Bayes-based dosing of infliximab in inflammatory bowel diseases: Short-term efficacy.

AIMS: Therapeutic drug monitoring of infliximab can guide clinical decisions in patients with loss of response and in those who can benefit from a de-intensification. The aim of this study was to determine the impact of therapeutic drug monitoring combined with Bayesian forecasting methodology on clinical response in a real-world dataset of patients suffering from inflammatory bowel disease. METHODS: We performed a single-centre prospective study with one-group pre-test/post-test design in 108 adult inflammatory bowel disease patients treated with model-based dosing of infliximab maintenance treatment. We recorded clinical activity scores (Harvey-Bradshaw index and partial Mayo) and inflammatory biomarkers per patient. RESULTS: The initial infliximab regimen was maintained in 49 (45.4%) patients and was adjusted in 59 (54.6%) patients (34 treatment intensifications, 9 de-intensifications and 16 treatment discontinuations or therapy replacements). The median time from intervention to index measurement was 126 (103-160) days. The overall proportion of patients in clinical remission increased from 65.7% to 80.4% (P < .0001) and the median infliximab trough concentrations increased from 3.21 (0.99-5.45) to 5.13 mg/L (3.57-6.53) (P < .0001). In the intensified group, the remission rate increased from 35.3% to 61.8% (P = .001) and the percentage of patients in clinical remission or with mild symptoms increased from 76.5% to 94.1%. In the de-intensification cohort, no patients experienced an increase in the Harvey-Bradshaw index or partial Mayo scores, and all patients maintained an infliximab trough concentration of >5 mg/L. CONCLUSION: In our cohort of inflammatory bowel disease patients, Bayes-based optimized dosing improved the short-term efficacy of infliximab treatment.

Early Versus Late Diagnosis of Complement Factor I Deficiency: Clinical Consequences Illustrated in Two Families with Novel Homozygous CFI Mutations.

The complement system is an important effector arm of innate immunity and plays a crucial role in the defense against common pathogens. But effective defense and maintenance of homeostasis requires a careful balance between complement activation and regulation. Factor I (FI) is one of the most important regulators of the complement system. Complete FI deficiency is a rare autosomal recessive disorder typically resulting in severe, recurrent infection by encapsulated bacteria. In the present study, we describe two patients from unrelated families with complete FI deficiency diagnosed at very different ages: Patient 1 is a 60-year-old man who had experienced several severe infections (pneumonia, meningitis, sepsis) since childhood, one of which caused significant and permanent neurologic sequelae. In contrast, patient 2 was diagnosed at the age of 4 years after a single infectious episode (otitis media) and through detection of a flat beta2 peak on serum protein electrophoresis. This early diagnosis of FI deficiency enabled prompt implementation of a therapeutic intervention consisting of vaccination with encapsulated bacteria and prophylactic antibiotics. The two patients had novel homozygous mutations in the CFI gene (p.Gly162Asp and p.His380Arg) that disrupted protein function. Interestingly, p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, and Ser525). This study illustrates the importance of early versus late diagnosis of FI deficiency and, in general, highlights the clinical relevance of prompt detection of complement system deficiencies.

The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: It has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia (CAP). The aim of this prospective, randomised, double-blind, placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines. SETTING: A tertiary teaching hospital in Barcelona, Spain. PARTICIPANTS: Thirty-four patients were randomly assigned and included in an intention-to-treat analysis (19 to the simvastatin group and 15 to the placebo group). INTERVENTION: Patients were randomly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days. OUTCOME: Primary end point was the time from hospital admission to clinical stability. The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen (PaO2/FiO2) at 48 h after treatment administration. RESULTS: The trial was stopped because enrolment was much slower than originally anticipated. The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups. No significant differences in the time from hospital admission to clinical stability were found between study groups (median 3 days, IQR 2-5 vs 3 days, IQR 2-5; p=0.47). No significant differences in PaO2/FiO2 (p=0.37), C reactive protein (p=0.23), tumour necrosis factor-α (p=0.58), interleukin 6 (IL-6; p=0.64), and IL-10 (p=0.61) levels at 48 h of hospitalisation were found between simvastatin and placebo groups. Similarly, transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation (p=0.19, 0.08 and 0.53, respectively). CONCLUSIONS: Our results suggest that the use of simvastatin, 20 mg once daily for 4 days, since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP. TRIAL REGISTRATION NUMBER: ISRCTN91327214.