Tocilizumab for the treatment of adult patients with severe COVID-19 pneumonia: A single-center cohort study.

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.

Efficacy and safety of switching Jak inhibitors in rheumatoid arthritis: an observational study.

OBJECTIVES: Different Jak inhibitors (jakinibs) have shown efficacy in rheumatoid arthritis (RA), but in a significant proportion of patients, an insufficient response leads to therapy withdrawal. We describe the efficacy and safety of a second jakinib in patients stopping the first due to insufficient response or side effects. METHODS: This is an observational retrospective multicentric study of 31 patients with RA sequentially treated with baricitinib or tofacitinib in any order in clinical practice in ten medical centres in Spain. RESULTS: We identified 31 patients, sequentially treated with both jakinibs. An equal proportion had received tofacitinib or baricitinib first. Most patients (87%) had previously received one or several bDMARD, median 4 (2-5). Median survival for the first jakinib was 5 (3-8) months, and the reasons for withdrawal were inefficacy in 61% and adverse effects in 39%. Most patients (23/31, 74%) maintained the response to the second jakinib after a mean follow-up of 19.5 (12-24) months. In all 8 patients who discontinued the second jakinib, the reason was inefficacy. The treatment suspension rate was similar among patients that had discontinued the first jakinib for inefficacy (26%) or for adverse effects (25%). CONCLUSIONS: Therapy of RA with a second jakinib seems a safe and efficacious option after discontinuation of the first, either for inefficacy or for side effects.

"There is something you must see": breaking down the remission concept in rheumatoid arthritis from a rheumatologist's perspective.

OBJECTIVES: To explore the remission concept in rheumatoid arthritis (RA) and the implications of the existing definitions when applied to clinical practice among rheumatologists with different profiles. METHODS: A qualitative study through focus groups was conducted. Three focus groups were organised from February to March 2016. Each group was composed of rheumatologists with extensive clinical experience with different profiles; experts in basic research (RBR), experts in imaging techniques research (RIR), and experts in clinical research (RCR). The data was collected with audio recording. Verbatim transcriptions of the audio files were made, and a subsequent reflexive thematic analysis assisted by ATLAS.ti (GmbH, Berlin, v. 7) software was performed. RESULTS: From the reflexive thematic analysis, three main themes were generated: (1) remission limitations, (2) instruments or measures to assess remission, and (3) a new definition of remission. Rheumatologists mentioned frequently that the following variables should be considered when developing a new remission definition: inflammatory activity, calprotectin, psychological variables, sex, disease stage, and sociocultural factors. Contrary to what could be expected, all groups acknowledged that their research field could contribute with domains for a gold standard remission instrument, but not in a hierarchical arrangement of importance. The dissonance existing in the entire remission evaluation process was outlined: remission in clinical practice versus remission in clinical trials, remission following the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean versus Musculoskeletal Ultrasound (US) remission, and remission from the rheumatologist's point of view versus the patient's point of view. CONCLUSIONS: Currently, rheumatologists would not accept a domain as more important than others in remission. Our suggestion is, not to generate a universal definition of remission - one that could cover all aspects - but rather to develop definitions of remission for the different settings that could be pondered by the patient's perspective.

Efficacy of tocilizumab monotherapy after response to combined tocilizumab and methotrexate in patients with rheumatoid arthritis: the randomised JUST-ACT study.

