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Ribi et al. 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.
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
We would like to add a few points to Ribi at al.’s 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. 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  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
1. C Ribi, R Sztajzel, J Delavelle, et al. Efficacy of TNF blockade
in cyclophosphamide resistant neuro-Behçet disease. J Neurol Neurosurg
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