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• Further evidence for the value of TNFα blockade in neuro Behçets disease
  Jane E Alty
  Published on: 13 April 2016

• Published on: 13 April 2016

  Further evidence for the value of TNFα blockade in neuro Behçets disease

  • Jane E Alty, Specialist Registrar in Neurology
  • Other Contributors:
    • Tanya Monaghan, John M. Bamford.

  Dear Editor,

  Ribi et al.[1] describe an interesting case of neuro Behçets disease (NB) being successfully treated with the tumour necrosis factor alpha (TNFα) monoclonal antibody infliximab. We report using the soluble recombinant human TNFα receptor protein, etanercept in a patient with longstanding NB. To the best of our knowledge there are no previous clinical reports on the use of etanercept in NB.

  A...

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  Dear Editor,

  Ribi et al.[1] describe an interesting case of neuro Behçets disease (NB) being successfully treated with the tumour necrosis factor alpha (TNFα) monoclonal antibody infliximab. We report using the soluble recombinant human TNFα receptor protein, etanercept in a patient with longstanding NB. To the best of our knowledge there are no previous clinical reports on the use of etanercept in NB.

  A 39 year old lady was diagnosed with NB in 1998 on the basis of recurrent episodes of brainstem signs, oral and genital ulceration, pathergy, pustulosis, arthralgia, and intermittent pyrexia. She had episodes of headache, drowsiness, right hemiparesis, dysarthria and diplopia that lasted 1-2 weeks and occurred every 2-3 months. During relapses there was evidence of aseptic meningitis with CSF analysis typically revealing white cell counts greater than 1000 cells/mm3 (90% neutrophils), negative culture, moderately elevated protein and normal glucose. Cranial MRI scans showed extensive white matter abnormalities particularly of the brainstem (figs 1a, 1b) that resolved almost completely between relapses (fig 1c, 1d).

  Figure 1. (a=top left; b=top right; c=bottom left; d=bottom right).

  In April 1998 she was commenced on 30mg prednisolone and 100mg azathioprine. She had three further neurological and mucocutaneous relapses and so was switched to 30mg prednisolone and 200mg cyclosporin in October 1998. She continued to have neurological relapses requiring hospital admissions for intravenous steroids. In the 1990s TNFα inhibitors were not available but there was already accumulating evidence that TNFα played a part in the pathogenesis of Behçets disease.[2] Therefore in December 1999 thalidomide 200mg daily was started for its putative anti TNFα activity and the cyclosporin was stopped. Despite this she continued to relapse over the next six months and so the thalidomide was stopped. She commenced 10mg methotrexate weekly but the regular relapses continued.

  In June 2001 bi-monthly infusions of infliximab 3mg/kg were commenced and the daily dose of prednisolone was tapered down to 5mg. She continued taking 10mg methotrexate weekly to prevent the formation of antibodies to infliximab. She responded extremely well with only two clinical relapses in the following 3 years. In May 2004 the methotrexate and infliximab regime was discontinued due to raised liver enzyme levels and she was started on twice weekly subcutaneous injections of 25mg etanercept. Following this she had no further relapses over the next year and the prednisolone was discontinued for the first time in 6 years.

  In June 2005 the etanercept was stopped when the patient had a cholecystectomy for acute cholecystitis. She remained off immunosuppression altogether for 3 months. In September 2005 she presented with a severe neurological relapse. She was treated with intravenous steroids and recommenced on etanercept. There have been no further relapses.

  We would like to add a few points to Ribi at al.’s[1] excellent review of the role of TNFα blockade in NB. Etanercept is a dimer of recombinant soluble human TNFα receptor proteins (p75) and the Fc portion of IgG1.[3] It acts by competitively inhibiting the binding of TNFα to its cell surface receptor. It is administered by subcutaneous injections at a dose of 25mg twice weekly or 50mg once weekly [4] and can be self-administered by the patient. This represents a significant advantage over infliximab which requires hospital admission for intravenous administration. Comparing a maintenance dose of infliximab at 3mg/kg given every eight weeks and etanercept at 50mg per week etanercept costs marginally more. However there are several additional costs necessary for a patient to receive infliximab: a concurrent methotrexate prescription, higher doses of infliximab for the initial doses and regular hospital admissions for intravenous infusions. Etanercept may be particularly useful for patients who have difficult venous access, who are intolerant to methotrexate or for those who develop neutralising antibodies to infliximab.

  Other novel treatments with anti-TNFα activity such as adalimumab (a TNFα monoclonal antibody) and pentoxifylline (which acts to inhibit the production of proinflammatory cytokines including TNFα) may hold useful therapeutic potential in Behçets disease although clinical trials have not yet been published.

  This report highlights several important points about the role of TNFα blockade in NB. We describe the efficacy of TNFα blockade in a longstanding case of NB poorly responsive to azathioprine, cyclosporin, thalidomide and methotrexate. TNFα blockade requires regular administration to be effective in suppressing NB and the patient is likely to relapse when the TNFα blockade is discontinued. Different modes of action to block TNFα are effective in treating NB i.e. monoclonal antibodies to TNFα (infliximab) and soluble recombinant TNFα receptor protein (etanercept). Etanercept appeared to be superior to infliximab in preventing NB relapses in our patient although this is only the first case described and further studies are needed.

  References

  1. C Ribi, R Sztajzel, J Delavelle, et al. Efficacy of TNF blockade in cyclophosphamide resistant neuro-Behçet disease. J Neurol Neurosurg Psychiatry 2005;76:1733-1735.

  2. Mege JL, Dilsen N, Sanguedolce V, et al. Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet’s disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol 1993;20(9):1544–9.

  3. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Ann Rev Med 2000;51:207-29.

  4. Nash PT, Florin THJ. Tumour necrosis factor inhibitors. MJA 2005;183:205-209.

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  Conflict of Interest:
  None declared.

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