Treatment of myositis with etanercept (Enbrel®), a recombinant human soluble fusion protein of TNF-{alpha} type II receptor and IgG1

H. Sprott, M. Glatzel1 and B. A. Michel

Department of Rheumatology and Institute of Physical Medicine, University Hospital Zurich and 1Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

Correspondence to: H. Sprott, Department of Rheumatology and Institute of Physical Medicine, University Hospital Zurich, Gloriastrasse 25, CH-8091 Zurich, Switzerland. E-mail: haiko.sprott{at}usz.ch

SIR, Polymyositis is an inflammatory myopathy that is related to progressive, proximal, symmetrical muscle weakness, increased concentrations of serum muscle enzymes, an abnormal electromyogram and an abnormal muscle biopsy showing inflammation. Standard drug therapy includes high-dose corticosteroids and immunosuppressive drugs (methotrexate, azathioprine or even cyclophosphamide). Recent data are in favour of the early introduction of a cytotoxic or immune-modulating drug in addition to corticosteroid therapy. In patients with corticosteroid- and immunosuppressive-resistant myositis, management approaches include intravenous high-dose pulse methylprednisolone combined with immunosuppressive drugs, and combination therapy with methotrexate and azathioprine, cyclosporin and/or intravenous immunoglobulin (Ig). Lack of efficacy occurs in some cases. Recent advances in the understanding of the role of cytokines and complement in the pathogenesis of myositis have led to preliminary therapeutic trials of biological agents: etanercept, infliximab and anti-C5 monoclonal antibody [1].

A 50-yr-old female gymnastics teacher reported increased loss of muscle strength in the area of the shoulder girdle, the upper arms and both legs. The lactate dehydrogenase (LDH) concentration was repeatedly increased (Fig. 1). The EMG (deltoideus, biceps brachii, rectus femoris and gastrocnemius) showed partial shortened and thickened action potentials of muscular units that was compatible with a myopathy, in particular in the right deltoideus. The muscle biopsy of the left deltoideus showed features consistent with a polymyositis such as considerable variation in muscle fibre diameter, areas of fibrosis, and perivascular and interstitial inflammatory infiltrates (Fig. 2A). Immunohistological characterization of inflammatory cells demonstrated the presence of CD4-positive T-helper cells (Fig. 2B) and to a lesser extent CD8-positive cytotoxic T-cells (Fig. 2C).



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FIG. 1. Characteristics of the enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) under therapy with diverse immunosuppressive medications. Reference ranges: CK, <167 U/l; LDH, 150–420 U/l. MTX, methotrexate; AZA, azathioprine. This figure can be viewed in colour as supplementary material at Rheumatology Online.

 


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FIG. 2. Muscle biopsy specimen demonstrating calibre variations and an endomysial infiltrate (A) consisting of CD4-positive T-helper cells (B) and CD8 positive cytotoxic T-cells (C). This figure can be viewed in colour as supplementary material at Rheumatology Online.

 
Therapy with 50 mg prednisone per day in combination with 12.5 mg intramuscular methotrexate (MTX) per week was started (Fig. 1). This treatment initially led to a diminution of the symptoms, e.g. an increase in muscle strength, but upon reduction of the prednisone dose to 30 mg per week loss of muscle strength reappeared. Elevated creatinine levels did not permit prolonged MTX therapy at high doses and intravenously administered Ig (2 g/kg body weight) did not lead to clinical improvement. Therefore, immunosuppressive therapy was started with azathioprine (AZA) (Fig. 1). Because of an unsatisfactory response to immune-suppressive therapy and elevated liver enzymes, this treatment regimen had to be stopped. In this situation a change to etanercept (Enbrel®) was considered (Fig. 1). Patient informed consent was obtained. With 25 mg Enbrel twice a week, a rapid reduction of LDH levels and an immediate drastic recovery of muscle strength was noted. The daily prednisone dose could be further reduced (Fig. 1). Acupuncture treatment was begun in August 2002 because of back pain, which caused a temporary increase in creatine kinase (CK). After the end of the acupuncture treatment the CK level normalized. The patient reported general well-being with increased muscle strength. The daily prednisone dose was slowly reduced and stopped.

Elevated concentrations of soluble tumour necrosis factor (TNF) receptors are found in the serum of patients with polymyositis and dermatomyositis [2]. Etanercept is a soluble fusion protein comprising an epitope derived from the p75 TNF receptor fused to the Fc portion of IgG [3]. It has been shown to bind TNF with high affinity and to block the effects of TNF-{alpha} in model systems [4]. Therapy with the TNF-{alpha} receptor antagonist etanercept may represent a valuable alternative in therapy-resistant disease, in which the standard regimen including MTX and AZA in addition to prednisone fails because of inefficacy or side-effects.

We demonstrated a case in which etanercept was efficient in a patient with polymyositis and a failure of ‘conventional’ immunosuppressive therapy. Prospective, randomized, placebo-controlled multicentre trials to evaluate the real potential of TNF blockers in myositis are overdue.

The authors wish to thank Leanne Pobjoy for her help in the preparation and translation of the manuscript.

References

  1. Fam AG. Recent advances in the management of adult myositis. Expert Opin Investig Drugs 2001;10:1265–77.[ISI][Medline]
  2. Shimizu T, Tomita Y, Son K, Nishinarita S, Sawada S, Horie T. Elevation of serum soluble tumour necrosis factor receptors in patients with polymyositis and dermatomyositis. Clin Rheumatol 2000;19:352–9.[CrossRef][ISI][Medline]
  3. Franklin CM. Clinical experience with soluble TNF p75 receptor in rheumatoid arthritis. Semin Arthritis Rheum 1999;29:172–82.[ISI][Medline]
  4. Mikuls TR, Moreland LW. TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept. Expert Opin Pharmacother 2001;2:75–84.[Medline]
Accepted 30 September 2003





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