Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkin's lymphoma

A. Protheroe, J. C. W. Edwards1, A. Simmons, K. Maclennan and P. Selby

ICRF Cancer Medicine Research Unit, St James' University Hospital, Leeds and
1 Centre for Rheumatology, University College London, UK

Correspondence to: J. C. W. Edwards, UCL Centre for Rheumatology, 4th Floor, Arthur Stanley House, 40 Tottenham Street, London W1P 9PG, UK.


    Abstract
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 Abstract
 Case history
 Discussion
 References
 
We describe a case involving a 53-yr-old male with a marginal zone B-cell lymphoma, associated with an IgM paraprotein and a rheumatoid factor-negative inflammatory polyarthropathy, treated with monoclonal anti-CD20 antibody. During the subsequent 12 weeks, evidence of synovitis reduced to a negligible level, despite no significant change in lymphoma bulk or paraprotein level. The relationship between the lymphoma and the arthropathy, and the likely mechanism of remission of the arthropathy, are discussed in the context of the potential value of anti-CD20 therapy in rheumatoid arthritis.

KEY WORDS: Anti-CD20, Lymphoma, Rheumatoid arthritis, B lymphocyte


    Case history
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 Abstract
 Case history
 Discussion
 References
 
A 53-yr-old male presented in 1989 with lethargy, weight loss and lymphadenopathy. Investigations revealed marginal zone non-Hodgkin's lymphoma with an IgM paraprotein (37.9 g/l). Over the subsequent 9 yr, the disease followed an indolent course, treated in chronological order with: cyclophosphamide/epirubicin/vindesine/prednisolone; chlorambucil; methylprednisolone; interferon-{alpha}; plasmapheresis; fludarabine; chlorambucil; fludarabine/methotrexate/dexamethasone; plasmapheresis and anti-CD20 antibody.

In 1993, he first developed musculoskeletal symptoms in the form of shoulder pain, settling after a few weeks. Musculoskeletal symptoms gradually became progressive and more generalized. In 1995, he reported pain in the elbows, knees, wrists and ankles. Swelling was noted along ulnar and flexor aspects of both wrists, consistent with extensor carpi ulnaris and flexor tenosynovitis. Musculoskeletal symptoms responded temporarily (although partially) to chemotherapy, as did tumour bulk, and relapse appeared to predict progression of lymphoma. In July 1998, he was suffering widespread debilitating pain, particularly severe in the feet, necessitating the use of a wheelchair. The lymphoma was widespread, with bulky inguinal, iliac, para-aortic and axillary nodes, and a paraprotein level of 36.8 g/l.

For his progressive disease and associated intractable arthropathy, he received four 700 mg infusions of chimeric monoclonal anti-CD20 antibody (Mabthera, Roche Products) at weekly intervals. Approximately 3 weeks after receiving the antibody, he noticed improvement in joint pain and stiffness. Over the next few weeks, improvement continued such that 3 months later he was virtually symptom free and walking up to 5 miles a day. Figure 1Go shows the patient's retrospective assessment of the time course of improvement in arthritic symptoms, obtained on 4 December 1998. This was the first complete resolution of his arthropathy, but CT scan showed no change in lymphoma bulk. The paraprotein level was 35.6 g/l. He remained essentially symptom free for 4 months, then pain and swelling recurred in the left midfoot, which settled 1 month later. The patient took diclofenac briefly at the time of monoclonal therapy, but no anti-rheumatic agents subsequently.



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FIG. 1.  Retrospective assessment by the patient of the course of regression of arthritic symptoms on a 0–100% scale.

 
Musculoskeletal examination on 4 December 1998 was normal other than the left foot. Mild oedema was present over the midfoot dorsum. Passive pronation and supination of mid-tarsal joints provoked pain. The first to third metatarsophalangeal joints were mildly thickened and tender. Rheumatoid factor (RF) and autoantibody screen were negative, and plasma urate normal (0.33 mmol/l). Foot and hand radiographs showed early erosions of one metatarsophalangeal joint and one ulnar styloid. After a second brief relapse in foot pain, the patient remains essentially free of musculoskeletal symptoms in March 1999.


    Discussion
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 Abstract
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The chimeric monoclonal anti-CD20 antibody C2B8 produces subtotal B-lymphocyte clearance both in cynomolgus monkeys and lymphoma patients [1, 2]. It is now licensed for use in B-cell lymphoma. Its use has also recently been considered for rheumatoid arthritis (RA) [3] and an open clinical trial is under way.

The onset of arthropathy following onset of lymphoma in this patient, and the initial correlation between rheumatic symptoms and tumour load, suggest that the arthropathy was a non-metastatic complication of the lymphoma. However, the remission following anti-CD20, independent of reduction in paraprotein, suggests that the arthropathy was not directly due to the paraprotein. It seems more likely to have been driven by a secondary autoimmune mechanism.

Remission of symptoms after anti-CD20 suggests that the arthropathy was immune complex mediated. By analogy with RA [3], it is likely that IgG- rather than IgM-based complexes were involved. A range of mechanisms can be envisaged, involving anti-idiotype responses, clonal relationships between tumour and immune complex-generating B cells and, conceivably, a triggering role for interferon-{alpha} [4]. However, although the context is distinct, the response to anti-CD20 therapy provides encouragement for trials in RA.

The use of anti-CD20 in RA is based on a specific proposal: that the condition is driven by self-perpetuating autoantibody-secreting B cells [5], in most cases committed to IgG RF production. IgG RF oligomers have the specific potential to initiate inflammation in synovium and documented extra-synovial sites in RA by inducing tumour necrosis factor release from macrophages via the receptor Fc{gamma}RIIIa [3]. IgG RFs also have the potential to feed back onto their parent B cells and perpetuate their own production, essentially because IgG RF is its own antigen.

This proposal led to the idea that long-term remission might be achieved by B-cell clearance. If sufficient autoantibody-committed B cells can be destroyed to break the cycle, then disease should be eradicated. Symptoms would be expected to decline much as observed in the case presented.

This is the first report of anti-CD20 producing a near complete resolution of an inflammatory arthropathy that we are aware of. Anti-CD20 therapy is now widely used in lymphoma. A few patients receiving this treatment will have coincidental RA or related autoimmune disorders. Documentation of the progress of such cases should be of great value in assessing the role of anti-CD20 therapy in such conditions.


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  1. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435–45.[Abstract/Free Full Text]
  2. Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994;84:2457–66.[Abstract/Free Full Text]
  3. Edwards JCW, Cambridge G. Rheumatoid arthritis: the predictable effect of small immune complexes in which antibody is also antigen. Br J Rheumatol 1998;37: 126–30.[ISI][Medline]
  4. Vial T, Descotes J. Immune-mediated side-effects of cytokines in humans. Toxicology 1995;105:31–57.[ISI][Medline]
  5. Edwards JCW. Is rheumatoid factor relevant? In: Bird HA, Snaith ML, eds. Challenges in rheumatoid arthritis. Chapter 1. Blackwell Scientific, 1999, pp. 1–24.
Submitted 28 January 1999; revised version accepted 28 April 1999.