladribine administration.

The use of oral cladribine among patients with relapsing-remitting multiple sclerosis (RRMS) should continue to be closely monitored, in light of the 32% who experienced at least 1 adverse skin-related condition in the first month following treatment with the purine analog, according to study findings published in Neurology: Neuroimmunology & Neuroinflammation.

“Skin-related adverse events (AEs) have been described in several disease-modifying therapies (DMTs) approved for treatment of RRMS. However, little is known about the incidence and clinical presentation of such AEs in patients treated with cladribine,” the authors from University Hospital Essen and University Hospital Munster, both in Germany, explained.

Just 2 skin-related AEs have been described as possibly linked to cladribine use thus far: dermatomal herpes infections and skin rashes.

Among the 77 patients (N = 239) with RRMS in whom skin-related AEs occurred (median [range], 1.5 [1-6]), in addition to the 32% who had these reactions within first month (range, 1-12) following treatment with cladribine, the most common AEs seen within 3 months of the last dose of cladribine were the following:

  • Diffuse hair thinning in 11.7%
  • Skin rash in 8.4% (5.4%, diffuse erythema; 2.1%, acneiform rash; 0.8%, nummular eczema)
  • Mucositis in 5%
  • Pruritus in 3%

Of the patients who developed rash, it co-occurred with pruritis in 2 cases. Six patients also developed rash after treatment was initiated with cladribine and following reexposure at the second cycle.

Close to 15% also developed a herpetic skin infection (6.7%, herpes zoster; 7.9%, herpes simplex) a median of 83 days (range, 10-305 days) after their last dose. Of this group, herpes zoster infection was severe enough in 88% (Common Terminology Criteria for Adverse Events grade ≥ 3) that they had to be hospitalized.

Most herpes zoster (88%) and herpes simplex (74%) infections appeared during lymphopenia. When this happened, the median lymphocyte counts were 570 cells/mcL (range, 220-1120) and 860 cells/mcL (range, 420-1150), respectively.

Additional delayed skin reactions—those seen 3 months or more after completion of a cladribine treatment cycle—were leukocytoclastic vasculitis (n = 1), alopecia areata (n = 2), precancerous lesions (n = 1 leukoplakia and n = 2 actinic keratosis in 2 patients), and squamous cell carcinoma (n = 1; this patient discontinued treatment).

The most common skin reactions were classified as acute, in that they occurred fewer than 3 months after a treatment cycle, and most resolved without specific treatment while cladribine treatment was ongoing, the investigators noted.

Possible underlying mechanisms for these results include nonhematologic toxicity (in alopecia, mucositis, and acneiform rash), immune-mediated skin phenomena (in skin rash or prutitus), and increased T cells expressing the activation marker HLA-DR (in alopecia areata).

“This study provides Class IV evidence that skin-related AEs are frequent in patients with MS following cladribine in a real-world setting,” the authors concluded. “Until risk management plans have been adjusted to include these phenomena, clinicians should perform a thorough clinical follow-up and in suspicious cases seek early interdisciplinary support.”

Further studies should also investigate expression of risk alleles for autoimimmune phenomena and evaluate the utility of cladribine in patients prone to skin irritation.


Rolfes L, Pfeuffer S, Hackert J, et al. Skin reactions in patients with multiple sclerosis receiving cladribine treatment. Neurol Neuroimmunol Neuroinflamm. Published online April 9, 2021. doi:10.1212/NXI.0000000000000990

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