The Journal of Pediatrics
Volume 148, Issue 5 , Pages 571-573, May 2006

Targeting B cells in the treatment of childhood-onset systemic lupus erythematosus

  • Jennifer L. Huggins, MD (Clinical Fellow)
    • ,
  • Hermine I. Brunner, MD, MSc (Assistant Professor)

      Affiliations

    • Corresponding Author InformationReprint requests: Dr Hermine I. Brunner, Assistant Professor, Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039

Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229-3039

Article Outline

Abbreviations:  ADCC, Antibody-dependent cell-mediated cytotoxicity , Pre-GC, Pre-germinal center , SLE, Systemic lupus erythematosus

 

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the production of pathogenic antibodies directed against self-antigens. The pathophysiology of SLE is complex. Undoubtedly, there are multiple immunologic mechanisms involved in its development, resulting in the clinical heterogeneity of the disease. Despite this, there is a growing body of evidence that B cells are central players in the pathogenesis of SLE. B cells produce antibodies against DNA that are involved in the development of SLE nephritis; they are the source of anti-cardiolipin and anti-Ro antibodies that can cause thrombosis and congenital heart block, respectively. Besides their ability to produce autoantibodies involved in a myriad of SLE manifestations, other B cell properties appear also to be at fault in SLE.

See related article, p 623

B cell dysregulation is likely instrumental in causing the disruption of the immune homeostasis observed with SLE. Abnormalities in B cell activation, signaling and migration, and constitutively enhanced expression of co-stimulatory molecules, such as the ligand for CD40 (CD154), have been reported. B cells with SLE overproduce several cytokines that further stimulate B cell function, including interleukin-10, interleukin-6, Blys, and interferon-α.1 Animal models support that B cells themselves, even in the absence of autoantibodies, cause some SLE manifestations. Genetically manipulated lupus-prone MRL lpr/lpr mice develop nephritis despite their inability to produce autoantibodies. Conversely, B-cell-deprived MRL lpr/lpr mice are protected from developing nephritis, suggesting a central role of B cells but not necessarily autoantibodies in SLE renal disease.2

Based on research supporting the central role of B cells in the pathogenesis of SLE, one could hypothesize that drugs specifically targeting B cells would be the long sought “ideal” medications for treatment of SLE. One of the medications developed for specifically targeting B cells is rituximab, a chimeric mouse-human monoclonal antibody against human CD20, which is a cell surface marker specific to B cells.3 CD20 is highly expressed throughout B cell differentiation, except at the plasma cell stage.4 Despite extensive investigation, the precise role of CD20 in B cell physiology is not completely clear. The clinical potential of CD20-targeted therapy is primarily based on the unexpected observation that antibody against CD20 induces B cell apoptosis.5 In vitro studies suggest several potential mechanisms by which rituximab can selectively deplete B cells: First, the interaction of CD20+ cells with rituximab induces complement-dependent cytotoxicity; second, in the presence of effector cells, rituximab promotes antibody-dependent cell-mediated cytotoxicity (ADCC).3 For ADCC to occur Fc-γ receptors are essential, especially the Fc- γ receptor subtype IIIa, which is expressed on a variety of cells including phagocytic cells. However, inheritance of low-affinity Fc-γ receptor alleles decreases receptor function and is thought to limit the degree of B cell depletion by rituximab.6

Sfikakis et al reviewed data of 100 rituximab-treated adult SLE patients with severe disease, refractory to traditional immunosuppressives.7 Three open-label, uncontrolled, prospective phase I/II studies performed at the Universities of London, UK,8 Rochester, NY,9 and Athens, Greece,10 were included in the above-mentioned review. Approximately 80% of these patients achieved marked and rapid reduction of global disease activity, whereas 20% did not. During a median follow-up period of 12 months, rituximab appeared to be tolerated when given in conjunction with other SLE treatments. This experience appears similar to the experience accumulated from rituximab use in more than 500,000 patients with lymphoma.

