Lymphomas Complicating Rheumatoid Arthritis: Results of a French Multi-Centre Case-Control Study

Joanna Kedra¹, Raphaèle Seror², Philippe Dieude³, Arnaud Constantin⁴, Eric Toussirot⁵, Elias Kfoury⁶, Charles Masson⁷, Divi Cornec⁸, Jean-Jacques Dubost⁹, Laurent Marguerie¹⁰, Sebastien Ottaviani¹¹, Franck Grados¹², Rakiba Belkhir¹³, Olivier Fain¹⁴, Philippe Goupille¹⁵, Christelle Sordet¹⁶, Bruno Fautrel¹⁷, Peggy Philippe¹⁸, Muriel Piperno¹⁹, Bernard Combe²⁰, Olivier Lambotte²¹, Christophe Richez²², Jeremie Sellam²³, Thomas Sené²⁴, Guillaume Denis²⁵, Thierry Lequerre²⁶, Xavier Mariette²⁷ and Gaetane Nocturne¹³, ¹Sorbonne Université, Institut Pierre Louis d'Epidémiologie et de Santé Publique, UMR S1136, Paris, France, Paris, France, ²Rheumatology Department, Bicetre Hospital, APHP, France, Paris, France, ³Université de Paris, Service de Rhumatologie Hôpital Bichat-Claude Bernard, AP-HP, Paris, Ile-de-France, France, ⁴Rheumatology Department, Toulouse University Hospital, Toulouse, France, ⁵CIC biotherapies, Besançon University Hospital, Besançon, France, ⁶Hematology Department, Brive La Gaillarde Hospital, Brive la Gaillarde, France, ⁷Rheumatology Department, Angers University Hospital, Angers, France, ⁸Rheumatology Department, Brest University Hospital, Brest, France, ⁹CHU Gabriel Montpied, Clermont-Ferrand, France, ¹⁰Department of medicine, rheumatology and neurology, Hopale hospital, Berck, France, ¹¹Rheumatology Department, Bichat hospital, APHP, Paris, France, ¹²Rheumatology Department, Amiens University Hospital, Amiens, France, ¹³Rheumatology Department, Bicetre Hospital, APHP, France, Le Kremlin-Bicêtre, France, ¹⁴Internal Medicine Department, Saint-Antoine hospital, APHP, Paris, France, ¹⁵CHU Tours, department of rheumatology, Tours, France, ¹⁶Rheumatology Department, Strasbourg University Hospital, Strasbourg, France, ¹⁷Sorbonne University, INSERM, IPLES; Pitié-Salpêtrière Hospital, Paris, Ile-de-France, France, ¹⁸Rheumatology Department, Lille University Hospital, Lille, France, ¹⁹Rheumatology Department, Lyon University Hospital, Lyon, France, ²⁰University of Montpellier, Montpellier, France, ²¹Internal Medicine Department, Bicetre Hospital, APHP, Le Kremlin-Bicêtre, France, ²²Rheumatology Hospital, Pelligrin Hospital, Bordeaux University Hospital, Bordeaux, France, ²³AP-HP, Hôpital Saint-Antoine, Service de Rhumatologie, Centre de Recherche Saint-Antoine, INSERM UMR_S 938,Sorbonne Université, Paris, 75012, France, Paris, France, ²⁴Department of internal medicine, Diaconesses-Croix Saint-Simon Hospital, Paris, France, ²⁵Hematology Department, Rochefort Hospital, Rochefort, France, ²⁶Rheumatology, University Teaching Hospital, Rouen, France, ²⁷Paris-Sud University, Rueil-Malmaison, France

Meeting: ACR Convergence 2020

Keywords: B-Lymphocyte, Epidemiology, genetics, Outcome measures, rheumatoid arthritis

Session Information

Date: Friday, November 6, 2020

Title: RA – Diagnosis, Manifestations, & Outcomes Poster I: Multimorbidity

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Rheumatoid arthritis (RA) is associated with an increased risk of non-Hodgkin B-cell lymphoma (B-cell NHL).

The objectives of this work were:

To study the characteristics of B-cell NHL complicating RA
To identify the factors associated with their occurrence.
To identify single nucleotide polymorphisms (SNP) associated with their occurrence.

Methods: A multi-centre retrolective case-control study was performed in France. Cases were patients with RA fulfilling the ACR-EULAR 2010 criteria, who developed a B-cell NHL after the diagnosis of RA. Cases were reported following a call for observations by the CRI-Imidiate network, registries from the French society of Rheumatology and the ESPOIR cohort. For each case, 2 control patients were drawn at random from patients fulfilling ACR-EULAR 2010 criteria in the ESPOIR cohort; cases and controls were matched on age (age at lymphoma diagnosis for cases and age at the 10-year ESPOIR visit for controls). Patients with associated Sjögren’s syndrome were excluded. Cases and controls characteristics were compared for parameters associated with the occurrence of lymphoma. Blood or saliva samples were collected whenever possible for genotyping, looking for 24 SNP of known interest for their association with lymphomas and/or for their implications in B-cell control pathways.

Results: A total of 54 cases were included and matched to 108 controls. Lymphomas were mostly diffuse large B-cell lymphomas (n=27, 50.0%) (Figure 1). EBV positivity was found in 4 cases among 27 tested (14.8%). Cases had a mean age of 63.5 years (SD=10.9) and had a mean RA duration of 12.4 years (SD=10.5) at the time of diagnosis of lymphoma; there was no significant difference with controls (p=0.47 and p=0.40 respectively). The mean duration of follow-up after the diagnosis of lymphoma was 5.2 years (SD=5.8).

