Summary Background Anti‐tumour necrosis factor (TNF) agents are effective in Crohn's disease but some patients lose response and require alternative biologic therapy. There are few data on comparative effectiveness of vedolizumab and ustekinumab in this setting. Aim To compare the effectiveness of ustekinumab and vedolizumab in anti‐TNF‐refractory Crohn's disease over 12 months. Methods Patients commencing ustekinumab or vedolizumab for anti‐TNF‐refractory Crohn's disease with minimum follow‐up of 12 months were included. The primary outcome measure was the difference in steroid‐free remission rates at end of induction (2 months) and at 12 months. We also assessed rates of clinical response and remission, treatment persistence, surgery and adverse events in both groups. We performed logistic regression analysis to assess factors associated with steroid‐free remission and clinical response and remission. Results We included 85 patients commencing vedolizumab and 45 commencing ustekinumab. In an unadjusted model, rates of steroid‐free and clinical remission were significantly higher among ustekinumab‐treated patients. After adjusting for confounders, steroid‐free remission was higher among ustekinumab‐treated patients at 2 months (odds ratio, OR 2.79, 95% confidence interval, CI 1.06‐7.39, P = 0.038) and 12 months (OR 2.01, 95% CI 0.89‐4.56, P = 0.095). More patients treated with ustekinumab remained on therapy at the end of 12 months (84.4% vs 61.5%, P = 0.007). Conclusions Ustekinumab appeared more effective in treating anti‐TNF‐refractory Crohn's disease and more patients persisted with therapy.

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Milk calcium exists in bound and ionized forms. Bound calcium is associated both with casein micelles and complexed to citrate and phosphate. Ionized calcium in milk is 1 to 4 millimolar, at least 1000 times its postulated concentration in the mammary alveolar cell. For this reason active transport mechanisms are necessary for transfer of this nutrient to the lumen of the mammary alveolus. Evidence that the major active transport system is a calcium adenosine triphosphatase residing in the membrane of the Golgi secretory vesicle is summarized. This adenosine triphosphatase appears to be activated by calcium concentrations in the micromolar range, to require magnesium ions, and to operate by phosphorylation of a 100,000 dalton enzyme intermediate. Metabolic processes are required to maintain a low concentration of calcium within the cytosol of the mammary alveolar cell. Because no evidence for sodium/calcium exchange could be found in the mammary gland of the lactating mouse, we suggest that these processes operate through a calcium adenosine triphosphatase in the basolateral membrane of the cell. Decreased calcium in the alveolar lumina decreased the integrity of the barrier between blood and milk. It is postulated from observations in other secretory systems that an increase in cystolic activity calcium may play a role in lactogenesis.

Crude particulate preparations from the mammary glands of lactating mice were shown to transport calcium against a concentration gradient in the presence of ATP and mitochondrial inhibitors. Density gradient centrifugation with both sucrose and Percoll gradients indicated the presence of ATP-dependent transport in more than one membrane fraction. A Golgi-enriched membrane fraction possessed the highest specific activity of calcium transport. Digitonin, which increases the permeability of plasma membranes to calcium, did not affect this process. The Golgi fraction contained a 100,000 Dalton protein whose phosphorylation by gamma-[32P]-ATP was enhanced by a micromolar concentrations of free calcium. The phosphorylation was acid-stable and hydroxylamine-sensitive. These properties suggest that Golgi membranes in an activity secreting mammary epithelium possess a calcium transport system which resembles the calcium ATPase present in the sarcoplasmic reticulum of skeletal muscle.