Conversely, adverse events during rituximab therapy were encountered by almost half of the French children reported by Willems et al in this issue of The Journal. Although episodes of thrombocytopenia and neutropenia during rituximab therapy might have been because of a disease flare, both are known side effects of rituximab described in other studies. Despite the fact that rituximab alone is unlikely the sole culprit responsible for the severe complications encountered during rituximab therapy, its addition to the commonly used intensive immunosuppressive regimen in pediatric SLE may be problematic. The potentially inferior safety profile suggested in this group of 11 children may be simply because of a selection bias. This would be supported by previously reported findings in an even smaller group of children with SLE reported by Marks et al.11 In this open-label prospective study of seven children with active SLE unresponsive to current standard therapies, rituximab was given in conjunction with intravenous cyclophosphamide and high-dose oral corticosteroids for a mean of 12 months. All seven children improved following this combination therapy, and no infusion-related adverse events or long-term side effects were observed. Based on the extremely limited experience with rituximab in childhood-onset SLE and the fact that both published studies lacked a control group, additional controlled studies are needed to establish the safety profile of rituximab when used in children with SLE.

Similar to the limited value of small uncontrolled case series to establish the safety of rituximab, these types of studies are also not well suited to evidence rituximab efficacy in childhood-onset SLE. In a study by Willems et al, 6 of 8 of the girls with SLE nephritis and both patients with autoimmune cytopenia experienced improvement of their disease symptoms with rituximab, which is referred to as “disease remission” by the authors, using definitions newly applied to children with SLE.12 Because subjects were treated with rituximab in combination with a plethora of other SLE medications and a control group was unavailable, it appears rather difficult to attribute any patient improvement to the use of rituximab only.

What is needed are larger controlled studies. Unfortunately, history is teaching us that clinical trials in children with SLE are difficult to conduct for a large array of reasons. Nonetheless, taking the easy route out of this problem by assuming that results of studies in adults also hold true in children with SLE may be too simple an answer. Despite similarities in the clinical features of adults and children with SLE, subtle immunologic differences between adults and children have long been recognized,13 and these differences may also be important when using rituximab treatment.

SLE is associated with disturbed peripheral blood B cell homeostasis, naïve lymphopenia, and an expansion in plasma cells in both adults and children with SLE.14, 15, 16 Although there is a positive correlation between disease activity and the levels of CD27high plasma cells in adults with SLE,17, 18 this appears not to hold true to the same extent in children with SLE.14, 15 In vivo, as part of the immune response to a pathogen, naïve B cells capable of binding antigen via their B cell receptor become activated, selected, and clonally expanded in germinal center reactions. Further differentiation into either memory B cells or plasma cells occurs in the germinal center. CD27 constitutes a useful B cell surface marker because it allows the identification of three major B cell subsets, namely naïve CD27− B cells, memory CD27+ B cells, and plasma cells CD27+++.19 Using the cell surface marker CD38 germinal center B cells can be distinguished.

Unique to children is an increased frequency of pre-germinal center (pre-GC) CD38++ B cells. In previous studies, response to rituximab with SLE paralleled the degree of B cell depletion in the patients. When studying factors involved with poor response to rituximab, Anolik et al found that adult SLE patients with a substantial expansion of circulating pre-GC CD38++ B cells at the beginning of rituximab therapy had either incomplete or transient B cell depletion with a relative increase of pre-GC CD38++ B cells after treatment.20 Thus, from a theoretical point of view, children with SLE with their expansion of pre-GC CD38++ B cells could also be relatively resistant to B cell depletion with rituximab. Given the immunologic differences between childhood-onset SLE and SLE in adults, it is possible that the therapeutic outcomes with rituximab are distinct between children and adults with SLE.

To date, the published literature on rituximab use in children with SLE is contradictory with regard to the safety of the drug. Rituximab may be effective in some patients when given in combination with other SLE medications. Like in adults, subgroups of children with SLE need to be identified who more likely will benefit from this not inexpensive therapy. Although case series and observational studies are undoubtedly important, high-quality clinical evidence from randomized clinical trials in SLE during childhood are essential for delineating the therapeutic potential of rituximab from the effects of concomitantly administered medications. Controlled clinical trials are the proper venue to establish pediatric dosing recommendations and are essential to provide trustworthy information for patients and physician regarding the safety of rituximab when used in children with SLE.

