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Natalizumab is a humanized monoclonal antibody directed against the cellular adhesion molecule α4 integrin. It binds to the α4 subunit of α4β1 and α4β7 integrins and blocks binding to their endothelial receptors (vascular cell adhesion molecule 1 and mucosal addressin-cell adhesion molecule 1, respectively), thereby decreasing the inflammation processes. It is indicated in Europe as monotherapy for the treatment of highly active relapsing-remitting multiple sclerosis (MS). Since the beginning of its use, 4 cases of melanomas occurring during treatment with natalizumab have been reported, suggesting that it might promote the development of melanomas.1- 3 Although the meta-analysis of the safety data from clinical trials of natalizumab showed that the incidence of melanoma was similar among patients who received natalizumab compared with those who received placebo,4 the severity of such potential adverse event requires further investigations. We followed the evolution of skin melanocytic lesions in patients with MS being treated with natalizumab.
In March 2008, we started a monocentric prospective follow-up of a cohort of patients with MS treated with natalizumab in our MS center (Nice, France). All the patients treated with natalizumab were included. Dermatologic follow-up was led by the Department of Dermatology of the University Hospital of Nice. Patients had a complete clinical and dermoscopic skin examination every 6 months. If natalizumab had to be stopped for any reason, a last visit was mandatory for a final assessment of their melanocytic lesions. For each patient, age, sex, date of the onset of treatment, and risk factors of melanoma (frequent sunburns, especially in childhood; familial and personal history of melanoma; dysplastic nevi; and having >50 nevi) were collected. We used the 2-step method of digital follow-up for each patient. The first step was a clinical and digital total body mapping. The second step was a digital dermoscopy. At each visit, a total body cutaneous examination was performed, and melanocytic nevi were compared side-by-side with baseline photographs. If the patients had only a few nevi, all the nevi were followed. If the nevi were numerous, only the most atypical were chosen. The digital computerized dermoscopy system was a Fotofinder dermoscope (Fotofinder Systems, Bad Birnbach, Germany). Two trained experienced investigators (E.C. and P.B.) reviewed all the monitoring melanocytic skin lesions. We used the same criteria for changes as defined by Kittler et al.5 Substantial and nonsubstantial modifications were differentiated. Substantial criteria were enlargement, changes in shape, regression, color changes (appearance of new colors), and structural dermoscopic changes (appearance of dermoscopic structures known to be associated with melanoma, eg, appearance of irregularly distributed black dots in the periphery, radial streaming, whitish veil, grayish-blue area, pseudopods, and appearance of a prominent and irregular pigment network). Nonsubstantial criteria were darker or lighter overall pigmentation of a lesion without other modifications, increase or decrease in the number of brown globules, inflammation, disappearance or decrease in the number of initially present black dots, and replacement of parts of the pigment network by a diffuse light brown pigmentation. Excision of the lesions was proposed on clinical (ABCDE rules) and dermoscopic criteria, such as asymmetric enlargement, focal changes in pigmentation and structure, regression features, or change in color (appearance of a new color).5,6
Forty-four patients were included (33 women and 11 men). Their mean age was 35 years (range, 18-58 years). A total of 248 pigmented lesions were monitored. An average of 8 lesions (range, 3-25 lesions) was followed for each patient. Considering the risk factors of melanoma, 19 patients had fair skin (phototypes I and II). The Fitzpatrick skin types of the patients were as follows:
Nineteen patients remembered experiencing frequent sunburns in childhood. Two patients had more than 50 nevi. One patient had a familial history of melanoma. One patient had a personal history of melanoma and was already being followed for an atypical nevus syndrome. Three patients had clinical signs of sun damage, including solar lentigines and elastosis. The mean delay between the onset of the follow-up and the first infusion was 5 months (range, 0-22 months). The mean duration of follow-up was 14 months (6-20 months), with a median duration of 13 months. Eight patients had to stop natalizumab treatment during the study (mean duration of follow-up in these patients, 14 months; range, 1-20 months). All of them had a last follow-up visit 6 months after discontinuation of treatment, except for 1 woman who received only 1 infusion and refused the follow-up visit.
