Cutaneous Vasculitis and Recurrent Infection Caused by Deficiency in Complement Factor I.

Cutaneous leukocytoclastic vasculitis arises from immune complex deposition and dysregulated complement activation in small blood vessels. There are many causes, including dysregulated host response to infection, drug reactions, and various autoimmune conditions. It is increasingly recognised that some monogenic autoinflammatory diseases cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of consanguineous parents who presented with chronic cutaneous leukocytoclastic vasculitis, recurrent upper respiratory tract infection, and hypocomplementaemia. A homozygous p.His380Arg mutation in the complement factor I (CFI) gene CFI was identified as the cause, resulting in complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum factor I, C3, and factor H. C4 and C2 levels were normal. The same homozygous mutation and immunological defects were also identified in an asymptomatic sibling. CFI deficiency is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4.

Enfermedades autoinflamatorias en dermatología pediátrica. Parte 2: síndromes histiocítico-macrofágicos y síndromes vasculopáticos / Autoinflammatory diseases in pediatric dermatology-part 2: histiocytic, macrophage activation, and vasculitis syndromes

El descubrimiento de nuevos síndromes autoinflamatorios y nuevas mutaciones está avanzando a una velocidad vertiginosa en los últimos años. La segunda parte de la revisión está centrada en el estudio de los síndromes histiocítico-macrofágicos y de los síndromes vasculopáticos, incluyendo al final del texto una tabla con las alternativas terapéuticas de estos síndromes autoinflamatorios y sus mutaciones genéticas (AU)

The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives (AU)

Do HLA-A markers predict skin-reactions from aromatic antiepileptic drugs in a Norwegian population? A case control study.

PURPOSE: Cutaneous adverse reactions (cADRs) from carbamazepine (CBZ) have been associated with human leukocyte antigens (HLA). Our aims were to assess the clinical usefulness of HLA-A*31:01 as a predictor of CBZ-induced cADRs in the Norwegian population and to explore whether cADRs from aromatic antiepileptic drugs (AEDs) in general might be linked with a common HLA-A-marker. MATERIALS AND METHODS: 86 ethnic Norwegians with a history of non-bullous cADRs from aromatic AEDs were included. 114 subjects tolerant to at least one aromatic AED were used as drug-specific controls. Complete HLA-A genotyping was performed. 1026 blood donors were used as population controls. RESULTS: Comparing all cADR subjects with controls and blood donors, there were no statistical differences for any HLA-A allele, except for HLA-A*24 (p=0.022 vs. controls and p=0.014 vs. blood donors). When comparing tolerant controls with patients having had a cADR to one of the two most used drugs, CBZ (n=48) and lamotrigine (n=28), we found no significant associations for CBZ to HLA-A*31:01 or HLA-A*24:02, but for lamotrigine there was an association with HLA-A*24:02 (p=0.027). In patients developing cross-reactivity (n=14) to aromatic AEDs, the presence of HLA-A*31:01 or HLA-A*24:02 was not different compared to patients with a single cARD tolerant to at least one other drug. CONCLUSION: We question the clinical usefulness of HLA-A*31:01 as a marker for CBZ rash in the Norwegian population. A previously suggested protective effect of aromatic AED cross-reactivity from HLA-A*24:02 was not confirmed. The association between HLA-A*24:02 and lamotrigine-induced rash should be further investigated.

Novel CFI mutation in a patient with leukocytoclastic vasculitis may redefine the clinical spectrum of Complement Factor I deficiency.

Factor I is an important regulator of the complement system. Lack of Factor I causes uncontrolled activation of the complement system leading to consumption of C3. Complete deficiency of Factor I is a rare condition and only around 40 cases has been reported in the literature. The clinical presentation of Factor I deficiency varies and includes severe recurrent bacterial infections, glomerulonephritis and autoimmune diseases. The patient, a 28-years old woman with consanguineous parents, presented with recurrent leukocytoclastic vasculitis in the lower extremities with no associated systemic involvement, and without increased infection tendency. Initial testing showed low C3 concentration and a detailed complement evaluation absence of complement Factor I. Sequencing revealed a homozygous missense mutation in exon 2 of the CFI gene (SCV000221312). Even though the clinical symptoms of CFI mutations vary among patients sole association with leukocytoclastic vasculitis redefines the clinical spectrum of complete Factor I deficiency.

Cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis in a child with interleukin-12 receptor beta-1 deficiency.