OBJECTIVES: The aim of the JUST-ACT study was to assess whether the add-on effect of tocilizumab (TCZ) to background methotrexate (MTX) observed in MTX-inadequate responders with active rheumatoid arthritis (RA), would be sustained when MTX is withdrawn. METHODS: A double-blind, parallel-group, phase 3 study in biologic-naïve RA patients with a disease activity score 28 (DAS28)>3.2 despite MTX which were treated with TCZ+MTX for an initial 16-week period. Patients who at week 16 achieved low disease activity (LDA) (DAS28≤3.2) were randomised to continue with TCZ+MTX or switch to TCZ + placebo (PBO) for an additional 12 weeks. The primary endpoint was the change in DAS28-ESR from the randomisation at week 16 to week 28. Non-inferiority was confirmed if the upper limit of the two-sided 95%CI for the treatment difference between TCZ+MTX and TCZ monotherapy groups was lower than the selected non-inferiority margin of 0.6. RESULTS: 261 patients completed the first 16 weeks of TCZ+MTX treatment and 165 were randomised (83 to TCZ+MTX and 82 to TCZ+PBO). For the primary endpoint, the adjusted treatment difference (95% CI) in mean change of DAS28-ESR was -0.06 (-0.40 to 0.27), and therefore the non-inferiority of switching to TCZ monotherapy versus continuing with TCZ+MTX was demonstrated. In both treatment groups, the percentage of patients in clinical remission from 16 to 28 weeks was similar as were the improvements in disease activity, functional disability and quality of life. CONCLUSIONS: In MTX non-responder patients achieving LDA with TCZ+MTX, switching to TCZ monotherapy is non-inferior to continuing the combination.

Exploring the remission concept in rheumatoid arthritis with patients and rheumatologists: time for a new approach?

OBJECTIVES: To explore the remission concept in rheumatoid arthritis (RA) and to compare remission definitions and related concepts between rheumatologists and patients with the purpose of identifying similarities and disparities to comprehend the different perspectives of the disease. METHODS: This was a qualitative study of discourse and content analysis through focus groups, conducted from February to March 2016. Four focus groups were set up, each one with different interests: rheumatologists involved in basic research (BR), rheumatologists with high specialisation in imaging techniques (IR), clinical rheumatologists (CR), and patients (PA). RESULTS: There is no consensus in a remission definition in RA; differences exist between-groups, rheumatologists and patients value remission differently, and there are discrepancies within the group of rheumatologists. Rheumatologists highlight quantifiable objective parameters, in contrast, patients did not consider objective measures as the best instruments, and they prefer subjective measures of remission. The data confirmed the existence of two sources of knowledge of the disease, technical (physicians) and experiential (patients). These sources of knowledge should concur in order to establish new remission criteria well-adjusted to reality. CONCLUSIONS: The lack of consensus between key groups implicated in defining remission and remission criteria suggests a new strategy for its operational definition. Our group proposes that subjects with a balance between experiential and technical knowledge, should be the ones in charge of this assignment.

Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A-dependent pro-inflammatory profile.

Rheumatoid arthritis (RA) is a chronic inflammatory disease whose pathogenesis and severity correlates with the presence of macrophage-derived pro-inflammatory cytokines within the inflamed synovium. Macrophage-derived cytokines fuel the pathological processes in RA and are targets of clinically successful therapies. However, although macrophage polarization determines cytokine production, the polarization state of macrophages in RA joints remains poorly defined. To dissect the molecular basis for the tissue-damaging effects of macrophages in RA joints, we undertook the phenotypic and transcriptomic characterization of ex vivo isolated CD14(+) RA synovial fluid (RA-SF) macrophages. Flow cytometry and gene profiling indicated that RA-SF macrophages express pro-inflammatory polarization markers (MMP12, EGLN3, CCR2), lack expression of markers associated with homeostatic and anti-inflammatory polarization (IGF1, HTR2B) and exhibit a transcriptomic profile that resembles the activin A-dependent gene signature of pro-inflammatory in vitro-generated macrophages. In fact, high levels of Smad-activating activin A were found in RA-SF and, accordingly, the Smad signalling pathway was activated in ex vivo-isolated RA-SF macrophages. In vitro experiments on monocytes and macrophages indicated that RA-SF promoted the acquisition of pro-inflammatory markers (INHBA, MMP12, EGLN3, CCR2) but led to a significant reduction in the expression of genes associated with homeostasis and inflammation resolution (FOLR2, SERPINB2, IGF1, CD36), thus confirming the pro-inflammatory polarization ability of RA-SF. Importantly, the macrophage-polarizing ability of RA-SF was inhibited by an anti-activin A-neutralizing antibody, thus demonstrating that activin A mediates the pro-inflammatory macrophage-polarizing ability of RA-SF. Moreover, and in line with these findings, multicolour immunofluorescence evidenced that macrophages within RA synovial membranes (RA-SM) also express pro-inflammatory polarization markers whose expression is activin A-dependent. Altogether, our results demonstrate that macrophages from RA synovial fluids and membranes exhibit an MMP12(+) EGLN3(+) CCR2(+) pro-inflammatory polarization state whose acquisition is partly dependent on activin A from the synovial fluid.

