Rheumatology Advance Access originally published online on February 8, 2007
Rheumatology 2007 46(4):718-719; doi:10.1093/rheumatology/kem003
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A case of Raynaud's phenomenon in mixed connective tissue disease responding to rituximab therapy
Department of Rheumatology, Waterford Regional Hospital, Dunmore Road, Waterford, Ireland
Correspondence to: Dr Donncha O'Gradaigh, Department of Rheumatology, Waterford Regional Hospital, Dunmore Road, Waterford, Ireland. E-mail: donncha.ogradaigh{at}maila.hse.ie
SIR, We wish to report the first successful use of rituximab in Raynaud's phenomenon associated with mixed connective tissue disease, with disappearance of associated anti-RNP antibodies.
A 40-yr-old lady presented in 1997 with swelling of the small joints of her hands, Raynaud's phenomenon and a restrictive lung defect on pulmonary function tests. She did not have features of other connective tissue diseases. She had a positive test for antibodies to ribonuclear protein (RNP) on two occasions and a diagnosis of mixed connective tissue disease was made. She remained stable on prednisolone 5–10 mg and hydroxycloroquine 200 mg bd until 2001.
Raynaud's phenomenon then worsened, requiring intravenous infusion of iloprost (titrated from 0.5 to 2 mcg/kg/min on three successive days) every 3 months. Later, bosentan (125 mg bd) and tadalafil (10 mg bd) were tried. A digital sympathectomy helped briefly, but 3-monthly iloprost infusion continued, with infection of a femoral line on two occasions.
Falling DLCO and changes on high resolution CT was successfully treated with three fortnightly infusions of cyclophosphamide 500 mg. As skin healing also improved, further immunosuppressive therapy was considered, and the descriptions of rituximab in rheumatology [1–3] were therefore of particular interest. She had iloprost on two successive days (titrated as before), followed by 100 mg methylprednisolone i.v. and 1000 mg rituximab on day three. On the fourth day, she had a further 100 mg methylprednisolone and 500 mg cyclophosphamide. Two weeks later, the full schedule was repeated. There was a marked improvement in her hands with healing of skin ulceration and pain relief.
Symptoms began to re-occur 3 months later, and the schedule was repeated with omission of cyclophosphamide. Over the next 3 months, symptoms were minimal, and she described the treatment effect as ‘magical’. She has been since treated with the 3-day protocol (without cyclophosphamide) on two further occasions, with no complications of treatment. Her RNP antibody test was negative when tested 3 months after the first, 2-week, schedule of treatment, and remained negative for over a year. However, her symptoms relapsed markedly in July 2006, with the RNP antibodies again detected (on two separate tests).
This is the first report of successful treatment of severe, refractory Raynaud's phenomenon with rituximab (in combination with methylprednisolone, cyclophosphamide and iloprost), with marked reduction in painful skin ulceration and disappearance of RNP antibodies. Recently RNP antibodies were again detected associated with symptom relapse.
Significant reductions have been reported in antibody titre and/or in the proportion with a positive antibody test in a range of conditions [4–7], while clinical relapse correlated with rising antibody titre [8]. This was less striking with respect to dsDNA antibodies in SLE [6, 7].
RNP autoantibodies have not been implicated in the pathogenesis of Raynaud's phenomenon. Senécal and colleagues [9] recently postulated a pathogenic role for autoantibodies in systemic sclerosis (though not for RNP). We suggest the improvement in Raynaud's and the clearance of RNP antibodies are causally unrelated manifestations of the improved control of the underlying MCTD in response to rituximab.
We re-treated our patient without cyclophosphamide without any loss of efficacy. In SLE, a range of rituximab protocols have now been used [6, 7, 10]. Leandro et al. cautions against the lower (<500 mg) doses of rituximab, while Weide [10] has retreated with 375 mg/m2 every 3 months. Out of 24 patients from Leandro's study [6], 13 remain in remission with a mean follow up of 23 months (range 7–51 months). Seven patients from this cohort have been re-treated (interval to re-treatment unknown).
The authors have declared no conflicts of interests.
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[Abstract/Free Full Text]
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