Defects in the interleukin 12 (IL-12)/interferon gamma (IFN-γ) pathway result in Mendelian susceptibility to mycobacterial disease (MSMD). IL-12 receptor beta 1 (IL-12Rß1) deficiency, the most common form of MSMD, is associated with weakly virulent mycobacteria and salmonella. Infections in patients with this deficiency are extraintestinal, or septicemic, recurrent infections with nontyphoid salmonellae. Here we report a case of an IL-12Rß1 deficiency with cutaneous leukocytoclastic vasculitis due to Salmonella enteritidis.

TWEAK enhances E-selectin and ICAM-1 expression, and may contribute to the development of cutaneous vasculitis.

Our previous work indicated that TWEAK is associated with various types of cutaneous vasculitis (CV). Herein, we investigate the effects of TWEAK on vascular injury and adhesion molecule expression in CV mice. We showed that TWEAK priming in mice induced a local CV. Furthermore, TWEAK priming also increased the extravasation of FITC-BSA, myeloperoxidase activity and the expression of E-selectin and ICAM-1. Conversely, TWEAK blockade ameliorated the LPS-induced vascular damage, leukocyte infiltrates and adhesion molecules expression in LPS-induced CV. In addition, TWEAK treatment of HDMECs up-regulated E-selectin and ICAM-1 expression at both mRNA and protein levels. TWEAK also enhanced the adhesion of PMNs to HDMECs. Finally, western blot data revealed that TWEAK can induce phosphorylation of p38, JNK and ERK in HDMECs. These data suggest that TWEAK acted as an inducer of E-selectin and ICAM-1 expression in CV mice and HDMECs, may contribute to the development of CV.

Hypocomplementemic urticarial vasculitis syndrome in three siblings.

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is relatively uncommon and generally seen in the fourth decade of life. There are very few pediatric cases with the diagnosis of HUVS in the literature. In this report, we describe the first familial cases of HUVS in three siblings. The disease onset was during childhood period in all patients. One of them developed severe renal involvement and died. The other two had ongoing skin and eye manifestations and the elder one developed lupus. Presence of these three patients is a strong evidence for the role of genetic factors in the pathogenesis of this rare vasculitis.

Genetic polymorphism of the growth arrest-specific 6 gene is associated with cutaneous vasculitis in Taiwanese patients with systemic lupus erythematosus.

The growth arrest-specific 6 (GAS6) gene product participates in platelet activation and granulocyte interaction with the endothelium. Our case-control study aimed to determine whether polymorphism of GAS6 was associated with predisposing risk or specific clinical manifestations of systemic lupus erythematosus (SLE). Two of the single-nucleotide polymorphisms (SNPs) of the GAS6 gene, GAS6 834 + 7G/A (rs8191974) and GAS6 +1332C/T (rs1803628), were investigated in 83 SLE patients and 89 non-lupus control subjects. We demonstrated that among lupus patients, the GAS6 +1332 T allele was more prevalent in patients with cutaneous vasculitis (allele T 41.7 % in patients with cutaneous vasculitis compared with 18.3 % in patients without vasculitis, odds ratio (OR) 3.2, 95 % confidence interval 1.3-8.0, p = 0.016). In conclusion, GAS6 polymorphism is positively associated with cutaneous vasculitis in SLE patients, which suggests that GAS6 polymorphism could be a genetic marker for SLE with cutaneous vasculitis.

Hypocomplementemic urticarial vasculitis syndrome is associated with high levels of serum IgG4: a clinical manifestation that mimics IgG4-related disease.

A 58-year-old Japanese woman presented with recurrent abdominal pain, chronic urticaria, and petechiae on her extremities, and hypocomplementemia, findings that were consistent with hypocomplementemic urticarial vasculitis syndrome (HUVS). A laboratory examination revealed that she had markedly elevated IgG levels (4,448 mg/dL; normal range, 870-1,700 mg/dL) with particularly high IgG4 levels (1,050 mg/dL; normal range, 48-105 mg/dL) and a high IgG4/total IgG ratio (0.22; normal range, 0.02-0.05). A skin biopsy demonstrated leukocytoclastic vasculitis with IgG4 deposition in the vascular lumen and vascular walls. A lymph node biopsy revealed reactive lymphoid hyperplasia with numerous IgG4-positive cells in the perifollicular area, but no sclerotic findings. A chromosomal analysis of an enlarged lymph node, without phytohemagglutinin (PHA) stimulation, demonstrated that one in every three analyzed cells had abnormalities, such as 44, XX, -13, add(15)(p11), -17, -17, and mar.

Lack of association between macrophage migration inhibitory factor gene (-173 G/C) polymorphism and cutaneous vasculitis.

