A Multicenter Double-Blinded Preclinical Randomized Controlled Trial (pRCT) on Jak1/2 Inhibition in Lupus Nephritis

Journal of the American Society of Nephrology, vol. 31, pp. 594

Abstract

Background: We conducted the first multicenter double-blinded pRCT in the field of nephrology and tested the Jak1/2 inhibitor baricitinib in experimental lupus nephritis. Methods: We conducted a pRCT at two Spanish and two German academic sites. One site included MRL/lpr mice from their own breeding colony and the other sites purchased MRL/lpr mice from the Jackson lab. Eligibility criteria included female and 13-14 weeks old. Mice were randomized at a 1:1 ratio and orally dosed with 20 mg/kg/d baricitinib or vehicle for 4 weeks. Samples were assembled for blinded analyses, including histology, which was assessed by an independent pathology institute. The primary endpoint was proteinuria. Results: A total of 55 mice were randomly assigned to the vehicle (n=28) and baricitinib group (n=27). Baricitinib-treated mice showed a trend towards decreased proteinuria, but this did not reach statistical significance (p=0.104). In contrast, plasma total IgG and lymphadenopathy score were significantly improved in the baricitinib group. In the vehicle group, at the initiation of treatment, self-breed mice had less proteinuria, less plasma total IgG, and worse skin lesion compared to commercial-source mice. Conclusions: In a pRCT, targeting Jak1/2 with baricitinib for 4 weeks had no significant effect on the primary end-point proteinuria in MRL/lpr mice, whereas total plasma IgG and lymphadonpathy score significantly improved. Mice of different origins had different lupus phenotypes and increased the variability. Placebo controlled multicenter trials are feasible in animal models of lupus, however, standard deviations may increase due to multiple factors, which requires higher numbers of animals.

Authors 10

1. Yutian Lei

   LMU Klinikum · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany;

2. Bettina Sehnert

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

3. Reinhard Edmund Voll

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

4. Conxita Jacobs Cachá

   Universitat Autònoma de Barcelona · Vall d'Hebron Institut de Recerca · Vall d'Hebron Hospital Universitari

   Affiliation as printed

   Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Nephrology Research Group, Vall d’Hebron Research Institute (VHIR) and REDINREN, Barcelona, Spain;

5. María José Soler

   Universitat Autònoma de Barcelona · Vall d'Hebron Institut de Recerca · Vall d'Hebron Hospital Universitari

   Affiliation as printed

   Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Nephrology Research Group, Vall d’Hebron Research Institute (VHIR) and REDINREN, Barcelona, Spain;

6. María Dolores Sánchez-Niño

   Fundación Renal Española · Universidad Autónoma de Madrid

   Affiliation as printed

   IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN and REDINREN, Madrid, Spain;

7. Alberto Ortíz

   Fundación Renal Española · Universidad Autónoma de Madrid

   Affiliation as printed

   IIS-Fundacion Jimenez Diaz, School of Medicine, Universidad Autonoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN and REDINREN, Madrid, Spain;

8. Roman David Bülow Aachen Institute of Pathology Department of Nephrology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology and Department of Nephrology, RWTH University of Aachen, Aachen, Germany;

9. Peter Boor Aachen Institute of Pathology Department of Nephrology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology and Department of Nephrology, RWTH University of Aachen, Aachen, Germany;

10. Hans‐Joachim Anders

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Division of Nephrology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany;