The Risk of Hyperglycaemia with the use of Rituximab in Rheumatoid Arthritis.

Results from a Meta-analysis of Randomised Clinical Trials

Authors: L. Velez-Nandayapa, L. DeVore, C. Parikh

1

Basel, Switzerland Novartis campus University of Basel

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Authors: Current affiliation Conflict of interest Luis Velez-Nandayapa 1 and 2 2 and 4 Laura DeVore 3 Chahna Parikh 2 2 and 4 1 PhD candidate at the Pharmacoepidemiology Unit of Basel, University of Basel 2 MSc candidate at the University of Portsmouth and the Drug Safety Research Unit

4 3

2 1

Disclaimer

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“The opinions expressed in this presentation and on the following slides are solely those of the presenter and not necessarily those of Novartis and/or the University of Basel. The presenter is the only responsible in the accuracy or reliability of the information provided herein.”

Disclaimer

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•  Hyperglycemia as a risk

•  Background Rituximab (RTX) and hyperglycemia

•  The systematic review

•  The meta-analysis

•  Results

Agenda

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•  Drug-induced hyperglycaemia (DIH) is often benign and most of the times, clinically asymptomatic[1-4].

•  Diabetic ketoacidosis and hyperglycemic coma may occur (severe manifestations DIH) [1-4].

•  Exact incidence of DIH in general is unknown; however, meta-analysis have estimated the incidence of DIH in glucocorticoids and immunosuppressive agents [2, 3].

•  Drugs may induce hyperglycaemia through a variety of mechanisms [1].

•  FDA in March 2004 requested a warning be added to the prescribing information for all atypical antipsychotics regarding the risk of hyperglycemia and diabetes [1].

Hyperglycemia as a risk

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Mechanisms of DIH & drugs implicated

Fathallah N, et al. Drug safety. 2015;38(12):1153-68. + Unknown

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•  RTX is an anti-CD20 monoclonal antibody

•  Indications: Non-Hodgkin’s lymphoma (NHL), Chronic lymphocytic leukaemia (CLL), and Rheumatoid arthritis (RA) in comb MTX.

•  In animal models RTX induced hyperglycaemia (CD20 transgenic non-obese-diabetic mouse models).

•  The association of hyperglycemia and RTX in patients with hematologic and solid tumors has been clearly confirmed [5].

•  Hyperglycemia in hematologic malignancies has been associated with poor outcomes including increased risk of infection, organ dysfunction, durability of remission, graft-versus-host disease, and mortality [6,7].

Background RTX

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Apoptosis MAC

Mechanism of Action

ADCT Opsonisation/phagocytosis

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•  Our protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (reg. no. CRD42015015655).

We followed (development protocol and project) ...

•  The PRISMA-Protocol statement (The Preferred Reporting Items for Systematic Reviews and Meta-analyses) Protocols 2015 Statement.

•  The PRISMA Statement

•  The Cochrane Handbook

•  and the Cochrane Adverse Effects Methods Group

The systematic review and Meta-analysis

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•  Search strategy: involved randomised CTs using RTX in RA, and it was performed from January 1990 to December 2015 in Medline, EMBASE and Cochrane Library databases.

•  Outcomes evaluated: were the number of AEs and hyperglycaemia reported as outcomes of interest.

•  Analysis of odds ratio (OR) as measure of effect and 95% confidence intervals (CI95%) and p-values as generated from the x2/Fisher’s exact test were calculated; heterogeneity was assessed using the I2 test.

•  Model: random effects models.

•  Software used: CMA and Endnote

The systematic review and Meta-analysis

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•  Search retrieval: 893 hits

•  After removal of duplications and other topics nine publications matched our inclusion and exclusion criteria involving 2,997 subjects of which two publications were included in the meta-analysis involving 322 subjects.

