Rituximab levels are associated with the B cell homeostasis but not with the clinical response in patients with rheumatoid arthritis

To study the levels of rituximab (RTX) and anti-RTX antibodies (ARAs) in patients with rheumatoid arthritis (RA) at 30, 90, and 180 days after the first infusion, in relation to clinical and serological parameters and B cell homeostasis. Thirty-four patients with RA who failed to respond to anti-tumor necrosis factor therapy received RTX. At baseline, 4, 12, and 24 weeks after the first infusion of RTX, we performed a clinical assessment and determined the levels of RTX, ARAs, B cells, rheumatoid factors, anti-cyclic citrullinated peptide antibodies, immunoglobulins, and complements. RTX levels varied widely among patients. No ARAs were detected during the follow-up. Patients with lower levels of RTX presented with higher decreases in erythrocyte sedimentation rate, immunoglobulins, and complement 6 months after the first infusion. Patients with higher levels of RTX showed a higher B cell depletion at 90 days but an earlier B cell recovery than those with lower levels of RTX. No differences in clinical response were observed between the two groups at 6 months after starting the treatment. Our findings suggest that RTX levels in the serum of patients with RA are related to B cell homeostasis and the severity of immunological parameters but not to the clinical response at 6 months

What Matters Most to Patients and Rheumatologists? A Discrete Choice Experiment in Rheumatoid Arthritis

Introduction: To determine patient and rheumatologist preferences for rheumatoid arthritis (RA) treatment attributes in Spain and to evaluate their attitude towards shared decision-making (SDM). Methods: Observational, descriptive, exploratory and cross-sectional study based on a discrete choice experiment (DCE). To identify the attributes and their levels, a literature review and two focus groups (patients [P] = 5; rheumatologists [R] = 4) were undertaken. Seven attributes with 2–4 levels were presented in eight scenarios. Attribute utility and relative importance (RI) were assessed using a conditional logit model. Patient preferences for SDM were assessed using an ad hoc questionnaire. Results: Ninety rheumatologists [52.2% women; mean years of experience 18.1 (SD: 9.0); seeing an average of 24.4 RA patients/week (SD: 15.3)] and 137 RA patients [mean age: 47.5 years (SD: 10.7); 84.0% women; mean time since diagnosis of RA: 14.2 years (SD: 11.8) and time in treatment: 13.2 years (SD: 11.2), mean HAQ score 1.2 (SD: 0.7)] participated in the study. In terms of RI, rheumatologists and RA patients viewed: time with optimal QoL: R: 23.41%/P: 35.05%; substantial symptom improvement: R: 13.15%/P: 3.62%; time to onset of treatment action: R: 16.24%/P: 13.56%; severe adverse events: R: 10.89%/P: 11.20%; mild adverse events: R: 4.16%/P: 0.91%; mode of administration: R: 25.23%/P: 25.00%; and added cost: R: 6.93%/P: 10.66%. Nearly 73% of RA patients were involved in treatment decision-making to a greater or lesser extent; however, 27.4% did not participate at all. Conclusion: Both for rheumatologists and patients, the top three decision-making drivers are time with optimal quality, treatment mode of administration and time to onset of action, although in different ranking order. Patients were willing to be more involved in the treatment decision-making process

The impact of gout as described by patients, using the lens of The International Classification of Functioning, Disability and Health (ICF) : a qualitative study

This project was supported by Arthritis New Zealand (grant reference R259 to WJT). The US data collection was funded by Pfizer (undertaken commercially by Adelphi Values). The NZ data collection was supported by the Maaori Gout Action Group of Counties Manukau District Health Board and the Auckland Rheumatology Fund (to KL). The Spanish data were collected with the direct support of the authors. The funders had no direct role in the conduct of the reported study, analysis of the data or writing of the manuscript.The International Classification of Functioning, Disability and Health (ICF) aims to comprehensively describe the ways in which a person's health condition affects their life. This study aimed to contribute to the development of an ICF core set for gout through patient opinion derived from focus groups and interviews. We conducted a secondary qualitative analysis of data from three studies investigating the patient experience of gout. In total there were 30 individual interviews and 2 focus groups (N = 17) comprising 47 participants. We conducted thematic analysis of the textual data to extract meaning units, which were then linked to the ICF. A large number of ICF categories were relevant to patients with gout. Participants mentioned 93 third level categories, 17 of which were mentioned by more than 50% of patients. The most references for a single category was for b280, Sensation of pain, followed by personal factors (not yet categorised by the ICF). The most participants mentioned the environmental factor e355, Health professional support, followed by b280, Sensation of pain. The categories identified in this study as relevant to patients with gout highlight the severe pain associated with this disease, the impact on mobility and corresponding life areas. The roles of health professional support, medication, and personal attitudes to disease management are also reflected in the data. These results will contribute to the development of the ICF core set for gout

