Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides During Rituximab Maintenance Therapy

Affiliations

¹ Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, CARPEM, Paris, France.
² Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
³ Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, and Bioinformatics Core Facility, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Université Paris Cité, Paris, France.
⁴ Institut du Cancer Paris CARPEM, AP-HP, APHP Centre, Department of Medical Oncology, ARIANE, Cochin Hospital, and INSERM U-1016, CNRS UMR-8104, Université Paris Cité, Institut Cochin, Paris, France.
⁵ Fédération de Génétique et Médecine Génomique, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, 27 rue du Faubourg-Saint-Jacques, Paris, France, and Université Paris Cité, Paris, France.
⁶ INSERM U-1016, CNRS UMR-8104, Université Paris Cité, Institut Cochin, Paris, France.
⁷ Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, and Université Paris Cité, UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, PRES Sorbonne Paris Cité, CARPEM, Paris, France.
⁸ Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, and Université Paris Cité, Paris, France.
⁹ Department of Internal Medicine, Institut Mutualiste Montsouris, Paris, France.

PMID: 37134130
DOI: 10.1002/art.42556

Randomized Controlled Trial

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides During Rituximab Maintenance Therapy

Nihel Khoudour et al. Arthritis Rheumatol. 2023 Nov.

. 2023 Nov;75(11):2003-2013.

doi: 10.1002/art.42556. Epub 2023 Aug 13.

Authors

Affiliations

¹ Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, CARPEM, Paris, France.
² Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
³ Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, and Bioinformatics Core Facility, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Université Paris Cité, Paris, France.
⁴ Institut du Cancer Paris CARPEM, AP-HP, APHP Centre, Department of Medical Oncology, ARIANE, Cochin Hospital, and INSERM U-1016, CNRS UMR-8104, Université Paris Cité, Institut Cochin, Paris, France.
⁵ Fédération de Génétique et Médecine Génomique, Hôpital Cochin, AP-HP, Centre-Université Paris Cité, 27 rue du Faubourg-Saint-Jacques, Paris, France, and Université Paris Cité, Paris, France.
⁶ INSERM U-1016, CNRS UMR-8104, Université Paris Cité, Institut Cochin, Paris, France.
⁷ Department of Pharmacokinetics and Pharmacochemistry, Cochin University Hospital, Assistance Publique-Hôpitaux de Paris, and Université Paris Cité, UMR8038 CNRS, U1268 INSERM, Faculté de Pharmacie, PRES Sorbonne Paris Cité, CARPEM, Paris, France.
⁸ Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, and Université Paris Cité, Paris, France.
⁹ Department of Internal Medicine, Institut Mutualiste Montsouris, Paris, France.

PMID: 37134130
DOI: 10.1002/art.42556

Abstract

Objective: Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes.

Methods: Patients included in the MAINRITSAN2 trial (ClinicalTrials.gov identifier: NCT01731561) were randomized to receive a 500-mg fixed-schedule rituximab infusion or an individually tailored regimen. Rituximab plasma concentrations at month 3 (CM3) were assessed. DNA samples (n = 53) were genotyped for single-nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models.

Results: One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/ml) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% versus 18.0%; P = 0.02, respectively). Low rituximab plasma concentration at 3 months (CM3 <4 μg/ml) was an independent risk factor for major relapse (odds ratio 6.56 [95% confidence interval (95% CI) 1.26-34.09]; P = 0.025) at month 28 (M28). A sensitivity survival analysis also identified CM3 <4 μg/ml as an independent risk factor for major relapse (hazard ratio [HR] 4.81 [95% CI 1.56-14.82]; P = 0.006) and relapse (HR 2.70 [95% CI 1.02-7.15]; P = 0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with CM3 but not with major relapse onset at M28.

Conclusion: These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase.

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References

REFERENCES

1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1-11.
1. Terrier B, Charles P, Aumaître O, et al. ANCA-associated vasculitides: recommendations of the French Vasculitis Study Group on the use of immunosuppressants and biotherapies for remission induction and maintenance. Presse Med 2020;49:104031. In French.
1. Terrier B, Darbon R, Durel CA, et al. French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and ANCA-associated vasculitides). Orphanet J Rare Dis 2020;15:351.
1. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.
1. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371:1771-80.

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Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides During Rituximab Maintenance Therapy

Affiliations

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides During Rituximab Maintenance Therapy

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

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Associated data

LinkOut - more resources

Full Text Sources

Medical

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