Cutaneous side-effects of immunomodulators in MS.
Abstract: Local skin reactions to subcutaneous injections of interferon beta (IFNB) or glatiramer acetate (GA) in multiple sclerosis (MS) are frequent, while severe cutaneous toxicity is rare. Both IFNB and GA are immunomodulatory drugs that have excellent safety profiles and are currently used for treatment of MS. They are administered by SC injection every other day for IFNB-1b, three times a week for IFNB-la or daily for 20 mg for GA. The most common adverse effects, which occur in approximately 20-60% of patients, include pain, inflammation and induration at the injection sites. Another adverse effect is frank panniculitis followed by localized lipoatrophy at the injection sites, which has been described in half of the patients receiving GA injections but is also described with Subcutaneous IFNB-1b. No guidelines have yet been established for the treatment of skin reactions, which is a frequent point for discussion between neurologists and dermatologists. In addition, no treatment has been found for established lipoatrophy. The prevention and management of cutaneous side-effects include patient education, regular examination and manual palpation of all injection sites. Non-steroid anti-inflammatory gels, local corticosteroids or endermology can help patients to resolve side-effects and to continue immunomodulatory treatment.

KEY WORDS:

Interferon beta, Glatiramer acetate, Multiple sclerosis, Side-effects, Lipoatrophy, Panniculitis
Article Type: Clinical report
Subject: Multiple sclerosis (Development and progression)
Multiple sclerosis (Care and treatment)
Glatiramer acetate (Complications and side effects)
Authors: Lebrun, C.
Bertagna, M.
Cohen, M.
Pub Date: 11/01/2010
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: Nov, 2010 Source Volume: 17 Source Issue: 3
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 256365667
Full Text: Introduction

Interferon beta (IFNB) and glatiramer acetate (GACopaxone[R], Teva Sanofi Aventis) are recognized today as the first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Injection-site reactions are a common complication of subcutaneous MS therapy three times per week for IFNB-1a (Rebif[R], Merck Serono) and every other day for IFNB-1 b (Betaferon[R]/Betaseron[R], Bayer Schering Pharma) or GA. This immune-altering therapy has been associated with a number of immunologically mediated side-effects, and women seem to be at a greater risk of skin reactions due to the higher incidence of autoimmune disease in women. A study reported an 8.1 higher incidence of cutaneous side-effects for women than men. (1) Subcutaneous injection of immunomodulators is frequently associated with transient injection-site erythema in 63-85% of treated patients. Less frequent reactions at injection sites include vascular thrombosis, mucinosis, dermal and SC sclerosis, necrosis, ulceration and rarely, lupus erythematosus-like lesions, sarcoidal granulomas, erythema nodosum, an acute septal panniculitis with neutrophils, lobular lymphocytic panniculitis and lipoatrophy. (2) These reactions are currently thought to represent an inflammatory response to the injected drug, which is influenced by the injection path and depth. This is consistent with the observation that skin reactions are more likely to occur after injection in the arms or thighs and less frequently in areas with a higher proportion of Subcutaneous fat (e.g. abdomen or buttocks). Risk factors include incorrect injection technique, insufficient needle length, a cold IFNB solution, repeated use of the same injection site and excessive exposure of recent injection sites to sunlight. Generally, intramuscular Intramusculor injections (Avonex[R], Biogen Idec) cause fewer skin reactions, and so far no skin necrosis has been reported.

Cutaneous Side-effects of GA

GA is an immunomodulatory drug containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine. It simulates myelin basic protein and is currently used for treatment of MS because it has been shown to be effective in reducing relapse of patients with relapsing-remitting RRMS. (3) The drug, administered in daily Subcutaneous injections of 20 mg, has an excellent safety profile. Transient immediate systemic reactions showing flushing have been described after injection with GA, but are not really considered as adverse cutaneous events. The most common adverse effects, which occur in approximately 20-60% of the patients, include pain and inflammation at the injection sites, all of which spontaneously disappear within hours or a few days. Another adverse effect is frank panniculitis followed by localized lipoatrophy at the injection sites, which has been described in half of the patients receiving treatment with GA. (4-8) In reports of this adverse effect, the authors only described lipoatrophy, in some cases, even without histopathological study of the lesions (4,6) and in others with a vague histopathological description of 'inflammatory infiltrate involving the subcutaneous tissue'. (5) A recent report noted progressive lipoatrophy after cessation of GA injections. (9)

