Safety, pharmacokinetics and pharmacodynamics of a topical SYK inhibitor in cutaneous lupus erythematosus: A double-blind Phase Ib study.

The immunoregulator spleen tyrosine kinase (SYK) is upregulated in cutaneous lupus erythematosus (CLE). This double-blind, multicentre, Phase Ib study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of the selective SYK inhibitor GSK2646264 in active CLE lesions. Two lesions from each participant (n = 11) were each randomized to topical application of 1% (w/w) GSK2646264 or placebo for 28 days; all participants received GSK2646264 and placebo. The primary endpoint was safety and tolerability of GSK2646264, assessed by adverse event incidence and a skin tolerability test. Secondary endpoints included change from baseline in clinical activity and mRNA expression of interferon-related genes in skin biopsies. Levels of several immune cell markers were evaluated over time. Eight (73%) participants experienced ≥ 1 adverse event (all mild in intensity), and maximal dermal response was similar for GSK2646264 and placebo. The expression of several interferon-related genes, including CXCL10 and OAS1, showed modest decreases from baseline after 28 days of treatment with GSK2646264 compared with placebo. Similar findings were observed for CD3 + T cell and CD11c + dendritic cell levels; however, overall clinical activity remained unchanged with GSK2646264 vs. placebo. Further studies are warranted to assess SYK inhibitors as potential treatment for CLE.

Clinical and economic burden of organ damage among patients with systemic lupus erythematosus in a real-world setting in Germany.

BACKGROUND: Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease, carries high risk of organ damage and burden to healthcare systems. SLE disease modification aims to reduce disease activity with minimal treatment toxicity and preventing or minimizing organ damage development. This real-world study utilizing healthcare administrative claims data assessed organ damage development, associated costs and healthcare resource utilization (HCRU) in patients with SLE in Germany. METHODS: Claims data from January 1, 2007, to December 31, 2017, were obtained from the Betriebskrankenkassen German Sickness Fund Database. Adults (> 18 years) with a confirmed SLE diagnosis between January 1, 2009, and December 31, 2014, (inclusion period) were included. The index date was calculated based on the first recorded SLE diagnosis during this period. Patients were propensity score-matched (1:3) to a comparator cohort without SLE by age, sex, and comorbidities (Charlson comorbidity index). Organ damage was identified using an algorithm developed based on conditions described in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), using ICD-10-GM diagnostic codes, healthcare procedures, and/or treatments. RESULTS: 2121 patients with SLE and 6308 comparator patients were included (mean follow-up time: 6.4 years). Organ damage prevalence increased from 60.5% at baseline to 83.0% during 6 years of follow-up in all patients with SLE, while 17.0% of patients with SLE did not develop organ damage. Patients with newly confirmed SLE diagnosis without organ damage at baseline were nearly twice as likely to develop organ damage within 5 years versus the comparator cohort (52.0% vs. 27.0%). Total annual costs per patient-year for patients with SLE with organ damage were more than double those of patients with SLE without organ damage; both the number of inpatient admissions and length of stay were higher. CONCLUSIONS: The application of a recently developed algorithm allowed us to use claims data to elucidate SLE organ damage, and its associated high clinical and economic burden, in a large, representative sample in Germany. To our knowledge, this is the first European analysis of its kind involving a broad cohort of patients with SLE treated in the routine care setting.

First Real-World Insights into Belimumab Use and Outcomes in Routine Clinical Care of Systemic Lupus Erythematosus in Germany: Results from the OBSErve Germany Study.

OBSErve Germany was the first observational study of belimumab as add-on treatment for systemic lupus erythematosus (SLE) in routine clinical care in Germany, retrospectively collecting data from 102 SLE patients, 6 months before and after belimumab initiation. Most patients had moderate or severe SLE and several SLE manifestations. After 6 months of belimumab treatment, 78% of patients showed an improvement in overall disease activity of at least 20% in their physician's judgment and for 42% of patients the improvement was at least 50%. Similar results were observed for the most common manifestations: arthritis, fatigue, rash, alopecia, increased anti-dsDNA antibody levels, and low complement. The SLE Disease Activity Index (SLEDAI/SELENA-SLEDAI) decreased from 10.6 to 5.6 (n = 65), with other indices also showing improvement. A notable dose reduction was seen for concomitant oral corticosteroids, from 13.7 to 7.6 mg/day overall (n = 91), and from 17.5 to 8.6 mg/day in patients with a high corticosteroid dose at belimumab initiation (≥7.5 mg; n = 63). Six patients discontinued belimumab therapy within 6 months. Overall, belimumab showed promising results for SLE patients in real-world settings. After 6 months of belimumab treatment, disease activity and corticosteroid use were reduced. The discontinuation rate was low and belimumab appeared to be well tolerated. Funding GlaxoSmithKline UK.

Post-thrombotic syndrome 3 years after deep venous thrombosis in the Thrombosis and Pulmonary Embolism in Out-Patients (TULIPA) PLUS Registry.

