Anti-CD20 monoclonal antibody for the treatment of refractory autoimmune haemolytic anaemia associated with idiopathic membranous nephropathy

P. Rossi, A. L. Demoux, B. Granel, D. Bagnères, S. Bonin-Guillaume and Y. Frances

Department of Internal Medicine, North Hospital, Chemin des Bourrely, 13105 Marseilles, France

Correspondence to: P. Rossi, Department of Internal Medicine, North Hospital, Chemin des Bourrely, 13015 Marseilles, France. E-mail: pascalrossi{at}yahoo.com

SIR, We report here the efficiency of anti-CD20 monoclonal antibody in two immune-mediated diseases occurring in a 46-yr-old man. The patient suffered from a corticoresistant autoimmune haemolytic anaemia associated with an idiopathic membranous nephropathy. He made a complete recovery with anti-CD20 monoclonal antibody (rituximab) infusions. Such a case has not been previously reported to our knowledge, and confirms the role of anti-CD20 monoclonal antibody in treatment of autoimmune disorders by the way of a B-cell depletion.

A 46-yr-old man was admitted to our department in January 2003, with a 3-month history of fatigue, mild pre-tibial oedema and dyspnoea. He had no medical history. Physical examination at admission was unremarkable, with the exception of pallor and mild jaundice. Full blood count at admission showed a normochromic and macrocytic anaemia (haemoglobin = 5.6 g/dl) with reticulocytosis (absolute reticulocyte count = 135 x 109/l) and normal white blood cell and platelet counts. Total and unconjugated bilirubin levels were increased (1.35 mg/dl and 1.02 mg/dl, respectively) as well as lactate dehydrogenase levels (2345 U/l; normal <600); serum haptoglobin level was undetectable. The direct Coombs test was positive and binding of IgG to the red blood cell surface was observed using anti-human globulin monospecific antibodies. Bone marrow aspirate and biopsy demonstrated normal representation of myeloid and megakaryocyte precursors, and high erythroblastic hyperplasia due to peripheral haemolysis. A nephrotic syndrome with hypoproteinaemia (49 g/l), hypoalbuminaemia (23 g/l) and a high level of urinary albumin (14 g/24 h). Cytobacteriological urinary tests were normal and no Bence-Jones protein was detected. Serum electrophoresis yielded no monoclonal gammopathy, and serum immunoglobulins were diminished for IgG (3.1 g/l, 6.9<normal range<14.0), whereas IgM and IgA were within the normal range. The following blood tests were within the normal range or negative: creatinine clearance, urea and electrolytes, glucose, cholesterol, triglycerides, thyroid function, liver function, creatine kinase, coagulation screening, vitamin B12, red cell folate, cryoglobulins, complement fractions C3/C4/CH50, antinuclear antibodies, anti-DNA and anti-SSA, anti-SSB, anti-RNP, anti-Sm anti-neutrophil cytoplasmic antibodies, peripheral lymphocyte immunophenotyping, serological tests for parvovirus B19, hepatitis B and C, human cytomegalovirus, HIV and Epstein–Barr virus, prostatic specific antigen and carcino-embryonic antigen. Moreover, a search for a hereditary haemolytic anaemia was negative (G6PD, pyruvate kinase, haemoglobin electrophoresis). Chest X-ray, body scan and digestive endoscopies were normal. Renal histology performed 2 weeks after admission showed stage I membranous glomerulonephritis.

Methylprednisolone, first at conventional doses (2 mg/kg/day) for 2 weeks, then at high doses (5 mg/kg/day) for 1 week, was administered, and proved to be ineffective on the haemolytic process and nephrotic syndrome. Moreover, a glucocorticoid-induced diabetes was noted.

