Case 1C -

Kikuchi-Fujimoto Disease in the Setting of Systemic Lupus Erythematosus Cynthia M. Magro Weill Medical College of Cornell University New York, New York

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Case 1C: Kikuchi-Fujimoto Disease in the Setting of Systemic Lupus Erythematosus Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a subacute inflammatory disorder most often seen in young women with clinical and pathologic features suggestive of an infectious etiology. Among the features are fever, neutropenia and localized lymphadenopathy. Approximately 10% of patients develop a skin rash. The most commonly suspected infectious agents in KFD are the human herpesviruses EBV, HHV6, HHV7 and HHV8. However there are many citations which suggest an autoimmune based etiology whereby the condition may presage SLE, occur concurrently with SLE and or develop subsequent to the initial diagnosis of SLE. Case 1c - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1c - Figure 1a Case 1c - Figure 2 Case 1c - Figure 3a Case 1c - Figure 3b Case 1c - Figure 4a Case 1c - Figure 4b Case 1c - Figure 5 Case 1c - Figure 6a Case 1c - Figure 6b When one considers the phenotypic profile of LE it is not that difficult to understand how a cytokine milieu can be generated that could produce a morphologic and phenotypic profile indistinguishable from so called idiopathic or virally triggered KFD. There are clearly unique features of KFD that closely parallels known pathogenetic mechanisms in SLE and perhaps one could use the phenotypic profile which defines KFD as the more extreme expression of the distinctive phenotypic profile typical of SLE. In particular a very unique aspect of the condition is one of extensive CD8 T cell and CD123 positive plasmacytoid dendritic cell infiltration along with enhanced leukocyte apoptosis and engulfment of nuclear debris by scavenger CD68 and lysozyme positive histiocytes. The strong MXA expression reflects the interferon alpha rich microenvironment. Recent studies suggest that all apoptosis-associated genes, especially caspases, are upregulated, while apoptosis inhibitory genes, including bcl-2 by immunohistochemistry, are downregulated in KFD. As with TEN/SJS where excessive soluble Fas Ligand Fas interaction at the level of the keratinocyte is associated with extensive and progressive apoptosis, the serum soluble FAS ligand is also markedly elevated in patients with KFD, a point which will be discussed further. In a recent study we completed examining the phenotypic profile of biopsies procured from patients with classic features of dermatomyositis (DM), SLE, discoid lupus erythematosus(DLE) we found that biopsies of SLE were characterized by a dominance of CD8 lymphocytes in the dermis and within the epidermis with numerous CD123 plasmacytoid dendritic cells concentrated around vessels and at sites of interface dermatitis with MXA, the signature protein indicative of an interferon alpha rich microenvironment, being significantly expressed in the epidermis and amidst inflammatory cells. Hence one can view KFD in the setting of SLE as really at the polar end of the normal phenotypic profile of SLE. It is possible that in patients with KFD the apoptotic response is unusually marked and serves as a substrate to trigger the induction and growth of interferon elaborating plasmacytoid dendritic cells. The role of Fas ligand gene polymorphisms has not been explored in KFD although is known to occur in patients with SLE. In addition an additional gene polymorphism controlling interferon production may also play some role in the pathogenesis of KFD. Patients with SLE demonstrate an IFN gene expression "signature" characterized by strong overexpression of IFN-responsive genes in leukocytes and target tissues. One of the key genes of the IFN-alpha pathway, IRF5, was found to be strongly associated with SLE. Various functional single nucleotide gene polymorphisms leads to upregulation of interferon regulatory 5 expression the sequelae of which would be one of excessive interferon alpha production. A very specific interferon gene polymorphism has been identified which could be operational in some cases of KD. IRF5 encodes an IFN induced transcription factor. Polymorphism at SNP rs2004640 creates a novel splice site in exon B allowing the expression of a novel IRF5 isoform. A second mutation rs 10954213 creates a functional polyadenylation site and hence a shorter and more stable gene transcript. Type I interferons are typically produced in response to infection. Large amounts are produced by plasmacytoid dendritic cells stimulated by viral RNA and DNA through toll receptors 7 and 9 . In SLE it may also be triggered in response to nucleic acid antigens released from apoptotic cells. Type I inteferons exert many downstream effects on the immune system stimulating the Th1 pathways and sustain activated T cells and also lower the threshold for B cell activation through the B cell receptor and promote B cell survival and differentiation. Therefore in summarizing the events leading to KFD an antibody response directed at either virus in the setting of idiopathic KFD or nucleosome in the setting of SLE may be the inciting trigger. The CD8 cells could be responding to antigen or represent secondary effector cells via the mechanism of antibody dependent cellular immunity. The soluble fas Ligand produced by these sensitized CD8 T cells would then bind in a nonspecific manner to any cell expressing Fas which in the context of skin would include not only keratinocytes but lymphocytes and histiocytes leading to upregulation of casspases and cell death via the apoptotic pathway. The apoptosis would in turn stimulate plasmacytoid dendritic cells to proliferate and produce more interferon alpha which in turn would enhance the local cytotoxic CD8 and histiocytic immune response. Inherent gene polymorphisms in Fas Ligand and interferon alpha regulation could produce higher levels of these critical factors which are conducive in producing the apoptotic microenvironment that characterizes KFD. References: Kikuchi's Disease Paradela S, Lorenzo J, Martínez-Gómez W, Yebra-Pimentel T, Valbuena L, Fonseca E. Interface dermatitis in skin lesions of Kikuchi-Fujimoto's disease: a histopathological marker of evolution into systemic lupus erythematosus? Lupus. 2008;17(12):1127-35. Atwater AR, Longley BJ, Aughenbaugh WD. Kikuchi's disease: case report and systematic review of cutaneous and histopathologic presentations. J Am Acad Dermatol. 2008 Jul;59(1):130-6. Chen HC, Lai JH, Huang GS, Gao HW, Chen CH, Kuo SY, Chang DM. Systemic lupus erythematosus with simultaneous onset of Kikuchi-Fujimoto's disease complicated with antiphospholipid antibody syndrome: a case report and review of the literature. Rheumatol Int. 2005 May;25(4):303-6. Santana A, Lessa B, Galrão L, Lima I, Santiago M. Kikuchi-Fujimoto's disease associated with systemic lupus erythematosus: case report and review of the literature. Clin Rheumatol. 2005 Feb;24(1):60-3. Yen HR, Lin PY, Chuang WY, Chang ML, Chiu CH. Skin manifestations of Kikuchi-Fujimoto disease: case report and review. Eur J Pediatr. 2004 Apr;163(4-5):210-3. Dominguez DC, Torres ML, Antony S. Is human herpesvirus 6 linked to kikuchi-fujimoto disease? The importance of consistent molecular and serologic analysis. South Med J. 2003 Mar;96(3):226-33. Papaioannou G, Speletas M, Kaloutsi V, Pavlitou-Tsiontsi A. Histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) associated with antiphospholipid syndrome: case report and literature review. Ann Hematol. 2002 Dec;81(12):732-5. Epub 2002 Nov 14. Review. Thongsuksai P, Kayasut K. Histiocytic necrotizing lymphadenitis (Kikuchi's disease): clinicopathologic characteristics of 23 cases and literature review. J Med Assoc Thai. 1999 Aug;82(8):812-8. Review. Chen YH, Lan JL. Kikuchi disease in systemic lupus erythematosus: clinical features and literature review. J Microbiol Immunol Infect. 1998 Sep;31(3):187-92. Review.