Identification of Target Golimumab Levels in Maintenance Therapy of Crohn's Disease and Ulcerative Colitis Associated With Mucosal Healing.

INTRODUCTION: Golimumab is approved as a therapy for ulcerative colitis (UC) patients. Recent data also demonstrate efficacy in Crohn's disease (CD); however, little is known about target drug levels to achieve endoscopic remission. METHODS: We performed a retrospective analysis of IBD patients on maintenance golimumab. Median trough levels were compared using Kruskal-Wallis test, and logistic regression was used to construct a probabilistic model to determine sensitivity and specificity of levels predicting mucosal healing. RESULTS: Fifty-eight patients on maintenance golimumab were included (n = 39 CD, n = 19 UC/IBD-unclassified [IBDU]). Forty percent (n = 23) were cotreated with an immunomodulator, 95% (n = 55) of patients were anti-TNF experienced, and 15.5% (n = 9) had 3 or more prior biologic therapies. Forty-four percent of patients achieved mucosal healing with endoscopic response in a further 26% of patients. Clinical remission was recorded in 41% of patients, and 82% had clinical response. Patients were treated with doses generally higher than the approved maintenance dose. In CD patients, median golimumab trough levels were higher in patients with mucosal healing (8.8 µg/mL vs 5.08 µg/mL, P = 0.03). After calculation of a receiver operating characteristic (ROC) curve for mucosal healing vs nonresponse, a trough level >8 µg/mL was associated with mucosal healing, with 67% sensitivity, 88% specificity, and a likelihood ratio of 3:4. CONCLUSION: Treatment with golimumab was associated with mucosal healing in 44% of all IBD patients. Higher golimumab levels were associated with mucosal healing in CD. These findings support the need for prospective studies to determine target golimumab levels in IBD, which may impact current clinical practices in relation to selection of maintenance dosing.

Elevated endogenous surfactant reduces inflammation in an acute lung injury model.

Acute lung injury (ALI) is associated with severe pulmonary inflammation and alterations to surfactant, and often results in overwhelming systemic inflammation, leading to multiple organ failure. The objective of this study was to determine the effect of increased endogenous surfactant pools on pulmonary and systemic inflammation in a model of lipopolysaccharide (LPS)-induced ALI. Mice received an instillation of liposome-encapsulated (i) dichloromethylene diphosphonic acid (DMDP) to increase surfactant pools via depletion of alveolar macrophages, or (ii) phosphate-buffered saline (PBS). Seven days after instillation, mice received an intranasal administration of LPS or saline. Following a 4-hour recovery period, mice were sacrificed and their lungs were isolated, mechanically ventilated, and perfused with 8 mL of recirculated perfusate through the pulmonary circulation for 2 hours. Perfusate and lavage fluid were collected for analysis of inflammatory mediators. Lavage analysis revealed a 5-fold increase in surfactant pools in DMDP-treated mice compared to PBS-treated controls. Lavage and perfusate analyses showed significant decreases in the concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha, and IL-1beta cytokines in DMDP-LPS mice compared to PBS-LPS controls. Elevated endogenous surfactant pools are protective against both LPS- and mechanical ventilation-induced inflammation, in addition to inflammation associated with the combination of these two insults.

Aseptic Abscesses and Inflammatory Bowel Disease: Two Cases and Review of Literature.

Background. Aseptic abscesses (AA) are sterile lesions that represent an extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD). Though Canada has the highest prevalence of IBD in the world, reports of IBD-associated AA are absent in Canada. This may represent a different IBD phenotype or underrecognition and underreporting. Purpose. To explore AA as a possible EIM of IBD and evaluate clinical and investigative findings among patients with IBD-associated AA. Methods. Retrospective chart and literature reviews were performed to find cases of IBD-associated AA at our institution and in the literature. Results. We identified 2 cases of IBD-associated AA in our institution. Both patients had ulcerative colitis and presented with fever, abdominal pain, and weight loss. Radiological workup and aspiration showed sterile splenic abscesses. The AA were unresponsive to antibiotics. One patient improved on corticosteroids and one underwent splenectomy. We retrieved 37 cases of IBD-associated AA from the literature. All patients showed no evidence of infection, failed to resolve with antibiotics, and, if attempted, improved on corticosteroids. Conclusions. Our cases are the first reported in Canada. They support literature which suggests AA as an EIM of IBD and may help increase recognition and reporting of this phenomenon.

Protective effects of elevated endogenous surfactant pools to injurious mechanical ventilation.

Depletion of alveolar macrophages (AM) leads to an increase in endogenous surfactant that lasts several days beyond the repletion of AM. Furthermore, impairment to the endogenous pulmonary surfactant system contributes to ventilation-induced lung injury. The objective of the current study was to determine whether increased endogenous surfactant pools induced via AM depletion was protective against ventilation-induced lung injury. Adult rats were intratracheally instilled with either control or dichloromethylene diphosphonic acid (DMDP) containing liposomes to deplete AMs and thereby increase endogenous surfactant pools. Either 3 or 7 days following instillation, rats were exposed to 2 h of injurious ventilation using either an ex vivo or in vivo ventilation protocol and were compared with nonventilated controls. The measured outcomes were oxygenation, lung compliance, lavage protein, and inflammatory cytokine concentrations. Compared with controls, the DMDP-treated animals had significantly reduced AM numbers and increased surfactant pools 3 days after instillation. Seven days after instillation, AM numbers had returned to normal, but surfactant pools were still elevated. DMDP-treated animals at both time points exhibited protection against ventilation-induced lung injury, which included superior physiological parameters, lower protein leakage, and lower inflammatory mediator release into the air space, compared with animals not receiving DMDP. It is concluded that DMDP-liposome administration protects against ventilation-induced lung injury. This effect appears to be due to the presence of elevated endogenous surfactant pools.