B-cell Numbers and Phenotype at Clinical Relapse Following Rituximab Therapy Differ in SLE Patients According to Anti-dsDNA Antibody Levels

Overview

Journal Rheumatology (Oxford)

Publisher Oxford University Press

Specialty Rheumatology

Date 2012 Feb 17

PMID 22337941

Citations 36

Authors

Mark N Lazarus

Tabitha Turner-Stokes

Konstantia-Maria Chavele

David A Isenberg

Michael R Ehrenstein

Affiliations

Soon will be listed here.

Abstract

Objectives: To correlate the kinetics of B-cell repopulation with relapse after B-cell depletion therapy in SLE patients and address whether variation in relapse rate, B-cell numbers and phenotype are related to anti-dsDNA antibody levels.

Methods: Sixty-one patients with refractory SLE were treated with a standard rituximab regimen. Clinical and serological measures of disease activity and B-cell numbers were assessed. B-cell phenotype was examined in a subgroup of patients by flow cytometry.

Results: Disease relapse was substantially delayed beyond B-cell repopulation, and early relapse was associated with a faster rate of repopulation. At relapse, B-cell numbers were significantly lower than at baseline in patients with high anti-dsDNA antibody levels (> 100 IU/ml) but not in patients with low anti-dsDNA antibody levels. Of the patients with high anti-dsDNA antibodies at baseline, levels fell significantly only in those patients who remained in remission after repopulation. Relapse with high anti-dsDNA antibody levels was associated with an increased percentage of IgD(-)CD27(hi) plasmablasts, whereas relapse with low anti-dsDNA antibody levels was accompanied by an increased percentage of IgD(-)CD27(-) B cells.

Conclusion: Anti-dsDNA antibody levels distinguished two patient groups, which differ in their B-cell number and phenotype at relapse following rituximab, and suggest that different B-cell pathologies exist in SLE. The data imply that B-cell numbers should be kept very low for a sustained period in patients with high dsDNA binding, therefore justifying a more aggressive regimen.

Citing Articles

Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study.

Aranow C, Allaart C, Amoura Z, Bruce I, Cagnoli P, Chatham W Ann Rheum Dis. 2024; 83(11):1502-1512.

PMID: 39159997 PMC: 11503042. DOI: 10.1136/ard-2024-225686.

Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares.

Zisa D, Zhang-Sun J, Christos P, Kirou K Lupus. 2024; 33(9):938-947.

PMID: 38860319 PMC: 11326872. DOI: 10.1177/09612033241260283.

Anti-topoisomerase 1 Antibody Level Changes after B Cell Depletion Therapy in Systemic Sclerosis.

Ananyeva L, Garzanova L, Koneva O, Starovoytova M, Desinova O, Ovsyannikova O Dokl Biochem Biophys. 2023; 511(1):212-218.

PMID: 37833608 PMC: 10739332. DOI: 10.1134/S1607672923700266.

A cell-level discriminative neural network model for diagnosis of blood cancers.

Robles E, Jin Y, Smyth P, Scheuermann R, Bui J, Wang H Bioinformatics. 2023; 39(10).

PMID: 37756695 PMC: 10563151. DOI: 10.1093/bioinformatics/btad585.

Current Treatment Approach, Emerging Therapies and New Horizons in Systemic Lupus Erythematosus.

Athanassiou P, Athanassiou L Life (Basel). 2023; 13(7).

PMID: 37511872 PMC: 10381582. DOI: 10.3390/life13071496.

