Insights to post-approval safety for CLAD tablets were provided by studies from two German MS centers [
22,
31]. These studies prospectively evaluated more than 200 patients with a median follow-up of 2 years. The studies disclosed a high overall incidence of CLAD-associated skin reactions [
31]. Every third patient (32%) was affected by at least one dermatological adverse event (AE). Skin reactions most commonly occurred within 3 months from CLAD administration (70%), and the predominant manifestations were hair thinning (11.7%) and skin rash (8.4%). Other frequent acute skin reactions included pruritus (2.6%) and transient mucositis (5.4%). Of the latter, 2 patients developed a dental abscess. Acute skin AE were generally temporary and resolved either spontaneously or following treatment with steroids and/or antihistamines. The exceptions were 9 patients who had manifestations that persisted throughout the study period (
n = 6 hair thinning,
n = 3 rash). Apart from this study cohort, an acute drug hypersensitivity has been reported in a male patient who developed lichenoid eruptions in close relationship to each CLAD cycle [
32]. After treatment with steroids and antihistamines, the acute skin rash resolved within 40 days.
Delayed skin AEs, defined as occurrence more than 3 months from of any CLAD intake, were less frequent (2.9%). They included, besides rash and hair thinning, alopecia areata in two individuals (27- and 34-year-old women) and leukocytoclastic vasculitis (42-year-old woman) in one case [
31]. Alopecia was diagnosed at 13 and 20 months from CLAD start and persisted throughout the follow-up. The clinical manifestation of vasculitis was at 22 months from the first CLAD intake and improved with oral steroids. Since no other explanatory triggers were identified, the authors hypothesized that these AE are autoimmune complications related to CLAD therapy [
31]. Another possible secondary autoimmune AE following treatment with CLAD is a case of histologically proven antibody-mediated glomerulonephritis (44-year-old woman) [
33]. Shortly after the fourth CLAD cycle, she developed renal failure and subsequently hemolysis and thrombocytopenia. Despite intensified treatment with pulsed steroids, plasmapheresis, and eculizumab, this patient remained hemodialysis dependent. Taken together, isolated cases of autoimmune events following CLAD have been reported since drug approval, but a causative relationship remains to be confirmed.
The evaluation of the safety data generated in the pivotal trials revealed that the AE of special interest was most frequently the occurrence of herpes zoster, followed by oral herpes and herpes simplex [
16]. In a bicentric study from Germany, herpes virus infections occurred in 14.6% at a median of 83 days (range 10–305 days) after the intake of CLAD tablets [
22]. In this cohort, the herpes virus infections related to both herpes-simplex virus (HSV) and VZV, and mostly occurred in year 1. Two patients had cranial nerve involvement among the 22 patients with VZV infection. No VZV encephalitis case was present in the cohort. While most HSV infections resolved following local treatment, all patients with VZV infection received intravenous acyclovir. Interestingly, the incidence of VZV reactivation but not that of HSV infection was significantly associated with low lymphocyte counts. Indeed, lymphocyte numbers were decreased among all patients during VZV manifestation, and every second patient had lymphopenia grades 3 and 4 (< 500 cells/µl) [
22]. In line with this, lymphocyte counts at manifestation of HSV disease (median 860 cells/μL; range: 420–1150 cells/μL) were lower for VZV infection (median 570 cells/µl; range: 220–1120 cells/μL) [
31]. Of note, previously DMF-exposed patients were more prone to develop severe lymphopenia (odds ratio: 5.0;
p < 0.001) compared to the remainder and had mainly VZV infections [
22]. Interestingly, the grade of lymphopenia in DMF-pretreated individuals was independent of the baseline lymphocyte count. Even though the data are insufficient to give recommendations on whether and when to consider antiviral prophylaxis, the authors conclude that patients switching from DMF to CLAD should be closely monitored for and eventually (booster) vaccinated against VZV. Interestingly, the incidence of VZV infection was much lower in an observational study from Canada (2%), which retrospectively compared the safety profile of ALEM (
n = 46) and CLAD (
n = 65; tablets and infusions) over 3 years [
29]. The CLAD-treated group was older (
p = 0.0002), with higher baseline EDSS (
p = 0.0015), and more likely to be secondary progressive (
p < 0.0001). They found better tolerability of CLAD, and ALEM was associated with significantly more infusion-related AE (80% vs. 17% for the IV CLAD treatment), VZV infections (22% vs. 2%), and secondary autoimmune events (56% vs. 3%). Interestingly, the authors classified two cases of hypothyroidism (3%) as autoimmune adverse reactions linked to CLAD treatment [
29]. This study also addressed the occurrence of malignancies. These were equally distributed among the two cohorts (2% each) and included follicular lymphoma (ALEM) and recurrent basal cell carcinoma (CLAD). In contrast, the integrated safety analysis of the CLAD development program recorded ten malignancies in 3754 patient-years compared to only three events among the placebo cohorts (2275 patient-years) [
3]. CLAD-associated malignancies consisted of melanoma (
n = 2) and one case each of basal cell carcinoma, squamous cell carcinoma, pancreatic, breast, ovarian, rectal, and papillary thyroid cancers, and bile duct adenocarcinoma. The wide spectrum indicates no clustering of any particular cancer type. Importantly, the incidence rate of malignancies under CLAD tablets was not different from the patient cohort treated with other DMDs [
34]. Although signals of carcinogenicity were ultimately disproved, long-term monitoring has been recommended by the EMA and the FDA [
35]. Due to the relatively short follow-up period in the pivotal trials compared to a long latency period for many cancers [
36], real-world data over many years are warranted to detect potential cancer side effects associated with immunotherapies. The German study (
n = 239) detected cancerous skin lesions (squamous cell carcinoma,
n = 2) in 0.8% of pwMS treated with CLAD tablets [
31]. For now, there is no evidence underscoring an increased rate of neoplasms following CLAD tablet therapy compared to the general population. The final safety analysis from the clinical development program, including the PREMIERE registry, confirmed the low level of serious treatment-emergent AEs associated with CLAD tablets [
17].