Julien Seneschal

Platelet CD154 Potentiates Interferon-α Secretion by Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus

In the autoimmune disease lupus, platelets activated by self-antigens contribute to pathology by triggering the secretion of interferon from immune cells. Taming the Big Bad Wolf Systemic lupus erythematosus (SLE)—a name some attribute to this disorder’s wolf-like ability to “devour” the affected organs—is an autoimmune inflammatory disease. It can affect virtually any part of the body, but often targets skin, kidney, and joints. A variety of immunological factors have been proposed to contribute to SLE, in particular the type I interferon (IFN) system, which is normally activated in response to viruses. Here, Duffau et al. point to platelets as the culprits in causing aberrant activation of IFN-α (a member of the type I IFN group) in lupus patients and suggest that a drug that blocks platelet activation could be a promising new treatment. A protein called CD154 (CD40 ligand) is found on T cells, where it helps to defend the body by activating cytotoxic immune cells during viral infections. It is also found on the surface of platelets that are activated for clotting and may contribute to the pathogenesis of inflammatory states such as atherosclerosis and autoimmune disorders, including SLE. Here, the authors collected platelets from patients experiencing SLE flare-ups of varying severity, as well as healthy controls, and demonstrated that CD154 abundance and shedding from platelets correlated with disease severity. Moreover, exposure of platelets from healthy donors to serum from patients with active SLE or to immune complexes similar to those in SLE patients triggered an increase in activation and CD154 production. These activated platelets, in turn, signaled to antigen-presenting cells to produce IFN-α, thus propagating an inflammatory cycle, both in vitro and in a murine model of lupus. To further test these ideas, Duffau et al. depleted the platelets in lupus-prone mice, which decreased inflammation in the animals’ kidneys, a commonly affected organ in lupus. They achieved a similar outcome by treating the mice with clopidogrel, an inhibitor of platelet activation already commonly used in patients with heart disease and stroke. In addition to experiencing less kidney damage, the clopidogrel-treated mice with lupus lived for an extra 3 months. The current mainstay of treatment for SLE is immunosuppressive therapy, achieved with steroids and chemotherapy-like medications. These drugs have numerous toxic effects, not the least of which is the immunosuppression itself, which predisposes patients to infections. Being able to treat lupus with an antiplatelet medication such as clopidogrel, which has few side effects, would markedly improve these patients’ safety and quality of life. A similar approach may prove useful in other autoimmune diseases such as rheumatoid arthritis, where it would also provide a badly needed alternative to immunosuppression. Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by the involvement of multiple organs and an immune response against nuclear components. Although its pathogenesis remains poorly understood, type I interferon (IFN) and CD40 ligand (CD154) are known to contribute. Because platelets are involved in inflammatory processes and represent a major reservoir of CD154, we hypothesized that they participate in SLE pathogenesis. Here, we have shown that in SLE patients, platelets were activated by circulating immune complexes composed of autoantibodies bound to self-antigens through an Fc-γ receptor IIa (CD32)–dependent mechanism. Further, platelet activation correlated with severity of the disease and activated platelets formed aggregates with antigen-presenting cells, including monocytes and plasmacytoid dendritic cells. In vitro, activated platelets enhanced IFN-α secretion by immune complex–stimulated plasmacytoid dendritic cells through a CD154-CD40 interaction. Finally, in lupus-prone mice, depletion of platelets or administration of the P2Y(12) receptor antagonist (clopidogrel) improved all measures of disease and overall survival; transfusion of activated platelets worsened the disease course. Together, these data identify platelet activation as an important contributor to SLE pathogenesis and suggest that this process and its sequelae may provide a new therapeutic target.

Cytokine imbalance with increased production of interferon-α in psoriasiform eruptions associated with antitumour necrosis factor-α treatments

Background  Psoriasiform eruptions occur in association with antitumour necrosis factor (TNF)‐α treatments in autoinflammatory diseases. The major reported clinical presentation is palmoplantar pustulosis, sometimes accompanied with plaque‐like psoriasis. In some reports, histological findings suggest psoriasis whereas others favour a lichenoid drug reaction. We present a case series with a comprehensive clinical, histopathological and immunohistochemical study.

Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study.

BACKGROUND & AIMS Although methotrexate (MTX) is used in the effective treatment of inflammatory disorders, its use is hampered by the risk of liver fibrosis. Non-invasive methods for the diagnosis of liver fibrosis, such as transient elastography (FibroScan) and FibroTest could be useful for monitoring MTX-liver toxicity. The aim of this case-control study was to determine factors associated with liver fibrosis in a large cohort of patients requiring MTX. METHODS Consecutive adults with various benign inflammatory diseases were prospectively assessed using FibroScan and FibroTest when they were treated with MTX (cases) or before beginning treatment (controls). RESULTS Among 518 included patients, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, factors associated with abnormal markers of liver fibrosis were the body mass index >28 kg/m(2) and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results. CONCLUSIONS Severe liver fibrosis is a rare event in patients treated with MTX and is probably unrelated to the total dose. Patients with other risk factors for liver disease should be closely monitored with non-invasive methods before and during MTX treatment.

Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse

In mouse and human skin, HIF-1α is constitutively expressed in the epidermis, mainly in the basal layer. HIF-1α has been shown to have crucial systemic functions: regulation of kidney erythropoietin production in mice with constitutive HIF-1α epidermal deletion, and hypervascularity following epidermal HIF-1α overexpression. However, its local role in keratinocyte physiology has not been clearly defined. To address the function of HIF-1α in the epidermis, we used the mouse model of HIF-1α knockout targeted to keratinocytes (K14-Cre/Hif1aflox/flox). These mice had a delayed skin phenotype characterized by skin atrophy and pruritic inflammation, partly mediated by basement membrane disturbances involving laminin-332 (Ln-332) and integrins. We also investigated the relevance of results of studies in mice to human skin using reconstructed epidermis and showed that HIF-1α knockdown in human keratinocytes impairs the formation of a viable reconstructed epidermis. A diminution of keratinocyte growth potential, following HIF-1α silencing, was associated with a decreased expression of Ln-322 and α6 integrin and β1 integrin. Overall, these results indicate a role of HIF-1α in skin homeostasis especially during epidermal aging.

Multivariate analysis of factors associated with early-onset segmental and nonsegmental vitiligo: a prospective observational study of 213 patients.

Background  Although mixed forms have been described recently, segmental (SV) and nonsegmental vitiligo (NSV) are considered as clinically distinct. However, limited epidemiological data are available to help distinguish associated factors, and recent genome‐wide association studies have been restricted to NSV. The higher prevalence of SV in children is helpful when comparing the two major presentations of the disease.

Psoriasiform drug eruptions under anti-TNF treatment of arthritis are not true psoriasis

Anti-tumour necrosis factor (TNF) agents are attrac-tive approaches to the treatment of auto-inflammatory disorders including psoriasis. Cutaneous side-effects resembling psoriasis or eczema have been reported, with various interpretations concerning a link with a true dermatological disorder, especially psoriasis (1–10). To clarify this issue, we report the detailed investigation of 8 patients with psoriasiform eruptions occurring during the administration of anti-TNF agents, including histopatho-logical and immunohistochemical patch-test studies. PATIENTS AND METHODS

Autoimmune thyroid disease in vitiligo: multivariate analysis indicates intricate pathomechanisms

Background  Vitiligo/nonsegmental vitiligo (NSV) is often associated with thyroid dysimmunity although very few reports have studied this association using multivariate logistic regression.

Halo naevi and leukotrichia are strong predictors of the passage to mixed vitiligo in a subgroup of segmental vitiligo.

Background  Until now, segmental vitiligo has been considered as a stable entity and mixed vitiligo, the association of segmental and nonsegmental vitiligo, has been reported rarely.

Pre‐ vs. post‐pubertal onset of vitiligo: multivariate analysis indicates atopic diathesis association in pre‐pubertal onset vitiligo

Background  Limited epidemiological data exist that compare clinical features of pre‐ and post‐pubertal nonsegmental vitiligo.

Interest of High-Dose Pulse Corticosteroid Therapy Combined with Methotrexate for Severe Alopecia Areata: A Retrospective Case Series

Background: The combination of systemic pulse corticosteroids and methotrexate in the treatment of severe alopecia areata has never been reported. Objective: The objective of this work was to give arguments for the efficacy and safety of this combined treatment. Methods: This was a retrospective case series of patients treated with intravenous 500 mg methylprednisolone per day for 3 consecutive days monthly during 3 months plus methotrexate initiated at the end of the second pulse regimen. We reviewed all case notes of patients who received this regimen between January 1 2007 and December 1 2010. Results: Twenty patients were treated. Data on hair regrowth at month 12 were available for all patients; 14 patients were still receiving the treatment on December 1 2010, 2 patients were lost of follow-up, and 4 patients had stopped the treatment. Of the 14 patients who were still receiving the treatment regimen at month 18, 10 (10/20, 50%) had total hair regrowth and 4 (4/20, 20%) had incomplete but satisfactory hair regrowth. The treatment was well tolerated. Conclusion: The initial treatment by pulse intravenous corticosteroids may influence the overall response. This approach should be evaluated in a larger series of patients.