Clinical factors associated with discontinuation of ts/bDMARDs in rheumatic patients from the BIOBADASER III registry

Altres ajuts: Spanish Agency of Medicines and Medical Devices (AEMPS); Biogen; Bristol Myers-Squibb (BMS); Celltrion Healthcare; Lilly; Merck; Novartis; Pfizer; Regeneron Pharmaceuticals; Samsung Bioepis.Biologic and targeted synthetic disease-modifying antirheumatic drugs (ts/bDMARDs) play a pivotal role in the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Persistence of therapy provides an index of a drug's overall effectiveness. The objective of the study was to identify factors associated with discontinuation of ts/bDMARDs in a real-world dataset. The study population comprised patients diagnosed with RA, PsA, and AS included in the BIOBADASER registry for whom follow-up data were available until November 2019. Patient features and treatment data were included in the analysis. The Kaplan-Meier method was used to study survival of the different drugs according to the reason for discontinuation. Factors associated with discontinuation were studied using Cox regression models and bivariate and multivariate analyses. P values of less than 0.05 were regarded as statistically significant. The study population comprised 4,752 patients who received a total of 8,377 drugs, of which 4,411 (52.65%) were discontinued. The Kaplan-Meier curves showed that survival for first-line treatment was greater in all 3 groups (p < 0.001). Patients with RA had a greater risk of discontinuation if they were younger (HR, 0.99; 95% CI 0.99-1.00), if they were receiving anti-TNFα agents (HR, 0.61; 95% CI 0.54-0.70), and if they had more comorbid conditions (HR, 1.09; 95% CI 1.00-1.17). Patients with PsA had a higher risk if they were women (HR, 1.36; 95% CI 1.15-1.62) and if they were receiving other ts/bDMARDs (HR, 1.29; 95% CI 1.05-1.59). In patients with AS, risk increased with age (HR, 1.01; 95% CI 1.00-1.02), as did the number of comorbid conditions (HR, 1.27; 95% CI 1.12-1.45). The factors that most affected discontinuation of ts/bDMARDs were line of treatment, age, type of drug, sex, comorbidity and the year of initiation of treatment. The association with these factors differed with each disease, except for first-line treatment, which was associated with a lower risk of discontinuation in all 3 diseases

Influence of age on the occurrence of adverse events in rheumatic patients at the onset of biological treatment : Data from the BIOBADASER III register

To assess whether age, at the beginning of biologic treatment, is associated with the time a first adverse event (AE) appears in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). All patients in the BIOBADASER registry diagnosed with RA, AS, and PsA, and classified as young ( 75 years old) at start of biological treatment were included. Factors associated with the appearance of a first AE using adjusted incidence rate ratios (IRR) (Poisson regression) were analyzed. Survival to first AE was studied by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. 2483 patients were included: 1126 RA, 680 PsA, and 677 AS. Age group stratification was as follows: 63 young, 2127 adults, 237 elderly, and 56 very elderly. Regression model revealed an increased probability of suffering a first AE at age 65 years or older [IRR elderly: 1.42 (CI95% 1.13-1.77)]. Other characteristics associated with AE were female gender, the use of DMARDs, including methotrexate, the presence of comorbidities, and the time of disease duration. Factors that had the greatest impact on survival over a first AE were age > 75 years [HR 1.50 (1.01-2.24)] and female gender [HR 1.42 (1.22-1.64)]. Age at the start of treatment and female gender are key factors associated with the appearance of a first AE with biologics. Other factors related to patient status and treatment were also associated with a first AE in rheumatic patients treated with biologics