Inflammatory mediators alter interleukin-17 receptor, interleukin-12 and -23 expression in human osteoarthritic and rheumatoid arthritis synovial fibroblasts: immunomodulation by vasoactive intestinal Peptide.

AIMS: To assess the contribution of fibroblast-like synoviocytes (FLS) to the inflammatory joint microenvironment under different pathogenic stimuli and their potential to respond to interleukin (IL)-17 and to determine whether the neuroimmunomodulatory vasoactive intestinal peptide (VIP) is able to modulate IL-17 receptor (IL-17R) and related cytokines. METHODS: The effect of proinflammatory cytokines [tumor necrosis factor α (TNFα) and IL-17] and Toll-like receptor (TLR) ligands [poly(I:C) and lipopolysaccharide (LPS)] on IL-17R expression and IL-12 and IL-23 production was studied in osteoarthritis (OA)- and rheumatoid arthritis (RA)-FLS, involved in Th1/Th17 differentiation. The effect of VIP was also determined. IL-17RA, IL-17RC, IL-12p35 and IL-23p19 expression was measured by real-time polymerase chain reaction. IL-12 and IL-23 protein levels were measured by ELISA in supernatant cultures. RESULTS: TNFα, LPS and poly(I:C) induced an increase in IL-17RA in RA-FLS, whereas TNFα, TNFα plus IL-17 and poly(I:C) enhanced IL-17RC transcripts in FLS. VIP diminished the upregulated expression of IL-17RA in RA-FLS following TNFα and poly(I:C). TNFα, LPS and poly(I:C) increased IL-12 and IL-23 levels in cells derived from patients presenting both pathologies. However, IL-17A DECREASED IL-12 AND AUGMENTED IL-23. VIP DECREASED IL-12P35 MRNA UPREGULATION BY POLY(I:C) AND IL-23P19 TRANSCRIPTS IN LPS-TREATED FLS. CONCLUSIONS: Inflammatory cytokines and TLR ligands modulate IL-17R, IL-12 and IL-23 possibly favoring the cross talk between FLS and Th1/Th17 cells. The ability of VIP to counteract the enhancing effect of proinflammatory molecules on IL-17R and the IL-12 family of cytokines corroborates and amplifies the beneficial effect of this endogenous neuroimmunopeptide in rheumatic diseases.

Expert Consensus: Main Risk Factors for Poor Prognosis in COVID-19 and the Implications for Targeted Measures against SARS-CoV-2.