References

Leandro M, Cambridge G, Edwards J, Ehrenstein M, Isenberg D . B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford). 2005; 44(12):1542-5. DOI: 10.1093/rheumatology/kei080. View

Scheinberg M, Cathcart E . B cell and T cell lymphopenia in systemic lupus erythematosus. Cell Immunol. 1974; 12(2):309-14. DOI: 10.1016/0008-8749(74)90083-5. View

Tseng C, Buyon J, Kim M, Belmont H, Mackay M, Diamond B . The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus: findings of a prospective, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006; 54(11):3623-32. DOI: 10.1002/art.22198. View

Petri M, Stohl W, Chatham W, McCune W, Chevrier M, Ryel J . Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008; 58(8):2453-9. DOI: 10.1002/art.23678. View

Rahman A, Isenberg D . Systemic lupus erythematosus. N Engl J Med. 2008; 358(9):929-39. DOI: 10.1056/NEJMra071297. View

Anolik J, Barnard J, Cappione A, Pugh-Bernard A, Felgar R, Looney R . Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum. 2004; 50(11):3580-90. DOI: 10.1002/art.20592. View

Hochberg M, Chang R, Dwosh I, Lindsey S, Pincus T, Wolfe F . The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 1992; 35(5):498-502. DOI: 10.1002/art.1780350502. View

Yan J, Harvey B, Gee R, Shlomchik M, Mamula M . B cells drive early T cell autoimmunity in vivo prior to dendritic cell-mediated autoantigen presentation. J Immunol. 2006; 177(7):4481-7. DOI: 10.4049/jimmunol.177.7.4481. View

Becker-Merok A, Nikolaisen C, Nossent H . B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time. Lupus. 2006; 15(9):570-6. DOI: 10.1177/0961203306071871. View

10.

Wei C, Anolik J, Cappione A, Zheng B, Pugh-Bernard A, Brooks J . A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus. J Immunol. 2007; 178(10):6624-33. DOI: 10.4049/jimmunol.178.10.6624. View

11.

Dorner T, Jacobi A, Lee J, Lipsky P . Abnormalities of B cell subsets in patients with systemic lupus erythematosus. J Immunol Methods. 2010; 363(2):187-97. DOI: 10.1016/j.jim.2010.06.009. View

12.

Jacquot S, Kobata T, Iwata S, Morimoto C, Schlossman S . CD154/CD40 and CD70/CD27 interactions have different and sequential functions in T cell-dependent B cell responses: enhancement of plasma cell differentiation by CD27 signaling. J Immunol. 1997; 159(6):2652-7. View

13.

Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B . Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum. 2010; 62(8):2458-66. DOI: 10.1002/art.27541. View

14.

Bootsma H, Spronk P, ter Borg E, Hummel E, de Boer G, Limburg P . The predictive value of fluctuations in IgM and IgG class anti-dsDNA antibodies for relapses in systemic lupus erythematosus. A prospective long-term observation. Ann Rheum Dis. 1998; 56(11):661-6. PMC: 1752296. DOI: 10.1136/ard.56.11.661. View

15.

Winfield J, Winchester R, KUNKEL H . Association of cold-reactive antilymphocyte antibodies with lymphopenia in systemic lupus erythematosus. Arthritis Rheum. 1975; 18(6):587-94. DOI: 10.1002/art.1780180609. View

16.

Favas C, Isenberg D . B-cell-depletion therapy in SLE--what are the current prospects for its acceptance?. Nat Rev Rheumatol. 2009; 5(12):711-6. DOI: 10.1038/nrrheum.2009.218. View

17.

Cambridge G, Isenberg D, Edwards J, Leandro M, Migone T, Teodorescu M . B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann Rheum Dis. 2007; 67(7):1011-6. DOI: 10.1136/ard.2007.079418. View

18.

Looney R, Anolik J, Campbell D, Felgar R, Young F, Arend L . B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 2004; 50(8):2580-9. DOI: 10.1002/art.20430. View

19.

Jacobi A, Reiter K, Mackay M, Aranow C, Hiepe F, Radbruch A . Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthritis Rheum. 2008; 58(6):1762-73. DOI: 10.1002/art.23498. View

20.

Ehrenstein M, Katz D, Griffiths M, Papadaki L, Winkler T, Kalden J . Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kidney Int. 1995; 48(3):705-11. DOI: 10.1038/ki.1995.341. View