Rheumatology Advance Access originally published online on February 3, 2006
Rheumatology 2006 45(4):490-491; doi:10.1093/rheumatology/kei271
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LETTER TO THE EDITOR |
Combination of immunoadsorption and CD20 antibody therapy in a patient with mixed connective tissue disease
Department of Rheumatology and Internal Medicine III, University Of Erlangen-Nuremberg, Erlangen, Germany
Correspondence to: J. Rech, Department of Rheumatology and Internal Medicine, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail: juergen.rech{at}med3.imed.uni-erlangen.de
SIR, Mixed connective tissue disease (MCTD) is a multivariant syndrome first defined in 1972, characterized by overlapping clinical symptoms known from systemic lupus erythematosus (SLE), polymyositis/dermatomyositis and rheumatoid arthritis (RA). Clinically MCTD presents with Raynaud's phenomenon, arthritis or polyarthralgia, hand oedema, inflammatory muscle disease, oesophageal dysmotility and pulmonary hypertension [1–3]. MCTD is characterized by the presence of high titres of ANA of the speckled banner type and/or anti-U1-RNP (formerly known as anti-ENA) antibodies in addition to elevated ESR and diffuse hypergammaglobulinaemia. In contrast, anti-double-stranded DNA antibodies and the presence of LE cells are rare in the presentation of MCTD [4, 5].
In general, MCTD is extremely responsive to steroids or other immunosuppressive agents, such as methotrexate, cyclosporin, mycophenolate mofetil, azathioprine, chloroquine, immunoglobulin (Ig) and cytotoxic agents such as cyclophosphamide, but not in all patients [6, 7].
Extracorporeal therapy as a treatment option in MCTD has been used previously with little success but appears to be a valuable adjunct in the management of the disease, especially when it is combined with drugs that may inhibit the reappearance of pathogenic autoantibodies [8]. We reasoned that the combination of extracorporeal therapy with monoclonal antibodies (mAbs) to CD20 might exert additive effects on the modulation of disease activity [9, 10].
Here we report a 61-yr-old female Caucasian patient diagnosed with MCTD in 1992. Treatment was initiated with azathioprine and cyclosporin but had to be stopped in 1993 because of toxicity. Plasmapheresis was employed in 1993, 1994 and 1995 and was followed by high-dose intravenous (i.v.) Ig. From 1993 to 1997 the basic medication was methotrexate. In 1997, because of central nervous system involvement, the patient was treated with i.v. cyclophosphamide pulse therapy according to the Fauci protocol, followed by oral cyclophosphamide. In 2003 etanercept in combination with methotrexate was employed because of progredient necrosis of the left index finger, but had to be stopped due to toxicity, while infection and progredient necrosis of the finger tip required amputation. Cyclophosphamide pulse therapy was restarted followed by oral cyclophosphamide at 150 mg/day but results were unsatisfactory. In this situation, immunoadsorption was initiated together with anti-CD20 mAb treatment. The patient had elevated levels of antibodies to CENP-B and antibodies to cardiolipin were detected in 2001, whereas pANCA were always negative.
The additional medical history of the patient revealed the diagnosis of hypertension, insulin-dependent diabetes mellitus, chronic bronchitis, anaemia, cataract operation of the right eye in 1995 and the left eye in 1999, pleurisy in 1995 and loss of vestibular function in 1997.
For the first five cycles of selective immunoadsorption with a column (Globaffin®) used repetitively for 4 days every 4 weeks, the patient was maintained on stable medication with low-dose steroids and oral cyclophosphamide. After the sixth cycle of immunoadsorption the CD20 antibody rituximab (375 mg/m2) was added on day 4 after the extracorporeal therapy. Corticosteroids (10 mg/day) were given continuously throughout the treatment. Oral cyclophosphamide was exchanged for mycophenolate mofetil in November 2004 after eight cycles of immunoadsorption Fig. 1.
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Combined therapy with immunoadsorption and CD20 antibody was well tolerated without any side-effects, and it could be employed for a prolonged time. Liver enzymes that were elevated at the beginning of therapy (GOT 61 mg/dl, GPT 162 mg/dl and
-GT 768 mg/dl) decreased after therapy to GOT 29 mg/dl, GPT 44 mg/dl and -GT 235 mg/dl. ANA was 1:320 at the beginning and negative after nine cycles. Serum CENP-B antibodies were 4.5 U/ml in April 2004 and declined to 1.9 U/ml by January 2005 after treatment. In each cycle a reduction of 80% of the initial amount of total IgG and 50% of total IgM was possible.
Importantly, the patient improved clinically, as indicated by increased mobility over time, which has now been apparent for 6 months after the end of treatment. However, Raynaud's phenomenon has been absent since the second cycle of treatment. The combination of plasmapheresis and anti-CD20 mAb might therefore be a promising treatment alternative for controlling disease in therapy-resistant MCTD.
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The authors have declared no conflicts of interest.
References
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