Lupus (2014) 23, 1445–1446

LETTER TO THE EDITOR A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab – comments on article by Fredericks et al. Sir, Fredericks et al.1 reported the case of a 40-yearold female patient, suffering from moderately active systemic lupus erythematosus (SLE) treated with belimumab and mycophenolate-mofetil (MMF) for 10 months who died of opportunistic progressive multifocal leukoencephalopathy (PML). The authors stressed the consequential relationship between belimumab/MMF and PML occurrence. However, two inaccuracies could undermine this causal link. First, the attribution of the aetiological cause of low blood CD19 levels to the administration of belimumab/MMF therapy could be misleading. In fact, genetic deficiencies of CD19 expression (or its coordinated protein CD81) have been described2–5 which were reported in association with autoimmune diseases including SLE.2,3,6 In some cases alteration of CD19 B cells’ surface expression was even hypothesized to play a role in the pathogenesis of SLE.3,6,7 In the case reported by Fredericks et al.,1 CD19 blood count was not evaluated before therapy, therefore it is possible that the patient had a genetic deficiency of CD19 expression, which can promote opportunistic infections, such as PML in this patient.2,4,5 It is worthy to note that abnormalities in CD19 expression were found to affect transitional B cells,5 which are likely to be the most susceptible to belimumab treatment, therefore a congenital deficiency in CD19 levels would expose patients to an unexpectedly great decrease in transitional B cells. As a second shortcoming, the analogy between high risk of PML on belimumab and the immunodeficiency due to X-linked agammaglobulinaemia (XLA) syndrome or secondary to rituximab treatment does not seem to be appropriate. During XLA syndrome a complete agammaglobulinaemia and a deficiency of all B cell types (pro B cells, preB cells, immature, transitional, naı¨ ve, plasma cells

Correspondence to: Andrea Doria, Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128 PADOVA, Italy. Email: [email protected] Received 20 March 2014; accepted 8 July 2014

(PCs) and memory B cells) are found due to the early interruption of the B-cell receptor (BCR) intracellular signalling pathway.8 On the other hand, the targeting of CD20 on rituximab therapy may drive an extensive suppression of B cells either at immature, transitional, naı¨ ve or memory stage, while sparing pro-B, pre-B, bone marrow long-lived PCs, and to a lesser extent circulating PCs, thereby only partially affecting serum antibody levels.6 In addition, rituximab may provide a moderate depletion and skewing of T CD4 cells towards a suppressive phenotype, resulting in higher risk for opportunistic infections.9,10 Conversely, immunosuppression under belimumab therapy appears usually mild, since B lymphocyte stimulator (BLyS) targeted therapy can influence only a limited fraction of the B cell pool, that is, B lymphocytes at the transitional stage, naı¨ ve B cells and to some extent short-lived PCs, whereas memory B cells and longlived PCs would be spared. Hence, a complete depletion of CD19 cells as that observed in this patient would not be expected. In conclusion, no direct link can be drawn between belimumab administration and PML occurrence; however, since SLE patients are at higher risk of infections and may display an altered basal CD19 expression, a preliminary count of CD19 lymphocytes should be performed before the introduction of the biologic treatment.

Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.

Conflict of interest statement The authors have no conflicts of interest to declare.

References 1 Fredericks C, Kvam K, Bear J, Crabtree G, Josephson S. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus 2014 (in press). 2 van Zelm MC, Smet J, Adams B, et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest 2010; 120: 1265–1274. 3 Kuroki K, Tsuchiya N, Tsao BP, et al. Polymorphisms of human CD19 gene: Possible association with susceptibility to systemic lupus erythematosus in Japanese. Genes Immun 2002; 3(Suppl. 1): S21–S30.

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Letter to the Editor F Benvenuti et al.

1446 4 van Zelm MC, Reisli I, van der Burg M, et al. An antibodydeficiency syndrome due to mutations in the CD19 Gene. N Engl J Med 2006; 354: 1901–1912. 5 Artac H, Reisli I, Kara R, et al. B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele. Genes Immun 2010; 11: 523–530. 6 Mei HE, Schmidt S, Do¨rner T. Rationale of anti-CD19 immunotherapy: An option to target autoreactive plasma cells in autoimmunity. Arthritis Res Ther 2012; 14(Suppl. 5): S1. 7 Del Nagro CJ, Otero DC, Anzelon AN, Omori SA, Kolla RV, Rickert RC. CD19 function in central and peripheral B-cell development. Immunol Res 2005; 31: 119–131.

8 Notarangelo LD. Primary immunodeficiencies. J Allergy Clin Immunol 2010; 125: S182–S194. 9 Avivi I, Stroopinsky D, Katz T. Anti-CD20 monoclonal antibodies: Beyond B-cells. Blood Rev 2013; 27: 217–223. 10 Me´let J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: Association with clinical response. Arthritis Rheum 2013; 65: 2783–2790.

F Benvenuti, M Gatto and A Doria Division of Rheumatology, University of Padova, Italy

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A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab--comments on article by Fredericks et al.

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