CASE REPORT
Eosinophilic Fasciitis Occurring under Treatment with Natalizumab for Multiple Sclerosis fanie Bujold, Catherine Boivin, Mohamed Amin, Jean-Pierre Bouchard, and Jacques Soucy
Background: Eosinophilic fasciitis is a rare sclerosing syndrome with a poorly understood etiology. Objective: We report a case of eosinophilic fasciitis in a 40-year-old man undergoing treatment with natalizumab for multiple sclerosis. Natalizumab is a selective adhesion molecule inhibitor that prevents interaction of leukocytes with endothelial cells. Peripheral blood eosinophilia has been described under treatment with natalizumab, but we herein report the first case to our knowledge of eosinophilic fasciitis as a possible complication of this medication. Contexte: La fasciite à éosinophiles est un syndrome sclérosant rare, dont les causes sont mal connues. Objectif: Sera exposé ici un cas de fasciite à éosinophiles chez un homme de 40 ans, traité par le natalizumab, pour la sclérose en plaques. Le natalizumab est un inhibiteur sélectif des molécules d'adhésion, qui empêche les interactions entre les leucocytes et les cellules endothéliales. Il a déjà été fait mention d'éosinophilie sanguine périphérique en cours de traitement par le natalizumab, mais ¡I s'agit, à notre connaissance, du premier exposé de cas de fasciite à éosinophiles, décrit comme une complication possible de l'utilisation de ce médicament.
OSINOPHILIC FASCIITIS is a rare sclerosing syndrome first reported by Shulman in 1975' as the association of diffuse fasciitis with blood eosinophilia. It presents clinically as edema and diffuse subcutaneous induration of the limbs and trunk. On biopsy specimens, a thickened muscular fascia with eosinophilic infiltration is observed. To date, the etiology of this syndrome is poorly understood. We report a case of eosinophilic fasciitis in a patient undergoing treatment with natalizumab for multiple sclerosis (MS). Natalizumab is a recombinant humanized monoclonal antibody that prevents adhesion of leukocytes to endothelial cells by binding to the 0L4 subunit of a4ßi and cx4ß7 integrins present on the surface of lymphocytes, eosinophils, basophils, and monocytes. It was approved by the Food and Drug Administration in 2004 for the
E
From the Department of Dermatology, Hotel-Dieu de Quebec, Quebec City, QC. Address reprint requests to: Janie Bujold, MD, FRCPC, Department of Dermatology, Hotel-Dieu de Quebec, 11 côté du Palais Quebec, Quebec City, QC GIR 2J6; e-mail: janie.bujold.Wulaval.ca.
DOI 10.2310/7750.2013.13026 (• 2014 Canadian Dermatology Association
treatment of relapsing-remitting MS. Natalizumab has been associated with peripheral blood eosinophilia.^"*
Case Report A 40-year-old man with long-standing treatment-resistant MS presented with bilateral erythematous to brownish indurated plaques of the pretibial areas. This had been progressing for 2 weeks following the completion of intensely physical renovation work that had lasted 2 weeks. He was not known for any other medical conditions. He had started treatment with natalizumab a year before, at a standard dose of 300 mg IV every 4 weeks. No other medication was taken by the patient. He first presented to the emergency service and was treated with multiple courses of systemic antibiotics for a presumed diagnosis of bilateral infectious cellulitis. The lack of improvement in his condition justified a consultation at our dermatology department, where the diagnosis of eosinophilic fasciitis was evoked due to the suggestive clinical appearance. A blood panel demonstrated a normal white blood cell count except for a slight hypereosinophilia of 1,800 X 10' cells/L. Hemoglobin and platelet counts were normal. A basic metabolic panel for renal and hepatic function was normal. The antinuclear antibody was negative. A biopsy of the fascia revealed an abundant
DECKEI^ ' Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol ¡8, No 1 (January/February), 2014: pp 69-71
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Bujolá et al
infiltrate of eosinophils (Figure 1, Figure 2). We interrupted treatment with natalizumab and initiated hydroxychloroquine at a dose of 200 mg once daily. He demonstrated rapid clinical improvement in 3 weeks. Complete clinical resolution allowed discontinuation of hydroxychloroquine after 3 months. Blood eosinophilia normalized in 6 months. Because of his progressive MS, a decision was taken to resume treatment with natalizumab, which had been interrupted for 2 months. Fortunately, our patient presented no recurrence of the fasciitis to date and now receives natalizumab every other month because of better control of his MS. Although prednisone is the treatment of choice for this condition, our patient declined this medication because of reported intolerance (general malaise and fatigue). Other reported alternatives include hydroxychloroquine, methotrexate, cyclosporine, sulfasalazine, and topical tacrolimus,^ usually in addition to the standard treatment of systemic corticosteroid. Our patient demonstrated an excellent clinical response to monotherapy with hydroxychloroquine, highlighting an interesting clinical option for patients with contraindications to systemic corticosteroids. In accordance with this, in one published case series, prednisone and hydroxychloroquine seemed equally beneficial in treatment.^^
Figure 2. Dense eosinophilic infiltrate (hematoxylin-eosin stain, X40 original magnification).
