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Severe local skin reactions to interferon beta-1b in multiple sclerosis-improvement by deep subcutaneous injection

European Journal of Dermatology. Volume 18, Number 5, 579-82, September-October 2008, Clinical report

DOI : 10.1684/ejd.2008.0494

Summary

Author(s) : Yoshiyuki Nakamura, Yasuhiro Kawachi, Junichi Furuta, Fujio Otsuka , Department of Dermatology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Ten-nodai, Tsukuba, Ibaraki 305-8575, Japan.

Summary : Severe local skin reactions to subcutaneous injection of interferon beta-1b in multiple sclerosis are rare, and only 12 cases of severe skin reaction due to interferon beta-1b have been reported to date. We report two cases of severe skin reactions in multiple sclerosis patients following the injection of subcutaneous interferon beta-1b. In case 1, after five years of treatment, a painful indurated erythematous lesion appeared at the injection site on the left buttock. On histological analysis, the lesion showed septal and lobular panniculitis with lymphocytic infiltration. In case 2, cutaneous ulceration was surrounded by painful induration, which developed at the injection site on the right thigh after four years of treatment. The lesions resolved rapidly after discontinuation of interferon beta-1b treatment in both cases. Here, we review cases of similar lesions caused by interferon beta-1b reported in the literature, and discuss the characteristics, mechanism, treatment, and prevention of such lesions.

Keywords : multiple sclerosis, skin reaction, interferon beta-1b

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ARTICLE

Auteur(s) : Yoshiyuki Nakamura, Yasuhiro Kawachi, Junichi Furuta, Fujio Otsuka

Department of Dermatology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Ten-nodai, Tsukuba, Ibaraki 305-8575, Japan

accepté le 8 Avril 2008

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Recombinant human interferon beta-1b was approved for the treatment of MS by the US Food and Drug Administration in 1993. A number of studies have demonstrated a decrease of approximately 30% in the frequency of exacerbation of MS in patients treated interferon beta-1b [1]. However, this therapeutic agent is associated with a high frequency of side effects, such as flu-like syndrome, headache, increased spasticity, anaphylactic shock, and psychological changes. In addition, local skin reactions at the site of injection also occasionally occur. The adverse effects are usually mild and self-limiting [2], but in rare cases they may become more severe and sometimes lead to the suspension of therapy. We report two cases of skin reactions following subcutaneous interferon beta-1b injection in MS.

Case reports

Case 1

Recombinant human interferon beta-1b therapy was begun in 2001 in a 43-year-old woman with a ten-year history of MS. The patient self-injected 8 million IU subcutaneously every other day into the abdomen and buttock. After five years of therapy, she developed painful, an indurated erythematous lesion at the site of injection on her left buttock (figure 1). She was given cefcapene for 10 days but the lesion did not resolve. The results of routine laboratory tests, including blood count and chemistry profile, were normal. Biopsy revealed moderate lymphocytic infiltration in the dermis and dense lymphocytic infiltration in the fat lobules and the septa (figure 2). No signs of vasculitis or evidence of thrombosis within the blood vessels were observed. No bacteria or fungi grew in tissue cultures. The lesion healed within about two weeks after the discontinuation of recombinant interferon beta-1b therapy, and the treatment has not been restarted, in accordance with the patient’s wishes.

Case 2

In 2002, recombinant human interferon beta-1b therapy was begun in a 62-year-old woman with a 22-year history of MS. The patient self-injected 8 million IU subcutaneously every other day into the abdomen and thigh. After four years of therapy, she developed an ulcerative lesion measuring 0.5 × 0.4 cm surrounded by painful induration at the site of injection on the right thigh (figure 3). The lesion was treated with bucladesine sodium ointment. The patient was given further training regarding the appropriate deep self-injection technique and continued interferon beta-1b therapy except at the site of the lesion. The pain and induration resolved within two weeks, and the ulcerative lesion showed epithelialization within four weeks. The patient has not developed any further skin reactions at the sites of injection.

Discussion

Local skin reactions to subcutaneous injections of interferon beta-1b in MS – usually consisting of mild and localized erythema without induration, which resolve spontaneously – are common and are seen predominantly in female patients although this may simply be related to the predominance of female patients among those with multiple sclerosis [3, 4]. In addition, eruption of psoriasis at the site of injection is common with type I interferon administration [5, 6], but severe skin reactions with ulceration or induration are rare. To our knowledge, 12 cases of severe skin reaction due to interferon beta-1b have been reported previously [7-16]. These 12 cases along with the two cases reported here are summarized in table 1. The mean age of the patients was 42.9 years and 78.6% were female. The time between the commencement of interferon treatment and onset of symptoms was less than 4 months in many cases, but more than 4 years in some cases, including our cases 1 and 2. Many cases had multiple lesions, located mostly on the thighs and abdomen, which are commonly used sites of injection. In most cases, the patient developed painful induration or indurated erythema with or without necrotic ulceration in the center, which developed from the induration. Biopsy specimens were obtained in eight cases, and two patterns of basic findings were observed: perivascular dermatitis in four cases and panniculitis in the remaining four cases. In addition, thrombosis of dermal vessels was detected in three cases, and one case showed leukocytoclastic vasculitis with perivascular fibrinoid material and some nuclear dust. Lymphocytes were the main cell type infiltrating the lesions in all of the eight cases for whom biopsy results were available.

