Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial.

BACKGROUND: Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation in lower extremities, which results in skin infarctions with painful ulcerations and irreversible scar formation. Rivaroxaban is a direct factor Xa inhibitor that prevents thrombus formation. We investigated whether rivaroxaban is effective for the treatment of livedoid vasculopathy. METHODS: We did this single-arm, open-label, multicenter, phase 2a, proof-of concept trial at three university hospitals in Germany. Patients with livedoid vasculopathy and a minimum pain score of 40 on the visual analogue scale were eligible to participate. Patients received oral rivaroxaban tablets for 12 weeks at an initial dose of 10 mg twice per day, which was reduced to once per day if a reduction of pain by 50% on the visual analogue scale was achieved. Subcutaneous enoxaparin at 1 mg per kg bodyweight once or twice per day was allowed as a backup treatment in case of insufficient efficacy and increased pain. The primary endpoint was change in pain on the visual analogue scale from baseline to 12 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EudraCT number 2012-000108-13-DE, and is closed to new participants. FINDINGS: Between Dec 28, 2012, and April 24, 2014, 36 patients were screened, 28 patients were recruited for the study, and 25 patients received treatment. During treatment, five patients dropped out of the study because of withdrawal of consent (one patient), lack of compliance (one patient), violation of inclusion criteria (two patients), and a serious adverse event (one patient). Median pain on the visual analogue scale decreased from 65·0 (IQR 52·0-78·0) at baseline to 6·0 (1·0-14·0) after 12 weeks of treatment (p<0·0001). Six of the 20 patients required additional treatment with enoxaparin. Eight treatment-related adverse events were recorded in six (24%) of the 25 patients: five cases of menorrhagia including one classified as both menorrhagia and dysmenorrhoea, one case of dyspnoea, and one case of gingival bleeding. The only serious adverse reaction to rivaroxaban during the study was one case of menorrhagia in a patient with concomitant endometriosis, which resulted in study discontinuation. INTERPRETATION: Rivaroxaban seems to effectively reduce pain in livedoid vasculopathy. Therefore we suggest that rivaroxaban with enoxaparin as a backup treatment is a suitable treatment option for patients with livedoid vasculopathy. FUNDING: Deutsche Forschungsgemeinschaft and Bayer Vital.

Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity.

OBJECTIVE: Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity. METHODS: Effects of UVB light were analyzed in a murine model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing-remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of the peripheral blood. RESULTS: Regulatory T cells (Tregs), which are induced locally in the skin-draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg-inducing tolerogenic dendritic cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation, because ablation of Langerhans cells abolished the UVB-induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D. INTERPRETATION: Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin-derived tolerogenic DCs and Tregs. Our data could have implications for the understanding or therapeutic modulation of environmental factors that influence immune tolerance.