Christiane Pfeiffer

Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus

TREX1 acts in concert with the SET complex in granzyme A–mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 × 10−7). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.

A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus

We recently described a novel autosomal-dominant genodermatosis, termed familial chilblain lupus, and mapped its genetic locus to chromosome 3p21. Familial chilblain lupus manifests in early childhood with ulcerating acral skin lesions and is associated with arthralgias and circulating antinuclear antibodies. In this study, we report the identification of a heterozygous missense mutation (D18N) in TREX1 encoding the 3′-5′repair exonuclease 1 in affected individuals of the family with chilblain lupus. The homodimeric TREX1 is the most abundant intracellular DNase in mammalian cells. We have recently shown that TREX1 plays a role in apoptotic single-stranded DNA damage induced by the killer lymphocyte protease granzyme A. D18N affects a highly conserved amino acid residue critical for catalytic activity. Recombinant mutant TREX1 homodimers are enzymatically inactive, while wild type/mutant heterodimers show residual exonucleolytic activity, suggesting a heterozygous loss of function. Lymphoblastoid cells carrying the D18N mutation are significantly less sensitive to granzyme A-mediated cell death, suggesting a novel role for this caspase-independent form of apoptosis in the pathogenesis of familial chilblain lupus. Our findings also warrant further investigation of TREX1 in common forms of lupus erythematosus.

Comparison of patients with and without digital ulcers in systemic sclerosis: detection of possible risk factors.

Background  Digital ulcers (DU) are a major complication in the course of systemic sclerosis (SSc). In recent years, efficacious, but expensive therapies (e.g. iloprost, sildenafil, bosentan) have been shown to improve healing or to reduce the recurrence of DU. For optimal management it would be useful to identify the risk factors for DU. Such statistical analyses have been rare because they require a high number of patients.

Familial Chilblain Lupus, a Monogenic Form of Cutaneous Lupus Erythematosus, Maps to Chromosome 3p

Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish-red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased susceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism-based genomewide linkage analysis, the locus was mapped to chromosome 3p. Haplotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04. This is the first description of a monogenic form of cutaneous lupus erythematosus. Identification of the gene responsible for familial chilblain lupus may shed light on the pathogenesis of common forms of connective-tissue disease such as systemic lupus erythematosus.

Chilblain lupus erythematosus--a review of literature.

The name of one of the authors, Min Ae Lee-Kirsch, was inadvertently omitted. The full authorship of the article is as given above. Dr. Lee-Kirsch’s affiliation is as follows: (1) Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Dresden, University Hospital “Carl Gustav Carus”, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany Clin Rheumatol (2008) 27:1341 DOI 10.1007/s10067-008-0975-0

High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy

IntroductionIn systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents.MethodsData on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS).ResultsA total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose ≥ 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties.ConclusionsDespite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.

S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid.

(1) Department of Dermatology and Allergology, Philipps-Universität Marburg, Germany (2) Department of Dermatology, University Hospital Erlangen, Erlangen, Germany (3) Helios Hospital Wuppertal, Department of Dermatology, Allergology and Dermatosurgery, Wuppertal, Germany (4) Department of Dermatology and Venereology, University of Cologne (5) Department of Dermatology, Medical Center, University of Freiburg, Germany (6) Dermatologist in Private Practice, Fulda, Germany (7) Department of Dermatology and Allergology, University Hospital Ulm, Germany (8) Pediatric Immunology and Rheumatology, University Hospital and Outpatient Clinic for Pediatrics, Leipzig, Germany (9) Department of Dermatology, Allergology, and Venereology, Campus Luebeck, University Hospital Schleswig-Holstein (UKSH), Luebeck, Germany (10) Department of Dermatology, Venereology, and Allergology, University Hospital Wuerzburg, Wuerzburg, Germany (11) Division of Evidence-based Medicine (dEBM), Department of Dermatology, Charité University Hospital Berlin, Germany (12) Shire Deutschland GmbH, Berlin, Germany (13) Department of Dermatology and Venereology, University Hospital Munich (LMU), Munich, Germany (14) Allergy Center, Department of Dermatology, Charité University Hospital Berlin, Germany

CCL18 is expressed in patients with bullous pemphigoid and parallels disease course.

Background  The autoimmune skin disease bullous pemphigoid (BP) is characterized by subepidermal blister formation and a strong dermal infiltrate of mononuclear cells and eosinophils as well as a T‐helper (Th) 2‐dominated cytokine milieu. CCL18 is a chemokine, with unknown receptor counterpart, frequently associated with inflammatory Th2‐type responses.

Up-regulation of CCL11 and CCL26 is associated with activated eosinophils in bullous pemphigoid

Eosinophils contribute to the pathogenesis of bullous pemphigoid (BP) by secretion of proinflammatory cytokines and proteases. Trafficking of eosinophils into tissue in animal models and asthma depends on interleukin‐5 and a family of chemokines named eotaxins, comprising CCL11, CCL24 and CCL26. Up‐regulation of CCL11 has been described in BP, but the expression of the other two members of the eotaxin‐family, CCL24 and CCL26, has not been investigated. In addition to these chemokines, expression of adhesion molecules associated with eosinophil migration to the skin should be analysed. We demonstrate that similar to CCL11, the concentration of CCL26 was up‐regulated in serum and blister fluid of BP patients. In contrast, the concentration of CCL24 was not elevated in sera and blister fluid of the same BP patients. In lesional skin, CCL11 and CCL26 were detected in epidermis and dermis by immunohistochemistry. In contrast to CCL11, CCL26 was expressed strongly by endothelial cells. In line with these findings, eosinophils represented the dominating cell population in BP lesional skin outnumbering other leucocytes. The percentage of eosinophils expressing very late antigen (VLA): VLA‐4 (CD49d) and CD11c correlated with their quantity in tissue. Macrophage antigen (MAC)‐1 (CD11b/CD18) was expressed constitutively by tissue eosinophils. In conclusion, these data link the up‐regulation of the eosinophil chemotactic factor CCL26 in BP to the lesional accumulation of activated eosinophils in the skin. Thereby they broaden the understanding of BP pathogenesis and might indicate new options for therapeutic intervention.

Successful therapy of pemphigus vulgaris with immunoadsorption using the TheraSorb™ adsorber

Pemphigus vulgaris (PV) is caused by autoantibodies to desmogleins. Standard immunosuppressive therapy may be limited by concomitant diseases or ineffective.In these cases, removal of circulating antibodies by immunoadsorption can induce remission.