Genetics of Rheumatoid Arthritis Remission; HLA-SE Associated with Remission in Anti-CCP Positive Patients

Marc Maurits¹, Samantha Jurado Zapata¹, Yann Abraham², Erik van den Akker¹, Anne Barton³, Philip Brown⁴, Andrew P Cope⁵, Isidoro Gonzalez-Alvaro⁶, Carl Goodyear⁷, Annette H.M van der Helm-van Mil¹, Xinli Hu⁸, Tom WJ Huizinga¹, Martina Johannesson⁹, Lars Klareskog¹⁰, Dennis Lendrem¹¹, Iain McInnes¹², Fraser Morton⁷, Caron Paterson⁷, Duncan Porter¹³, Arthur Pratt¹¹, Luis Rodriguez Rodriguez¹⁴, Daniela Sieghart¹⁵, Paul Studenic¹⁶, Suzanne Verstappen¹⁷, Leonid Padyukov⁹, Aaron Winkler¹⁸, John Isaacs¹⁹ and Rachel Knevel¹, ¹Leiden University Medical Center, Leiden, Netherlands, ²Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium, ³University of Manchester, Manchester, United Kingdom, ⁴Newcastle University, Newcastle, United Kingdom, ⁵King's College London, London, United Kingdom, ⁶Rheumatology Service. La Princesa University Hospital, Madrid, Spain, ⁷University of Glasgow, Glasgow, United Kingdom, ⁸Pfizer, Saint Peters, MO, ⁹Karolinska Institutet, Stockholm, Sweden, ¹⁰Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, ¹¹Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, ¹²University of Glasgow, School of Medicine, Glasgow, Scotland, United Kingdom, ¹³University of Glasgow, Bearsden, United Kingdom, ¹⁴Hospital Clinico San Carlos, Madrid, Spain, ¹⁵Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, Vienna, Austria, ¹⁶Karolinska Institute; & Medical University of Vienna, Stockholm, Sweden, ¹⁷School of Social Sciences, The University of Manchester, Manchester, United Kingdom, ¹⁸Pfizer, Cambridge, MA, ¹⁹Newcastle University, Newcastle upon Tyne, United Kingdom

Meeting: ACR Convergence 2021

Keywords: genetics, GRS, HLA-SE, Multi-Cohort, remission

Session Information

Date: Sunday, November 7, 2021

Title: Genetics, Genomics & Proteomics Poster (0517–0533)

Session Type: Poster Session B

Session Time: 8:30AM-10:30AM

Background/Purpose: Rheumatoid Arthritis (RA) patients capable of reaching clinical remission potentially have a specific genetic profile that allows them to regain immune tolerance. The identification of these genes could provide insights into the etiology of RA, as well as immunological pathways which could serve as novel drug targets.

We set out to test the association between established RA genetic risk variants and achieving remission at 6 months.

Methods: We computed genetic risk scores (GRS) comprised of RA susceptibility variants¹ and HLA-shared epitope (SE) allele status separately in 3,984 DMARD naïve patients across 9 datasets from inception cohorts. Remission was assessed at 6 months and defined as DAS28CRP values below 2.6. Values were imputed where necessary using predictive mean matching by MICE. We first tested whether baseline DAS28CRP changed with increasing GRS using linear regression. Next, we used logistic regression to determine the relationship between the GRS and HLA-SE alleles and 6 month DAS28CRP remission in all cohorts independently. Using inverse variance weighted meta-analysis we concatenated these results into a singular effect estimate.

Due to the known differences in genetic background of anti-CCP positive and negative RA, we also repeated the analyses in only anti-CCP positive patients.

