Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions.
BackgroundUpadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis (PsA). We evaluated upadacitinib in patients with PsA and prior inadequate response or intolerance to at least one biologic disease-modifying antirheumatic drug (DMARD).MethodsIn this 24-week randomised, placebo-controlled, double-blind, phase 3 trial, 642 patients were randomised (2:2:1:1) to once per day upadacitinib 15 mg or 30 mg, placebo followed by upadacitinib 15 mg or placebo followed by upadacitinib 30 mg at week 24. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 12. Achievement of minimal disease activity (MDA) was assessed at week 24. Treatment-emergent adverse events are reported for all patients who received at least one dose of trial drug.ResultsAt week 12, significantly more patients receiving upadacitinib 15 mg and 30 mg versus placebo achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1%) and 30 mg-treated patients (28.9%) versus placebo (2.8%; p<0.001 for both comparisons). Generally, the rates of treatment-emergent adverse events were similar with placebo and upadacitinib 15 mg and higher with upadacitinib 30 mg at week 24. Rates of serious infections were 0.5%, 0.5% and 2.8% with placebo, upadacitinib 15 mg and upadacitinib 30 mg, respectively.ConclusionIn this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA.Clinical trial registration numberNCT03104374
Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.
Complement activation plays a key role in the pathogenesis of lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE). We prospectively evaluated 15 LN subjects and two control groups: 13 non-SLE renal subjects (control A) and 239 SLE subjects without LN (control B). All had C4d levels on circulating erythrocytes (E-C4d), reticulocytes (R-C4d) and platelets (P-C4d) measured by flow cytometry, while C4d deposition in renal tissue was semiquantitatively assessed in LN subjects and control A using immunoperoxidase staining. Compared with control A, LN biopsies had higher glomerular-C4d scores (p = 0.003), which were associated with more frequent granular glomerular immunofluorescence staining and electron dense deposits (p < 0.001). Compared with control A and B groups, LN subjects had higher E-C4d (p = 0.002 and p = 0.005) and R-C4d levels (p = 0.002 and p = 0.008), respectively. LN subjects were more likely to have P-C4d compared with control A (p = 0.016). In LN, only E-C4d correlated with National Institutes of Health (NIH) activity index (r = 0.55, p = 0.04). In conclusion, LN biopsies showed frequent glomerular-C4d staining associated with immune complex deposits. LN subjects had higher E-C4d and R-C4d levels compared with both control groups. E-C4d levels also correlated with NIH activity index. These findings suggest a potential role of C4d on circulating cells as a biomarker for lupus nephritis.
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