Sex Differences in Treatment Response to Three Different Biological Treatments and Corticosteroids in Patients with Early Rheumatoid Arthritis

Kristina Lend¹, Ronald F van Vollenhoven², Jon Lampa³, Merete Hetland⁴, Espen Haavardsholm⁵, Dan Nordström⁶, Michael Nurmohamed⁷, Bjorn Gudbjornsson⁸, Anna Rudin⁹, Mikkel Ostergaard¹⁰, Till Uhlig¹¹, Gerdur Grondal⁸, Kim Hørslev-Petersen¹², Marte S Heiberg⁵, Tuulikki Sokka-Isler¹³, Jos Twisk¹⁴ and Irene van der Horst-Bruinsma¹⁵, ¹Department of Medicine, Rheumatology Unit, The Karolinska Institute, Stockholm, Sweden, ²Amsterdam University Medical Centers, Department of Rheumatology and Clinical Immunology, Rheumatology and Immunology Center ARC, Amsterdam, Netherlands, ³Karolinska University Hospital, Department of Medicine, Rheumatology Unit, The Karolinska Institute, Stockholm, Sweden, Stockholm, Sweden, ⁴DANBIO and COPECARE, Centre for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark, ⁵Diakonhjemmet Hospital, Oslo, Norway, ⁶Division of Internal Medicine and Rheumatology, Helsinki University Hospital, Helsinki, Finland, ⁷Amsterdam University Medical Centers, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands, ⁸Landspitali University Hospital, University of Iceland, Reykjavik, Iceland, ⁹Rheumatology Clinic, Sahlgrenska University Hospital, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden, ¹⁰Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, and Department of Clinical Medicine, University of Copenhagen, Glostrup, Denmark, ¹¹Diakonhjemmet Hospital, University of Oslo, Oslo, Norway, ¹²Danish Hospital for Rheumatic Diseases, University of Southern Denmark, Reykjavik, Iceland, Haderslev, Denmark, ¹³University of Eastern Finland, Jyväskylä Central Hospital, Jyväskylä, Finland, ¹⁴Department of Epidemiology and Biostatistics, Amsterdam University Medical Centres, Amsterdam, Netherlands, ¹⁵Department of Rheumatology, VU University Medical Centre, Amsterdam, Netherlands

Meeting: ACR Convergence 2021

Keywords: Abatacept, corticosteroids, rheumatoid arthritis, Tocilizumab

Session Information

Date: Monday, November 8, 2021

Session Title: RA – Treatments Poster II: PROs, Biomarkers, & Systemic Inflammation (1223–1256)

Session Type: Poster Session C

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

Background/Purpose: To investigate sex differences in clinical response to three different biological treatments in combination with methotrexate (MTX) versus MTX plus corticosteroids (active conventional treatment; ACT), in early RA. We hypothesized that men and women differ in their response to one or several treatments.

Methods: DMARD-naïve patients with symptom duration < 2 years, moderate to severe disease activity (DAS28-CRP >3.2) and RF or ACPA positivity, or increased CRP (≥10 mg/L) were randomized in the phase IV NORD-STAR trial (NCT01491815) on 1:1:1:1 ratio, stratified by country, sex and ACPA status to 1)ACT; 2)certolizumab pegol (CPZ); 3)abatacept (ABA); 4)tocilizumab (TCZ)¹. Remission outcomes were analyzed with longitudinal logistic generalized estimating equations analysis. The model included treatment, time (4, 8, 12, 16, and 24 weeks) and sex. The primary and secondary clinical results of the trial after 24 weeks have been published¹. For this sub-study, the co-primary outcomes were differences in clinical disease activity index remission (CDAI≤2.8) over 24 weeks and at 24 weeks with ACT as the reference. Sex differences were assessed by interaction terms (males vs. females within each treatment comparison).

Results: This study included all 812 patients in the NORD-STAR trial (251 men and 561 women). The mean age was 56.5 (SD 14.0) and 53.2 (SD 15.0) years in males and females, respectively. Corresponding baseline DAS28-CRP was 5.0 (SD 1.0) and 5.0 (SD 1.1) and CDAI 27.5 (SD 11.6) and 28.1 (SD 12.0).
The crude CDAI remission rates at 24 weeks were 55.0% in males and 50.0% in females for ACT, 57.1% and 52.4% for CZP, 65.0% and 51.1% for ABA and 61.1% and 39.6% for TCZ (Figure 1). The analyses were adjusted for the stratification variables, age, BMI and DAS28-CRP at baseline. Using ACT as the reference, the adjusted overall odds ratios (OR) for achieving CDAI remission (95% confidence intervals, CI) with CZP were 1.26 (0.73-2.19) and 1.26 (0.88-1.81) in males and females, respectively, with ABA 1.25 (0.74-2.13) and 0.86 (0.60-1.24) and with TCZ 1.70 (1.01-2.87) and 0.76 (0.51-1.13). Corresponding odds ratios at 24 weeks with CZP were 1.41 (0.62-3.18) and 1.12 (0.66-1.89), with ABA 2.19 (0.96-4.97) and 1.04 (0.62-1.73) and with TCZ 1.54 (0.68-3.49) and 0.66 (0.38-1.14). For the primary and several secondary outcomes, women responded significantly poorer than men to TCZ compared with ACT (Table 1).
The percentage of males and females who experienced at least one adverse event with ACT was 85.7% and 86.1%, respectively, with CZP 82.5% and 82.7%, with ABA 70.3% and 84.3% and with TCZ 93.2% and 96.0%. The percentage of men and women who stopped treatment early with ACT was 6.3% and 11.1%, respectively, with CZP 12.5% and 10.8%, with ABA 6.3% and 5.0% and with TCZ 6.8% and 14.0%.