The most commonly described injection-site reactions to GA include erythema (66% of patients), inflammation (49%), pain (73%) and pruritus (40%). Cases of skin necrosis with involvement of muscle tissue after injection of GA have been reported. (10) Embolia cutis medicamentosa (Nicolau's syndrome) is very rare and accidental; peri- or intravascular injection of the drug, which leads to vascular spasms and consecutive tissue thrombosis, is thought to be responsible. Lipoatrophy and localized panniculitis are more classical. They have been described as complications of daily Subcutaneous GA injections for the treatment of RRMS. It was initially reported to be a relatively rare event; however, more recent studies indicate that it affects 45-64% of MS patients treated with GA. (6) Drago et al (8) were the first to report localized lipoatrophy at the sites of Subcutaneous injections in six female patients receiving treatment with GA for MS. They reported that the lesions developed without any preceding inflammation and the overlying skin did not exhibit inflammation, sclerosis or hyperpigmentation. Finally, Edgar et al (6) described five female patients with lipoatrophy at the sites of GA injection, but a biopsy was performed only in two cases.

Lipoatrophy is localized loss of Subcutaneous adipose tissue without significant inflammation (Figures 1-2). It is a well-described and common reaction at injection sites. Most injection-site reactions show involutional lipoatrophy or a foreign-body reaction. Other described histological reactions at injection sites include allergic contact dermatitis, lipogranulomas, local necrosis, sterile and infectious abscesses, necrotizing, necrobiotic and sarcoidal granulomas, cutaneous lymphoid hyperplasia, lupus profundus-like and morphea-like reactions.

Soos et al (4) were the first to recognize a panniculitic stage previous to the lipoatrophy induced by GA injections. Lipoatrophy secondary to Subcutaneous injections has been described in conjunction with several drugs, including insulin, corticosteroids, vasopressin, antibiotics, human growth hormone, iron dextran, diphtheria-pertussis-tetanus immunization serum and antihistamines. The mechanism is probably different for each drug and predominates in females, perhaps due to specificities in fat tissue. Trauma alone, like acupuncture, may induce lipoatrophy, possibly via secretion of cytokines by macrophages that enhance lipocyte catabolism and inhibit lipogenesis. In acupuncture-related lipoatrophy there is an involutional pattern with thin and elongated fat lobules. Although different pathogenic mechanisms have been proposed for each of these drugs, lipoatrophy is the common late or residual stage of a previous drug-induced localized panniculitis.

[FIGURE 1 OMITTED]

In the literature on biopsied cases, in more than half of the GA-treated patients, typical epidermal and dermal changes of discoid lupus erythematosus are described. These include atrophy of the epidermis, a vacuolar change at the dermoepidermal junction, thickened basement membrane, interstitial mucin between collagen bundles of the dermis and superficial and deep perivascular inflammatory infiltration of lymphocytes into the dermis. (11) These cases seem to be related to long-term GA treatment. In the other half of the cases, the changes are confined to the Subcutaneous fat, with no anomalies in the dermis or epidermis. Lobular panniculitis with an inflammatory infiltrate, predominantly composed of lymphocytes, occurs often. A characteristic feature, found in more than half of the patients, is the presence of lymphoid follicles. It could probably correspond to a Koebner phenomenon or an isomorphic response, referring to skin lesions appearing on lines of trauma for patients with autoimmune diseases.

Generally, panniculitis appears within 2 months of starting GA therapy and spontaneous involution of panniculitis within 3 months of cessation of therapy is usual. (12) It is likely that the drug itself induces a local inflammatory response as a result of a direct toxic effect on adipocytes, and this inflammatory stage is followed by a hypersensitivity reaction and residual lipoatrophy. (13) When GA injections are discontinued, the cutaneous lesions disappear, but they recur when the injections are renewed. This adverse event appears to be independent of the injection technique. A recent case reported lipoatrophy that continued to progress despite cessation of GA in the absence of any other known causative agent. (9) Magnetic resonance imaging (MRI) examination of lipoatrophy by other causes shows a reduction in the T2-hypersignal due to disappearance of Subcutaneus fat (Figure 3).

[FIGURE 2 OMITTED]

Cutaneous Toxicity of IFNB

Several dermatological adverse events have been reported in the literature for MS patients treated with IFNB. Most of these events are related to the injection-site reaction and are usually mild-to-moderate local inflammatory reactions. Other events including panniculitis, skin necrosis or ulceration have also been reported. (14) Generalized dermatological events, sometimes associated with systemic manifestations, occur less frequently.