hypereosinophilia. A generalized erythematous pruriginous skin drug eruption with accompanying peripheral eosinophilia has been previously described.'° However, this is the first case report to our knowledge of a pathologic tissue infiltration of eosinophils in the form of an eosinophilic fasciitis associated with treatment with natalizumab. As our patient was able to resume natalizumab without recurrence, it is possible that this adverse effect represents a more complex interaction between medication-induced hypereosinophilia and other unknown environmental and/or genetic factors. As intense physical exertion is a known provoking factor, it is possible that it played an important role in unmasking this adverse reaction in our patient.
Discussion A recent review of drug-induced inflammatory myopathies with cutaneous manifestations reports that L-tryptophan is the first agent linked with eosinophilic fasciitis.'' Druginduced eosinophilic fasciitis has also been reported from phenytoin^ and antituberculous therapy.'' Natalizumab is a selective adhesion molecule inhibitor that prevents interaction of leukocytes with endothelial cells. Consequently, it has been associated with blood
Conclusion Although the underlying physiopathologic mechanisms are not well understood, it is possible that eosinophilic fasciitis represents a rare drug-induced complication of treatment with natalizumab and thus should be considered in patients with onset of woody edema under this medication.
Acknowledgment Financial disclosure of authors and reviewers: None reported. References
Figure 1. Thickened subcutaneous fascia with numerous eosinophils (hematoxylin-eosin stain, X40 original magnification).
'70
1. Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Assoc Am Physicians 1975;88:70-86. 2. Abbas M, Lalive PH, Chofflon M, et al. Hypereosinophilia in patients with multiple sclerosis treated with natalizumab. Neurology 2011;77:1561^, doi:10.1212/WNL.0b013e318233b391. 3. Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007:356:2622-9, doi:10.1056/NEIMct071462.
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 1 (January/February), 2014: pp 69-71
Fosinophilic Fasciitis Occurring under Treatment with Natalizumab for MS
Stiive O, Gold R, Chan A, et al. alpha4-Integrin antagonism with natalizumab: effects and adverse effects. J Neurol 2008;255 Suppl 6:58-65, doi: 10.1007/s00415-008-6011 -0. Bischoff L, Derk CÏ. Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review ofthe literature Int J Dermatol 2008;4729-35, doi:10.1111/j.l365-4632.2007.03544.x. 6. Lakhanpal S, Ginsburg WW, Michet CJ, et al. Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases. Semin Arthritis Rheum 1988;17:221-31, doi:10.1016/0049-0172(88)90008-X. Dourmishev LA, Dourmishev AL. Activity of certain drugs in inducing of inflammatory myopathies with cutaneous manifestations.
Expert Opin Drug Saf 2008;7:421-33, doi:10.1517/14740338.7.4. 421. Buchanan RR, Gordon DA, Muckle TJ, et al. The eosinophilic fasciitis syndrome after phenytoin (düantin) therapy. J Rheumatol 1980;7:733-6. Seaman JM, Goble M, Madsen L, et al. Fasciitis and polyarthritis during antituberculous therapy. Arthritis Rheum 1985;28:1079-84, doi:10.1002/art.l780281017. 10. André MC, Pacheco D, Antunes J, et al. Generalized skin drug eruption to natalizumab in a patient with multiple sclerosis. Dermatol Online J 2010;16(6):14.
