The diagnosis and treatment of rheumatoid arthritis (RA) have been constantly evolving for decades, pointing towards early diagnostic and therapeutic interventions. Synovial biopsy has emerged as a pivotal tool in precision medicine, transitioning from a research procedure to a clinically feasible approach. Modern ultrasound-guided techniques allow safe, reproducible access to inflamed joints, enabling direct analysis of the synovial tissue, which reveals biological heterogeneity undetectable in peripheral blood. Histological scoring, including the Krenn synovitis score, discriminates inflammatory from non-inflammatory pathology, supporting targeted escalation of immunosuppressive therapy. Molecular and histological profiling has defined distinct synovial pathotypes—lympho-myeloid, diffuse-myeloid, and fibroid/pauci-immune—with reproducible associations to therapeutic responsiveness. Moreover, biopsy-driven trials, such as R4RA and STRAP, demonstrate that pathotype-guided strategies can predict outcomes: diffuse-myeloid synovitis responds to IL-6 receptor blockade, lympho-myeloid synovitis to B cell depletion, and fibroid synovitis exhibits multidrug resistance. In difficult-to-treat RA, synovial biopsy differentiates inflammatory from non-inflammatory drivers of persistent symptoms, providing a rational basis for therapy selection. Ongoing biomarker-driven initiatives, including PRECISion and 3TR Precis-The-RA, aim to embed biopsy findings into clinical decision-making. In this review, it is underscored that the integration of histology, molecular profiling, and clinical context positions synovial biopsy as a patient-centered precision approach, guiding individualized therapy and bridging RA stratification with clinical practice.

Background: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Despite the implementation of the treat-to-target (T2T) strategy and the introduction of several classes of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), a considerable proportion of patients continues to exhibit active, refractory disease. In 2021, the European Alliance of Associations for Rheumatology (EULAR) defined this condition as Difficult-to-Treat Rheumatoid Arthritis (D2T-RA). This study aimed to identify clinical, laboratory, and therapeutic factors associated with D2T-RA. Methods: A total of 344 patients with established RA were retrospectively evaluated. Among them, 164 fulfilled the 2021 EULAR criteria for D2T-RA (D2T group), while 180 did not (NO-D2T group). Clinical (age, sex, disease duration, BMI, smoking, comorbidities), laboratory (RF, ACPA, ESR, CRP), clinimetric (DAS28, CDAI, PhGA, PGA, HAQ), and therapeutic data (glucocorticoid use, methotrexate treatment and dose, monotherapy, advanced therapy exposure, number of failed advanced therapies, current DMARD regimen) were analyzed. Results: Factors significantly associated with D2T-RA included female sex, longer disease duration, higher RF and ACPA titers, elevated ESR levels, glucocorticoid therapy, and a greater number of failed advanced therapies. Although both groups achieved low disease activity or remission by DAS28 and CDAI, JAK inhibitors—particularly Filgotinib and Upadacitinib—were significantly more common in the D2T cohort and appeared associated with clinical stabilization. Conclusions: This study strengthens the understanding of the predictive profile of D2T-RA, confirming the role of disease chronicity and persistent inflammation in the development of treatment resistance. Importantly, the observed trend toward clinical stabilization achieved under JAK inhibitor therapy reinforces their potential to address unmet therapeutic needs in D2T-RA, providing a mechanistically grounded strategy for patients refractory to conventional and biologic DMARDs.

Objective: To evaluate the impact of recommendations issued by the Pharmacovigilance Risk Assessment Committee (PRAC) and endorsed by the European Medicines Agency (EMA) and the Italian Medicines Agency (AIFA) on rheumatologists’ prescribing patterns of Janus kinase inhibitors (JAK inhibitors) and biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA), within a personalized, risk-adapted care framework. Methods: A brief survey was conducted across 21 Italian rheumatology centers. This retrospective multicenter study included 4421 RA patients assessed before PRAC recommendations (1 January 2022–1 January 2023) and 4376 patients evaluated afterward (2 January 2023–1 January 2024). Prescribing behaviors, cardiovascular risk management, and clinical outcomes were compared between cohorts. Results: Following PRAC recommendations, a more individualized cardiovascular risk management strategy was observed, with increased use of targeted treatments for hypercholesterolemia, hypertension, and diabetes. The post-PRAC cohort showed a significant reduction in myocardial infarction incidence (0.90% vs. 0.47%; p = 0.02) and increased statin use (8.25% vs. 11.1%; p = 0.05). No increase in cardiovascular risk was observed among JAK inhibitor users. Notably, upadacitinib utilization remained stable despite regulatory restrictions. Conclusions: PRAC recommendations promoted safer prescribing practices and improved cardiovascular risk stratification in RA. These findings support a shift toward precision medicine, integrating real-world evidence with advanced diagnostic and decision-support tools, including future artificial intelligence-based approaches, to optimize personalized therapeutic strategies in autoimmune diseases.