The clinical evolution of patients infected with the Severe Acute Respiratory Coronavirus type 2 (SARS-CoV-2) depends on the complex interplay between viral and host factors. The evolution to less aggressive but better-transmitted viral variants, and the presence of immune memory responses in a growing number of vaccinated and/or virus-exposed individuals, has caused the pandemic to slowly wane in virulence. However, there are still patients with risk factors or comorbidities that put them at risk of poor outcomes in the event of having the coronavirus infectious disease 2019 (COVID-19). Among the different treatment options for patients with COVID-19, virus-targeted measures include antiviral drugs or monoclonal antibodies that may be provided in the early days of infection. The present expert consensus is based on a review of all the literature published between 1 July 2021 and 15 February 2022 that was carried out to establish the characteristics of patients, in terms of presence of risk factors or comorbidities, that may make them candidates for receiving any of the virus-targeted measures available in order to prevent a fatal outcome, such as severe disease or death. A total of 119 studies were included from the review of the literature and 159 were from the additional independent review carried out by the panelists a posteriori. Conditions found related to strong recommendation of the use of virus-targeted measures in the first days of COVID-19 were age above 80 years, or above 65 years with another risk factor; antineoplastic chemotherapy or active malignancy; HIV infection with CD4+ cell counts < 200/mm3; and treatment with anti-CD20 immunosuppressive drugs. There is also a strong recommendation against using the studied interventions in HIV-infected patients with a CD4+ nadir <200/mm3 or treatment with other immunosuppressants. Indications of therapies against SARS-CoV-2, regardless of vaccination status or history of infection, may still exist for some populations, even after COVID-19 has been declared to no longer be a global health emergency by the WHO.

Chemokine CXCL12 uses CXCR4 and a signaling core formed by bifunctional Akt, extracellular signal-regulated kinase (ERK)1/2, and mammalian target of rapamycin complex 1 (mTORC1) proteins to control chemotaxis and survival simultaneously in mature dendritic cells.

Chemokines control several cell functions in addition to chemotaxis. Although much information is available on the involvement of specific signaling molecules in the control of single functions controlled by chemokines, especially chemotaxis, the mechanisms used by these ligands to regulate several cell functions simultaneously are completely unknown. Mature dendritic cells (maDCs) migrate through the afferent lymphatic vessels to the lymph nodes, where they regulate the initiation of the immune response. As maDCs are exposed to chemokine CXCL12 (receptors CXCR4 and CXCR7) during their migration, its functions are amenable to be regulated by this ligand. We have used maDCs as a model system to analyze the mechanisms whereby CXCL12 simultaneously controls chemotaxis and survival in maDCs. We show that CXCL12 uses CXCR4, but not CXCR7, and the components of a signaling core that includes G(i)/Gßγ, PI3K-α/-δ/-γ, Akt, ERK1/2 and mammalian target of rapamycin complex 1 (mTORC1), which organize hierarchically to control both functions. Downstream of Akt, Forkhead box class O (FOXO) regulates CXCL12-dependent survival, but not chemotaxis, suggesting that downstream of the aforementioned signaling core, additional signaling molecules may control more selectively CXCL12-dependent chemotaxis or survival. Finally, the data obtained also show that CXCR4 uses a signaling signature that is different from that used by CCR7 to control similar functions.

[Prevention of therapeutic inertia in the treatment of arterial hypertension by using a program of home blood pressure monitoring]. / Eficacia de un programa de automedida domiciliaria de la presión arterial como estrategia para disminuir la inercia terapéutica.

OBJECTIVE: To evaluate the efficacy of a program of home blood pressure monitoring (HBPM) on therapeutic Inertia (TI) in mild-to-moderate hypertension (AHT). DESIGN: Controlled, randomised clinical trial. SETTING: Forty six clinics in 35 primary care centres. Spain. PARTICIPANTS: A total of 232 patients with uncontrolled hypertension were included. INTERVENTION: Two groups with 116 patients were formed: 1) Control group (CG): standard health intervention; 2) Intervention group (IG): patients who were included in the HBPM program. MAIN MEASUREMENTS: TI was calculated by the ratio: Number of patients whose pharmacological treatment was not changed in each visit/Number of patients with an average BP 140mmHg and/or 90mmHg in the general population or 130 and/or 90 mmHg in diabetics. The mean BPs and the percentage of controlled patients were calculated. The mean number of people that required an intervention in order to avoid TI was calculated (NI). RESULTS: A total of 209 patients completed the study, with TI in 35.64% (95% CI=29.85%-41.43%) of the sample, and in 71.63% (95% CI=63.9-79.36%) of the uncontrolled hypertensive patients. The TI was 22.42% (95% CI=24.2-37%) in the IG and 50% (95% CI=37.75-62.25) in the CG (p<.05) in visit 2, and 25.23% (95% CI=14.84-35.62) and 46.07% (95% CI=33.85-58.29) in the final visit for IG and CG, respectively (P<.05). The NI was 4.3. CONCLUSIONS: TI was very significant among the uncontrolled hypertensive patients. The studied interventions are effective for improving TI.

