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

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(1)Letters to the Editor. Rheumatology 2004;43:524 doi:10.1093/rheumatology/keh060. Painful hips in a shipyard worker SIR, A 41-yr-old Caucasian man was referred with a 4-yr history of bilateral groin pain. This had increased in severity in the preceding year, more so on the right, resulting in him having to give up his job as a labourer. On X-ray in 2002 there was patchy sclerosis, osteolysis and collapse of the right femoral head. There was relative preservation of the joint space. The left femoral head showed patchy sclerosis with a subcortical crescentic lucency and a break in the cortex (Fig. 1). The findings were consistent with bilateral avascular necrosis (AVN). This diagnosis was confirmed on histological examination following right total hip replacement. It was noted that there was no histological evidence for thrombosis or a vasculitic process. He is subsequently awaiting orthopaedic intervention for the AVN of the left femoral head. ‘Avascular necrosis’ is the term given to death of bone resulting in the collapse of the architectural bony structure, leading to joint pain, bone destruction and loss of function. It is most commonly associated with trauma. Non-traumatic associations include prolonged corticosteroid use, alcoholism, infections, hyperbaric events, storage disorders, marrow infiltrating diseases, coagulation defects and some autoimmune diseases [1]. In this man’s initial history there was little to suggest any recognized cause for his bilateral AVN. There was no history of alcohol abuse, major trauma to the hips, connective tissue disease or chronic oral corticosteroid use. His corticosteroid use has been limited to a single 1-week course of oral prednisolone (30 mg daily) 16 yr previously and regular use of a Becotide inhaler (500 g twice daily) for his mild asthma. Further investigations included a normal full blood count and autoimmune profile, normal levels of anticardiolipin antibodies and a negative test for lupus anticoagulant. There seemed to be no obvious explanation for the bilateral hip AVN described here. However, a more detailed occupational history resulted in a possible explanation for his presentation. He had previously worked at the Falmouth shipyard for a period of 3 yr, ending 2 yr prior to his being seen in the rheumatology clinic. His job consisted of stripping paint from ships using an ultra-high-pressure water-blaster. He used this device by resting one end in either groin while directing the other end into the air so that the paint was blasted away. The device vibrated and caused mild discomfort in both groins during its use. This work was undertaken for 5 h per day for 3 yr. His persistent groin pains began 1 yr into the use of the water-blaster. There are scanty reports of AVN occurring in the bones of workers handling vibrating machinery. This has occurred. principally in the lunate and capitate [2, 3]. In these cases, delayed onset of symptoms was noted after the patient began to use the vibrating machinery, as was the case here. The most well-known complication of handling vibrating machinery is the development of vibration white finger [2]. This is thought to occur principally due to vibration-induced vasospasm. The accepted final common pathway for avascular necrosis of bone is compromise of the blood supply to that bone [1]. Kakosy’s review article [2] suggests that vibrating machinery may induce a similar process, with the circulatory disturbance resulting in interruption of the bone vasculature. In this case we propose that the hips were involved because of the particular method of use of the vibrating machinery. It is our suggestion that this man’s AVN is a result of vibration-induced injury. This case illustrates the necessity of taking a thorough current and past occupational history. We therefore suggest that a thorough current and past occupational history is taken for all patients presenting with AVN. We, the authors, declare that there are no conflicts of interest and that we have contributed equally to the planning and writing of the report. Both of us have seen and approved the final version.. Rheumatology. 524. Key Messages Use of vibrating machinery may lead to avascular necrosis of the hips, and a full and thorough occupational history should be taken from patients presenting with this condition.. D. HUTCHINSON, R. MASCARENHAS Rheumatology Unit, Royal Cornwall Hospital, Truro, UK Accepted 24 September 2003 Correspondence to: R. Mascarenhas, Rheumatology Unit, Royal Cornwall Hospital, Truro, Cornwall, R1 3LJ, UK. E-mail: ravik25@hotmail.com 1. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124. 2. Kakosy T. Vibration disease. Bailliere’s Clin Rheumatol 1989;3: 25–50. 3. James ET, Burke FD. Vibration disease of the capitate. J Hand Surg [Br] 1984;9:169–70.. Rheumatology 2004;43:524–526 doi:10.1093/rheumatology/keh062. Treatment of myositis with etanercept (EnbrelÕ), a recombinant human soluble fusion protein of TNF-a type II receptor and IgG1. FIG. 1. Pelvic X-ray of patient (see text for details).. 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. Rheumatology Vol. 43 No. 4 ß British Society for Rheumatology 2004; all rights reserved.

(2) Letters to the Editor. 525. 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.. 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. 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). 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 (EnbrelÕ) 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.. Rheumatology Vol. 43 No. 4 ß British Society for Rheumatology 2004; all rights reserved.