Seventeen lesions (6.8%) showed modifications over time. In most cases, these modifications were not reported by the patients and were not noticed during clinical examination. Only 4.8% presented substantial dermoscopic changes (Table). The most common modifications were signs of regression (observed in 47% of the cases) and structural changes (observed in 42% of the cases). The only structural change observed was an extension of the network. Most of the lesions that showed substantial changes kept a symmetrical structure. We observed the occurrence of a new nevus for one 25-year-old patient. No cutaneous adverse effects were noted.
Five melanocytic lesions were removed (Figure). One lesion localized on the arm had at the first visit an asymmetric and irregular dermoscopic pattern, which led to a histologic examination. A junctional nevus with signs of regression without mitotic activity or a sign indicating a melanoma was found. Two nevi in a same patient, both localized on the thigh, showed focal modifications at the 6-month follow-up. These were minor but increased after 1 year of follow-up. Both presented a focal appearance of a prominent pigment network. The histologic examination revealed 2 junctional nevi. At the first visit of a third patient, 1 lesion of the arm had an asymmetric network with a central dark network. Because the lesion was not clinically suspected to be melanoma, an intermediate follow-up at 3 months was decided on. Three months later, an area of regression had replaced the dark network; histologic examination revealed a junctional nevus. The last lesion was thoracic and had a pattern that had clearly changed after 12 months of follow-up. The histologic examination showed a pigmented spindle cell nevus. The patient with a personal history of melanoma did not experience any modification of his nevi.
Dermoscopic changes and histologic aspects of the lesions excised. A, Lesion 1. Left, Dermoscopic findings at the first visit. Right, Pathologic image: junctional nevus. There is no dermoscopic follow-up photograph for this lesion because it was removed at the first visit owing to its atypical clinical and dermoscopic signs. B, Lesion 2. Left, Dermoscopic findings at first visit. Middle, Dermoscopic findings after 18 months of follow-up. Right, Pathologic image: junctional nevus. C, Lesion 3. Left, Dermoscopic findings at first visit. Middle, Dermoscopic findings after 18 months of follow-up. Right, Pathologic image: junctional nevus. D, Lesion 4. Left, Dermoscopic findings at first visit. Middle, Dermoscopic findings after 3 months of follow-up. Right, Pathologic image: junctional nevus. E, Lesion 5. Left, Dermoscopic findings at first visit. Middle, Dermoscopic findings after 12 months of follow-up. Right, Pathologic image: junctional proliferation with nest and lymphocytic infiltration. (For all panels in the right-hand column: hematoxylin-eosin, original magnification ×10.)
In our series of 248 monitored melanocytic skin lesions, dermoscopic changes were noted in 6.8% of cases, and substantial dermoscopic changes were observed in only 4.8% of the cases. All the excised lesions were benign, and no melanoma was diagnosed. This percentage of changes is comparable with that observed in an untreated population.5 In this population, substantial dermoscopic changes were observed in about 4% of common and atypical nevi after a median total follow-up interval of 11 months (range, 3-21 months). The comparison between these 2 studies has to be made carefully because the patients were not matched according to recognized risk factors for melanoma, such as the phototype, the number of nevi, and the personal or familial history of melanoma. However, the low rate of significant modifications of the nevi that we observed in our population of patients treated with natalizumab strongly supports the absence of malignant transformation of nevi owing to the inhibition of α4 integrin by natalizumab.