[Therapeutic non-compliance with insulin in the treatment of diabetes mellitus 2]. / El cumplimiento terapéutico con insulina en el tratamiento de la diabetes mellitus tipo 2: estudio CUMINDIAB.

OBJECTIVE: To determine the percentage of therapeutic noncompliance among type 2 diabetes patients on treatment with insulin. DESIGN: Prospective multicentre study. SETTING: Nine Primary Care Health Centre in Huelva (Spain). PARTICIPANTS: A total of 121 type 2 diabetics, who, in the opinion of their doctor, need to start treatment with insulin or have their insulin treatment modified. MAIN MEASUREMENTS: Five visits were made (enrolment, 6, 12, 18 and 24 months). The variables analysed were, fasting blood glucose, glycosylated haemoglobin, compliance with insulin treatment, measured by counting insulin units. The percentage compliance (PC) was calculated by (PC = Total No. of insulin units expected to be consumed / Total No. of insulin units that should have been taken x 100). A complier was considered as one who achieved a PC between 80 and 100%. RESULTS: There were 103 evaluable subjects (85.8%) with a mean age of 66.4 (SD 11.6) years, and 45 were male (42.8%). The mean percentage compliance with insulin was 90.9% (95% CI, 84.2-97.6%). At the 6, 12, 18 and 24 months visits it was 92.1% (95% CI, 85.6-98.6%), 92.3, 90.1 and 89.2% (95% CI, 81.7-96.7%), respectively. Overall patient compliance was 74.75% (95% CI, 64.3-85.2%). For the visits, compliance was 82.5% (95% CI, 73.3-91.7%), 77.7%, 73.8% and 71.8% (95% CI, 60.9-82.7%), respectively (P<.05 initial-final). CONCLUSIONS: A quarter of the diabetic patients did not comply with their insulin treatment.

Analysis of the factors predicting clinical response to tocilizumab therapy in patients with severe COVID-19.

BACKGROUND: Controversy remains about the efficacy of tocilizumab (TCZ) for the treatment of severe COVID-19. We aimed to analyze the profile of TCZ-respondent patients. METHODS: We retrospectively analyzed a cohort of patients with severe COVID-19 who received off-label TCZ after recommendation by a local committee and were admitted to the University Hospital "12 de Octubre" until May 2020. The primary end point was a significant clinical improvement (SCI) on day 14 after administration of TCZ. Factors independently related to SCI were analyzed by multivariate logistic regression models. RESULTS: Of 428 (63.3%) patients treated with TCZ, 271 (63.3%) experienced SCI. After adjustment for factors related to unfavorable outcomes, TCZ administration within the first 48 hours from admission (odds ratio [OR]: 1.98, 95% confidence Interval [95% CI]: 1.1-3.55; P = 0.02) and ALT levels >100 UI/L at day 0 (OR: 3.28; 95% CI: 1.3-8.1; P = 0.01) were independently related to SCI. The rate of SCI significantly decreased according to the time of TCZ administration: 70.2% in the first 48 hours from admission, 58.5% on days 3-7, and 45.1% after day 7 (P = 0.03 and P = 0.001, respectively). CONCLUSION: TCZ improves the prognosis of patients with COVID-19 the most if treatment starts within the first 48 hours after admission.

Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: A single-centre retrospective comparative study.