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References 

  1. Lipsky PE . Systemic lupus erythematosus (an autoimmune disease of B cell hyperactivity) . Nat Immunol . 2001;2:764–766
  2. Chan OT , Madaio MP , Shlomchik MJ . The central and multiple roles of B cells in lupus pathogenesis . Immunol Rev . 1999;169:107–121
  3. Reff ME , Carner K , Chambers KS , et al.   Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20 . Blood . 1994;83:435–445
  4. Stashenko P , Nadler LM , Hardy R , et al.   Characterization of a human B lymphocyte-specific antigen . J Immunol . 1980;125:1678–1685
  5. Shan D , Ledbetter JA , Press OW . Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells . Cancer Immunol Immunother . 2000;48:673–683
  6. Anolik JH , Campbell D , Felgar RE , et al.   The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus . Arthritis Rheum . 2003;48:455–459
  7. Sfikakis PP , Boletis JN , Tsokos GC . Rituximab anti-B-cell therapy in systemic lupus erythematosus (pointing to the future) . Curr Opin Rheumatol . 2005;17:550–557
  8. Leandro MJ , Edwards JC , Cambridge G , et al.   An open study of B lymphocyte depletion in systemic lupus erythematosus . Arthritis Rheum . 2002;46:2673–2677
  9. Looney RJ , Anolik JH , Campbell D , et al.   B cell depletion as a novel treatment for systemic lupus erythematosus (a phase I/II dose-escalation trial of rituximab) . Arthritis Rheum . 2004;50:2580–2589
  10. Sfikakis PP , Boletis JN , Lionaki S , et al.   Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand (an open-label trial) . Arthritis Rheum . 2005;52:501–513
  11. Marks SD , Patey S , Brogan PA , et al.   B lymphocyte depletion therapy in children with refractory systemic lupus erythematosus . Arthritis Rheum . 2005;52:3168–3174
  12. Willems M , Haddad E , Niaudet P , et al.   Rituximab therapy for childhood-onset systemic lupus erythematosus . J Pediatr . 2006; xxxx
  13. Janwityanujit S , Totemchokchyakarn K , Verasertniyom O , et al.   Age-related differences on clinical and immunological manifestations of SLE . Asian Pac J Allergy Immunol . 1995;13:145–149
  14. Arce E , Jackson DG , Gill MA , et al.   Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus . J Immunol . 2001;167:2361–2369
  15. Odendahl M , Keitzer R , Wahn U , et al.   Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus . Ann Rheum Dis . 2003;62:851–858
  16. Odendahl M , Jacobi A , Hansen A , et al.   Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus . J Immunol . 2000;165:5970–5979
  17. Jacobi AM , Odendahl M , Reiter K , et al.   Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus . Arthritis Rheum . 2003;48:1332–1342
  18. Dorner T , Lipsky PE . Correlation of circulating CD27high plasma cells and disease activity in systemic lupus erythematosus . Lupus . 2004;13:283–289
  19. Klein U , Rajewsky K , Kuppers R . Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes (CD27 as a general marker for somatically mutated (memory) B cells) . J Exp Med . 1998;188:1679–1689
  20. Anolik JH , Barnard J , Cappione A , et al.   Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus . Arthritis Rheum . 2004;50:3580–3590

PII: S0022-3476(06)00164-8

doi:10.1016/j.jpeds.2006.03.011

Refers to article:

  • Rituximab therapy for childhood-onset systemic lupus erythematosus

    M. Willems, E. Haddad, P. Niaudet, I. Koné-Paut, A. Bensman, P. Cochat, G. Deschênes, F. Fakhouri, T. Leblanc, B. Llanas, C. Loirat, P. Pillet, B. Ranchin, R. Salomon, T. Ulinski, Brigitte Bader-Meunier, French pediatric-onset SLE study group
    The Journal of Pediatrics May 2006 (Vol. 148, Issue 5, Pages 623-627.e3)

The Journal of Pediatrics
Volume 148, Issue 5 , Pages 571-573, May 2006

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