In univariate analysis, factors associated with occurrence of B-cell NHL were: male gender (OR=3.3, 95%CI: 1.7-6.7), positive ACPA (OR=5.1, 95%CI: 2.0-15.7), positive Rheumatoid Factor (RF) (OR=3.9, 95%CI=1.6-12.2), erosions on X-rays (OR=15.4, 95%CI: 6.9-37.7) and DAS28 (OR=2.0, 95%CI: 1.5-2.7). Erosions and DAS28 remained significant in multivariate analysis, and there was a trend for ACPA positivity (Table 1). Methotrexate, TNF-blockers and the number of previous biologics were not associated with the occurrence of B-cell NHL (Table 2). Previous use of hydroxychloroquine and sulfasalazine were more frequent in cases versus controls, which could be linked to a date bias; since the mean year of RA diagnosis was earlier in cases than in controls (1997±10.6 vs 2003±0.7, p< 0.0001), they were more susceptible to have received these drugs than more recent RA.

The exploratory genetic analysis suggested an association of the BLK rs2736340 minor allele (encoding for B-cell lymphocyte kinase BLK) with B-cell NHL (OR=1,8, 95%CI: 1.0-3,2, crude p=0.03).

Conclusion: B-cell NHL complicating RA are mostly DLBCL. This study revealed an association between markers of activity (DAS28), severity (erosions) and the risk of B-cell NHL in patients with RA, and suggested the possible role of B-cell activation (RF, ACPA, BLK gene), supporting the paradigm of a continuum between autoimmunity and lymphomagenesis in RA.

Figure 1: lymphomas histology

Table 1: association between RA characteristics and B-cell NHL in univariate and multivariate analysis

Table 2: association between RA treatments and B-cell NHL in univariate analysis

Disclosure: J. Kedra, None; R. Seror, None; P. Dieude, None; A. Constantin, None; E. Toussirot, None; E. Kfoury, Pfizer, 9, Roche SAS, 9, Takeda France, 9; C. Masson, Bristol-Myers Squibb, 5, Novartis, 5, 9, Pfizer, 5, 9, Sanofi-Aventis, 5, 9, Biogen, 9; D. Cornec, Sanofi-Aventis, 9, Novartis, 9; J. Dubost, None; L. Marguerie, Roche SAS, 9; S. Ottaviani, None; F. Grados, None; R. Belkhir, None; O. Fain, Shire France, 9, Roche SAS, 9, Alnylam France SAS, 9; P. Goupille, MSD France, 1, 2, Abbvie, 1, Amgen, 1, Biogaran, 1, 2, BMS, 1, Celgene, 1, Chugai, 1, Lilly, 1, Hospira, 1, Janssen, 1, Medac, 1, Nordic Pharma, 1, Novartis, 1, Sanofi-Genzyme, 1, Pfizer, 1, UCB Pharma, 1; C. Sordet, MSD France, 9, Sanofi-Aventis, 9, Swedish Orphan Biovitrum, 9, Amgen SAS, 9, Lilly, 9; B. Fautrel, MSD France, 1, 2, Abbvie, 1, 2, Pfizer, 1, 2, Biogen, 1, BMS, 1, Boehringer Ingelheim, 1, Celgene, 1, Janssen, 1, Lilly, 1, Medac, 1, Nordic Pharma, 1, Novartis, 1, Roche, 1, Sanofi-Aventis, 1, SOBI, 1, UCB Pharma, 1; P. Philippe, Abbvie, 9, MSD France, 9, Sanofi-Aventis, 9, Pfizer, 8, Novartis, 8, Sandoz, 8; M. Piperno, Abbvie, 9, Janssen, 9, Biogen, 9, Pfizer, 9, Chugai, 9, Bristol-Myers Squibb, 9, Sandoz, 9; B. Combe, AbbVie, 5, 8, Janssen, 5, Eli Lilly, 2, 5, 8, Novartis, 2, Gilead Sciences, Inc., 5, 8, Roche-Chugai, 5, 8, Sanofi, 5, Pfizer, 2, 8, MSD, 8, Bristol-Myers Squibb, 8; O. Lambotte, Incyte International, 9, Live ! By GL Events, 9, Octapharma, 9, MSD France, 9, Janssen, 5, Gilead, 5, Bristol-Myers Squibb, 5, Astra Zeneca, 5; C. Richez, Bristol-Myers Squibb, 9, Amgen SAS, 5; J. Sellam, None; T. Sené, Sanofi-Aventis, 9, Allergan France, 9; G. Denis, None; T. Lequerre, None; X. Mariette, None; G. Nocturne, None.

To cite this abstract in AMA style:

Kedra J, Seror R, Dieude P, Constantin A, Toussirot E, Kfoury E, Masson C, Cornec D, Dubost J, Marguerie L, Ottaviani S, Grados F, Belkhir R, Fain O, Goupille P, Sordet C, Fautrel B, Philippe P, Piperno M, Combe B, Lambotte O, Richez C, Sellam J, Sené T, Denis G, Lequerre T, Mariette X, Nocturne G. Lymphomas Complicating Rheumatoid Arthritis: Results of a French Multi-Centre Case-Control Study [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/lymphomas-complicating-rheumatoid-arthritis-results-of-a-french-multi-centre-case-control-study/. Accessed .

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