Necrotizing skin lesions with involvement of muscle tissue after subcutaneous injection of glatiramer acetate

ARTICLE

Auteur(s) : Robert Feldmann¹, Michael Schierl¹, Helmut Rauschka², Paul-Gunther Sator¹, Friedrich Breier¹, Andreas Steiner¹

¹Department of Dermatology and Venerology, Hospital Hietzing, Wolkersbergenstrasse 1, A-1130 Vienna, Austria
²Department of Neurology, Hospital Hietzing, Vienna

Glatiramer acetate (GA) is a random mixture of synthetic polypeptides composed of L-glutamic acid, L-lysine, L-alanine and L-tyrosine. It is approved for the treatment of multiple sclerosis and administered by daily subcutaneous injections. We report a patient treated with GA who developed necrotizing cutaneous lesions at an injection site.

A 55-year-old woman with a three year history of multiple sclerosis had been treated with 20 mg GA per day subcutaneously for two years prior to admission. The injections were self-administered without any complications during this period. Two days before consultation, she felt an intense pain immediately after subcutaneous injection of GA at the right lower abdominal area. Subsequently the patient developed irregularly circumscribed areas of inflamed skin with bizarrely shaped necrosis in the center (figure 1).

Histological examination revealed hydropic degeneration of keratinocytes and fibrin thrombi in the dermal and subcutaneous blood vessels, surrounded by extravasated erythrocytes and lymphocytes (figure 2). Thus, the diagnosis of embolia cutis medicamentosa was confirmed. Blood analysis showed elevated serum creatine kinase (2220 U/L, normal value: < 170 U/L). Ultrasound of soft parts within the necrotic skin area revealed superficial edema of the underlying musculus rectus abdominis, suggesting involvement of muscle tissue. The patient’s history had been negative for recent falls or intramuscular injections.

The patient received treatment with a nonsteroidal antiinflammatory agent (75 mg diclofenac i.v. twice daily) and low molecular weight heparin (40 mg enoxaparin-sodium s.c. daily) for one week. In addition, we administered bacitracine and neomycin powder twice a day in order to prevent secondary infection. Within ten days the level of serum creatine kinase returned to a normal value. The skin necrosis stopped extending within a few days and then became clearly demarcated. As a consequence, surgical intervention was not necessary. Treatment with glatiramer acetate was then continued and our patient has remained free from further side effects ever since.

Embolia cutis medicamentosa (Nicolau’s syndrome) was originally described in 1925 by Nicolau, occurring after intramuscular injection of bismuth salt for the treatment of syphilis. Basically the suspected pathogenetic mechanism is the accidental peri- or intravascular injection of a drug, which leads to vascular spasms and consecutive intravascular thrombosis.

Embolia cutis medicamentosa following administration of GA was first reported by Gaudez et al. [1]. A review of the literature reveals several case reports on this topic [2, 3] including reports of localized panniculitis secondary to subcutaneous GA injections [4, 5]. According to the literature, there is no evidence for any specific risk factor promoting these side effects. In this regard it is of particular interest that our patient showed damage of muscle tissue underneath the necrotic skin area.

An accidental intramuscular injection seems unlikely in our case for two reasons: first, the patient was obese (body mass index: 30.1) and exclusively used small needles for subcutaneous injections. Secondly, she was well trained in the administration of the regimen since she had been under treatment with GA for two years prior to the adverse event.

From an anatomical point of view the affected skin area is vascularized by an anastomosis of the superficial epigastric artery with branches of the inferior epigastric artery. Arterial blood supply herein is maintained via plexus formed by small perforating arterioles entering the upper skin layers from the underlying subcutis and muscles. Hence, a propagation of arterial thrombi into muscular tissue with consecutive partial ischemia of the rectus abdominis is a feasible hypothesis in our case.

We recommend monitoring of serum levels of creatine kinase in extensive embolia cutis following subcutaneous injections of GA or any other drug in order to maintain renal function, if applicable.

Acknowledgements

References

2 Bosca I, Bosca M, Belenguer A, Evole M, Hernandez M, Casanova B, Coret F. Necrotising cutaneous lesions as a side effect of glatiramer acetate. J Neurol 2006; 253: 1370-1.

3 Harde V, Schwarz T. Embolia cutis medicamentosa nach subcutaner Injektion von Glatirameracetat. JDDG 2007; 5: 1122-3.

4 Soares Almeida LM, Requena L, Kutzner H, Angulo J, de Sa J, Pignatelli J. Localized panniculitis secondary to subcutaneous glatiramer acetate injections for the treatment of multiple sclerosis: A clinicopathologic and immuno-histochemical study. J Am Acad Dermatol 2006; 55: 968-74.

5 Ball NJ, Cowan BJ, Moore GR, Hashimoto SA. Lobular panniculitis at the site of glatiramer acetate injections for the treatment of relapsing-remitting multiple sclerosis. A report of two cases. J Cutan Pathol 2008; 35: 407-10.