Rheumatology Advance Access originally published online on September 1, 2007
Rheumatology 2007 46(10):1628-1629; doi:10.1093/rheumatology/kem208
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Comment on: A case of Raynaud's phenomenon in mixed connective tissue disease responding to Rituximab therapy
Department of Rheumatology, Harrogate Health Care NHS Trust, Lancaster Park Road, Harrogate HG2 7SX, UK
Correspondence to: Dr Mike Green, Consultant Rheumatologist, Harrogate Health Care NHS Trust, Lancaster Park Road, Harrogate HG2 7SX, UK. E-mail: mike.green{at}hdft.nhs.uk
SIR, We wish to respond to the recent case report of a patient with mixed connective tissue disease whose Raynaud's phenomenon responded to Rituximab therapy [1]. We would like to report a patient with undifferentiated, anti-nuclear antibody (ANA)-positive, connective tissue disease whose Raynaud's phenomenon did not respond to Rituximab.
A 32-yr-old woman presented in 2004 with severe triphasic Raynaud's, livedo, large joint arthralgia and a strongly positive ANA (nucleolar staining, 1: 1600 titre). She had normal nail fold capillaries, no sclerodactyly and cardio-respiratory examination and investigation were normal. She had a history of mild asthma since childhood. Nifedipine SR increasing to 30 mg t.d.s. was commenced, in combination sequentially with aspirin 75 mg o.d., ramipril 2.5–5 mg o.d., fluoxetine 40 mg o.d. and cessation of smoking (previously 5–10 cigarettes per day).
Over the following 12 months she developed multiple digital ulcers, on occasions infected and required multiple hospital admissions for i.v. antibiotics and iloprost (5 days, 12 h/day at 6 g/h maximum tolerated). Her Raynaud's became increasingly severe, with symptoms even on holiday abroad, and she required regular opiate analgesia for digital pain (morphine sulphate slow release tablets 60 mg b.d.).
Due to ongoing severe Raynaud's and persistence of high titre ANA, immunosuppression was considered. Unfortunately, 6 months’ treatment with azathioprine 200 mg daily and prednisolone 10 mg (with higher doses up to 60 mg o.d. at induction) failed to improve the clinical picture.
A year after initial presentation she developed increasing shortness of breath. High resolution computed tomography (HRCT) of the chest showed mosaic attenuation throughout, maximal in the bases and linear atelectasis in the right middle and lower lobes. Pulmonary function tests showed mild obstructive spirometry with reduced transfer factor (FeV1 78% predicted, FVC 90% predicted, TLCO 63% predicted). An echocardiogram was normal. Subsequent VATS-assisted lung biopsy showed brown pigment-laden macrophages in the small airways consistent with respiratory bronchiolitis interstitial lung disease (non-progressive, smoking related interstitial lung disease) [2]. She was treated with inhalers, salbutamol p.r.n., symbicort 200/6 two puffs b.d. and montelukast 10 mg o.d. In combination with smoking cessation, her respiratory symptoms and pulmonary function tests improved and her HRCT chest has remained stable to date.
Increasing global [3] and local experience with B cell depletion in antibody driven auto-immune disease suggested Rituximab as a further therapeutic option. Twenty-two months after initial presentation, she was treated with two infusions of 1000 mg Rituximab + 100 mg methylprednisolone, 2 weeks apart. CD20 B cells were successfully depleted at 2 and 6 months post-Rituximab but the ANA remained strongly positive throughout.
Ten months post-Rituximab the patient continues to have severe, disabling Raynaud's with intermittent digital ulceration. Addition of sildenafil 25 mg t.d.s. and switching from ramipril to losartan [4] has not been of benefit. Further, options such as low molecular weight heparin [5] and bosentan [6] are being considered.
There has only been one other case report of Rituximab treatment in a patient with severe Raynaud's [7]. This patient had ANA-positive, mixed connective tissue disease with previous episodes of central nervous system involvement. Prior treatment over a period of 12 yr had included azathioprine, cyclosporin, methotrexate, i.v. immunoglobulin, plasmapharesis and etanercept. The authors report complete resolution of Raynaud's symptoms after a course of immunoadsorption and Rituximab but note that, in fact, the Raynaud's disappeared after two cycles of lone immunoadsorption, some time before Rituximab was administered. Their patient became ANA negative after Rituximab and remains well on prednisolone and mycophenolate maintenance.
Review of the wider literature reveals that there have only been anecdotal reports of Rituximab use in scleroderma spectrum disorders [8, 9]. The pathogenic role of B and T cells in these conditions has yet to be fully elucidated [9] and widespread experience of Rituximab across the whole spectrum of auto-immune disease has not suggested a beneficial effect of Rituximab on Raynaud's phenomenon [8, 10]. This would support our finding that in a patient with an undifferentiated scleroderma spectrum disease, and high titre nucleolar staining ANA, Rituximab may not be successful in controlling severe Raynaud's phenomenon. Further research will be required to determine the role of Rituximab in patients such as these. It might be that patients with true mixed connective tissue disease represent a subset of patients whose Raynaud's may be successfully treated with B cell depletion, where those with a scleroderma spectrum disorder may not. This may reflect differential involvement of B cells in the underlying pathology of these conditions and underlines the critical role of patient selection if controlled trials are going to provide the answers we need.
The authors have declared no conflicts of interest.
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