Head-To-Head Comparison of the Effectiveness of Tocilizumab, Rituximab, Mycophenolate Mofetil, and Cyclophosphamide in Patients with SSc-ILD from the EUSTAR Database

Qingran Yan¹, Cosimo Bruni², Alexandru Garaiman², Carina Mihai², Suzana Jordan², Mike Becker³, Muriel Elhai⁴, Rucsandra Dobrota², liubov Petelytska³, Anna-Maria Hoffmann-Vold⁵, Joerg Henes⁶, Eric Hachulla⁷, Elise Siegert⁸, Alexandra Balbir-Gurman⁹, Giovanna Cuomo¹⁰, Gabriela Riemekasten¹¹, Stefan Heitmann¹², valeria Riccieri¹³, Susanne Ullman¹⁴, Petros Sfikakis¹⁵, Francesca Ingegnoli¹⁶, Vera Bernardino¹⁷, Marie-Elise Truchetet¹⁸, Francesco Del Galdo¹⁹, SHUANG YE²⁰ and Oliver Distler², ¹Department of Rheumatology, University Hospital Zurich, Zurich, Swaziland, ²Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, ³Department of Rheumatology, University Hospital Zurich, University of Zurich, Zürich, Switzerland, ⁴University Hospital zurich, University of Zurich, Zurich, Switzerland, ⁵Oslo University Hospital, Oslo, Norway, ⁶University Hospital Tuebingen, Tuebingen, Germany, ⁷University of Lille, Lille, France, ⁸Department of Rheumatology, Charité University Hospital, Charité Platz 1, D-10117, Berlin, Germany, ⁹Rheumatology Institute, Rambam Health Care Campus and Rappaport Faculty of |Medicine, Technion, Haifa, Israel, ¹⁰Department of Precision Medicine, “Luigi Vanvitelli” University of Campania, Naples, Italy, ¹¹University Clinic Schleswit-Holstein (UKSH), Lübeck, Germany, ¹²Department of Rheumatology, Marienhospital Stuttgart, Böheimstrasse 37, D-70199, Stuttgart, Germany, ¹³Department of Clinical, Internal and Cardiovascular Specialities, Sapienza University of Rome, Roma, Italy, ¹⁴Department of Dermatology, University Hospital of Copenhagen, Hospital Bispebjerg, Copenhagen, Denmark, ¹⁵National Kapodistrian University of Athens Medical School, Athens, Greece, ¹⁶Universita' degli Studi di Milano, Milano, Italy, ¹⁷Centro Hospitalar Lisboa Central, Lisbon, Portugal, ¹⁸Bordeaux University Hospital, Bordeaux, France, ¹⁹University of Leeds - Leeds Institute of Rheumatic and Muskuloskeletal Medicine, Leeds, United Kingdom, ²⁰Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Meeting: ACR Convergence 2023

Keywords: Disease-Modifying Antirheumatic Drugs (Dmards), interstitial lung disease, Intervention, Systemic sclerosis

Session Information

Date: Wednesday, November 15, 2023

Title: Abstracts: Systemic Sclerosis & Related Disorders III: Clinical Trials

Session Type: Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Tocilizumab (TCZ), rituximab (RTX), mycophenolate mofetil (MMF), and cyclophosphamide (CYC) are the immunosuppressants (IS) with the current best evidence for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD)^1-4. However, limited information is available from comparison studies, and these treatments have often been tested in diverse populations. This study aimed to compare the effectiveness of TCZ, RTX, MMF, and CYC in SSc-ILD patients from the EUSTAR database.

Methods: We included SSc patients from the EUSTAR database who fulfilled the following criteria: 1/ radiologically confirmed ILD; 2/ database record on the use of TCZ, RTX, MMF, or CYC; 3/ baseline and follow-up lung function associated with the treatment period. The primary endpoint was the change of forced vital capacity (FVC) % predicted from baseline to follow-up. Secondary endpoints included changes in diffusing capacity (DLCO) % predicted, modified Rodnan Skin Score (mRSS), and categorical changes in lung function tests and mRSS. Missing data were processed using multiple imputations with chained equations. Selection bias of the medications was reduced to a minimum using propensity score-based inverse probability of treatment weighting (IPTW). For paired therapy comparisons, we used average treatment effects (ATE). Subgroup analysis included previous IS use, background IS, and treatment duration (less than 18 months).