Results: Baseline clinical variables did not differ between patients who achieved remission and those who did not (Table 1). Distribution of the GRS was consistent between datasets. Neither GRS nor HLA-SE alleles were associated with baseline DAS28CRP (OR 1.01; 95% CI 0.99 – 1.04). A fixed effect meta-analysis showed no significant effect of the GRS (OR 0.99; 95% CI 0.94 – 1.03) or HLA-SE alleles (OR 0.90; 95% CI 0.79 – 1.04) on remission at 6 months (Figure 1). In the seropositive analyses we did observe one significant association; HLA-SE alleles positivity reduced the likelihood of 6 months DAS28CRP remission in the anti-CCP positive stratum (OR 0.79; 95% CI 0.62 – 93) (Figure 2).

Conclusion: Of the known RA genetic risk variants only HLA-SE alleles are associated with a decreased chance of obtaining remission in the anti-CCP positive population in these combined cohorts. Studies encompassing broader genetic profiles are needed to further elucidate the genetics of RA remission.

References:
1). Knevel R et al. Sci Transl Med. 2020;12(545):eaay1548.

Table 1. Summary of the data separated by disease activity after 6 months.

Figure 1. Inverse weighted meta-analysis of (A) the GRS + HLA and (B) the HLA-SE. Includes the dataset name (Study), sample size (N), odds ratio (OR), 95% confidence intervals (95%-CI) and the weights of the fixed and random effect models. I2 = percentage of variation across studies due to heterogeneity.

Figure 2. Inverse weighted meta-analysis of the HLA-SE in CCP positive patients. Includes the dataset name (Study), sample size (N), odds ratio (OR), 95% confidence intervals (95%-CI) and the weights of the fixed and random effect models. I2 = percentage of variation across studies due to heterogeneity.

Disclosures: M. Maurits, None; S. Jurado Zapata, None; Y. Abraham, Pfizer, 3; E. van den Akker, None; A. Barton, None; P. Brown, None; A. Cope, None; I. Gonzalez-Alvaro, None; C. Goodyear, Astra Zeneca, 5, Bristol-Meyers Squibb, 5, Galvani, 5, Istesso, 5, Janssen, 5, Lilly, 1, 5, MedAnnex, 1, 5, MedinCell, 1, MiroBio, 1, Oxford BioDynamics, 5, ThermoFisher, 5, UCB, 5; A. van der Helm-van Mil, None; X. Hu, Pfizer, 3; T. Huizinga, None; M. Johannesson, None; L. Klareskog, None; D. Lendrem, None; I. McInnes, Bristol Myers Squibb, 2, 5, Celgene, 2, 5, Eli Lilly, 2, 5, Janssen, 2, 5, Novartis, 2, 5, UCB, 2, 5, Gilead, 2, AbbVie, 2, AstraZeneca, 5, Boehringer Ingelheim, 2, Amgen, 2, 5, 6, Pfizer, 2, 5, 6; F. Morton, None; C. Paterson, None; D. Porter, Galvani, 5, Abbvie, 12, Sponsorship to attend scientific meetings; A. Pratt, None; L. Rodriguez Rodriguez, None; D. Sieghart, None; P. Studenic, None; S. Verstappen, Bristol Meyer Squibb, 5, Pfizer, 6; L. Padyukov, None; A. Winkler, Pfizer, 3; J. Isaacs, None; R. Knevel, Pfizer, 5.

To cite this abstract in AMA style:

Maurits M, Jurado Zapata S, Abraham Y, van den Akker E, Barton A, Brown P, Cope A, Gonzalez-Alvaro I, Goodyear C, van der Helm-van Mil A, Hu X, Huizinga T, Johannesson M, Klareskog L, Lendrem D, McInnes I, Morton F, Paterson C, Porter D, Pratt A, Rodriguez Rodriguez L, Sieghart D, Studenic P, Verstappen S, Padyukov L, Winkler A, Isaacs J, Knevel R. Genetics of Rheumatoid Arthritis Remission; HLA-SE Associated with Remission in Anti-CCP Positive Patients [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/genetics-of-rheumatoid-arthritis-remission-hla-se-associated-with-remission-in-anti-ccp-positive-patients/. Accessed .

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