Incident psoriasis under treatment with tumor necrosis factor-α inhibitors in juvenile idiopathic arthritis patients-analysis of the BiKeR registry.

The efficacy of tumor necrosis factor inhibitors (TNFi) for the treatment of psoriasis is well established, but patients may develop psoriasis for the first time while on TNFi as a paradoxical effect. Limited data on this association in patients with juvenile idiopathic arthritis (JIA) are available. Safety data from patients registered to the German Biologics registry (BiKeR) were analyzed. Patients were grouped by treatment regime: single TNFi, multiple TNFi, non-TNFi biologics or bDMARD-naïve control group receiving methotrexate. TNFi-associated psoriasis was defined as incident diagnosis of psoriasis after starting TNFi treatment. Patients with a history of psoriasis or psoriasis arthritis prior to TNFi therapy were excluded. Event rates using AEs reported after first dose were compared by Wald's test. A total of 4149 patients were treated with a TNFi (etanercept, adalimumab, golimumab, infliximab), 676 with a non-TNFi biologic (tocilizumab, abatacept, anakinra, canakinumab) and 1692 with methotrexate only. A total of 31 patients were diagnosed with incident psoriasis while on one of the above treatments. Compared with methotrexate, psoriasis was more frequent in the TNFi cohorts (RR 10.8, p = 0.019), specifically in the subgroup of TNF antibodies (RR 29.8, p = 0.0009), whereas no significant signal was observed with etanercept. Also, non-TNFi-treated patients presented high incident psoriasis rates (RR 25.0, p = 0.003). Our findings indicate a higher rate of incident psoriasis in JIA patients treated with TNFi monoclonal antibodies or non-TNFi biologic treatment. JIA patients receiving monoclonal antibody TNFi or non-TNFi bDMARD should be monitored for incident psoriasis. Medication change, if topical skin treatment remains insufficient, may be considered.

Cerebral effects of resuscitation with either epinephrine or vasopressin in an animal model of hemorrhagic shock.

PURPOSE: The use of epinephrine (EN) or vasopressin (VP) in hemorrhagic shock is well established. Due to its specific neurovascular effects, VP might be superior in concern to brain tissue integrity. The aim of this study was to evaluate cerebral effects of either EN or VP resuscitation after hemorrhagic shock. METHODS: After shock induction fourteen pigs were randomly assigned to two treatment groups. After 60 min of shock, resuscitation with either EN or VP was performed. Hemodynamics, arterial blood gases as well as cerebral perfusion pressure (CPP) and brain tissue oxygenation (PtiO2) were recorded. Interstitial lactate, pyruvate, glycerol and glutamate were assessed by cerebral and subcutaneous microdialysis. Treatment-related effects were compared using one-way ANOVA with post hoc Bonferroni adjustment (p < 0.05) for repeated measures. RESULTS: Induction of hemorrhagic shock led to a significant (p < 0.05) decrease of mean arterial pressure (MAP), cardiac output (CO) and CPP. Administration of both VP and EN sufficiently restored MAP and CPP and maintained physiological PtiO2 levels. Brain tissue metabolism was not altered significantly during shock and subsequent treatment with VP or EN. Concerning the excess of glycerol and glutamate, we found a significant EN-related release in the subcutaneous tissue, while brain tissue values remained stable during EN treatment. VP treatment resulted in a non-significant increase of cerebral glycerol and glutamate. CONCLUSIONS: Both vasopressors were effective in restoring hemodynamics and CPP and in maintaining brain oxygenation. With regards to the cerebral metabolism, we cannot support beneficial effects of VP in this model of hemorrhagic shock.

Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock.

BACKGROUND: Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. MATERIALS AND METHODS: Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. RESULTS: The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. CONCLUSIONS: Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock.

Inflammatory Bowel Disease in Juvenile Idiopathic Arthritis Patients Treated with Biologics.