Results: 995 patients with 1050 treatment observations were included in this study. TCZ patients had more arthritis, higher baseline FVC and DLCO, more reticular change in chest CT, and less ground glass opacity. RTX and CYC patients had more elevations of C-reaction protein, and TCZ and RTX patients had higher baseline mRSS, more digital ulcers, and fewer IS naive cases (Table 1).

The median follow-up time was 11 months (interquartile range: 8-14 months). After IPTW, the changes of FVC % predicted were not significantly different between the four treatment arms by the Kruskal Wallis test (P=0.058, Figure 1). Among paired comparisons, only the treatment difference between CYC vs. RTX was significant (mean difference of FVC % predicted, 2.29; 95% CI, 0.18-4.40; P=0.034, Table 2).

In the multivariate logistic regression, only CYC was associated with stable or improved FVC among the four agents. The treatment differences in change of FVC% predicted among the four groups were not significant in patients with previous IS, background IS, or treatment duration > 18 months. Interestingly, MMF showed better FVC responses in patients with previous IS than in IS naive patients [Mean adjusted change of FVC % predicted (95% CI): 1.90 (0.36 to 3.45) vs. -0.04 (-1.35 to 1.26), P=0.047].

Conclusion: In this first large real-world observational study, the treatment effectiveness on FVC change of SSc-ILD patients was not statistically different between TCZ, RTX, MMF, and CYC. CYC showed clinically marginal but statistically significantly better effectiveness in some sub-analyses. Head-to-head randomized clinical trials on IS with longer follow-up are needed for SSc-ILD.

Table1. Patient parameters pre- and post-IPTW. IPTW, inverse probability of treatment weighting; CYC, cyclophosphamide; MMF, mycophenolate mofetil; RTX, rituximab; TCZ, tocilizumab; CRP, C-reaction protein; DU, digital ulcer; SRC, scleroderma renal crisis; ACA, anti-centromere antibody; ATA, anti-topoisomerase I antibody; ESR, erythrocyte sediment rate; LVEF, left ventricular ejection fraction; RHC, right heart catheter; PH, pulmonary hypertension; FVC, forced vital capacity; DLCO, diffusing capacity of the lungs for carbon monoxide; HRCT, high-resolution computational tomography; GGO, ground-glass opacity; AZA, azathioprine; LEF, leflunomide; MTX, methotrexate.

Figure 1. Post IPTW accumulative probability of the change of FVC% predicted with the treatment of cyclophosphamide (CYC), mycophenolate mofetil (MMF), rituximab (RTX), and tocilizumab (TCZ).

Table 2. Paired comparisons between the effectiveness of cyclophosphamide (CYC), mycophenolate mofetil (MMF), rituximab (RTX), and tocilizumab (TCZ) in ∆FVC% predicted from the baseline to the one-year follow-up. Average treatment effects were used for paired comparisons after IPTW.

