Luis Sainz

Introduction: We conducted a comprehensive comparative analysis of the Okazaki, Umehara, and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for diagnosing immunoglobulin G4-related disease (IgG4-RD). Materials and Methods: A retrospective study was conducted in a single tertiary hospital, using expert clinical judgment as the gold standard. We compared the diagnostic accuracy of the Okazaki, Umehara, and ACR/EULAR criteria in a cohort of 41 patients with suspected IgG4-RD. We assessed sensitivity, specificity, and positive and negative predictive values for each criterion, and conducted a separate analysis based on four IgG4-RD subtypes. Results: A total of 30 patients were confirmed to have IgG4-RD and 11 were identified as mimickers. The Umehara criteria demonstrated the highest sensitivity (83.33%), followed by the ACR/EULAR 2019 (66.67%) and Okazaki (60.0%) criteria. All three criteria exhibited 100% specificity, with overall diagnostic accuracy ranging from 70% to 88%. The areas under the curve (AUC) were 0.917 (Umehara), 0.800 (Okazaki), and 0.833 (ACR/EULAR 2019), indicating significant diagnostic effectiveness (p < 0.000). Subtype analysis revealed that the Umehara and ACR/EULAR 2019 criteria were more effective in diagnosing pancreato-hepato-biliary involvement (subtype 1), while the Okazaki and ACR/EULAR 2019 criteria were more effective in diagnosing retroperitoneal fibrosis and/or aortitis (subtype 2). Conclusions: Our study provides valuable insights into the diagnostic performance of the Okazaki, Umehara, and ACR/EULAR criteria for a cohort of patients with suspected IgG4-RD. The Umehara criterion demonstrated the highest sensitivity, suggesting its potential utility for screening purposes, while all three criteria showed consistent specificity.

Objectives: Cryoglobulinemia (CG) is marked by abnormal immunoglobulins (Ig) in serum, precipitating at temperatures below 37 °C. Current classification categorizes CG into three subtypes (types I, II, and III) based on Ig clonality. The features distinguishing patients with CG based on their etiology remain unidentified. Aiming to characterize clinical and serological profiles of CG individuals, we conducted an observational analysis of a large cohort of patients and compared their characteristics based on underlying causes: hepatovirus (HV) infections, rheumatic diseases (RD), hematological disorders, and unidentified etiology (essential CG). Methods: We analyzed 252 cryoglobulin-positive serum samples from 182 patients and classified these into the four etiological groups. A separate sub-analysis was carried out for 10 patients meeting criteria for multiple diseases. We collected demographic, clinical, and laboratory data: CG characterization, complement (C3 and C4) levels, antinuclear antibodies (ANA), and rheumatoid factor (RF). Kruskal–Wallis and Wilcoxon–Mann–Whitney U-tests were used for comparisons. Results: Most patients (93.3%) had mixed cryoglobulinemia (types II + III), with 6.7% having type I. HV infection, predominantly hepatitis C, was the main (52.9%) associated condition within the cohort, followed by rheumatic (27.3%) and hematological (9.8%) disorders. In our cohort, ANA were frequent (45.3%) and often associated with RF positivity (43.6%) and decreased complement levels (C3: 42.4%, C4: 32.5%). Essential CG and CG associated with RD had a higher prevalence of cutaneous manifestations (p < 0.01) and renal involvement (p = 0.017). Hematological disorder-related CG showed higher cryoglobulin and RF concentrations (p < 0.01), despite milder symptoms. Conclusions: Our study underscores a mixed prevalence of CG across disease subgroups, with hepatitis-C virus as the primary factor, followed by rheumatic and hematological disorders. Four clinical and serological profiles of CG were identified based on their etiologies.

Introduction: Integrated care pathways (ICPs) are crucial for delivering individualised care. However, the development of ICPs is challenging and must be well designed to provide the expected benefits. Regarding this, healthcare organisations are increasingly adopting management systems based on Lean Thinking to improve their organisational processes by eliminating non‐value‐added steps. This study elucidates the process and evaluates the impact of applying Lean Thinking to redesign an ICP for patients with spondyloarthritis, a chronic inflammatory disease affecting young adults.Methods: A multidisciplinary team was assembled and trained in Lean Thinking. Patient's perspective was gathered through a focus group. Guided by an expert methodologist, the team constructed a value stream map of the entire care pathway and analysed each step. Five work streams were defined to increase value at each step, leading to targeted process improvements. Key process and outcome metrics were collected and compared in 2‐month baseline and post‐implementation audits.Results: A total of 118 patients were included in the baseline audit (September–October 2022), and 116 in the post‐implementation audit (January–February 2023). Process redesign resulted in statistically significant improvements (p < 0.05), including a reduction in the mean number of hospital visits per patient over a 2‐month period from 2.54 (SD = 0.93) to 1.84 (SD = 0.79), an increase in complementary exams scheduled on the same day (81.4% to 94.8%) and an increase in baseline disease and treatment education (from 22.2% to 84.2% and from 18.2% to 84.6%, respectively). Regarding standardisation of clinical practice, there were significant increases in collecting data for medical records on composite activity indices (76.3% to 95.7%), reporting of pharmacological treatment adherence (68.6% to 94%) and providing nonpharmacological recommendations (31.3% to 95.7%).Conclusions: The application of Lean Thinking to redesign the spondyloarthritis ICP led to significant improvements in outpatient appointment scheduling, reduced patient hospital visits, improved interdepartmental coordination and standardised clinical practice.

