This study examines the differences which may distinguish systemic lupus erythematosus (SLE) presenting in adult life or childhood. A common database was established, with analysis of clinical, serological and outcome features of a cohort of patients with SLE, with disease diagnosed before the age of 16 (n = 39) or after the age of 16 (n = 165). Disease onset was generally more severe in the childhood-onset patients. Cardiopulmonary disease was more common in the older-onset group, but major haematological manifestations were more frequent in the childhood-onset group. Serologically, anti-DNA, anti-Sm and anti-RNP antibodies and a low C3 were all found more frequently in the younger patients. Twice as many adult-onset cases had died at the time of the last follow-up (10 vs 5%), but this group had been followed for a longer period (average 7.5 yr, S.D. 3.9 for adults vs average 4.8 yr, S.D. 3.2 for children). However, the younger patients were twice as likely (82 vs 40%) to require high-dose prednisone, although the requirement for immunosuppressive agents was similar in the two groups. Clinicians should anticipate that children with SLE have a more severe disease onset than adults in general.

Coronavirus disease 2019 (COVID‐19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID‐19 antivirals are needed urgently. Nirmatrelvir (PF‐07321332), the first orally bioavailable, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) M pro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double‐blind, placebo‐controlled, phase I study. Two interleaving single‐ascending dose (SAD) cohorts were evaluated in a three‐period crossover. Multiple‐ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well‐tolerated. Nirmatrelvir exposure and half‐life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro . The QSP model suggested that a 5‐day regimen would significantly decrease viral load in SARS‐CoV‐2‐infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation (NCT04756531).

Objective. To determine the relationship between persistently raised anticardiolipin antibody (aCL) levels and neuropsychological performance in patients with systemic lupus erythematosus (SLE). Methods. Forty-five patients with SLE underwent a detailed neuropsychological assessment on 2 occasions 12-18 months apart. Serum samples stored since the time of previous assessments as well as samples obtained 6 months to 2 years before the first neuropsy-chological assessment were tested for IgG aCL levels. Patients were divided into 4 groups according to the number of times their aCL levels were elevated (never, once, twice, 3 times). A wide-ranging battery of new neuropsychological tests was utilized, and the results were compared with double-stranded DNA (dsDNA) antibody levels, C3 levels, and results of magnetic resonance imaging (MRI). Results. Analysis of variance revealed that the group with persistently elevated aCL levels performed less well than the other groups. At the first neuropsy-chological assessment, poorer performance by this group was noted for letter cancellation (P 0.02), trail making task B (P 0.04), and digit span (P 0.03). At the second assessment, letter cancellation (P 0.01), trail making task A (P 0.03), trail making task B (P 0.01), word fluency (P 0.01), and reaction time (P 0.05) were impaired. In contrast, no significant differences in neuropsychological test results were identified with respect to DNA antibody or C3 levels. MRI abnormalities were associated with both persistent elevation of aCL levels and low C3 levels. Conclusion. Levels of IgG aCL that were persistently elevated over a 2-3-year period (as opposed to never or occasionally elevated) were associated with significantly poorer performance in cognitive function by patients with SLE. Tasks requiring speed of attention and concentration appear to be particularly affected. The presence of antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE) correlates strongly with a history of thromboem-bolic complications and a variety of neurologic syndromes (1). A broad spectrum of cerebrovascular manifestations ranging from transient ischemic attacks, chorea, recurrent strokes, and multi-infarct dementia has been described (2). Studies that have used magnetic resonance imaging (MRI) of the brains of patients with aPL suggest that the associated neurologic damage is focal, does not resolve with steroid treatment, and may well be irreversible (3,4). A broader picture of any possible link between patients' neurologic status and the presence of aPL can also be obtained by examining their neuropsychological status, which can serve as an indicator of neurologic problems that have no obvious, or specific, structural component. Neuropsychological assessment examines the performance of individuals on a range of tests that evaluate different areas of cognition, such as attention, memory, and language function. The tests have been found to be sensitive in detecting mild cerebral dysfunc-tion and have been widely appl...

These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.