It is concluded that precision medicine in RA will require integrated biomarker panels combining clinical, pharmacological, molecular, and synovial tissue data, and the development of scalable, externally validated, and clinically interpretable models capable of assigning synovial endotypes and supporting mechanism-based therapeutic selection.
Abstract
Rheumatoid arthritis (RA) is a biologically heterogeneous immune-mediated disease characterized by substantial variability in therapeutic response. Despite the availability of multiple conventional synthetic, biologic, and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), many patients fail to achieve adequate disease control or experience secondary loss of efficacy, underscoring the need for predictive biomarkers that can guide treatment selection. This narrative review was based on a structured literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, covering publications from January 2000 to June 2026, with earlier landmark studies included when relevant. Literature selection followed PRISMA-informed principles, although the review was not designed as a formal systematic review. Unlike previous reviews that mainly catalogue RA biomarkers by analytical platform, drug class, or clinical use, this review integrates conventional and emerging biomarkers within a tissue-immunophenotype-centered framework. We critically evaluate clinical, serological, pharmacological, molecular, imaging, and tissue-based biomarkers according to biological plausibility, reproducibility, level of validation, clinical actionability, and translational readiness. Established markers such as rheumatoid factor, anti-citrullinated protein antibodies, acute-phase reactants, drug concentrations, and anti-drug antibodies remain clinically useful but provide incomplete insight into mechanism-specific therapeutic response. In contrast, synovial pathotypes, fibroblast and macrophage subsets, B-cell niches, tertiary lymphoid structures, single-cell and spatial omics, and ligand–receptor interaction networks offer a mechanistically richer view of treatment response and resistance. We conclude that precision medicine in RA will require integrated biomarker panels combining clinical, pharmacological, molecular, and synovial tissue data. The key future direction is the development of scalable, externally validated, and clinically interpretable models capable of assigning synovial endotypes and supporting mechanism-based therapeutic selection.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic erosive synovitis, progressive bone destruction, and marked inter-patient heterogeneity in disease course and treatment response. This review critically examines the mechanisms underlying RA immunological heterogeneity, including genetic susceptibility, epigenetic regulation, autoantibody diversification, synovial pathotypes, and gut-joint axis-related immune-metabolic interactions. We further discuss how peripheral blood multi-omics, synovial molecular pathology, and biopsy-driven clinical trial evidence may inform early stratification and prediction of primary non-response. Rather than proposing a deterministic precision-medicine model, this review emphasizes an evidence-weighted framework in which molecular and tissue-level biomarkers are integrated with clinical phenotype and longitudinal treatment response. Emerging approaches, including pharmacomicrobiomics, local drug delivery, nanomedicine, and cell-based therapies, are evaluated as investigational strategies that require further validation. Overall, this review highlights how a more critical understanding of RA heterogeneity may improve patient stratification and support more rational therapeutic selection.
Yan-Mei Li, Kairui Zhu, Yushan Ding et al.· Frontiers in Immunology· 0 citations
Although inflammatory biomarkers provide a biologically grounded framework for assessing treatment response, their clinical implementation remains limited and further large-scale, standardized studies are required to validate candidate markers and support the development of integrated, multi-omics approaches for personalized management.
J. Lewandowska, A. Owczarczyk-Saczonek, B. Nedoszytko· International Journal of Mol...· 0 citations
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, structural damage, and disability. Methotrexate (MTX) is the first‐line treatment; however, up to one‐third of patients exhibit an inadequate response. This systematic review aimed to identify clinical, serological, genetic, pharmacogenomic, and treatment‐related predictors of MTX response in RA.
A systematic search of PubMed/MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted for studies published up to May 22, 2024. Randomized controlled trials, prospective cohort studies, and registry‐based studies evaluating predictors of MTX efficacy were included. In total, 87 studies met the eligibility criteria and were included in the review. Predictors were categorized as demographic/clinical, disease‐related, serological/immunological, genetic/pharmacogenomic, treatment‐related, and emerging. Evidence was synthesized narratively, with consideration of methodological quality and consistency.