•  Outcomes reviewed: 110 different PTs

•  I will show you the results of ONE outcome - hyperglycemia

Results

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Results

Ref Author RTX RTX+ MTX

RTX+ CFM

PLC+ MTX

1 Tak PP, 2012 499 2 Rubbert-Roth A, 2010 343 3 Greenwald MW, 2011 33 18 4 Emery P, 2006 337 149 5 Mease PJ, 2008 320 155 6 Cohen SB, 2006 309 208 7 Emery P, 2010 316 149

8,9 Edwards+Keystone, 2012 40 40 41 40 40 2,197 41 719

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Results

Group (cases/controls)

OR 95%CI p-value x2

p-value Fisher’s*

I2

RTX (2/38) vs PLC-MTX (3/37)

0.64 0.05-6.04 0.6442 0.5000 0.000

RTX-MTX (3/37) vs PLC-MTX (3/37)

1.00 0.19-5.28 1.000 0.6624 0.000

RTX-CFM (3/38) vs PLC-MTX (3/37)

0.97 0.19-5.14 0.975 0.6504 0.000

RTX rituximab MTX methotrexate PLC placebo CFM cyclophosphamide * Fisher’s exact test

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Conclusion

•  Our results suggest no evidence of association between rituximab in RA and the risk of hyperglycaemia, but the possibility of type II error is likely due to the fact that only two publications, using the same sample, reported the outcome of hyperglycaemia with a frequency between 5 to 7.5%. Further studies are needed to confirm/reject our findings.

Note

In 2010, the CONSORT Statement, (Consolidated Standards of Reporting Trials) was published, which provides the recommendations for better reporting of harms.

In 2007, the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) provided recommendations/guidelines for better reporting of published case reports.

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Strengths and limitations

Strengths of the study

•  The major strength of this review is the systematic approach for selection of studies and the performance of the varied meta-analyses for safety outcomes, with strict adherence to the PRISMA-Protocol 2015 Statement, the PRISMA Statement, the Cochrane Handbook and the Cochrane Adverse Effects Methods Group.

Limitations of the study

•  The most important limitation is the fact that only one study (TWO studies with same sample) report hyperglycemia as safety outcome (reporting bias). More comprehensive reporting would have an important impact in the effect size for hyperglycemia.

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1.  Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA. 2001;286(16):1945-8. 2.  Fathallah N, Slim R, Larif S, Hmouda H, Ben Salem C. Drug-Induced Hyperglycaemia and

Diabetes. Drug safety. 2015;38(12):1153-68. 3.  Liu XX, Zhu XM, Miao Q, Ye HY, Zhang ZY, Li YM. Hyperglycemia induced by glucocorticoids in

nondiabetic patients: a meta-analysis. Ann Nutr Metab. 2014;65(4):324–32. 4.  Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving

calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant. 2004;4:583–95. 5.  Brunello A, Kapoor R, Extermann M. Hyperglycemia during chemotherapy for hematologic and solid

tumors is correlated with increased toxicity. Am J Clin Oncol. 2011;34(3):292-6. 6.  Healy SJ, Dungan KM. Hyperglycemia in patients with hematologic malignancies. Curr Diab Rep.

2015;15(3):8. 7.  Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, et al. Morbidity and

mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004;104(5):1550-8.

8.  Tak PP, Rigby W, Rubbert-Roth A, Peterfy C, van Vollenhoven RF, Stohl W, et al. Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE. Annals of the rheumatic diseases. 2012;71(3):351-7.

9.  Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis and rheumatism. 2011;63(3):622-32.

Bibliography

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10.  Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)). Annals of the rheumatic diseases. 2010;69(9):1629-35.

11.  Rubbert-Roth A, Tak PP, Zerbini C, Tremblay JL, Carreno L, Armstrong G, et al. Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR). Rheumatology. 2010;49(9):1683-93.

12.  Mease PJ, Cohen S, Gaylis NB, Chubick A, Kaell AT, Greenwald M, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. The Journal of rheumatology. 2010;37(5):917-27.

13.  Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis and rheumatism. 2006;54(9):2793-806.

14.  Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis and rheumatism. 2006;54(5):1390-400.

15.  Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. The New England journal of medicine. 2004;350(25):2572-81.

16.  Keystone EC, Cohen SB, Emery P, Kremer JM, Dougados M, Loveless JE, et al. Multiple courses of rituximab produce sustained clinical and radiographic efficacy and safety in patients with rheumatoid arthritis and an inadequate response to 1 or more tumor necrosis factor inhibitors: 5-year data from the REFLEX study. The Journal of rheumatology. 2012;39(12):2238-46.

Bibliography

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Thank you For your attention

luis.velez@novartis.com luis.velez@unibas.ch