BACKGROUND: Reported post-thrombotic syndrome (PTS) rates may be confounded by including patients with a history of deep venous thrombosis (DVT) before the index event, varicose veins, or chronic venous insufficiency independent of PTS. We were interested in assessing PTS incidence rates of patients without these pre-existing disease conditions. METHODS: A prospective registry with a 3-year follow-up after an initial DVT was assessed. Available for analysis were 135 ambulatory patients without a history of DVT (before the index DVT), signs of varicose veins, or chronic venous insufficiency affecting the ipsilateral or contralateral leg, and Villalta score. RESULTS: PTS was detected in 24.5% of patients, with 17.0% having mild (Villalta score, 5-9), 6.0% moderate (score, 10-14), and 1.5% severe PTS (score ≥15) after a first DVT. Of these, 52.6% had proximal and 47.4% distal DVT; 63.7% were provoked and 35.6% unprovoked (one patient missing). Patients with proximal DVT (32.4%) significantly more often developed any PTS compared with patients with distal DVT (15.6%; P = .024); however, groups were similar with regard to severity of PTS by the four-level Villalta score (P = .109). In univariate analysis, PTS was more frequent (odds ratio, 95% confidence interval) with higher age (1.06 per year; 1.02-1.09), a body mass index of 25 to 30 kg/m(2) (2.38; 0.71-7.97) and ≥30 kg/m(2) (6.08; 1.75-21.14), proximal vs distal DVT (2.59; 1.12-5.98), and calf swelling ≥3 cm larger than the asymptomatic leg (3.77; 1.66-8.55). In a multivariate analysis, age (1.05; 1.01-1.09) and calf swelling ≥3 cm larger than the asymptomatic leg (2.94; 1.20-7.20) remained predictive for PTS. Compression therapy was used by 78.5% of patients at the 1-year follow-up and by 46.7% at the 3-year follow-up. Both rates were higher in patients with PTS (93.9%) vs no PTS (66.7%). CONCLUSIONS: This prospective survey demonstrates a low rate of PTS in patients with a first DVT and no pre-existing DVT, varicose veins, or chronic venous insufficiency, and a high adherence rate to compression therapy, within the first 3 years of follow-up. Age and marked calf swelling were independent predictors of PTS.

Impact of gender on the clinical presentation and diagnosis of deep-vein thrombosis.

It is uncertain whether gender influences the clinical presentation of deep-vein thrombosis (DVT) and the discriminative value of the Wells diagnostic pretest probability score. The aim of the study was to determine whether gender impacts the clinical presentation and diagnosis of DVT. The study analysed a cohort of 4,976 outpatients with clinically suspected DVT of the leg prospectively recruited by 326 vascular medicine physicians in the German ambulatory care sector between October and December 2005. The diagnosis of DVT was based on compression ultrasonography in 96% of patients. Among 4,777 patients who had a diagnostic work-up for DVT there were more women (n=2,998) than men (n=1,779). However, the prevalence of confirmed DVT was 37.0% (658/1779) in men vs. 24.3% (730/2,998) in women (p<0.001). Among patients with confirmed DVT, proximal DVT was more common in men (59.6% vs. 44.5% in women, p<0.001). Swelling of the leg, pitting oedema and dilated superficial veins were more frequently reported by men (p<0.001). The percentage of patients with a high probability Wells clinical pretest score was higher in men than in women (67.0% vs. 57.0%, p<0.001). However, overall, the score equally discriminated risk groups for DVT in both sexes. In conclusion, women were more frequently referred for a diagnostic work-up for DVT than men, but the prevalence of DVT was higher in men and their thrombotic events were more severe. Nevertheless, the Wells clinical pretest probability score correctly identified low- and high-risk groups in both genders.

Diagnosis of deep-vein thrombosis: adherence to guidelines and outcomes in real-world health care.

Current guidelines recommend optimised algorithms for diagnosis of suspected deep-vein thrombosis (DVT). There is little data to determine to what extent real-world health care adheres to guidelines, and which outcome in terms of diagnostic efficiency and safety is achieved. This registry involved patients with clinically suspected DVT of the leg recruited in German ambulatory care between October and December 2005. Registry items were: diagnostic methods applied, diagnostic categories at day 1, and venous thromboembolic events up to 90 days in patients without firmly established DVT. A total of 4,976 patients were recruited in 326 centres. Venous ultrasonography was performed in 4,770 patients (96%), D-dimer assay in 1,773 patients (36%) and venography in 288 patients (6%). At day 1, DVT was confirmed in 1,388 patients (28%), and ruled out in 3,389 patients (68%), and work-up was inconclusive in 199 patients (4%). The rate of venous thromboembolism at 90 days was 0.34% (95% confidence interval [CI]: 0.09 to 0.88) in patients in whom the diagnosis of DVT had been ruled out, and 2.50% (95% CI: 0.69 to 6.28) in patients with inconclusive diagnostic workup. This nationwide evaluation in German ambulatory care revealed that the diagnostic work-up for suspected DVT did not adhere to current guidelines. However, the overall diagnostic safety was excellent, although there is potential for improvement in a well defined minority of patients.