The synovial and blood monocyte DNA methylomes mirror prognosis, evolution, and treatment in early arthritis

Identifying predictive biomarkers at early stages of inflammatory arthritis is crucial for starting appropriate therapies to avoid poor outcomes. Monocytes (MOs) and macrophages, largely associated with arthritis, are contributors and sensors of inflammation through epigenetic modifications. In this study, we investigated associations between clinical features and DNA methylation in blood and synovial fluid (SF) MOs in a prospective cohort of patients with early inflammatory arthritis. DNA methylation profiles of undifferentiated arthritis (UA) blood MOs exhibited marked alterations in comparison with those from healthy donors. We identified additional differences both in blood and SF MOs after comparing patients with UA grouped by their future outcomes, i.e., good versus poor. Patient profiles in subsequent visits revealed a reversion toward a healthy level in both groups, those requiring disease-modifying antirheumatic drugs and those who remitted spontaneously. Changes in disease activity between visits also affected DNA methylation, which was partially concomitant in the SF of UA and in blood MOs of patients with rheumatoid arthritis. Epigenetic similarities between arthritis types allow a common prediction of disease activity. Our results constitute a resource of DNA methylation-based biomarkers of poor prognosis, disease activity, and treatment efficacy for the personalized clinical management of early inflammatory arthritis.We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. The authors thank all the patients who graciously donated their time and samples to further arthritis research. We are also thankful to Núria Sapena, Marta Bassas, and Cristina González, nurses from the outpatient clinic of the Department of Rheumatology, for their help in the management of biologic samples. This research was funded by Fondo de Investigación en Salud (FIS) grant PI17/00993 from the Institute of Health Carlos III (ISCIII) (to JDC); by grants SAF2017-88086-R and PID2020-117212RB-I00 / AEI / 10.13038/501100011033) from the Spanish Ministry of Science and Innovation (MICINN) (to EB); and by the Thematic Networks for Cooperative Research (RETICS) grant provided by ISCII, Research Network for Inflammation and Rheumatic Diseases (RIER) RD16/0012/0013, cofinanced by the European Fund for Regional Development’s (FEDER) Una manera de hacer Europa program (to JDC and EB).Peer reviewe

Avances clínicos e inmunológicos en la respuesta al tratamiento con terapia deplectora de linfocitos B (Rituximab®) en pacientes con artritis reumatoide

