Case Reports

Glatiramer Acetate–Induced Lobular Panniculitis and Skin Necrosis

Cutis. 2015 March;95(3):E26-E30

References

1. Anderson G, Meyer D, Herrman CE, et al. Tolerability and safety of novel half milliliter formulation of glatiramer acetate for subcutaneous injection: an open-label, multicenter, randomized comparative study. J Neurol. 2010;257:1917-1923.

2. Soares Almeida LM, Requena L, Kutzner H, et al. Localized panniculitis secondary to subcutaneous glatiramer acetate injections for the treatment of multiple sclerosis: a clinicopathologic and immunohistochemical study. J Am Acad Dermatol. 2006;55:968-974.

3. Ford CC, Johnson KP, Lisak RP, et al. A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients. Mult Scler. 2006;12:309-320.

4. Frohman EM, Brannon K, Alexander S, et al. Disease modifying agent related skin reactions in multiple sclerosis: prevention, assessment, and management. Mult Scler. 2004;10:302-307.

5. Ziemssen T, Neuhaus O, Hohlfeld R. Risk-benefit assessment of glatiramer acetate in multiple sclerosis. Drug Saf. 2001;24:979-990.

6. Ball NJ, Cowan BJ, Moore GR, et al. 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;35:407-410.

7. Rauschka H, Farina C, Sator P, et al. Severe anaphylactic reaction to glatiramer acetate with specific IgE. Neurology. 2005;64:1481-1482.

8. Hwang L, Orengo I. Lipoatrophy associated with glatiramer acetate injections for the treatment of multiple sclerosis. Cutis. 2001;68:287-288.

9. Edgar CM, Brunet DG, Fenton P, et al. Lipoatrophy in patients with multiple sclerosis on glatiramer acetate. Can J Neurol Sci. 2004;31:58-63.

10. Soós N, Shakery K, Mrowietz U. Localized panniculitis and subsequent lipoatrophy with subcutaneous glatiramer acetate (Copaxone) injection for the treatment of multiple sclerosis. Am J Clin Dermatol. 2004;5:357-359.

11. Segura S, Requena L. Anatomy and histology of normal subcutaneous fat, necrosis of adipocytes, and classification of the panniculitides. Dermatol Clin. 2008;26:419-424, v.

12. Bosca I, Bosca M, Belenguer A, et al. Necrotising cutaneous lesions as a side effect of glatiramer acetate. J Neurol. 2006;253:1370-1371.

13. Feldmann R, Schierl M, Rauschka H, et al. Necrotizing skin lesions with involvement of muscle tissue after subcutaneous injection of glatiramer acetate. Eur J Dermatol. 2009;19:385.

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Based on a search of the MeSH (Medical Subject Headings) database using the terms panniculitis and glatiramer acetate, there only are 10 reported cases of panniculitis as an adverse effect of GA injections.^2,6,10 Lesions were described as either subcutaneous erythematous nodules or atrophic areas that demonstrated panniculitis on histologic examination. Injections preceding the development of panniculitis often were described as remarkably painful.⁴ Residual lipoatrophy and/or hyperpigmentation at the site of panniculitis development is common.² It has been suggested that GA-induced panniculitis may be an early underlying mechanism for the development of lipoatrophy, and thus may be more common than originally suspected.¹⁰

Histopathologic examination of GA-induced panniculitis typically reveals a localized, mostly lobular, panniculitis with lipophagic granulomas, lymphocytes, and thickened septa. The lipophagic granulomas (a characteristic finding in panniculitis) form from local macrophages that engulf the lipids released from necrotic adipocytes.¹¹ A large, pale, granular or vacuolated cytoplasm typically can be observed on microscopic examination of the macrophages (Figure 2C). Connective tissue septa typically are widened with cell infiltrates, usually lymphocytes. Other cell types, including macrophages, eosinophils, and neutrophils, also have been identified in both the septa and fat lobules. These histologic elements may change and evolve over time.

Necrosis in association with panniculitis, as seen in our patient, rarely has been reported.^4,12 All of the necrotic reactions described occurred after at least 1 year of GA therapy and took several weeks to resolve.^4,12 When presented with the development of skin necrosis at the site of GA injection, it is essential to distinguish between an adverse effect associated with the drug itself and Nicolau syndrome (embolia cutis medicamentosa).¹³ Necrosis at multiple injection sites or recurrence with later injections supports a GA-specific effect.¹²

Nicolau syndrome is a well-known traumatic reaction that leads to microembolization and resultant vasospasm as well as necrosis throughout the skin and possibly the underlying muscular layer.¹⁴ Although more commonly associated with intramuscular injections, Nicolau syndrome has been described with subcutaneous injections of GA in a few rare instances.^13,15 Because of the associated severe systemic reaction as well as the histologic examination (Figure 2D), we believe the skin necrosis seen in our patient was from a reaction to GA rather than Nicolau syndrome. Our patient was not interested in restarting GA therapy; therefore, it is unknown if this reaction would have recurred, but we suspect high probability of recurrence without desensitization attempts.

Preventative measures can be taken to decrease the risk for LISRs, and patients should be educated on these techniques. Applying ice to the injection site for at least 30 seconds before cleaning the skin for injection may reduce local adverse effects.⁴ Proper instruction on injection techniques should be provided by a knowledgeable health care professional and topical anesthetics and/or steroids may be offered to reduce pain associated with injection. There have been no proven measures for prevention of lipoatrophy, panniculitis, or necrosis, and these adverse effects are not thought to be attributed to improper injection techniques.¹⁴ Rotation of injection sites is the only suggested means of decreasing the potential risk for more severely and permanently disfiguring local reactions.

If panniculitis following GA injection is suspected, a large biopsy that encompasses the entire subcutaneous fat layer is necessary for proper dermatopathologic classification.¹¹ Glatiramer acetate injections should be stopped immediately. These reactions disappear when the injections are stopped but recur when restarting treatment.² The efficacy of GA in the treatment of RRMS has led to the possible use of this drug in the treatment of other autoimmune diseases.¹⁶ Thus, it is important for clinicians to be aware of all adverse effects of subcutaneous injections of GA, including the rare occurrence of panniculitis and necrosis, and when discontinuation of therapy is indicated.

Conclusion

Daily subcutaneous injection of GA for the treatment of RRMS can result in the rare but characteristic development of localized panniculitis and necrosis. Glatiramer acetate is a common and highly effective therapy used for the treatment of RRMS. Common adverse effects include LISRs and transient acute systemic reactions. Less commonly observed but characteristic of GA injections is localized lipoatrophy and mostly lobular panniculitis. Necrosis rarely can develop in association with these cutaneous reactions. It is essential to differentiate between necrosis secondary to Nicolau syndrome and skin necrosis as a unique reaction to GA; the latter is an indication for discontinuation of GA injections. Dermatologists should be made aware of adverse cutaneous reactions seen with GA therapy, especially with the potential for expansion of the use of GA to treat other autoimmune processes. Further research is needed regarding the histopathologic evolution and mechanisms behind the development of lipoatrophy, panniculitis, and necrosis at the site of GA injection.