OBJECTIVES: A subgroup of patients with SARS-CoV-2 infection was thought to have developed cytokine release syndrome and were treated with tocilizumab; however, a significant percentage of patients evolved. This study aimed to determine the usefulness of anakinra as a rescue treatment for patients with tocilizumab-refractory COVID-19 disease. METHODS: A prospective cohort of patients with COVID-19 pneumonia who received anakinra as salvage therapy after failure of tocilizumab were compared (1:1) with selected controls in a historical cohort of patients treated with tocilizumab. Cases and controls were matched by age, comorbidities, pulse oximetry oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio at baseline, and time elapsed since the initiation of treatment with tocilizumab. The primary outcome was the improvement in clinical status measured by a 6-point ordinal scale, from baseline to day 21. RESULTS: The study included 20 cases and 20 controls (mean age 65.3 ± 12.8 years, 65% males). No differences were found in the clinical improvement rates at 7, 14 and 21 days of follow-up. The in-hospital mortality rate for patients receiving anakinra was 55% vs. 45% in the control group (P = 0.527). CONCLUSIONS: Treatment with anakinra was not useful in improving the prognosis of patients with tocilizumab-refractory severe COVID-19.

Effect of temperature - humidity index on the onset of post- partum ovarian activity and reproductive behavior in Bos indicus cows.

The effect of climatic factors on ovarian activity and reproductive behavior (RB) was evaluated in 46 Bos indicus cows kept under grazing conditions. Temperature-humidity index (THI) was used as an indicator of stress and divided in alert, damage and emergency levels. Fat thickness (FAT) was taken during the last trimester of gestation (LTG) to approximately 90d postpartum (PP). At 30d PP animals received a progesterone (P4)-releasing device (CIDR) which was withdrawn 9d later. Ovarian activity was assessed by blood progesterone on days 21, 24, 27, 30, 49, 51, and 54 PP. Animals were divided into three groups, higher, and moderate RB and non-behavior. Sixty percent presented a THI >74 increasing dramatically from June to September up to >78. During LTG, animals lost 27% of their body reserves contrasting to PP where an increase of 2.6% (P=0.002) was observed. The percentages of cyclic and non-cyclic animals were 57 and 43%, respectively (P> 0.05). Seventy-two percent displayed RB and 28% were non-behavior (P<0.05). A negative correlation (r = -0.307; P = 0.038) between THI and RB, and a positive correlation (r = 0.427; P = 0.003) between the onset of ovarian activity and RB were observed. Differences in THI during the LTG (P<0.01) were observed between cyclic and non-cyclic animals. Non-behavior cows in the LTG had a higher THI (P <0.05). High levels of THI have a negative effect on the resumption of ovarian activity and RB in Bos indicus especially if high THI occurs during the last trimester of gestation.

Efficacy, safety and cost-effectiveness of a web-based platform delivering the results of a biomarker-based predictive model of biotherapy response for rheumatoid arthritis patients: a protocol for a randomized multicenter single-blind active controlled clinical trial (PREDIRA).

BACKGROUND: Rheumatoid arthritis (RA) is one of the leading chronic inflammatory rheumatism. First-line therapy with synthetic disease-modifying antirheumatic drugs (sDMARD) is insufficiently effective in 40% of cases and these patients are treated with biotherapies. The increased use of these drugs each year is becoming a public health issue with considerable economic burden. This cost is 20 times higher than that of sDMARD. However, among patients treated with biotherapies, clinical practice shows that about one third will not respond to the selected drug. In nonresponse cases, practitioners currently have no choice but to perform an empirical switching between different treatments, because no tool capable of predicting the response or nonresponse to these molecules is currently available. METHODS: The study is a prospective, phase III, controlled, multicenter, and randomized, single-blind (patient) clinical trial, including RA patients with a previous failure to anti-TNF therapies. The main objective is the analysis of the clinical and pharmacoeconomic impact after 6 months of treatment. Intervention arm: prescription of biotherapy (rituximab, adalimumab, abatacept) using SinnoTest® software, a prediction software based on proteomic biomarkers. Control arm: prescription of biotherapy based on current practice, without the SinnoTest® software (any biotherapy). In addition, a substudy will be carried out within this trial to generate a biobank and further analyze the proteomic profile of the patients and their modification throughout the study. DISCUSSION: This clinical trial study will be the first validation study of a biotherapy response prediction software, bringing personalized medicine into the management of RA. We expect that the findings from this study will bring several benefits for the patient and the Health Care System. TRIAL REGISTRATION: ClincalTrials.gov NCT04147026 . Registered on 31 October, 2019.