Conclusion: After 24 weeks, higher remission rates were observed in men than in women for all four treatment arms, suggesting that this generalized sex difference is related to the disease itself rather than to the treatments. In contrast, a distinctly lower treatment response was seen in female patients treated with tocilizumab versus conventional treatment, suggesting a sex-effect that is specific for IL-6 blockade.

References
1.Hetland et al. BMJ 2020; 371:m4328

Disclosures: K. Lend, None; R. van Vollenhoven, Bristol-Myers Squibb, 2, 5, 6, GlaxoSmithKline, 2, 5, 6, Eli Lilly, 5, Pfizer, 2, 5, 6, Roche, 5, UCB, 2, 5, 6, AbbVie, 2, 6, AstraZeneca, 2, 6, Biogen, 2, 6, Biotest,, 2, 6, Galapagos, 2, 6, Gilead, 2, 6, Janssen, 2, 6, Sanofi, 2, 6, Servier, 2, 6, Velabio, 2, 6, BMS, 5, GSK, 5, Celgene, 2, 6; J. Lampa, None; M. Hetland, Biogen, 2, 5, 6, Celltrion, 2, 6, Janssen Biologics B.V, 2, 6, MSD, 2, 6, Pfizer, 2, 5, 6, Samsung Bioepis, 2, 6, AbbVie, 5, BMS, 5, Eli Lilly Denmark A/S, 5, 12, personal fees, Lundbeck Fond, 5, Roche, 5, Sandoz, 5, Novartis, 5, Merck, 5, Orion Pharma, 12, personal fees, Medac, 6; E. Haavardsholm, Pfizer, 6, AbbVie, 2, 6, Celgene, 2, Janssen, 2, Gilead, 2, Eli-Lilly, 2, UCB, 2, 6, Novartis, 12, personal fees; D. Nordström, Abbvie, 6, BMS, 6, Lilly, 6, MSD, 6, Novartis, 6, Pfizer, 6, Roche, 6, UCB, 6, Celgene, 5; M. Nurmohamed, BMS, 5, Abbvie, 5, Celltrion, 12, personal fees, MSD, 5, Pfizer, 5, Amgen, 5, Eli Lilly, 12, personal fees; B. Gudbjornsson, Novartis Healthcare, 2, Amgen, 6; A. Rudin, AstraZeneca, 12, financial support; M. Ostergaard, AbbVie, 2, 5, 6, Bristol-Myers Squibb, 2, 6, Celgene, 2, 6, Novartis, 2, 5, 6, Boehringer Ingelheim, 2, 6, Eli Lilly, 2, 6, Hospira, 2, 6, Janssen, 2, 6, Merck, 2, 5, 6, Novo, 2, 6, Orion, 2, 6, Pfizer Inc, 2, 6, Regeneron, 2, 6, Roche, 2, 6, UCB, 2, 6, GSK, 2, 6, Mundipharma, 2, 6, Schering-Plough, 2, 6, Takeda, 2, 6, Wyeth, 2, 6, Centocor, 2, 5, 6; T. Uhlig, None; G. Grondal, None; K. Hørslev-Petersen, None; M. Heiberg, Roche, 6; T. Sokka-Isler, AbbVie, 2, Amgen, 2, BMS, 2, Celgene, 2, DiaGraphIT, 2, Medac, 2, MSD, 2, Novartis Healthcare, 2, Orionpharma, 2, Pfizer, 2, Roche, 2, Sandoz, 2, UCB, 2; J. Twisk, None; I. van der Horst-Bruinsma, None.

To cite this abstract in AMA style:

Lend K, van Vollenhoven R, Lampa J, Hetland M, Haavardsholm E, Nordström D, Nurmohamed M, Gudbjornsson B, Rudin A, Ostergaard M, Uhlig T, Grondal G, Hørslev-Petersen K, Heiberg M, Sokka-Isler T, Twisk J, van der Horst-Bruinsma I. Sex Differences in Treatment Response to Three Different Biological Treatments and Corticosteroids in Patients with Early Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 10). https://acrabstracts.org/abstract/sex-differences-in-treatment-response-to-three-different-biological-treatments-and-corticosteroids-in-patients-with-early-rheumatoid-arthritis/. Accessed May 25, 2022.

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