Treatment for giant cell arteritis with 8 weeks of prednisone in combination with tocilizumab: a single-arm, open-label, proof-of-concept study.

BACKGROUND: Even after the approval of tocilizumab, substantial glucocorticoid exposure (usually ≥6 months) and toxicity continue to be important problems for patients with giant cell arteritis. We aimed to assess the outcomes of a group of patients with giant cell arteritis treated with tocilizumab in combination with 8 weeks of prednisone. METHODS: This prospective, single arm, proof-of-concept study was conducted at Massachusetts General Hospital (Boston, MA, USA). Individuals aged 50 years or older who had new-onset or relapsing giant cell arteritis with active disease were eligible for inclusion. Participants received 12 months of tocilizumab 162 mg weekly subcutaneously in combination with 8 weeks of prednisone. The primary endpoint was sustained prednisone-free remission at week 52. Adverse events were also evaluated. This trial is registered with ClinicalTrials.gov (NCT03726749), and is complete. FINDINGS: Between Nov 28, 2018, and Nov 2, 2020, we enrolled 30 patients (mean age 73·7 years [SD 8·1], 18 [60%] women and 12 [40%] men, 30 [100%] White race, 15 [50%] new-onset disease, 23 [77%] temporal artery biopsy-proven, 14 [47%] imaging-proven). The initial prednisone doses were 60 mg (n=7), 50 mg (n=1), 40 mg (n=7), 30 mg (n=6), and 20 mg (n=9). All patients entered remission within 4 weeks from baseline. 23 (77%) of 30 patients were in sustained prednisone-free remission at week 52 and seven (23%) patients relapsed, with a mean time to relapse of 15·8 weeks (SD 14·7). Overall, four (13%) participants developed a serious adverse event, including one related or probably related to prednisone exclusively, two related or probably related to tocilizumab exclusively, and one related or probably related to prednisone, tocilizumab, or both. Two of the non-responder patients stopped tocilizumab and withdrew from the study prematurely after having a second disease relapse. No cases of giant cell arteritis-related permanent vision loss occurred during the study. INTERPRETATION: These results suggest that 12 months of tocilizumab in combination with 8 weeks of prednisone could induce and maintain remission in patients with giant cell arteritis. Confirmation of these findings in a randomised controlled trial is required. FUNDING: Genentech.

Pharmacological studies of effort-related decision making using mouse touchscreen procedures: effects of dopamine antagonism do not resemble reinforcer devaluation by removal of food restriction.

RATIONALE: Effort-based decision-making tasks offer animals choices between preferred reinforcers that require high effort to obtain vs. low effort/low reward options. The neural mechanisms of effort-based choice are widely studied in rats, and evidence indicates that mesolimbic dopamine (DA) and related neural systems play a key role. Fewer studies of effort-based choice have been performed in mice. OBJECTIVES: The present studies used touchscreen operant procedures (Bussey-Saksida boxes) to assess effort-based choice in mice. METHODS: CD1 mice were assessed on a concurrent fixed ratio 1 panel pressing/choice procedure. Mice were allowed to choose between rearing to press an elevated panel on the touchscreen for a preferred food (strawberry milkshake) vs. consuming a concurrently available less preferred alternative (high carbohydrate pellets). RESULTS: The DA D2 antagonist haloperidol (0.05-0.15 mg/kg IP) produced a dose-related decrease in panel pressing. Intake of food pellets was not reduced by haloperidol, and in fact, there was a significant quadratic trend, indicating a tendency for pellet intake to increase at low/moderate doses. In contrast, reinforcer devaluation by removing food restriction substantially decreased both panel pressing and pellet intake. In free-feeding choice tests, mice strongly preferred milkshake vs. pellets. Haloperidol did not affect food intake or preference. CONCLUSION: Haloperidol reduced the tendency to work for food, but this reduction was not due to decreases in primary food motivation or preference. Mouse touchscreen procedures demonstrate effects of haloperidol that are similar but not identical to those shown in rats. These rodent studies may be relevant for understanding motivational dysfunctions in humans.

An evaluation of strengthening precursors to increase preschooler compliance.

We evaluated the strategy of increasing precursors to compliance on the compliance of 2 preschool boys. Modeling and differential reinforcement were used to increase specific responses to his name being called prior to the opportunity to comply with an instruction. The precursors were stopping the ongoing activity and orienting to, making eye contact with, and saying "yes" to the instructor. High levels of precursors occurred during treatment, and increases in compliance also were observed, even though the consequences for compliance and noncompliance did not change.