Several articles about successful treatment with anti-CD20 monoclonal antibody (rituximab) had been published for corticodependent autoimmune haemolytic anaemia (AIHA) [1, 2] and idiopathic membranous nephropathy (IMN) [3, 4], thus we reasoned that selective destruction of B cells producing antibodies might be more effective than other immunosuppressive drugs in our case. Moreover, rituximab therapy has been used for treatment of several autoimmune diseases such autoimmune thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, cold agglutinin disease, mixed cryoglobulinaemia, neuropathies associated with autoantibodies, myasthenia gravis, Wegener's granulomatosis and dermatomyositis [5]. Rituximab is well tolerated and has a toxicity profile limited to relatively rare allergic reactions. The infusional protocol for rituximab administration as treatment for autoimmune disorders is not yet consensual. In a study by Zaja et al. [2], patients with autoimmune haemolytic anaemia previously refractory to conventional treatments were successfully treated with weekly infusions of rituximab, 375 mg/m2, for 4 weeks. To treat idiopathic membranous nephropathy, Remuzzi et al. [4] gave the patients infusions of rituximab (375 mg/m2) every 4 weeks, for 5 months. Because in our case the aim of rituximab administration was to treat both autoimmune haemolytic anaemia and idiopathic membranous nephropathy, we chose to give rituximab infusions intravenously at a dose of 375 mg/m2 as a 4-h infusion, once weekly for a total of four doses then once monthly for a total of five doses. Methylprednisolone was slowly tapered and discontinued. The drug was well tolerated and the patient did not present any adverse reactions or side-effects. Shortly after the first rituximab infusion, the patient showed a rise in haemoglobin level (haemoglobin around 9 g/dl) and in serum total protein level, and a decrease in lactate dehydrogenase level and proteinuria (<1 g/24 h) (Table 1). Bilirubin and haptoglobin levels also normalized. Six months after rituximab therapy the patient had made a complete recovery, and did not need any hypoglycaemic treatment.


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TABLE 1. Follow-up of major laboratory data

 
We concluded idiopathic AIHI and IMN as there was no evidence for malignancy, infection, vasculitis, systemic autoimmune disorders or other underlying disease. As both conditions improved in a similar way, we assumed that both may have a common immunological basis. An association of AIHA with IMN has not to our knowledge been previously published. Rare cases of membranous glomerulonephritis associated with idiopathic thrombocytopenic purpura, or crescentic glomerulonephritis with positive anti-neutrophil cytoplasmic autoantibody specific for myeloperoxidase associated with autoimmune haemolytic anaemia and thrombocytopenic purpura [6, 7] have, however, been reported.

In view of studies describing effects of rituximab in patients with immune-mediated diseases, and the major side-effects (Cushing's syndrome, glucocorticoid-induced diabetes, leucopenia, cancer, renal toxicity and opportunistic infections) associated with the use of steroids and/or other aspecific immunosuppressive drugs, rituximab could be a valuable treatment for concomitant autoimmune disorders.

The authors have declared no conflicts of interest.

References

  1. Quartier P, Brethon B, Philippet P, Landman-Parker J, Le Deist F, Fischer A. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet 2001;358:1511–13.[CrossRef][ISI][Medline]
  2. Zaja F, Iacona I, Masolini P et al. B-cell depletion with rituximab as treatment for immune hemolytic anemia and chronic thrombocytopenia. Haematologica 2002;87:336.[ISI]
  3. Ruggenenti P, Chiurchiu C, Brusegan V et al. Rituximab in idiopathic membranous nephropathy: a one-year prospective study. J Am Soc Nephrol 2003;14:1851–7.[Abstract/Free Full Text]
  4. Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P. Rituximab for idiopathic membranous nephropathy. Lancet 2002;360:923–4.[CrossRef][ISI][Medline]
  5. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003;48:1484–92.[CrossRef][ISI][Medline]
  6. Robles NR, Lopez Gomez JM, Lobos JM, Valderrabano F. Membranous glomerulonephritis associated with idiopathic thrombocytopenic purpura. Rev Clin Esp 1989;185:402–4.[ISI][Medline]
  7. Ohhashi J, Miyamoto M, Ishikawa S et al. Crescentic glomerulonephritis with positive antineutrophil cytoplasmic autoantibody specific for myeloperoxidase associated with autoimmune hemolytic anemia and thrombocytopenic purpura. Intern Med 2000;39:650–4.[ISI][Medline]
Accepted 5 October 2004





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