It has been shown that patients with MS do not have an increased risk of cancer, including melanoma.7 The fear of an increased risk of melanoma in patients with MS treated with natalizumab is actually supported by 4 case reports. Owing to the potential severity of a melanoma development, the reports of such cases are very important, but the responsibility of the natalizumab treatment as a cause remains highly questionable when the cases are analyzed in detail.1- 3 The first report came from the AFFIRM study,1 in which 1 patient died of malignant melanoma. He had a history of malignant melanoma and had noted a new lesion at the time of receiving the first dose of natalizumab. He had received a total of 5 doses of natalizumab before this lesion was confirmed to be a melanoma. The second case was that of a 46-year-old woman who noticed a rapidly changing mole on her shoulder shortly after receiving her first dose of natalizumab. It proved to be a thick, nonulcerated melanoma with metastatic disease in the regional lymph nodes.2 The same authors also reported the case of a 45-year-old woman who had a long-standing ocular nevus that developed into an ocular melanoma, which was diagnosed after the administration of several doses of natalizumab. She had a family history of melanoma and many atypical moles. The last case was that of a 48-year-old woman who, 5 months after stopping the natalizumab treatment, experienced an increase in the size of a preexisting mole that had remained unchanged for many years. She had no history of melanoma or atypical nevi. The pathologic examination revealed an in situ melanoma.3 Thus, the first patient most probably already had melanoma before the onset of natalizumab treatment because he noticed the lesion before the first infusion. The lesion of the second patient was observed to change shortly after the first infusion. When it was removed the lesion was already very thick, suggesting that it might also have been in existence before the natalizumab treatment. As always for ocular melanoma, it is difficult to determine when the nevus changed, but the disease was already advanced when the melanoma was diagnosed in the third patient. The last patient presented with a completely different story because her melanoma had developed 5 months after the end of natalizumab treatment, and this melanoma was at a very early stage (intraepidermal).
Moreover, the meta-analysis of the safety data from clinical trials of natalizumab showed that the incidence of melanoma was similar among patients who received natalizumab compared with those who received placebo.4
Because most melanomas are developing de novo and not from an existing nevus, this study is not designed to assess the risk of developing melanoma during treatment with natalizumab but to further investigate if the systemic inhibition of α4 integrin could promote changes in preexisting melanocytic lesions. Recently, the use of melanocyte-stimulating hormone analogues was demonstrated to rapidly change the pattern of a preexisting nevus, showing that a systemic drug can lead to dramatic changes in melanocytic lesions.8 In vitro studies showed that the α4β1 integrin could be linked to the invasiveness of melanoma.9,10 However, some authors suggest that the integrin-endothelium contact could promote metastatic dissemination,11,12 whereas others hypothesize a protective effect of those integrins.13 To our knowledge, there are no data suggesting that inhibiting the α4 integrin could promote the transformation of melanocytes. Thus, we can hypothesize that if natalizumab has any action on melanoma, it could only be by promoting the invasiveness of a preexisting melanoma and not by promoting the transformation of melanocytes. Our results are consistent with this hypothesis, showing no increased modifications of nevi during treatment with natalizumab.
Correspondence: Thierry Passeron, MD, PhD, Department of Dermatology, and INSERM U895 Team 1, University Hospital of Nice, Archet 2 Hospital, Rte de St Antoine de Ginestiere, 06200 Nice, France (email@example.com).
Accepted for Publication: June 8, 2010.
Published Online: September 20, 2010. doi:10.1001/archdermatol.2010.243
Author Contributions: Drs Castela and Passeron had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Lebrun-Frenay, Laffon, Rocher, Cohen, Cardot Leccia, Lacour, Ortonne, and Passeron. Acquisition of data: Castela, Lebrun-Frenay, Laffon, Rocher, and Cohen. Analysis and interpretation of data: Castela, Lebrun-Frenay, Laffon, Rocher, Cohen, Bahadoran, Lacour, and Passeron. Drafting of the manuscript: Castela, Lebrun-Frenay, Laffon, Cohen, Cardot Leccia, and Passeron. Critical revision of the manuscript for important intellectual content: Castela, Lebrun-Frenay, Rocher, Bahadoran, Lacour, Ortonne, and Passeron. Statistical analysis: Passeron. Obtained funding: Ortonne and Passeron. Administrative, technical, and material support: Lebrun-Frenay, Laffon, Rocher, Cohen, and Bahadoran. Study supervision: Lebrun-Frenay, Lacour, and Passeron.
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by the University Hospital of Nice, France.
Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
Castela E, Lebrun-Frenay C, Laffon M, Rocher F, Cohen M, Leccia NC, Bahadoran P, Lacour J, Ortonne J, Passeron T. Evolution of Nevi During Treatment With NatalizumabA Prospective Follow-up of Patients Treated With Natalizumab for Multiple Sclerosis. Arch Dermatol. 2011;147(1):72-76. doi:10.1001/archdermatol.2010.243