Background: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. Methods: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. Results: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. Conclusions: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Introduction: Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disease characterized by salivary gland involvement. Some patients may develop systemic extra glandular manifestations that can determine the prognosis of the disease. The influence of serological and immunological biomarkers on the clinical expression of the disease is still not fully known, nor is their role as prognostic factors of the disease. Objectives: The aim of the study was to assess the prevalence of extraglandular involvement in pSS, as well as to determine the relationship between immunological and serological biomarkers, disease activity, and extraglandular manifestations in patients with pSS. Methods: A cohort of patients with pSS who met the ACR/EULAR classification criteria for pSS in 2016 followed up in our Systemic Autoimmune Diseases Unit between 2000 and 2022 was carried out. The sociodemographic, clinical, serological and immunological data and the Disease activity measures calculated with the ESSDAI index (EULAR Sjögren's Syndrome disease activity index) were collected. For the comparison of qualitative and/or quantitative variables, Fisher's exact test or the T-test was performed when necessary. Results: 175 patients with pSS were included (85% were women), with a mean age at diagnosis of 58.8±12.2 years and a disease evolution time of 7.6±5.4 years. 62 patients (35%) had extraglandular manifestations. Anti-Ro60 positivity was found in 68%, Anti-Ro52 in 35.3% and anti-Ro60 and anti-La in 47.4% of patients. A higher risk of renal involvement was found in anti-Ro60, meanwhile a lung involvement, hypocomplementemia and higher levels of rheumatoid factor and hypergammaglobulinemia were associated with anti-Ro52 positivity. Constitutional symptoms, hematological involvement, lymphadenopathy, higher erythrocyte sedimentation rate and ESSDAI score were associated with both anti-Ro and anti-La positivity. Cutaneous involvement was specifically associated with anti-Ro52, C3 levels, IgG and IgM levels. Articular involvement was associated with higher rheumatoid factor levels. Renal involvement was associated with C3 levels, rheumatoid factor, ESR levels, IgG levels and anti-Ro60. Lung involvement was associated with ESR levels and C-reactive protein, IgG, C3 levels and anti-Ro52 positivity. CNS involvement was associated with C3 levels, C-reactive protein and beta2microglobulin and hematological involvement with C3, rheumatoid factor, beta2microglobulin and IgG levels. Conclusion: Our results have demonstrated the role of immunological and serological biomarkers in the clinical expression of pSS and as prognostic factors for disease progression, as well as their applicability in clinical practice.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Background: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease of unknown etiology. Tocilizumab (TCZ) is a first-line biological disease-modifying anti-rheumatic drug (bDMARD) which inhibits Interleukin 6 (IL-6) pathway through blockade of its receptor. At present, there is a lack of evidence to recommend the treatment of one bDMARD over another.(1) Seeking for genetic biomarkers to predict response to treatment could be key towards a personalized treatment strategy in rheumatology.(2) Objectives: We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict response and/or toxicity to TZC in Caucasian patients diagnosed with RA. Methods: Retrospective analytical preliminar study of a cohort of 31 patients diagnosed with RA (ACR/EULAR 2010 criteria) who received treatment with TCZ within the last 10 years. Epidemiological, clinical and laboratory data were collected. DNA was extracted from EDTA blood samples. Three SNPs in the IL-6 receptor gene (rs12083537, rs2228145, rs4329505) were genotyped by real-time PCR with TaqMan probes. The associations between polymorphisms and clinicopathological features were evaluated using parametric tests. Efficacy was assessed as the difference of DAS-28 CRP at 6 months. The toxicities recorded were hepatotoxicity, infections, hypersensibility, gastrointestinal, hematological and dyslipidemia. Results: The 31 DNA samples from patients included were mainly female (83.9%) and had a mean age at diagnosis of 46.8 years. The mean duration of treatment was 51.3 months and, previously to initiate TCZ, they received a mean of 2,6 csDMARD and 1,7 bDMARD. The more frequent adverse effects were hypertransaminasemia (22.6%) and neutropenia (32.3%). Most relevant epidemiologic and clinical data is shown in Table 1. Clinical characteristics. RA=Rheumatoid Arthritis. CCP= anti-Cyclic Citrullinated Peptides. RF=Rheumatoid factor. csDMARDs= conventional synthetic Disease-modifying antirheumatic drug. bDMARD= biological Disease-modifying antirheumatic drug. BMI=Body Mass Index. Sc=subcutaneous. Ev=endovenous. DAS28= Disease Activity Score in 28 joints The univariate analyses showed that the rs2228145 variant was statistically associated with differences in DAS28 reduction at 6 months (p=0.042). Regarding efficacy, we also found a trend with the SNP rs4329505 (p=0.173), which could achieve statistical significance with the projected inclusion of more patients. No associations were found regarding adverse effects. Conclusion: The rs2228145 polymorphisms in the IL6R gene may be considered as a pharmacogenetic biomarker of TCZ response in RA patients. More studies are required in order to investigate the clinical use of pharmacogenetic biomarkers in rheumatic diseases. References: [1]Smolen, Josef S., Robert B., et al. 2020. “EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs: 2019 Update.” Annals of the Rheumatic Diseases 79 (6): 685–99. [2]Tarnowski, Maciej, Agnieszka Paradowska-Gorycka, et al. 2016. “The Effect of Gene Polymorphisms on Patient Responses to Rheumatoid Arthritis Therapy.” Expert Opinion on Drug Metabolism & Toxicology 12 (1): 41–55. Disclosure of Interests: None declared