(3) Letters to the Editor. 526. 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- in model systems [4]. Therapy with the TNF- receptor antagonist etanercept may represent a valuable alternative in therapyresistant 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.. Rheumatology. Key messages Etanercept, a TNF- receptor antagonist, appears to be efficient in polymyositis.. H. SPROTT, M. GLATZEL1, B. A. MICHEL Department of Rheumatology and Institute of Physical Medicine, University Hospital Zurich and 1Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland Accepted 30 September 2003 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@usz.ch 1. Fam AG. Recent advances in the management of adult myositis. Expert Opin Investig Drugs 2001;10:1265–77. 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. 3. Franklin CM. Clinical experience with soluble TNF p75 receptor in rheumatoid arthritis. Semin Arthritis Rheum 1999;29:172–82. 4. Mikuls TR, Moreland LW. TNF blockade in the treatment of rheumatoid arthritis: infliximab versus etanercept. Expert Opin Pharmacother 2001;2:75–84.. Rheumatology 2004;43:526–527 doi:10.1093/rheumatology/keh066. Periodic fever due to a novel TNFRSF1A mutation in a heterozygous Chinese carrier of MEFV E148Q SIR, The hereditary periodic fever syndromes are characterized by recurrent episodes of fever due to multisystemic inflammation. In the case of autosomal dominantly inherited tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), these attacks are associated with severe abdominal pain, localized myalgia, painful migratory erythematous skin rash, conjunctivitis. and/or periorbital oedema. TRAPS is caused by sequence alterations in the TNFRSF1A gene, which encodes the 55-kDa TNF receptor [1]. Familial Mediterranean fever (FMF) is the most common autosomal recessively inherited periodic fever syndrome. Attacks of FMF are of 1–3 days’ duration and characterized by polyserositis (mainly peritonitis) and colchicine responsiveness [2]. FMF is caused by mutations in the MEFV gene, which encodes the protein pyrin/marenostrin [3]. E148Q is one of the five most common MEFV mutations and has a high allele frequency among healthy Chinese controls, being present on 15% of the alleles [4]. In combination with a second MEFV mutation, E148Q has an aggravating effect, while homozygosity or heterozygosity for this mutation is generally not associated with disease. Asymptomatic E148Q heterozygotes may, however, show a subclinical inflammatory syndrome with increased baseline erythrocyte sedimentation rate (ESR) and increased plasma levels of C-reactive protein (CRP) and serum amyloid A (SAA), reflecting chronic non-specific inflammation [4]. We report a 12-yr-old Chinese male patient presenting with recurrent episodes of fever up to 40 C since the age of 1 yr. These episodes were preceded by severe abdominal pain, lasting 2–3 weeks, and occurred at intervals of about 3 months. Since the age of 11 yr, the febrile attacks have shortened to about 4 days and symptom-free intervals have reduced to 2–4 weeks. Regularly associated symptoms included headache, pharyngitis and mild exudative tonsillitis, with occasional arthralgias, diarrhoea and non-specific rashes. Lymphadenopathy, splenomegaly, myalgia, conjunctivitis and periorbital oedema were absent. During attacks, a pronounced acute-phase response was observed, with leucocytosis (maximum 19.8 103/l), a high ESR (maximum 123/145 mm/ h), CRP levels up to 26.4 mg/dl, and SAA values up to 116 mg/l. Elevated serum immunoglobulin (Ig) A (maximum 627 mg/dl) and IgM (maximum 277 mg/dl) were continuously present. Colchicine treatment over 4 yr had no effect. The attacks disappeared completely within a few hours after a single dose of prednisone (2 mg/kg), given during the first day of the febrile episode. Non-steroidal anti-inflammatory agents also had a temporary effect in reducing high temperatures and arthralgias. The boy is thriving normally, and all other family members are healthy. In view of the possibility of periodic fever, the TNFRSF1A and MEFV genes were screened for mutations after written informed consent for blood drawing and the genetic analyses were obtained from the patient’s parents. Soluble tumour necrosis factor receptor superfamily member 1A (sTNFRSF1A) was measured in plasma samples of the asymptomatic boy and family members, and cellular TNFRSF1A expression and shedding analyses were performed by FACS (fluorescence-activated cell sorter), using monocytes from the patient and his healthy father [1]. The study was approved by the Ethics Committee of the Ludwig-Maximilians-University in Munich and was conducted according to the Helsinki Committee standards. DNA sequence analysis revealed that the boy was a heterozygous carrier of a novel T145!G transversion in exon 2 of the TNFRSF1A gene, leading to the replacement of tyrosine (TAT) by aspartic acid (GAT) at amino acid position 20 (Y20D; Fig. 1). This nucleotide substitution was not present in the genomic DNA of his parents and his two siblings. In addition, the proband and his asymptomatic father were heterozygous carriers of the MEFV E148Q variant. sTNFRSF1A concentrations were within the normal range in all family members. FACS analysis showed that shedding of TNFRSF1A receptor was entirely normal in monocytes of both the patient and his healthy father. This de novo Y20D mutation is the first TNFRSF1A mutation reported in a Chinese patient with a clinical picture compatible with TRAPS. Therefore, the Chinese population has to be considered as a further population at risk of TRAPS.. Rheumatology Vol. 43 No. 4 ß British Society for Rheumatology 2004; all rights reserved.

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