OBJECTIVE: Evolving inflammatory bowel disease (IBD) is a matter of interest in patients with juvenile idiopathic arthritis (JIA) and might be associated with JIA therapy. METHODS: Data from the German biologics registry (Biologika in der Kinderrheumatologie; BiKeR) from 2001 to 2013 were analyzed. RESULTS: There were 3071 patients with 8389 patient-years (PY) of observation followed. IBD was diagnosed in 11 patients, 8 with Crohn disease and 3 with ulcerative colitis. IBD incidence in patients with JIA was 1.31/1000 PY and higher than published IBD incidences in pediatric populations. Compared with the total BiKeR cohort, patients with IBD more commonly had enthesitis-related arthritis, extended oligoarthritis, psoriatic arthritis, and also rheumatoid factor (RF)-negative polyarthritis. No IBD occurred in patients with systemic JIA or RF-positive polyarthritis. In patients treated with methotrexate (MTX), the IBD incidence was significantly lower compared with patients not treated with MTX. Etanercept (ETN) monotherapy, but not the combination of ETN and MTX, was associated with an increased incidence of IBD. CONCLUSION: Incidence of IBD in patients with JIA is higher than in the population. MTX turned out to be protective, even in combination with ETN.

Cerebral metabolism during experimental endotoxin shock and after preconditioning with monophosphoryl lipid A.

PURPOSE: Preconditioning with low doses of monophosphoryl lipid A (MPL) has been shown to induce endotoxin tolerance and to reduce the metabolic and hemodynamic consequences of endotoxin shock. However, no data are available about the effects of endotoxin preconditioning on cerebral metabolism during endotoxemia. The study was designed to determine the effects of endotoxin preconditioning with MPL on cerebral metabolism via microdialysis compared to muscle tissue metabolism during experimental endotoxemia. METHODS: In a controlled animal study, continuous endotoxin infusion (1µg/kg b.w. per h) was administrated to 7 female mixed-breed pigs after pretreatment with MPL in incremental doses of endotoxin during days 5-2 before the experiments. In the control group, 7 animals received a saline pretreatment. In addition to hemodynamic monitoring and blood gas analyses, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle and cerebral tissue were measured using in vivo microdialysis. RESULTS: There were no significant differences between the two groups with respect to hemodynamic parameters, while mixed venous oxygen saturation (SvO2), arterial blood pH and mean pulmonary arterial pressure (MPAP) were significantly higher in the preconditioned group. Cerebral perfusion pressure (CPP) and brain tissue oxygen pressure (ptiO2) values stayed stable throughout the experiment with no inter-group differences. While interstitial concentrations of lactate and glycerol as well as the lactate/pyruvate (LP) and the lactate/glucose (LG) ratio in muscle tissues were significantly increased in control animals compared to those who had been pretreated with MPL; the results of cerebral microdialysis showed no significant changes in interstitial lactate or glycerol levels in both groups. However, the lactate/glucose (LG) ratio in the control group showed a significantly higher increase than in the preconditioned group. CONCLUSIONS: Preconditioning with low doses of MPL ameliorates the negative metabolic effects of endotoxin shock in muscle tissue. With regard to cerebral metabolism, the present study suggests that MLP preconditioning provides moderate advantages, at least in an experimental model of endotoxin shock.

Distinct effects of methotrexate and etanercept on the B cell compartment in patients with juvenile idiopathic arthritis.

OBJECTIVE: B cells have been shown to play an important role in the pathogenesis of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). Current treatments include the disease-modifying antirheumatic drugs methotrexate (MTX) and tumor necrosis factor α inhibition with etanercept. This study was undertaken to determine how these drugs influence the B cell compartment in patients with JIA. METHODS: B cell subpopulations and follicular helper T (Tfh) cells in the peripheral blood of JIA patients were investigated by multicolor flow cytometry. Serum immunoglobulin and BAFF levels were determined by enzyme-linked immunosorbent assay. RESULTS: There was a significant decrease in transitional B cells and significantly lower serum immunoglobulin levels in patients receiving MTX than in untreated patients and those receiving etanercept. In contrast, etanercept treatment had no effect on most of the B cell subpopulations, but resulted in significantly lower BAFF levels and increased numbers of Tfh cells. Thus, our findings indicate an unexpected and previously unknown direct effect of low-dose MTX on B cells, whereas etanercept had a more indirect influence. CONCLUSION: Our results contribute to a better understanding of the potency of MTX in autoantibody-mediated autoimmune disease and present a possible mechanism of prevention of the development of drug-induced antibodies to biologic agents. The finding that MTX and etanercept affect the B cell compartment differently supports the notion that combination therapy with etanercept and MTX is more effective than monotherapy.