Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria

Juvenile idiopathic arthritis (JIA) is the most common diagnosis in children and adolescents with rheumatic disorders. In many children and adolescents, JIA is successfully treated with non-steroidal anti-inflammatory drugs (NSAID) and physiotherapy. However, in a significant number of cases the disease is resistant to this therapy, and treatment with second line disease-modifying antirheumatic drugs (DMARDs) is required. Methotrexate (MTX) is frequently referred to as first-choice second-line agent for the treatment of JIA. To increase drug safety, the Working Groups for Children and Adolescents with Rheumatic Diseases in Germany (AGKJR) and Pediatric Rheumatology Austria have initiated the formulation of evidence-based recommendations. Evidence is based on consensus expert meetings, a MEDLINE search with the key words Methotrexate and juvenile arthritis limited to age 0–18 years, standard textbooks and review articles, data from the central registry of the German Research Center for Rheumatic Diseases (Deutsches Rheumaforschungszentrum Berlin DRFZ), experience with MTX in adults with rheumatoid arthritis (RA), and recommendations of the German Society of Rheumatology (DGRh). Based on these data, evidence and recommendations are graded, and evidence-based recommendations for the use of MTX in children and adolescents with rheumatic disease are presented.Section Pharmacotherapy of the Working Group Pediatric Rheumatology Germany and Austria: I. Foeldvari; J.P. Haas, A. Haeffner, D. Hobusch,G. Horneff, A. Hospach, R. Keitzer, G. Klaus, M. Metzler, H. Michels, T. Niehues, I. Pilz, M. Sailer Höck, M. Schöntube, L. Schuchmann, K. Schumacher, H.W. Seyberth, E. Siemers, A. Urban, E. Weißbarth-Riedl. Working Group Pediatric Rheumatology North-Rhine-Westfalia: S. Benseler, G. Bürk, S. Fahl, I. Foeldvari, D. Föll, M. Frosch, G. Ganser, S. Kastner, I. Kleine, E. Lainka, K. Mönkemöller, J. Neubert, U. Neudorf, T. Niehues, J. Roth, S. Seeliger, N. Wagner, R. Wieland, H. Winowski.     

Experimental calibration of a two-stage prism-grating system for measuring cell velocity

A new optical system for the measurement of the erythrocyte velocity in microvessels is extensively applied for the first time. It is based on the projection of the erythrocyte image onto two photodiodes through a prism grating. The differential signal of the photodiodes is proportional to the velocity. The system is comparable to those of M. Anliker, M. Casty, P. Friedli, R. Kubli, and H. Keller ((1977). Noninvasive measurement of blood flow. In “Cardiovascular Flow Dynamics and Measurement” (N. H. Hwang and N. Normann, eds.), pp. 43–88. Univ. Park Press, Baltimore) and D. W. Slaaf, J. P. S. M. Rood, G. J. Tangelder, and T. Arts ((1979). Microvasc. Res.17, S173). It measures an instantaneous velocity. The system is calibrated by a velocity which is constant over the total measuring field and by a known flow rate and profile. Concerning applicability and results the device is compared to the two-slit methods, the laser-Doppler-anemometry and high-speed cinematography.     

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5(-/-) bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5(-/-) bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms.     

Low Hemoglobin and Radiographic Damage Progression in Early Rheumatoid Arthritis: Secondary Analysis From a Phase III Trial

Objective

To study low blood hemoglobin concentrations as a predictor of radiographic damage progression in patients with rheumatoid arthritis (RA).

Methods

Post hoc analyses were performed in patients from the PREMIER trial with early RA undergoing 2 years of adalimumab (ADA), methotrexate (MTX), or ADA + MTX combination therapy. Low disease activity was defined as a score <3.2 on the 28‐joint Disease Activity Score using the C‐reactive protein level (DAS28‐CRP), and clinical response by the American College of Rheumatology criteria for 20% improvement at week 24. Baseline or mean hemoglobin concentrations over time, or anemia as defined using sex‐specific World Health Organization criteria, were analyzed in mixed‐effects models for longitudinal data in men and women as predictors of progressive joint damage, as measured by the modified total Sharp/van der Heijde score (ΔSHS). Data were adjusted for treatment and other patient characteristics, including the DAS28‐CRP.

Results

Baseline hemoglobin was inversely associated with ΔSHS in adjusted analyses (P < 0.05 for both sexes). Baseline anemia predicted greater ΔSHS in MTX‐treated patients over 104 weeks, and in ADA‐ and combination‐treated patients over 26 weeks. Lower hemoglobin concentrations over time, as well as time with anemia, were associated with greater damage progression (P < 0.001). The effect of low hemoglobin concentrations on joint damage progression remained significant, even in patients achieving low disease activity.

Conclusion

Low hemoglobin is a DAS28‐CRP‐independent predictor of radiographic joint damage progression in MTX‐treated patients with early RA. This effect decreases over time in ADA‐ and combination‐treated patients, and in clinical responders irrespective of treatment modality.

     

Periods of differing mortality distribution during the first year after acute myocardial infarction

The mortality rate after acute myocardial infarction (AMI) has generally been modeled by a single exponential function. The present study was undertaken to determine, in 3 different populations, whether or not periods exist during the first year after AMI which have mortality distributions that differ from this pattern. The 3 patient populations included San Diego (346 patients, 71 deaths), Vancouver (704 patients, 146 deaths), and Copenhagen (1,140 patients, 262 deaths). Hospital admission was within 24 hours of the onset of symptoms, and patients dying within the first 24 hours after hospital admission or of noncardiac or unknown causes were not analyzed. The mortality between 2 and 21 days in the combined data base was 11.4% (range 10.9 to 11.7) and from 3 weeks to 1 year 10.5% (range 9.0 to 11.3). A high degree of similarity was noted among the shapes of the 3 survival curves. The hypothesis of an exponential mortality rate during the entire first year was rejected. Using a special statistic, changepoints at days 17,23, and 24 in the 3 populations (21 days for the combined data base) were identified and used thereafter to divide the year into 2 separate periods of mortality within which exponentiality for the mortality rate was not rejected. The point by which exactly 50% of deaths had occurred was day 19, with 75% of deaths occurring by day 100. These data further define the natural history after AMI and indicate optimal follow-up periods for short- and longer-term management strategies based on risk assessment or trials of risk reduction after AMI.     

European consensus proposal for immunoglobulin therapies

The use of immunoglobulin (Ig) preparations (intravenous, IVIg, subcutaneous, SCIg) for replacement and immunomodulation therapy worldwide has tripled in the past 20 years and represents an ever‐increasing cost factor for healthcare organizations. The limited access to the starting material of this essential medicinal product is currently the driving force for human plasma collection. Increasing awareness and improved diagnosis of human primary immunodeficiencies and a broadening of immunomodulatory indications are responsible for this development, and on a longer run might lead to plasma supply shortages. Consensus recommendations for the optimal use of Ig in clinical practice, including priority rankings for the most urgent indications, are therefore urgently needed. During a recent meeting in Kreuth, Germany, expert nominees from 36 Council of Europe states, together with colleagues from observer countries and regulatory agencies came up with this consensus statement.