Consistent predictors of favorable MTX response included lower baseline disease activity, better functional status, early MTX initiation, and absence of erosive disease. Male sex, older age, and moderate alcohol consumption were associated with improved outcomes, although these associations may be influenced by treatment‐related and behavioral confounders, whereas smoking and higher body mass index were linked to reduced efficacy. Several inflammatory and cellular biomarkers were associated with MTX response, although individual pharmacogenetic variants showed limited reproducibility. Treatment‐related factors, including subcutaneous administration, rapid dose escalation, glucocorticoid co‐therapy, and folate supplementation, were associated with improved efficacy and tolerability. Emerging proteomic, epigenetic, and metabolomic signatures demonstrated potential for early response prediction.
Overall, early disease control and optimized treatment strategies appear to be more reliable predictors of MTX response than isolated demographic or genetic factors. Integration of clinical predictors with emerging molecular biomarkers may support personalized treatment approaches and earlier identification of MTX non‐responders.
CRD42023464365.
J. Rodrigues, Helena Donato, S. Azevedo et al.· Rheumatology & Autoimmun...· 0 citations
Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease. Despite established serological classification and advances in therapeutic strategies, around 40% of patients exhibit inadequate responses to first-line DMARDs. Current clinical tools remain limited in their ability to predict treatment response and risk of joint erosion, posing a significant challenge to precision medicine. There is a critical need for novel biomarkers that can reliably forecast disease outcomes and guide therapeutic decisions. Integrating protein signatures with clinical features may enhance risk stratification in rheumatic diseases.[1] In this study, we employed data-independent acquisition mass spectrometry (DIA-MS) to perform a comprehensive longitudinal serum proteomic analysis in RA patients, aiming to identify biomarkers predictive of disease activity and progression.
This study was conducted on serum samples collected from 107 DMARD- and steroid-free RA patients (48 seronegative, 59 seropositive) enrolled in the EUPA cohort (
NCT00512239
), between 2005 and 2019, at the CIUSSS de l’Estrie-CHUS, Québec, Canada.[2] Serial sera collected at baseline and at the 12-month follow-up visit were analyzed by DIA-MS. MS data were analyzed using DIA-NN software for peptides/proteins identification and quantification. Statistical analyses were performed using R: Differentially abundant proteins (DAPs) across clusters were identified by Mann-Whitney U test with Bonferroni correction. KEGG enrichment analyses were conducted using the PathfindR R package, with BH correction. Generalized estimating equations (GEE) models were adjusted for age, sex, serology, and symptom duration, with FDR correction using Storey’s q-value.
Proteomic profiling quantified 869 serum proteins, of which 368 passed quality control and filtering for downstream statistical analyses. 1-Principal component analysis (PCA) followed by hierarchical clustering of baseline (Figure 1A), and 12-month proteomic data suggested patients could be grouped into 2 clusters. 2-KEGG pathway analysis of DAPs between patient clusters showed significant enrichment of complement and coagulation cascades pathway. 3-These clusters exhibited distinct serum levels of complement-related proteins (Figure 1B). 4-C68omparison of patient trajectories between baseline and 12-month serum-based clusters (Figure 1C), revealed that transitions between clusters were accompanied by significant modulation of complement-related protein levels (Figure 1D). 5-GEE models identified 29 proteins (q-value ≤0.05) associated with binomial 12-month disease activity, defined as DAS28-CRP ≤2.6 or ≥3.2, which were enriched for KEGG complement and coagulation cascades pathway.
Figure 1.
A)
Hierarchical Clustering on PCA was performed on RA patients’ baseline serum proteome.
B)
Baseline serum complement pathway (KEGG hsa04610) protein levels were normalized by z-scores. Average z-scores per patient are shown as a color gradient over PCA plot.
C)
Sankey plot of patient trajectories between baseline and 12-month proteome-based clusters.
D)
Average serum complement proteins z-scores of patients grouped by cluster trajectories BH-adjusted p ≤ 0.05 = * and ≤ 0.001 = ***.
This study highlights the heterogeneity of circulating complement components in early RA patients, suggesting that complement protein profiles may reflect underlying disease mechanisms beyond general inflammation and could inform future biomarker-driven approaches to RA management.
[1.] Carrasco-Zanini J. Nat Med 2024;30:2489-98. [2.] Carrier N. J Rheumatol 2024;52:119-27.