OBJECTIVE: To assess whether polymorphism of the macrophage migration inhibitory factor (MIF) gene at position -173 was implicated in the incidence of Henoch-Schönlein purpura (HSP) and cutaneous leukocytoclastic angiitis (CLA). A further objective was to determine if any relationship existed with severe systemic complications of HSP, in particular with severe renal involvement and permanent renal dysfunction. METHODS: Unselected patients from Northwest Spain with primary cutaneous vasculitis classified as HSP or hypersensitivity vasculitis (HV) according to proposed criteria were studied. Patients with HV were included in this study if they fulfilled the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis definitions for CLA. Patients and controls were genotyped for a single nucleotide polymorphism (SNP) in the 5'-flanking region at position -173 of the MIF gene, using SNapshot ddNTP primer extension, followed by capillary electrophoresis (ABI 3100). RESULTS: Ninety-five Caucasian patients (57 classified as having HSP and 38 who fulfilled definitions for CLA) and 122 healthy controls were studied. No allele or genotype differences between the whole group of HSP or CLA patients and controls were observed. This was also the case when HSP patients were stratified by the presence of gastrointestinal complications, nephritis, and permanent renal involvement (renal sequelae). CONCLUSION: The polymorphism in MIF gene promoter (-173 G/C) does not appear to be genetic risk factors for cutaneous vasculitis in Northwest Spain.

A transgenic mouse model of autoimmune glomerulonephritis and necrotizing arteritis associated with cryoglobulinemia.

Mice implanted with hybridoma secreting 6-19 IgG3 anti-IgG2a rheumatoid factor (RF) with cryoglobulin activity develop acute glomerulonephritis and cutaneous leukocytoclastic vasculitis. As the RF activity is implicated in the skin, but not glomerular lesions, it is still unclear whether the renal pathogenicity is determined by 6-19 H chains alone or their combination with L chains. To address this question, we have generated transgenic mice expressing only the H chain gene or both H and L chain genes of the 6-19 IgG3 anti-IgG2a RF and determined the development of glomerular and vascular lesions. H-single and H/L-double transgenic mice displayed comparable high amounts of IgG3 cryoglobulins, but only H/L-double transgenic mice having 10-fold higher levels of IgG3 anti-IgG2a RF progressively developed chronic, lethal glomerulonephritis. The severe glomerular lesions observed at 8-10 mo of age were very heterogeneous (membranoproliferative changes, crescents, and sclerosis); in addition, one-third of them had necrotizing arteritis in the kidneys and skeletal muscles. These renal and vascular changes were very different from those observed in the acute cryoglobulinemia, characterized by mainly "wire-loop" glomerular lesions and a cutaneous leukocytoclastic form of vasculitis. Thus, our data demonstrate the importance of a unique combination of the H and L chains for the expression of the pathogenic activity of IgG3 cryoglobulins and that a single autoantibody is able to induce different types of glomerular and vascular complications, depending on its production levels and kinetics.

Interleukin 1 receptor antagonist gene polymorphism is associated with severe renal involvement and renal sequelae in Henoch-Schönlein purpura.

OBJECTIVE: To assess the influence of interleukin 1 receptor antagonist gene polymorphism (IL1RN) in the incidence of Henoch-Schönlein purpura (HSP) and cutaneous leukocytoclastic angiitis (CLA) and to determine if implications exist with severe systemic complications of HSP, in particular with severe renal involvement and permanent renal dysfunction (renal sequelae). METHODS: Patients from Northwest Spain with primary cutaneous vasculitis classified as HSP or hypersensitivity vasculitis (HV) according to proposed criteria were studied. Patients with HV were included if they had a biopsy proven small size blood vessel leukocytoclastic vasculitis limited to skin and also fulfilled the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis definitions for CLA. All patients were required to have had at least 2 years' followup. Patients and ethnically matched controls were genotyped for IL-1 receptor antagonist intron 2 VNTR polymorphism. RESULTS: We examined 96 Caucasian patients (58 HSP and 38 CLA) and 109 controls. No allele or genotype differences between the whole group of HSP or CLA patients and controls were observed. We found a significant association between carriage of IL-1 receptor antagonist allele 2 (ILRN*2) and severe renal involvement, manifested as nephrotic syndrome and/or renal insufficiency (p = 0.016), and permanent renal involvement (renal sequelae) (p = 0.012). CONCLUSION: In unselected patients with cutaneous vasculitis, carriage of ILRN*2 alleles influences disease severity rather than susceptibility.

Henoch-Schönlein purpura and cutaneous leukocytoclastic angiitis exhibit different HLA-DRB1 associations.