La depleción de las células B en enfermos con artritis reumatoide debe comportar un serie de cambios en el resto del sistema inmunológico. Estos cambios podrían ser distintos en diferentes subtipos de enfermos. La respuesta, evolución y comportamiento de los enfermos tras el tratamiento con rituximab nos permitirá entender mejor la patogenia de la artritis reumatoide. Objetivos: Valorar el comportamiento de los linfocitos T ante la depleción de células B producida por rituximab. Se analizará el comportamiento del número total de células T y de sus subclases (memoria, naïve y reguladoras) y su relación con la clínica. Analizar la evolución y relación de IL-15 (tanto en suero como transmembrana) y de IL-17 con las distintas clases de células T y la actividad de la enfermedad tras el tratamiento con rituximab. Valorar a la vez si los enfermos con y sin IL-15 en suero presentan respuestas biológicas distintas. Estudiar los niveles de rituximab en sangre tras la primera infusión y su relación con la actividad de la enfermedad y con la depleción y reaparición de los linfocitos B en sangre.. Resultados: Se estudiaron 33 enfermos con artritis reumatoide tratados con rituximab según práctica clínica habitual a lo largo de tres ciclos de tratamiento. Rituximab fue un fármaco efectivo tanto a nivel de respuesta clínica como de depleción de células B periféricas. Se observó además una disminución de inmunoglobulinas, factor reumatoide y anticuerpos anticitrulinados. No hubo una disminución del número total de linfocitos T, ni de CD4+ ni de CD8+, pero se observó una disminución del número de linfocitos T de memoria, con un aumento de los naïve. La ratio de células T de memoria/naïve se correlacionó con la respuesta clínica. Dos terceras partes de los enfermos presentaron IL-15 en suero. Los enfermos con artritis reumatoide tenían niveles de IL-15 mayores que los controles sanos. Todos los enfermos presentaron IL-15 transmembrana. Los niveles de IL-15 en suero y transmembrana disminuyeron progresivamente tras cada ciclo del tratamiento. La IL-17 también disminuyó progresivamente con el tratamiento con rituximab. Al contrario, el número de células T reguladoras aumentó. Los enfermos con y sin IL-15 inicial en suero se comportaron de manera similar. La disminución de IL-15 se asoció a la disminución de la ratio de los linfocitos CD45RO+/CD45RA. Los niveles de rituximab encontrados fueron muy variables entre los enfermos, con un máximo a los 30 días y un descenso muy importante a los 90 días. Esta variabilidad permitió clasificar a los enfermos en dos grupos, niveles altos y bajos de rituximab. Los enfermos con niveles altos de rituximab consiguieron una mayor depleción periférica de linfocitos B, pero la reaparición de células B fue anterior. Tras el primer ciclo de tratamiento no se encontraron diferencias clínicas entre los dos grupos. Conclusiones: El tratamiento con rituximab induce una disminución de la IL-15. Esta disminución de la IL-15 podría provocar una serie de cambios en el sistema inmune. Estos cambios pasarían por una disminución de la IL-17 y de la ratio de células CD45RO+/CD45RA+, con un aumento de las células T reguladoras, y a partir de aquí la mejoría clínica. Los pacientes con niveles elevados de rituximab en sangre a los 30 días presentan una mejor depleción periférica de células B inicial, pero una reaparición de las mismas más temprana.B cell depletion in rheumatoid arthritis patients should cause a series of changes in the rest of the immune system. These changes may be different in different subtypes of patients. The evolution of these patients after rituximab treatment can be useful to better understand rheumatoid arthritis pathogenesis. Objectives: To assess the behavior of T lymphocytes to B cell depletion produced by rituximab. Total number of T cells and its subclasses (memory, naïve and regulators) and its relationship to the clinic will be analyzed. To analyze the evolution and relation of IL-15 (both serum and transmembrane) and IL-17 with the different kinds of T cells and the disease activity following rituximab treatment. To study if patients with and without serum IL-15 have different biological responses. To asses rituximab levels after the first infusion and its relation with disease activity and B cell depletion and repletion. To look for new biomakers of response to rituximab treatment in rheumatoid arthritis patients. Results: We studied 33 rheumatoid arthritis patients treated with rituximab following usual clinical practice during three treatment cycles. Rituximab was effective both in clinical response and in B-cell depletion. A decrease of immunoglobulins, rheumatoid factor and anti-citrullinated antibodies was observed. No decrease in the total number of T cells, nor CD4 + or CD8 + was observed, but memory T cells decreased and naïve T cells increased. The ratio of memory/naïve T cells correlated with clinical response. About two thirds of the patients had IL-15 in serum. Rheumatoid arthritis patients had levels of IL-15 higher than healthy controls. All patients had transmembrane IL-15. Serum and transmembrane IL-15 decreased progressively after each treatment cycle. The IL-17 also decreased progressively with rituximab treatment. On the contrary, the number of regulatory T cells increased. Patients with and without initial serum IL-15 behaved similarly. IL-15 decrease was associated with the ratio of CD45RO+/ CD45RA+ lymphocytes. Rituximab levels were highly variable among patients, with a maximum at day 30 and an important decrease at day 90. This variability let us classify patients into two groups, with high or low levels of rituximab. Patients with high levels of rituximab achieved a greater depletion of peripheral B cells, but there was an earlier B cell repletion. After the first cycle of treatment there was no clinical difference between the two groups.. Conclusions: Rituximab treatment induces an IL-15 decrease. This decrease may induce a series of changes in the immune system. These changes would go through a decrease of IL-17 and the CD45RO+/CD45RA+ cells ratio and an increase of regulatory T cells, and from all these to the clinical improvement. Patients with higher levels of rituximab at day 30 had a better peripheral B cell depletion and an earlier repletion