r Canadian Dermatology Association I Journal of Cutaneous Mediane and Surgery, Vol 18, No 1 (January/February), 2014: pp 69-71
71
Copyright of Journal of Cutaneous Medicine & Surgery is the property of Decker Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Eosinophilic Fasciitis Occurring under Treatment with Natalizumab for Multiple Sclerosis fanie Bujold, Catherine Boivin, Mohamed Amin, Jean-Pierre Bouchard, and Jacques Soucy
Background: Eosinophilic fasciitis is a rare sclerosing syndrome with a poorly understood etiology. Objective: We report a case of eosinophilic fasciitis in a 40-year-old man undergoing treatment with natalizumab for multiple sclerosis. Natalizumab is a selective adhesion molecule inhibitor that prevents interaction of leukocytes with endothelial cells. Peripheral blood eosinophilia has been described under treatment with natalizumab, but we herein report the first case to our knowledge of eosinophilic fasciitis as a possible complication of this medication. Contexte: La fasciite à éosinophiles est un syndrome sclérosant rare, dont les causes sont mal connues. Objectif: Sera exposé ici un cas de fasciite à éosinophiles chez un homme de 40 ans, traité par le natalizumab, pour la sclérose en plaques. Le natalizumab est un inhibiteur sélectif des molécules d'adhésion, qui empêche les interactions entre les leucocytes et les cellules endothéliales. Il a déjà été fait mention d'éosinophilie sanguine périphérique en cours de traitement par le natalizumab, mais ¡I s'agit, à notre connaissance, du premier exposé de cas de fasciite à éosinophiles, décrit comme une complication possible de l'utilisation de ce médicament.
OSINOPHILIC FASCIITIS is a rare sclerosing syndrome first reported by Shulman in 1975' as the association of diffuse fasciitis with blood eosinophilia. It presents clinically as edema and diffuse subcutaneous induration of the limbs and trunk. On biopsy specimens, a thickened muscular fascia with eosinophilic infiltration is observed. To date, the etiology of this syndrome is poorly understood. We report a case of eosinophilic fasciitis in a patient undergoing treatment with natalizumab for multiple sclerosis (MS). Natalizumab is a recombinant humanized monoclonal antibody that prevents adhesion of leukocytes to endothelial cells by binding to the 0L4 subunit of a4ßi and cx4ß7 integrins present on the surface of lymphocytes, eosinophils, basophils, and monocytes. It was approved by the Food and Drug Administration in 2004 for the
E
From the Department of Dermatology, Hotel-Dieu de Quebec, Quebec City, QC. Address reprint requests to: Janie Bujold, MD, FRCPC, Department of Dermatology, Hotel-Dieu de Quebec, 11 côté du Palais Quebec, Quebec City, QC GIR 2J6; e-mail: janie.bujold.Wulaval.ca.
DOI 10.2310/7750.2013.13026 (• 2014 Canadian Dermatology Association
treatment of relapsing-remitting MS. Natalizumab has been associated with peripheral blood eosinophilia.^"*
Case Report A 40-year-old man with long-standing treatment-resistant MS presented with bilateral erythematous to brownish indurated plaques of the pretibial areas. This had been progressing for 2 weeks following the completion of intensely physical renovation work that had lasted 2 weeks. He was not known for any other medical conditions. He had started treatment with natalizumab a year before, at a standard dose of 300 mg IV every 4 weeks. No other medication was taken by the patient. He first presented to the emergency service and was treated with multiple courses of systemic antibiotics for a presumed diagnosis of bilateral infectious cellulitis. The lack of improvement in his condition justified a consultation at our dermatology department, where the diagnosis of eosinophilic fasciitis was evoked due to the suggestive clinical appearance. A blood panel demonstrated a normal white blood cell count except for a slight hypereosinophilia of 1,800 X 10' cells/L. Hemoglobin and platelet counts were normal. A basic metabolic panel for renal and hepatic function was normal. The antinuclear antibody was negative. A biopsy of the fascia revealed an abundant
DECKEI^ ' Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol ¡8, No 1 (January/February), 2014: pp 69-71
69
Bujolá et al
infiltrate of eosinophils (Figure 1, Figure 2). We interrupted treatment with natalizumab and initiated hydroxychloroquine at a dose of 200 mg once daily. He demonstrated rapid clinical improvement in 3 weeks. Complete clinical resolution allowed discontinuation of hydroxychloroquine after 3 months. Blood eosinophilia normalized in 6 months. Because of his progressive MS, a decision was taken to resume treatment with natalizumab, which had been interrupted for 2 months. Fortunately, our patient presented no recurrence of the fasciitis to date and now receives natalizumab every other month because of better control of his MS. Although prednisone is the treatment of choice for this condition, our patient declined this medication because of reported intolerance (general malaise and fatigue). Other reported alternatives include hydroxychloroquine, methotrexate, cyclosporine, sulfasalazine, and topical tacrolimus,^ usually in addition to the standard treatment of systemic corticosteroid. Our patient demonstrated an excellent clinical response to monotherapy with hydroxychloroquine, highlighting an interesting clinical option for patients with contraindications to systemic corticosteroids. In accordance with this, in one published case series, prednisone and hydroxychloroquine seemed equally beneficial in treatment.^^
Figure 2. Dense eosinophilic infiltrate (hematoxylin-eosin stain, X40 original magnification).