OBJECTIVE: To examine the HLA-DRB1 genotype of patients with cutaneous leukocytoclastic angiitis (CLA), a small-sized blood vessel vasculitis limited to skin, and determine if differences exist with Henoch-Schönlein purpura (HSP), a small-sized blood vessel vasculitis with cutaneous and systemic complications. METHODS: A retrospective study was performed on an unselected population of patients from Northwest Spain with primary cutaneous vasculitis classified according to proposed criteria. Patients who fulfilled classification criteria for hypersensitivity vasculitis were included in this study if they had a biopsy proven leukocytoclastic vasculitis limited to skin and, due to this, they also met the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis definitions for CLA. Patients were included in this study if they had at least 2 years' followup. We studied 96 Caucasian patients (58 HSP, 38 CLA). Patients and ethnically matched controls (n = 145) were HLA-DRB1 genotyped from DNA using molecular based methods. RESULTS: No HLA-DRB1 genotype differences between patients with CLA and controls were seen. HLA-DRB1*01 was increased and HLA-DRB1*07 reduced in HSP patients compared to controls. When HLA-DRB1 genotypes of patients with CLA and HSP were compared a significant increase of HLA-DRB1*15/16 and especially of HLA-DRB1*07 was observed in the patients fulfilling definitions for CLA compared to those with HSP. CONCLUSION: HSP and CLA exhibit different HLA-DRB1 genotype associations.

MCP-1 promoter polymorphism in Spanish patients with systemic lupus erythematosus.

The possible role of the functional polymorphism located in the regulatory region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to systemic lupus erythematosus (SLE) was investigated. Two hundred and seventy-six SLE patients (among them, 99 with lupus nephritis and 55 with cutaneous vasculitis) and 194 ethnically matched healthy controls were included in the study. Genotyping for -2518 (A/G) MCP-1 gene polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to SLE nor to lupus nephritis was found. However, a significant increase in the frequency of genotype AG and a decrease in the frequency of genotype AA were found among patients with cutaneous vasculitis (51% of AG vs. 32% in individuals without cutaneous vasculitis; P=0.008, OR=2.2, 95% CI: 1.18-4.25; and 47% of AA vs. 64%; P=0.03, OR=0.5, 95% CI: 0.27-0.96, respectively). These results indicate an association between the presence of G at position -2518 in the MCP-1 promoter region and the presence of cutaneous vasculitis among patients with SLE. This polymorphism does not seem to influence the susceptibility to SLE nor the appearance of lupus nephritis. Further studies are necessary in order to elucidate the role of this polymorphism in the pathogenesis of other inflammatory autoimmune diseases.

The time course and characterization of mercuric chloride-induced immunopathology in the brown Norway rat.

Mercuric chloride (HgCl2) induces an autoimmune syndrome in the Brown Norway (BN) rat which includes widespread tissue injury. There is necrotizing leucocytoclastic vasculitis in the gut with maximal injury occurring 2 weeks after the start of HgCl2 injections. There is evidence that disease is driven by Th2-like cell (CD4+CD45RClow) activity and that Th1-like cells (CD4+CD45RChigh) may be protective. Using the established protocol of five injections of HgCl2 over 10 days, we have studied in greater detail the presence and extent of vasculitis and changes in T cell subsets from 12 h to 20 days after the first injection. Animals were killed at various time points and necropsies performed. Tissue injury was scored both macroscopically and histologically, with immunohistochemistry for T cell subsets. Flow cytometry was used to determine T cell subsets in peripheral blood, mesenteric lymph node (LN) and spleen. Tissue injury was seen as early as 24 h after the first injection of HgCl2. The size of lesions and extent of vasculitis increased over the next two weeks with partial resolution at day 20. We confirmed that of peripheral blood T cells in the BN rat, less than 20% were CD8+ and a similar proportion were CD4+CD45RChigh, but found that less than 75% of CD8+ T cells were CD45RChigh (in other strains of rat more than 90% CD8+ T cells are CD45RChigh). Within 48 h, HgCl2 caused a rise in the proportion of CD4+ T cells in spleen, LN and peripheral blood which then fell towards normal at peak tissue injury. The proportion of CD4+CD45RClow T cells rose in the first week, but subsequently fell, with reciprocal changes in CD4+CD45RChigh T cells. There was an increase in CD8+ T cells towards peak disease. The speed of onset of tissue injury suggests that cells other than T cells may be involved in the primary induction of vasculitis, although Th2-like cells may be important in further tissue injury and in B cell activation. The rise in CD8+ and Th1-like cells towards peak disease supports the hypothesis that they are involved in disease regulation.