The mechanism by which interferon beta-1b induces skin reactions is unknown. Similar skin lesions have also been reported after subcutaneous injection of interferon alpha [17-19], which shares receptor sites and immunological effects with interferon beta, and therefore the same mechanism associated with multiple proinflammatory properties of both interferons is likely to be involved in the induction of adverse reactions. In addition, inflammatory cytokines, such as interluekin-1 beta, interluekin-6, and tumor necrosis factor-alpha, released from subcutaneous adipose tissue even after minimally invasive trauma may play a role in the pathogenesis of the inflammatory reaction [20]. Although these reactions are suspected to involve an allergic reaction such as localized insulin allergy [21-23], no specific allergic reaction has yet been found in these cases. No allergic work-up, including patch tests or intradermal testing, was performed in our cases. However, resumption and continuation of the injection therapy after training regarding the appropriate self-injection technique without local complications suggested the lack of significant involvement of an allergic mechanism in case 2. The frequency of thrombosis of the dermal venules in skin biopsies suggests a clotting abnormality due to the injection of interferon beta that may increase platelet aggregation [19, 24] and leukocytoclastic vasculitis, as reported by Feldmann et al. [10], may be involved in specific inflammation of vessels induced by the injection, although case 1 showed neither vascular thrombosis nor vasculitis. Inafuku et al. reported that skin reactions were dependent on the depth of injection and that no local reactions occurred following deep subcutaneous injection [15]. They suggested that local cytokine-mediated mechanisms may initiate adverse immune reactions or that non-specific inflammation may be more likely to follow intradermal administration, and recommended vertical injection with the aim of injecting interferon beta-1b into deep subcutaneous fatty tissues and to avoid the possibility of penetration into the dermis. In case 2, the patient did not develop any local skin reactions after training regarding the appropriate deep self-injection technique. An automated injection device using an interferon-free needle was made, to aid patients in deep self-injection and to minimize contact between interferon beta-1b and dermal tissue. Use of this device reduced the incidence of injection site reactions by over 60%, and is convenient for MS patients [25]. Although the precise mechanism responsible for panniculitis following intradermal injection of interferon as observed in case 1 remains unclear, case 1 showed not only panniculitis but also perivascular lymphocytic infiltration in the deep dermis and we speculated that an immune reaction or thrombosis in the dermis, induced by the interferon injection, triggers and promotes inflammation in subcutaneous fatty tissue in some cases.

Even in cases in which severe cutaneous reactions occur, avoiding interferon beta-1b injection into the lesion sites and routine wound care usually lead to resolution, and as in case 2 in the present study, most patients can resume interferon beta-1b treatment without additional skin reactions after training regarding the appropriate self-injection technique [9, 11]. On the other hand, once skin reactions occur, patients are often reluctant to perform self-injection and drop out of therapy, as in case 1 in the present study. As interferon beta-1b has a significant effect in slowing disease progression and disability in MS patients [1, 26], cessation of interferon beta-1b injection is highly disadvantageous for these patients. Physicians should educate MS patients regarding the appropriate technique to achieve deep and quick self-injection to prevent local skin reactions, and the recommendation of an automated injection device is one option to avoid discontinuing an effective therapy.
Table 1 Characteristics of severe reactions at sites of interferon beta-1b injection

Author	Age, Sex	Location	Onset of symptoms	Clinical appearance	Pathological findings
Sheremata et al. (1995) [5]	38, F	Thighs	One month	Necrotic ulceration	Perivascular dermatitis with lymphocytic infiltration and thrombosis of vessels.
Weinberg et al. (1997) [6]	54, M	Abdomen	One month	Ulceration surrounded by induration	Not obtained
42, F	Abdomen	4 months	Necrotic ulceration	Not obtained
52, M	Thighs	3 months one week	Necrotic ulceration	Not obtained
van Rengen et al. (1997) [7]	36, F	Arms and abdomen	Unknown	Infiltrated, red, vesicular lesion	Not obtained
Feldmann et al. (1997) [8]	34, F	Thighs and abdomen	3 months	Necrotic ulceration surrounded by livedoid vascular pattern	Perivascular dermatitis with predominantly lymphocytic infiltration and leukocytoclastic vasculitis in reticular dermis
Albani (1997) [9]	38, F	Thighs and abdomen	4 months	Ulceration surrounded by erythema	Not obtained
Villalta et al. (2001) [10]	44, F	Thighs and buttocks	6 months	Nodular indurated erythema and necrotic ulceration	Perivascular dermatitis with lymphocytic infiltration and thrombosis of vessels.
Heinzerling et al. (2002) [11]	44, F	Arms, thighs, and abdomen	4 years	Painful induration	Septal panniculitis with predominantly lymphocytic infiltration.
Casoni et al. (2003) [12]	43, F	Thighs, arms, and abdomen	2 months	Necrotic ulceration surrounded by painful erythema	Perivascular dermatitis with lymphocytic infiltration and thrombosis of deep vessels.
Inafuku et al. (2004) [13]	34, F	Left arm and right thigh	8 months	Ulceration surrounded painful erythema	Perivascular dermatitis with predominantly lymphocytic infiltration.
O’Sullivan et al. (2006) [14]	37, M	Left thigh	2 years 3 months	Swelling and painful erythema	Septal panniculitis with lymphohistiocytic infiltration.
Case 1	43, F	Left buttock	5 years	Painful indurated erythema	Moderate perivascular dermatitis and septal and lobular panniculitis with lymphocytic infiltration
Case 2	62, F	Right thigh	4 years	Necrotic ulceration surrounded by painful induration	Not obtained

Acknowledgements

Financial support: none. Conflict of interest: none.

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