Benoît Marchand, N. Carrier, Elizabeth Beaulieu et al.· Journal of Rheumatology· 0 citations
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated condition with substantial global burden and rising incidence, requiring an expanding range of advanced therapies. This focused narrative review examines the mechanistic rationale, comparative clinical evidence, and translational implications of approved and emerging targeted therapies for adult IBD. A structured literature search was conducted in PubMed, Scopus, and Web of Science for publications from January 2021 to March 2026. Thirty-eight articles were selected as the core evidence set with landmark trials and clinical guidelines added when needed for historical or practice context. Evidence was synthesised narratively, with an explicit distinction between direct head-to-head comparisons, placebo-controlled trials, indirect network comparisons, and observational data. In UC, VARSITY showed higher week-52 clinical remission and endoscopic improvement with vedolizumab than adalimumab; in CD after anti–tumour necrosis factor (anti-TNF) failure, SEQUENCE showed risankizumab noninferior to ustekinumab for week-24 clinical remission and superior for week-48 endoscopic remission. Agents targeting tumour necrosis factor-like cytokine 1A (TL1A) have shown encouraging activity in phase 2/2b trials, but long-term effectiveness and safety remain uncertain. The current evidence supports mechanism-informed rather than biomarker-defined treatment selection. Confidence in comparative conclusions is greatest when supported by direct randomised evidence, whereas observational and indirect comparisons require caution because of confounding, heterogeneity, and differences in populations and outcome definitions. Clinical translation therefore requires the integration of the disease phenotype, prior treatment exposure, safety risks, and patient preference, with objective reassessment after therapy initiation.
C. Pavel, A. Popa, M. Ilie et al.· Journal of Clinical Medicine· 0 citations
RATIONALE
After inadequate response to first-line biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drug (DMARD) therapy in adults with rheumatoid arthritis, there are numerous alternative DMARD options, and current understanding of their comparative benefits and harms is limited.
OBJECTIVES
The aim of this living systematic review and network meta-analysis was to compare the benefits and harms of DMARDs after failure of biologic or targeted synthetic DMARDs in adults with rheumatoid arthritis.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and the WHO ICTRP) from inception until 28 November 2025, with no restrictions on language or date of publication.
ELIGIBILITY CRITERIA
We included randomised controlled trials (RCTs) of adults aged 18 years or older diagnosed with rheumatoid arthritis according to 1958, 1987, or 2010 classification criteria who previously demonstrated inadequate response to a b/ts DMARD. Eligible interventions included conventional synthetic DMARDs (methotrexate, antimalarials, sulfasalazine, leflunomide, ciclosporin, and azathioprine), biologic DMARDs (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, tocilizumab, sarilumab, and anakinra), and targeted synthetic DMARDs (tofacitinib, baricitinib, and upadacitinib).
OUTCOMES
Our critical outcomes were American College of Rheumatology 50% (ACR50) response, withdrawals due to adverse events, radiographic progression, Disease Activity Score 28 (DAS28) remission, pain as measured by visual analogue scale, function as measured by the Health Assessment Questionnaire (HAQ), and serious adverse events. Important outcomes included ACR20, ACR70, serious infections, fatigue, and quality of life.
RISK OF BIAS
We used Cochrane's RoB 1 tool to assess risk of bias in the included studies.
SYNTHESIS METHODS
We first screened the records using an approach that combined machine learning and crowdsourcing to identify probable RCTs. We then reviewed the records identified as RCTs for eligibility and simultaneously classified them to the appropriate Population, Intervention, Comparator, and Outcome (PICO) question(s). Two review authors then extracted relevant data from the included studies in duplicate and independently, with any disagreements resolved by a third review author. A Bayesian random-effects network meta-analysis was conducted using a semi-informative prior probability distribution. We assessed the certainty of evidence for each outcome using the GRADE approach.
INCLUDED STUDIES
We included 19 unique studies (4779 participants) in the review, all of which were parallel-design RCTs. Eleven trials were placebo controlled; two trials had an inactive comparator arm; and six trials had an active comparator arm. The trials were performed in a well-established rheumatoid arthritis population, with the median baseline disease duration ranging from 6.4 to 14 years, median age of participants ranging from 49 to 58 years, and median baseline disease activity (DAS28) ranging from 4.87 to 6.79.