Local Reactions

Local reactions are the most reported dermatological events in treated patients. (2) The incidence of those reactions seems to be higher for Subcutaneous compared to IM injection. Unless a severe reaction occurs, IFNB therapy should not be discontinued. Injection-site inflammation is the most often reported event. Underlying mechanisms of inflammation are unknown. Such events are more likely to occur after injection in the arms or thighs. (2)

Several cases of panniculitis have been reported in patients treated with IFNB. (14,15) It is rarely followed by lipoatrophy. (16,17) Patients usually report extremely painful erythematous local induration with infiltration of Subcutaneous tissues. Fever and a biological inflammatory syndrome can be associated with panniculitis, mimicking infectious disease. Poulin et al reported a case of a 43-year-old patient, treated with IFNB-1b, who experienced panniculitis of the abdominal right lower quadrant with fever mimicking acute appendicitis. (18) The patient presented with fever and blood samples showed mild leukocytosis. Abdominal tomography revealed SC fat infiltration and histological examination confirmed panniculitis. Other reported injection-site reactions include granulomatous dermatitis in a patient treated with IFNB-1 b. (19) A lupus-like reaction at the injection site has also been reported in two treated MS patients. (20) Blood tests did not find antinuclear or anti-DNA antibodies.

Severe Cutaneous Side-effects: Cutaneous Necrosis and Ulceration

Cutaneous necrosis was first reported with Subcutaneous IFNB-1b in 1995. (21) It is reported in 5% of patients1 and can sometimes cause discontinuation of therapy. It has not been reported with IM injection of IFNB-1a. The exact mechanisms involved are not known. Histological analysis usually reveals processes of microthrombosis and vasculitis. Association with local mononeuropathy has been reported exceptionally. (22) Incorrect injection technique, depth of injection, repeating injections in the same site and the cold temperature of a IFNB solution have been identified as risk factors. In a cohort of 400 patients, (23) cutaneous ulceration at the site of injection was reported in six patients. Two of them developed SC abscesses and had to discontinue IFNB therapy.

Generalized Cutaneous Adverse Events

Generalized events are less frequently reported. In these cases, it is sometimes difficult to differentiate an adverse event related to IFNB therapy from coexistence of another autoimmune disease. Some authors reported cases of a widespread maculopapular rash occurring after the second Intramuscular injection of IFNB-1a. (24) A re-challenging test and an interferon prick test were positive.

Several cases of cutaneous vasculitis have been reported. (25,26) In one case, the patient experienced cutaneous vasculitis after the third Subcutaneous injection of IFNB-1b, with a positive re-challenging test. The second case was reported after 10 months' therapy with IFNB. Cutaneous lesions were associated with proteinuria and macroscopic haematuria. Biological tests did not find any abnormality consistent with autoimmune vasculitis and the outcome was favourable after discontinuation of IFNB therapy.

In other reported manifestations, co-existence of another immune disease could be suspected. Some authors reported exacerbation of psoriasis with onset of psoriasis arthritis 2 months after initiation of interferon therapy. (27) Onset of severe dermatomyositis 5 years after initiation of therapy has been reported in one patient. (28) In both cases, IFNB was discontinued. The patient who experienced dermatomyositis was treated with intravenous immunoglobulins, corticosteroids and immunosuppressants. Sclerosing skin disorders have been reported in 12 MS patients. (29) In five of these cases, IFNB therapy was initiated between 1 and 8 years before onset of skin sclerosis. The authors considered that initiation of therapy could have triggered onset of skin manifestations, but whether IFNB should be discontinued in such cases remains unclear.

Comparison of Cutaneous Side-effects with GA or IFNB

While cutaneous side-effects have been reported in all the GA and IFNB Phase III studies, only the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study has compared the two treatments. (30) The BEYOND trial is a Phase III clinical trial of treatment of naive patients with early RRMS. This study compared the efficacy, safety and tolerability of 250 [mirco]g (the currently approved dose) with 500 [micro]g IFNB-1b on clinical and MRI measures. The proportion of patients who had an injection-site reaction at least once was significantly higher in the patients treated with GA than in patients treated with IFNB-1 b (P=0.0005). Only comparison of the approved dose of GA and IFNB showed a significantly higher incidence of pain (17% for GA versus 8% for IFNB), pruritus (8% versus 1%), induration (5% versus 1%), swelling (4% versus 1%) and irritation (3% versus 1%) at the injection site with GA. Erythema at the injection sites was not statistically significant. Lipoatrophy occurred only in the patients treated with GA.

