Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial

Humby, Frances; Durez, Patrick; Buch, Maya H; Lewis, Myles; Rizvi, Hasan; Rivellese, Felice; Nerviani, Alessandra; Giorli, Giovanni; Mahto, Arti; Montecucco, Carlomaurizio; Lauwerys, Bernard; Ng, Nora; Ho, Pauline; Bombardieri, Michèle; Romão, Vasco C; Verschueren, Patrick; Kelly, Stephen; Sainaghi, Pier Paolo; Gendi, Nagui; Dasgupta, Bhaskar; Cauli, Alberto; Reynolds, Piero; Cañete, Juan D.; Moots, Robert J.; Taylor, Peter; Edwards, Christopher J; Isaacs, John D.; Sasieni, Peter; Choy, Ernest; Pitzalis, Costantino; Thompson, Charlotte; Bugatti, Silvia; Bellan, Mattia; Congia, Mattia; Holroyd, Christopher; Pratt, Arthur G.; Fonseca, João Eurico; White, Laura; Warren, Louise; Peel, Joanna; Hands, Rebecca; Fossati-Jimack, Liliane; Hadfield, Gaye; Thorborn, Georgina; Ramírez, Julio; Celis, Raquel

doi:10.1016/s0140-6736(20)32341-2

Cited by 189 publications

(161 citation statements)

References 31 publications

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“…Unlike in oncology, DNA analyses and biopsies of disease tissue are not readily available in the care of patients with RA because synovial biopsies outside of clinical studies are rare and DNA sequence variations provide limited actionable information in RA [ 54 – 56 ]. In the R4RA trial, RNA sequencing-based identification of patients with RA with a low or absent B cell lineage gene expression signature in synovial tissue significantly correlated with a superior response to tocilizumab than rituximab, thus suggesting that gene expression may be used to predict response to other targeted therapies in RA [ 57 ]. Studies of the AMPLE, AVERT, GO‐BEFORE, and GO‐FORWARD trials have used baseline disease assessments such as DAS28, RAPID3, CDAI, or SDAI to predict radiographic progression or magnetic resonance imaging-detected synovitis in response to treatment with a targeted therapy [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study

Cohen

Wells²,

Curtis

et al. 2021

Rheumatol Ther

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Introduction Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. Methods The protein–protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. Results The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0–8.3, p value 0.0001). Odds ratios (3.4–8.8) were significant ( p value < 0.01) for additional endpoints at 3 and 6 months, with AUC values up to 0.74. Among TNFi-exposed patients, the MSRC had an AUC of up to 0.83 and was associated with significant odds ratios of 3.3–26.6 by ACR, DAS28-CRP, and CDAI metrics. Conclusion The MSRC stratifies patients according to likelihood of inadequate response to TNFi therapy and provides patient-specific data to guide therapy choice in RA for targeted therapy-naïve and TNFi-exposed patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00330-y.

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Section: Discussionmentioning

confidence: 99%

A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study

Cohen

Wells²,

Curtis

et al. 2021

Rheumatol Ther

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“…However, in the synovial biopsies classified as B-cell poor with RNA sequencing the TCZ group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 (36%) of 33 patients vs TCZ group 20 (63%) of 32 patients; difference 26% (2 to 50), p=0·035). 35 Since the synovium is the ultimate target of RA, it is very likely that we could identify potential treatment biomarkers. Indeed, in the study mentioned above, in patients with RA with low or absent B-cell expression in the synovium, TCZ seems to be more effective than rituximab, a B-cell depleting agent.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in the first-ever biopsy-based randomised controlled trial in RA, in patients histologically classified as B-cell poor, there was no statistically significant difference in the primary endpoint (50% improvement in CDAI50% from baseline) between the rituximab-treated group and the TCZ group. However, in the synovial biopsies classified as B-cell poor with RNA sequencing the TCZ group 35 Since the synovium is the ultimate target of RA, it is very likely that we could identify potential treatment biomarkers. Indeed, in the study mentioned above, in patients with RA with low or absent B-cell expression in the synovium, TCZ seems to be more effective than rituximab, a B-cell depleting agent.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL

et al. 2021

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ObjectivesOur knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.ResultsDisease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.ConclusionsTCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.

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“…This multiplicity of treatment options poses relevant questions about how to best interfere with different proinflammatory processes in individual PsA patients because clinicians lack reliable tools to select the best therapeutic pathway to target to optimize clinical response. A priori, tissue-specific biomarkers are the most promising candidates to stratify patients based on the actual ongoing pathogenic process and are suitable for targeting by pharmacological treatments, as demonstrated by some attempts in other chronic inflammatory joint diseases, such as rheumatoid arthritis (RA) ( Humby et al, 2021 ). Despite important discoveries in this field, there are still great obstacles to the goal of “personalized arthritis medicine’ in the context of PsA ( Jadon et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…The possibility of translating this seminal evidence into clinical practice is fascinating. In a similar condition such as RA, a recent RCT, for the first time, exploited information derived from synovial histology and mRNA expression analysis to inform selected treatment decisions ( Humby et al, 2021 ). The combination of peripheral T-cell phenotyping ( Miyagawa et al, 2018 ) with single-cell analysis at target tissue levels might also be used to inform treatment schedules in the context of PsA.…”

Section: Introductionmentioning

confidence: 99%

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis

et al. 2021

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Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically “predictive”: the expected response is based on stratification according to clinical, imaging, and laboratory data, with a “heuristic” approach based on “trial and error”. Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially “broad-spectrum” mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of “refractory to a treatment” patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.

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Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial

Cited by 189 publications

References 31 publications

A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study

A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study

Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis

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