SYNTHESIS OF RESULTS
ACR50 response We found moderate-/high-certainty evidence that using a tumour necrosis factor (TNF) inhibitor not previously tried, interleukin-6 (IL-6) inhibitors, abatacept, rituximab, and Janus kinase (JAK) inhibitors was more effective than placebo: TNF inhibitor not previously tried (odds ratio (OR) 6.04, 95% credible interval (CrI) 2.49 to 16.3; high-certainty evidence), sarilumab (OR 3.11, 95% CrI 1.25 to 7.76; high-certainty evidence), tocilizumab 4 mg/kg intravenous (OR 5.31, 95% CrI 2.09 to 12.09; high-certainty evidence), tocilizumab 8 mg/kg intravenous (OR 10.03, 95% CrI 3.65 to 31.27; high-certainty evidence), subcutaneous abatacept (OR 4.31, 95% CrI 0.97 to 18.28; moderate-certainty evidence), intravenous abatacept (OR 4.57, 95% CrI 2.21 to 10.18; high-certainty evidence), rituximab (OR 5.50, 95% CrI 2.31 to 13.12; high-certainty evidence), upadacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), tofacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), baricitinib 2 mg (OR 2.00, 95% CrI 0.77 to 5.23; moderate-certainty evidence), baricitinib 4 mg (OR 2.79, 95% CrI 1.10 to 7.22; high-certainty evidence). With an assumed risk for placebo of 78 out of 1000 patients, the expected effects for the active drugs ranged from 143 (baricitinib 2 mg) to 455 (tocilizumab 8 mg/kg). Withdrawals due to adverse events For most interventions, there were sparse data with low-certainty evidence, except for TNF inhibitor not previously tried (risk ratio (RR) 0.32, 95% CrI 0.07 to 1.1; moderate-certainty evidence), which is probably less harmful than placebo, and sarilumab (RR 1.98, 95% CrI 0.57 to 7.19; moderate-certainty evidence), which is probably more harmful than placebo. Low-certainty evidence suggests that intravenous abatacept (RR 0.92, 95% CrI 0.34 to 2.79), upadacitinib (RR 0.41, 95% CrI 0.08 to 1.83), and baricitinib 2 mg (RR 0.93, 95% CrI 0.22 to 4.01) may be less harmful than placebo. Low-certainty evidence suggests that tocilizumab 4 mg/kg (RR 1.39, 95% CrI 0.39 to 5.28), tocilizumab 8 mg/kg (RR 1.49, 95% CrI 0.51 to 4.81), subcutaneous abatacept (RR 3.11, 95% CrI 0.05 to 249.6), rituximab (RR 2.38, 95% CrI 0.44 to 23.31), tofacitinib (RR 1.37, 95% CrI 0.35 to 5.58), and baricitinib 4 mg (RR 1.43, 95% CrI 0.38 to 5.81) may be more harmful than placebo. Data were insufficient to perform a network meta-analysis for radiographic progression. For DAS28 and the HAQ, there was mostly moderate-/high-certainty evidence of a benefit, with some exceptions for comparisons with indirect evidence only that was of low or very low certainty. For the other efficacy outcomes, data were sparse with wide credible intervals, and the certainty of evidence was typically low.
AUTHORS' CONCLUSIONS
We found high-certainty evidence that nine therapies and moderate-certainty evidence that two therapies provide a clinically important benefit in improving disease activity compared to placebo for people with rheumatoid arthritis after failure of b/ts DMARD therapy. There was significant uncertainty surrounding treatment-related harms, with the evidence having been downgraded for serious or extremely serious imprecision. Pair-wise comparisons showed no significant differences among therapies, although the certainty of evidence was low. The lack of clarity regarding safety and comparative efficacy suggests that treatment decisions should be guided by individual patient characteristics and preferences.
FUNDING
This work was supported by grants from the Canadian Institutes for Health Research (CIHR) [Funding Reference Numbers (FRN) 178375 and 180324] and the National Health and Medical Research Council (NHMRC) Cochrane Collaboration. This research was supported by Arthritis Society Canada (Doctoral Studentship TGP-23-0211).
REGISTRATION
This study was outlined in a Cochrane protocol (CD013562; DOI 10.1002/14651858.CD013562).
Jocelyn Thomas, M. Kamso, Samuel L. Whittle et al.· Cochrane Database of Systema...· 0 citations
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