hypereosinophilia. A generalized erythematous pruriginous skin drug eruption with accompanying peripheral eosinophilia has been previously described.'° However, this is the first case report to our knowledge of a pathologic tissue infiltration of eosinophils in the form of an eosinophilic fasciitis associated with treatment with natalizumab. As our patient was able to resume natalizumab without recurrence, it is possible that this adverse effect represents a more complex interaction between medication-induced hypereosinophilia and other unknown environmental and/or genetic factors. As intense physical exertion is a known provoking factor, it is possible that it played an important role in unmasking this adverse reaction in our patient.
Discussion A recent review of drug-induced inflammatory myopathies with cutaneous manifestations reports that L-tryptophan is the first agent linked with eosinophilic fasciitis.'' Druginduced eosinophilic fasciitis has also been reported from phenytoin^ and antituberculous therapy.'' Natalizumab is a selective adhesion molecule inhibitor that prevents interaction of leukocytes with endothelial cells. Consequently, it has been associated with blood
Conclusion Although the underlying physiopathologic mechanisms are not well understood, it is possible that eosinophilic fasciitis represents a rare drug-induced complication of treatment with natalizumab and thus should be considered in patients with onset of woody edema under this medication.
Acknowledgment Financial disclosure of authors and reviewers: None reported. References
Figure 1. Thickened subcutaneous fascia with numerous eosinophils (hematoxylin-eosin stain, X40 original magnification).
'70
1. Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Assoc Am Physicians 1975;88:70-86. 2. Abbas M, Lalive PH, Chofflon M, et al. Hypereosinophilia in patients with multiple sclerosis treated with natalizumab. Neurology 2011;77:1561^, doi:10.1212/WNL.0b013e318233b391. 3. Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007:356:2622-9, doi:10.1056/NEIMct071462.
Canadian Dermatology Association I Journal of Cutaneous Medicine and Surgery, Vol 18, No 1 (January/February), 2014: pp 69-71
Fosinophilic Fasciitis Occurring under Treatment with Natalizumab for MS
Stiive O, Gold R, Chan A, et al. alpha4-Integrin antagonism with natalizumab: effects and adverse effects. J Neurol 2008;255 Suppl 6:58-65, doi: 10.1007/s00415-008-6011 -0. Bischoff L, Derk CÏ. Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review ofthe literature Int J Dermatol 2008;4729-35, doi:10.1111/j.l365-4632.2007.03544.x. 6. Lakhanpal S, Ginsburg WW, Michet CJ, et al. Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases. Semin Arthritis Rheum 1988;17:221-31, doi:10.1016/0049-0172(88)90008-X. Dourmishev LA, Dourmishev AL. Activity of certain drugs in inducing of inflammatory myopathies with cutaneous manifestations.
Expert Opin Drug Saf 2008;7:421-33, doi:10.1517/14740338.7.4. 421. Buchanan RR, Gordon DA, Muckle TJ, et al. The eosinophilic fasciitis syndrome after phenytoin (düantin) therapy. J Rheumatol 1980;7:733-6. Seaman JM, Goble M, Madsen L, et al. Fasciitis and polyarthritis during antituberculous therapy. Arthritis Rheum 1985;28:1079-84, doi:10.1002/art.l780281017. 10. André MC, Pacheco D, Antunes J, et al. Generalized skin drug eruption to natalizumab in a patient with multiple sclerosis. Dermatol Online J 2010;16(6):14.
r Canadian Dermatology Association I Journal of Cutaneous Mediane and Surgery, Vol 18, No 1 (January/February), 2014: pp 69-71
71
Copyright of Journal of Cutaneous Medicine & Surgery is the property of Decker Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
![[Natalizumab treatment in multiple sclerosis].](/assets/img/hold.png)