Disclosures: Q. Yan: Simcere, 6; C. Bruni: AbbVie/Abbott, 5, Boehringer-Ingelheim, 2, 12, Travel Support, Eli Lilly, 6; A. Garaiman: None; C. Mihai: Boehringer-Ingelheim, 2, 5, 6, Janssen, 2, MED Talks Switzerland, 2, Mepha, 2, PlayToKnow AG, 2; S. Jordan: None; M. Becker: Amgen, 6, Bayer, 6, GSK, 6, Mepha, 6, MSD, 6, Novartis, 6, Vifor, 6; M. Elhai: AstraZeneca, 12, Travel to Congress support, Janssen, 12, Congress support; R. Dobrota: Actelion, 5, 6, Amgen, 5, Articulum Fellowship, sponsored by Pfizer, 5, Boehringer-Ingelheim, 6; l. Petelytska: None; A. Hoffmann-Vold: Arxx Therapeutics, 2, Boehringer-Ingelheim, 2, 5, 6, 12, Support for travel, Genentech, 2, Janssen, 2, 5, 6, Medscape, 2, 6, 12, Support for travel, Roche, 2, 6, 12, Support for travel; J. Henes: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, Bristol-Myers Squibb(BMS), 2, 6, GlaxoSmithKlein(GSK), 2, 6, Janssen, 2, 6, Novartis, 2, 6, Pfizer, 2, 6, UCB, 2, 6; E. Hachulla: Bayer, 2, CSL Behring, 5, GlaxoSmithKlein(GSK), 2, 5, 6, johnson&Johnson, 2, 5, 6, Novartis, 2, 5, Otsuka, 6, Roche-Chugai, 2, 5, 6, sanofi-genzyme, 2, 5, Sobi, 5; E. Siegert: None; A. Balbir-Gurman: None; G. Cuomo: None; G. Riemekasten: None; S. Heitmann: None; v. Riccieri: None; S. Ullman: None; P. Sfikakis: AbbVie/Abbott, 2, 5, Amgen, 2, 5, Boehringer-Ingelheim, 2, 5, Celgene, 2, 5, Eli Lilly, 2, 5, Janssen, 2, 5, Novartis, 2, 5, Pfizer, 2, 5; F. Ingegnoli: None; V. Bernardino: None; M. Truchetet: AbbVie/Abbott, 2, 6, Boehringer-Ingelheim, 2, 6, Gilead, 5, 6, Merck/MSD, 6, UCB, 6, 12, support for conferences; F. Del Galdo: AbbVie/Abbott, 5, arxx, 2, AstraZeneca, 2, 5, Boehringer-Ingelheim, 2, 5, capella, 2, Chemomab, 2, GlaxoSmithKlein(GSK), 2, Janssen, 2, Mitsubishi-Tanabe, 2, 5; S. YE: None; O. Distler: 4P-Pharma, 2, 5, 6, AbbVie, 2, 5, 6, Acceleron, 2, 5, 6, Alcimed, 2, 5, 6, Altavant Sciences, 2, 5, 6, Amgen, 2, 5, 6, AnaMar, 2, 5, 6, Arxx, 2, 5, 6, AstraZeneca, 2, 5, 6, Bayer, 2, 5, 6, Blade Therapeutics, 2, 5, 6, Boehringer Ingelheim, 2, 5, 6, Citus AG, 12, Co-Founder, Corbus Pharmaceuticals, 2, 5, 6, CSL Behring, 2, 5, 6, Galapagos, 2, 5, 6, Galderma, 2, 5, 6, Glenmark, 2, 5, 6, Gossamer, 2, 5, 6, Horizon Therapeutics, 2, 5, 6, Janssen, 2, 5, 6, Kymera, 2, 5, 6, Lupin, 2, 5, 6, Medscape, 2, 5, 6, Miltenyi Biotec, 2, 5, 6, Mitsubishi Tanabe, 2, 5, 6, MSD, 2, 5, 6, Novartis, 2, 5, 6, Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143), 10, Prometheus Biosciences, 2, 5, 6, Redx Pharma, 2, 5, 6, Roivant, 2, 5, 6, Topadur, 2, 5, 6.

To cite this abstract in AMA style:

Yan Q, Bruni C, Garaiman A, Mihai C, Jordan S, Becker M, Elhai M, Dobrota R, Petelytska l, Hoffmann-Vold A, Henes J, Hachulla E, Siegert E, Balbir-Gurman A, Cuomo G, Riemekasten G, Heitmann S, Riccieri v, Ullman S, Sfikakis P, Ingegnoli F, Bernardino V, Truchetet M, Del Galdo F, YE S, Distler O. Head-To-Head Comparison of the Effectiveness of Tocilizumab, Rituximab, Mycophenolate Mofetil, and Cyclophosphamide in Patients with SSc-ILD from the EUSTAR Database [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/head-to-head-comparison-of-the-effectiveness-of-tocilizumab-rituximab-mycophenolate-mofetil-and-cyclophosphamide-in-patients-with-ssc-ild-from-the-eustar-database/. Accessed .

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