Background/Objectives: Immune-mediated necrotizing myopathy (IMNM) is a severe inflammatory myopathy marked by proximal muscle weakness, elevated creatine kinase (CK), and the presence of anti-HMGCR antibodies. Statin exposure is a recognized trigger for anti-HMGCR-positive IMNM, which may persist despite statin withdrawal. This pilot case series explores, for the first time, the use of bempedoic acid—a liver-specific lipid-lowering agent with minimal muscle toxicity—as an alternative to statins in these patients. Methods: We report 10 anti-HMGCR-antibody-positive IMNM patients (6 females, 4 males) previously on statins for primary prevention (8 on atorvastatin, 2 on simvastatin) without prior cardiovascular events. Statins were discontinued at myositis onset. All patients received prednisone and immunosuppressants (methotrexate in 7, mycophenolate in 3), plus bempedoic acid. Anti-HMGCR antibodies were measured using a chemiluminescence method. Results: Their mean anti-HMGCR antibody levels decreased significantly from 390.93 ± 275.22 to 220.89 ± 113.37 CU/L (p = 0.027) after 6 months of treatment. Their CK levels dropped from 1278.9 ± 769.39 to 315.1 ± 157.72 IU/L (p = 0.001), and aldolase dropped from 11.63 ± 2.18 to 6.61 ± 1.22 U/L (p = 0.0001). The mean LDL-C value was 96.1 ± 8.16 mg/dL. No disease recurrence was observed. Autoimmune panels were negative for other myositis-associated and/or -specific antibodies. Conclusions: Bempedoic acid appears to be a safe, effective, and cost-efficient lipid-lowering alternative in statin-intolerant IMNM patients. Larger studies are warranted to confirm its efficacy across different subgroups and to optimize dyslipidemia management in this setting.

Introduction. The Italian Committee for Tailored BIOlogic Therapy (ITABIO), in a first report, has reviewed the literature to identify the best strategy for the choice of second-line biologic therapy in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). To verify the application of ITABIO recommendations in real life and how the recommendations perform in maintaining the health status of patients affected by inflammatory arthritis (RA, SpA, PsA), a database has been developed by Pharmaceutical Governance to evaluate the appropriateness of prescriptions. Methods. We have analyzed retrospectively 616 patients, 288 (46.7%) affected by RA, 117 (19%) affected by SpA, and 211 (34.3%) affected by PsA. Age, sex, diagnosis, current treatment, previous treatments with csDMARDs, b-DMARDs, ts-DMARDs, presence of risk factors for cardiovascular (CV) events, liver disease, infections, extra-articular manifestations such as interstitial lung disease (ILD) for RA, enthesitis, dactylitis, uveitis, inflammatory bowel disease for SpA and PsA, neoplasms, diabetes, presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) for RA were evaluated. Results. The percentage of treatments with anti-TNF biosimilars was 65.1, 52.4, and 24.3% in SpA (76 patients(pt)), PsA (110 pt), and RA (69 pt), respectively. The percentage of monotherapy was 68% (418 pt) in the three diseases. For RA, 34.2% of patients were difficult to treat (D2T) (98 pt), 54.8% (157 pt) were in monotherapy (tocilizumab-sarilumab-upadacitinib-filgotinib). Abatacept was the most prescribed treatment in RF and ACPA-positive patients and in those with ILD. The anti-IL-17A secukinumab was prescribed in 12% of SpA, of which 71% had enthesitis and dactylitis (14 pt). Ixekizumab was prescribed in 10.4% of PsA patients over 65 years with previous CV events, enthesitis, and dactylitis (21 pt). Apremilast was present in 71% of PsA with previous cancer. Conclusions. The cross-sectional analysis of prescriptions in patients with RA, SpA, and PsA demonstrates how the ITABIO recommendations can guide towards the correct appropriateness of prescription. RA and especially D2T-RA remains the disease with the greatest therapeutic failures, with the highest percentage of monotherapy (anti-IL-6 and Jak-i) and of discontinuation of MTX.

Background: Polymyalgia rheumatica (PMR) is a clinically heterogeneous inflammatory disorder in which conventional acute-phase reactants may inadequately reflect the complexity and biological variability of disease activity. Precision medicine approaches integrating multidimensional clinical and laboratory data may offer a more comprehensive characterization of inflammatory phenotypes. This study investigated whether the combined assessment of cytokine profiles, routine laboratory biomarkers, ultrasound findings, and clinical variables could improve disease activity stratification in PMR. Methods: A total of 103 consecutive patients with PMR were retrospectively analyzed. Disease activity was assessed using the PMR Activity Score (PMR-AS) and, for exploratory purposes, dichotomized according to the cohort median (≥11 vs. <11). Group differences were evaluated using non-parametric statistical methods. The multidimensional structure of the dataset was explored through Spearman correlation analysis, principal component analysis (PCA), and unsupervised clustering. Predictive models, including logistic regression, random forest, and gradient boosting, were developed to evaluate the potential contribution of integrated analytical approaches to patient stratification. Results: The study cohort included 103 patients (63.1% female), with a median age of 76 years (IQR 71–81); 57 patients (55.3%) presented PMR-AS ≥11. Patients with higher disease activity exhibited significantly increased levels of CRP, fibrinogen, platelet count, IL-6, serum amyloid A (SAA), and myeloid-related protein (MRP), together with a higher prevalence of joint effusion and Power Doppler positivity. Among the evaluated biomarkers, SAA demonstrated the strongest correlation with disease activity (Spearman ρ = 0.878; p < 0.001). Multivariate predictive modeling showed high discriminative performance, with random forest achieving the highest cross-validated AUC (0.934), whereas gradient boosting demonstrated the best overall accuracy (0.883). Unsupervised clustering analysis identified a subgroup characterized by a more pronounced inflammatory signature associated with higher PMR-AS values. Conclusions: These findings support the concept that disease activity in PMR may be more effectively represented through an integrated multidimensional inflammatory profile rather than isolated biomarkers. The combined evaluation of routine laboratory parameters, cytokines, and imaging features may contribute to more refined patient stratification within a precision medicine framework. Although exploratory, these results highlight the potential value of advanced data integration strategies for supporting biologically informed disease characterization in PMR, while underscoring the need for external validation before translation into clinical practice.