Rheumatology Advance Access originally published online on September 5, 2008
Rheumatology 2008 47(11):1729-1730; doi:10.1093/rheumatology/ken354
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Successful bosentan treatment of critical ischaemia induced by vasculitis in an SCLE patient
1Department of Internal Medicine, State Hospital Muerzzuschlag, Muerzzuschlag, 2Department of Internal Medicine, Division of Angiology, Medical University Graz, Graz and 3Department of Radiology, State Hospital Leoben, Leoben, Austria
Correspondence to: R. Thonhofer, Landeskrankenhaus Mürzzuschlag, Grazer Strasse 63-65, 8680 Mürzzuschlag, Austria. E-mail: rene_thonhofer{at}hotmail.com
SIR, Bosentan, an oral dual endothelin receptor antagonist, has been established in the treatment of primary and secondary pulmonary arterial hypertension [1, 2] and in the prevention of digital ulcers in SSc [3, 4]. Case reports indicate the improvement of RP [5], severe ischaemia secondary to lcSSc [6] and PAN [7].
We report on a 44-yr-old white female who has been diagnosed with subcutaneous lupus erythematosus (SCLE) for 8 yrs. The diagnosis of SCLE was initially based on the appearance of the typical non-scarring and non-fixed polycyclic skin lesions of SCLE and confirmed by skin biopsies showing immune deposits on the dermal–epidermal border. ANA, dsDNA, ANCA and complement factors were negative during the overseen timeframe of 8 yrs. Screening for organ involvement was done on a regular basis, providing no evidence of systemic manifestations. The patient was admitted to our department due to severe pain, pallor and cold skin on her feet. The clinical picture and colour-coded duplex sonography indicated an occlusion of the distal segment of the arteria dorsalis pedis and arteria tibialis posterior on both lower extremities. An MRI angiography (MRA) revealed the diagnosis of an obstructive vasculitis. Oscillography showed critical ischaemia on both legs (Fig. 1a), worsening after cold exposure and affecting the toes bilaterally. Therapy with prednisolone (2 mg/kg body weight) and iloprost (2 ng/kg body weight and minute), which had been administered intravenously for 10 days, showed no clinical effect. Consequently, iloprost was discontinued and therapy was switched to alprostadil (40 µg, twice daily), which was unsuccessful as well. As an off-label therapeutic alternative, bosentan 62.5 mg twice daily, was started. Bosentan was well tolerated and the patient's condition improved substantially. Within 1 week of treatment no clinical signs of ischaemia were present any more and the patient was pain-free. She was discharged on bosentan and gradually tapered doses of oral prednisolone. After 1 month on bosentan, additional treatment of an unspecific viral infection including paracetamol and acetyl salicylic acid led to significantly increased liver enzymes. For this reason bosentan was halted, which caused a relapse of severe ischaemia within 3 days with similar symptoms as seen prior to the start of the therapy with bosentan. With worsening ischaemic symptoms and declining liver parameters, bosentan was restarted 10 days later and again a rapid improvement was documented, with full relief of iscahemic symptoms after 1 week. Clinical and laboratory controls on a regular basis showed no signs of ischaemia or side-effects due to bosentan therapy (especially the liver parameters stayed in normal ranges after bosentan had been started again). Repeated oscillography (Fig. 1b) documented a marked improvement of blood flow in the lower extremities. A control MRA 3 months after bosentan had been initiated showed normal blood flow in the formerly obstructed arteries of the feet.
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To the best of our knowledge, the use of bosentan in a case of SCLE-associated vasculitis inducing critical ischaemia has not been reported before. Off-label bosentan treatment was started after some frustrated therapy attempts, including two vasodilatators as well as high doses of prednisolone, especially because of the critical ischaemia associated with the risk of tissue necrosis. The striking success of bosentan treatment in our patient (complete reversal of the clinical symptoms of ischaemia) was objectified by a marked improvement of repeated oscillography and a once again normal MRA.
Endothelial cells are a main site of ET production but also targets for ET (e.g. expression of pro-adhesive molecules). Vasculitis, a condition characterized by the inflammation of blood vessels, leads to endothelial injury that may possibly be accompanied by increased concentrations of ET. ET is known to be a potent vasoconstrictor and has several pro-inflammatory facets [8]. Especially ET-1 enhances neutrophil chemotaxis [9] and activation, as well as the release of MMPs. ET-1 may lead to NF-
B stimulation and may subsequently stimulate the production of pro-inflammatory cytokines like IL-6, IL-8 and TNF-
[10]. The use of an oral ET dual receptor antagonist in our patient led to a rapid remission of ischaemia. This fast and sustained response had probably been achieved by potent vasodilatation. The reversal of the obstructive vasculitis documented by MRA might also at least partially be related to bosentan. The blockade of ET might have caused a down-regulation of pro-inflammatory cytokines and cells by a mechanism mentioned earlier. Corticosteroids were already terminated 4 weeks after the start of the bosentan therapy. Now, 9 months later, there is no evidence of reoccurrence of vasculitis. Bosentan might, therefore, be responsible for sustained remission. This could be interpreted as further piece of evidence of its anti-inflammatory potential in this case.
In conclusion, we think that bosentan, in this individual patient, exhibited compelling vasodilatatory and anti-inflammatory effects leading to a rapid and sustained clinical improvement of the ischaemia, probably achieved by antagonization of endothelin. Bosentan might, for this reason, be regarded as therapeutic alternative in ischaemic complications caused by vasculitic syndromes resistant to standard treatment regimes.
Disclosure statement: The authors have declared no conflicts of interest.
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