Panniculitis after subcutaneous injection of interferon beta in a multiple sclerosis patient

ARTICLE

Interferons have characteristic biological effects such as antiviral, immunoregulatory and antitumor activities [1] and are currently applied in the treatment of multiple sclerosis, Kaposi's sarcoma, hepatitis, cutaneous T cell lymphoma and melanoma [2]. One limitation of the success of interferon treatment is its immunogenicity that leads to the formation of neutralizing antibodies in about 30%-50% of treated patients within the first six months of treatment [3-7]. These antibodies are responsible for treatment failure as suggested by various biological assays [4, 7].

Another limitation is local reactions at injection sites. Cutaneous ulcerations have been described after subcutaneous injection of interferon beta-1b in patients with multiple sclerosis (n = 23) [8-13], HIV associated Kaposi's sarcoma (n = 8), and in patients suffering from chronic hepatitis C (n = 1) [14]. Interferon-alpha and pegylated interferon-alpha [15] have also been reported to cause cutaneous ulcerations in patients with HIV associated Kaposi's sarcoma (n = 4) [16-18] and in one patient each with chronic myelogenous leukemia [19], hepatitis [20, 21] and melanoma [16].

Here we report a case of a septal panniculitis at and adjacent to injection sites during subcutaneous treatment with interferon beta in a patient with multiple sclerosis.

Case report

Clinical history. A 44-year-old patient with multiple sclerosis received adjuvant immune therapy with recombinant 6 Mio IU interferon-beta (Betaferon^®) for four years. Subcutaneous injections were carried out injecting alternately in thighs, arms and abdomen every other day and resulted in a reduced disease activity. Additionally 50 mg baclofen (Lioresal^®) per day were taken orally. Under this therapy the residual neurologic symptoms were a slight paraspastic of the right extremity, and minor alterations in bladder voidance and defecation.

Shortly after initiation of the therapy erythematous patches developed at the subcutaneous injection sites. After 4 years of interferon injections painful indurations were noticed in the vicinity of the injection sites, first only on the right thigh, later also on the left thigh, arms and abdomen. Pain in the legs kept the patient from walking, and ultimately the patient was wheel chair-bound and she required pain therapy with opiate analgesics. The patient was otherwise healthy. She had no fever, weight loss, or night sweats and no known allergies or intolerances.

Examination. Tender reddish indurations of 10 cm in diameter on both thighs, and smaller indurations on the arms and abdomen were seen. The erythematous skin at the lesions was fixed over the induration and was indented (Fig. 1). Lymph nodes were not enlarged. Mucosae and skin in all other parts of the body appeared normal. Muscle function was normal. X-ray of the thighs revealed no calcifications. Computed tomography of the thorax and abdomen and coloscopy showed no signs of underlying malignant disease.

Blood tests. Differential blood count and blood chemistry were within normal limits. Alpha-1 antitrypsin was normal and the patient presented with a MM alpha-1 antitrypsin phenotype. Elevations were found in total hemolytic factor CH-50 with 59 U/ml (reference < 23 U/ml), ANA (anti-nuclear antibodies) 1:160, anti-cardiolipin IgA with 14.3 U/ml (reference < 10 U/ml). Other autoantibodies were not elevated. Interferon antibodies were not measurable in the serum. Interferon-gamma in the serum was elevated with a concentration of 0.3 U/ml (reference < 0.1 U/ml). IL-2R was within normal limits.

Histology. In the first deep biopsy epidermis and dermis appeared normal. Subcutaneous fatty tissue showed thickened fibrosed septa infiltrated with mononuclear cells including a few plasma cells and neutrophil granulocytes. Vasculitis was not present. No necrosis and no mucin or lipoid deposits were detected (Fig. 2). Gram, Grocott and PAS stainings were negative. A direct immunofluorescence with staining for fibrinogen, C3, IgG, IgA and IgM was negative. In the second biopsy the infiltrate consisted mainly of plasma cells and demonstrated pronounced fibrosis. Again PAS and Gram stainings were negative. The histological diagnosis of predominantly septal panniculitis was made.

Therapeutic approach. Prednisone at a dose of 100 mg per day (1.5 mg/kg body weight) was started. The pain improved and the patient was able to walk again. However, symptoms reappeared upon reduction to 10 mg Prednisone. Clinical findings persisted even at high doses. A cushingoid aspect developed so other means to reduce the local symptoms had to be found as the therapy with interferons could not be stopped.

We advised the patient to inject intracutaneously or intramuscularly, to dilute the preparation in order to inject at lower concentration and to distribute it within the tissue by multiple injections. Injection together with triamcinolone (Kenacort^®) was recommended as well as the use of an alternative interferon-beta preparation (Avonex^®, Rebif^®).

Switching to another interferon-beta preparation injected intramuscularly once a week improved the situation within the next year. However slightly painful nodules persisted on both thighs and arms and evolved to sclerotic lesions. A subsequent treatment with 100 mg doxycycline twice daily over three weeks did not further improve the symptoms and was thus stopped.

Discussion

This patient developed tender subcutaneous indurations at injection sites 4 years after initiation of interferon-beta therapy for multiple sclerosis. Histologic findings of the injected sites showed panniculitis. No vasculitis was seen. Other possible reasons for panniculitis were excluded. No signs were found for lupus erythematosus, scleroderma or dermatomyositis. Bacterial or other infectious agents were excluded.

Therefore, we concluded that interferon-beta injections were the most probable cause of panniculitis in this patient. The preparation does not contain lipids or preservatives known to induce foreign body reactions. Whereas other drugs have been described to induce panniculitis like atenolol [22], ciprofloxacin [23], protease inhibitors [24], apomorphine [25], and contraceptives [26] interferon-beta is not known to cause panniculitis. In one previous report interferon alpha has been described to be associated with the development of a histiocytic cytophagic panniculitis [27]. Interferon-beta has been described to induce painful and irritated skin lesions [13, 28] which have not been found to represent specific Type I or IV allergic reactions [29]. Inflammatory reactions and necrosis showed a clear dose response relationship [30]. Most of these injection site complications appeared during the first month of treatment and diminished upon subsequent injections [31].

IFN-mediated effects include augmentation of cytotoxic function and activation of monocyte/macrophage function with the release of proinflammatory cytokines (TNF-alpha, IL-1, IL-6) and increased expression of MHC class I molecules. Indirect evidence for a T cell or natural killer (NK) cell activation is the elevated level of interferon-alpha in the serum of the patient. Previously, lobular panniculitis has been observed after subcutaneous administration of interleukin-2 [32].

Treatment options for panniculitis include tetracyclines for idiopathic circumscribed panniculitis [33,] for cold panniculitis [34] and Lyme associated panniculitis [35], and doxycycline [36] or colchizine [37] for panniculitis associated with alpha1-antitrypsin deficiency. The rationale for the use of these antibiotics in panniculitis is their anticollagenase activities [38] as well as the inhibitory effects on neutrophil chemotaxis [39]. In our patient switching to another interferon-beta preparation greatly improved the situation. As both interferon preparations consist of recombinant protein we attributed the improvement of symptoms mainly to the change of site of injection (intramuscularly versus subcutaneously). A three week course of treatment with doxycycline did not further improve the symptoms.

Article accepted on 21/11/01

CONCLUSION

Acknowledgements

We thank Dr. Anton Gehler, Zurich, who kindly referred the patient to our department, Dr. Paul Scheidegger for carefully reading the manuscript and Dr. Werner Kempf for taking the histologic pictures.

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