Assessment of nutritional status by dual X-Ray absorptiometry in women with rheumatoid arthritis : A case-control study

Rheumatoid arthritis (RA) has been related to an impairment of the nutritional status. Body mass index (BMI) has been used but questions arise about how to properly evaluate nutritional status in RA patients. Few studies have evaluated it by dual-energy X-ray absorptiometry.In women with RA, to analyze:(1)their nutritional status compared to that of a control population,(2)differences between the prevalence of impairment of nutritional status measured by dual energy X ray absorptiometry (DXA) and by classical methods used in clinical care,(3)determinants of nutritional status,(4)prevalence of sarcopenia.Case-control study including 89 women with RA. The control group was composed by 100 patients affected by non-inflammatory rheumatic disorders. Study variables included age, RA duration, history, activity and disability, and in relation to nutritional status: BMI, serum albumin (ALB), whole body DXA assessment, and skeletal muscle index (SMI).Mean age of patients was 62±8 years, mean duration of RA was 14±9 years, mean disease activity score (DAS28) was 3.7±1.4 and mean Health Assessment Questionnaire was 0.88±0.77. BMI was 27.43±5.16Kg/m in patients and 27.78±3.98Kg/m in controls (P: ns). ALB was within normal range in all patients.By whole body DXA, RA patients presented a statistically significant lower lean mass in all locations and lower fat mass in limbs than controls. Patients had a redistribution of fat mass to trunk. Lean mass directly correlated with fat mass.Neither BMI nor ALB correlated with DXA parameters.BMI, appendicular lean mass and SMI correlated inversely with disease duration. Trunk lean mass correlated inversely, and fat mass directly, with RA disability parameters.RA patients fulfilled criteria of sarcopenia in 44% of cases versus 19% of controls (P <.001). In RA patients, regarding SMI, BMI showed a high specificity to detect sarcopenia (94% of the patients with low BMI had sarcopenia) but low sensitivity (47% of the patients with normal BMI or overweight had sarcopenia).RA patients have an impairment of nutritional status associated to disease duration that looks like sarcopenia and that is not predicted by BMI

Patient-related factors influencing the effectiveness and safety of Janus Kinase inhibitors in rheumatoid arthritis : a real-world study

In real-world scenarios, Janus Kinase (JAK) inhibitors are often offered to "difficult-to-treat" rheumatoid arthritis patients, quite different from those included in randomized controlled trials. Our study aimed to evaluate the influence of patient-related factors on the effectiveness and safety of JAK inhibitors in real-world clinical practice. This observational retrospective study involved rheumatoid arthritis patients who received treatment with either tofacitinib, baricitinib, upadacitinib, or filgotinib. At 12 months of treatment, reasons for and rates of JAK inhibitor treatment discontinuation were examined. Treatment retentions were analyzed through Cox proportional hazard regression models and Kaplan-Meier estimates. Patient-related factors that could influence treatment retention were evaluated for the discontinuation reasons of lack of effectiveness and adverse events. At 12 months of treatment, discontinuation rates for 189 JAK inhibitor treatments were: lack of effectiveness (24.3%), adverse events (20.6%), and other reasons (3.7%). The remaining 51.4% represents the treatment continuation rate. No patient-related factors evaluated had an influence on treatment discontinuation due to lack of effectiveness. Ae significantly increased the risk of treatment discontinuation due to adverse events (p = 0.030). In terms of age, at 12 month of treatment, discontinuation rates due to adverse events were: < 65 years, 14.4% vs. 65 years or older, 26.3% (p = 0.019). Rheumatoid arthritis patients aged 65 years or older showed an increased risk of JAK inhibitor treatment discontinuation due to adverse events. Factors not related to treatment discontinuation were: sex, rheumatoid arthritis disease duration, rheumatoid arthritis disease activity, seropositivity for rheumatoid factor, seropositivity for anti-cyclic citrullinated peptides, number of prior biologic treatments, number of prior JAK inhibitor treatments, concomitant use of glucocorticoids, and concomitant use of conventional synthetic disease-modifying antirheumatic drugs