[FIGURE 3 OMITTED]

Prevention and Management of Injection-Site Reactions

When mild or moderate injection-site reactions occur, the injection technique should be checked. (1) Rotation of injection sites, increase of injection depth and adjusting the solution to ambient temperature are commonly recommended. Potential differences between autoinjectors or needles recommended by the different pharmaceutical companies have not been studied. The severity of local skin reactions to IFNB-1b can be diminished by deepening the Subcutaneous injections, with or without the autoinjector. (31) Steroidal (1% hydrocortisone) or nonsteroidal anti-inflammatory drugs or ointments are commonly used, but there is no evidence of efficacy of such treatments. (2) IFNB therapy can be continued in most cases. Infected necroses should be treated with antibiotics, and surgical intervention is sometimes necessary. Patients who experience severe reactions usually have to discontinue therapy and in these cases, the Intramuscular injection route should be considered. In most cases, a skin biopsy is not necessary.

[FIGURE 4 OMITTED]

A recent pilot study described the efficacy of endermology in treating GA-induced lipoatrophy. (32) In all cases, lipoatrophy developed in areas in which the patients had complained of transient burning and pain or induration. Routine laboratory tests were always normal, excluding systemic diseases.

The LPG Cellu M6 Keymodule (LPG Systems, France) is a unique mechanotransduction machine. The treatment head stimulates the surface of the skin and simultaneously signals to cells that trigger targeted actions (lipolysis and collagen production).33 Endermology was originally developed in the late 1970s in France by Louis Paul Guitay to soften scars and standardize physical therapy. However, patients treated with the LPG machine showed improvement in body contour and skin texture. Since then, endermology has been used in France, the USA and many other nations as an alternative method to altering fat distribution in the Subcutaneous plane. (33) It is also used in radiotherapy-induced fibrosis, lymphoedema or scleroderma. Because this technique is operator dependant, which may explain the variable results that have been reported, the opinion as to its efficacy in the plastic surgery community varies widely, from those who condemn it openly, without having any experience with it, to enthusiastic believers.

In the study into LPG use for GA-induced lipoatrophy, all patients underwent LPG therapy twice a week for 30 minutes. (32) A cycle of 2 months was initially proposed. All patients showed asymptomatic, well-circumscribed skin depressions on the lateral side of the thighs, upper arms (Figure 4) and the periumbilical area, the usual injection site. The overlying skin did not exhibit inflammation, sclerosis or hyperpigmentation. In general, the lesions developed after inflammation and were about 12-60 [cm.sup.2] in area and 1-2 cm deep (Figure 1). They were located at the injection sites, and all patients developed Subcutaneous erythematous nodules in several areas (periumbilical skin, upper side aspects of arms, hips and front of thighs) during treatment. Only occasionally, a transient burning sensation, mild pain and wheals followed GA injection. Localized panniculitis at the injection sites generally occurred 1-2 months after the beginning of GA injections. In all patients, residual lesions of lipoatrophy developed in previously inflamed sites without hyperpigmentation. The LPG sessions were well tolerated without pain. All patients reported to be well after each session and cutaneous benefits began to be visible after 3 weeks. To date, there is no other treatment proposed for these cutaneous side-effects. The injections of GA can be continued during and after the LPG treatment.

The prevention and management of cutaneous side-effects include patient education, regular examination and manual palpation of all injection sites. No treatment has been proposed when lipoatrophy is established.

Key Points

* Cutaneous side-effects of immunomodulatory drugs are frequent.

* Panniculitis and lipoatrophy are more frequent with GA than with IFNB.

* IFNB can induce either erythema or panniculitis.

* Other cutaneous side-effects such as lupus-like lesions or psoriasis are rare.

* Cutaneous side-effects can be limited if auto injection is taught properly.

Conflict of Interest

Christine Lebrun has received honoraria for lecturing, travelling and as a member of scientific boards, from BayerSchering, Merck-Serono, Teva-Sanofi-Aventis and Biogen Idec.

Mikael Cohen has received honoraria for travelling from BayerSchering, Merck-Serono, Teva-Sanofi-Aventis and Biogen Idec.

Marc Bertagna has received honoraria for travelling from BayerSchering, Merck-Serono, Teva-Sanofi-Aventis and Biogen Idec.

Received: 2 August 2010

Accepted: 4 August 2010

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C Lebrun, M Bertagna, M Cohen

Service de Neurologie, Hopital Pasteur, Nice, France

Address for Correspondence

Christine Lebrun

Service de Neurologie

Hopital Pasteur

30 voie romaine

06002 Nice

France

Tel: + 33 4 92 03 78 96

Fax: + 33 4 92 03 79 97

E-mail: Lebrun.c@chu-nice.fr
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