Patient Decision Aid (PDA) for Patients with Rheumatoid Arthritis Reduces Decisional Conflict and Improves Readiness for Treatment Decision Making.

OBJECTIVES: The aim of this study was to develop and assess the effectiveness of a patient decision aid (PDA) to support treatment decision making in Spanish patients with moderate-to-severe rheumatoid arthritis (RA) who fail to achieve the therapeutic goal with the current disease-modifying antirheumatic treatment strategy. METHODS: The PDA was developed in accordance with the International Patient Decision Aids Standards recommendations. A steering group led the project. Three literature reviews and two focus groups were performed to develop the PDA prototype. To check its comprehensibility, acceptability, and feasibility, alpha-testing was performed using the Decision Support Acceptability Scale (DSAS). Beta-testing was conducted to assess preliminary evidence of PDA efficacy using the Decisional Conflict Scale (DCS) before and after PDA use. Readiness was evaluated using the Preparation for Decision Making Scale (PDMS). RESULTS: The PDA included (1) a brief description of RA, (2) treatment information, and (3) a values clarification section. Alpha-testing revealed that most patients considered that the information was presented in a good or excellent way and it could help clarify their values and facilitate treatment decision making. Most rheumatologists agreed that the PDA was easy to understand, to use, and allowed them to reach a shared decision. Beta-testing showed that PDA significantly reduced overall patients' decisional conflict [33.2 (DE: 21.4) vs 24.6 (23.5); p < 0.001] and prepared the patient for decision making [PDMS: 67.5 (21.0)]. CONCLUSIONS: We developed a PDA for Spanish patients with moderate-to-severe RA that reduces patients' decisional conflict and increases their readiness for decision making. The use of this PDA in routine clinical practice may improve the quality of the decision-making process and the quality of the choices made.

Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies.

Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.

VIP reverses the expression profiling of TLR4-stimulated signaling pathway in rheumatoid arthritis synovial fibroblasts.

Since recent evidences point out the potential involvement of Toll-like receptors (TLRs) in the therapeutic effect of vasoactive intestinal peptide (VIP), the purpose of this study is to elucidate the role of VIP as a negative regulator of TLR-signaling. To this aim, we analyzed in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), the expression profile of TLR-pathway related molecules, as well as the alterations induced by LPS stimulation in RA-FLS and the effect of VIP treatment. Cultured FLS were obtained from patients with RA or OA. RA-FLS were next stimulated with lipopolysaccharide (LPS) in presence or absence of VIP. The gene expression profiling of molecules involved in LPS-mediated TLR4-signaling was studied by cRNA microarray analysis. Twenty three molecules involved in TLR signaling resulted over-expressed at mRNA level in basal RA-FLS compared to OA-FLS. Moreover, in RA-FLS, 23 of the analyzed genes were found to be up-regulated by LPS stimulation whereas 30 were not affected. VIP down-regulated the LPS-induced RNA expression of molecules involved in TLR signaling pathway. Up-regulation of RNA expression of CD14, MD2, TRAM, TRIF, IRAK4, TAB2, TRAF6 and TBK1 was corroborated by RT-PCR as well as the VIP regulatory effect. Increased protein levels of TRAF6, TBK1 and pIRAK1 after exposure to LPS, and the inhibitory effect of VIP, were described by Western blotting. As functional consequences, it was observed the VIP-induced impaired production of IL-6 and RANTES/CCL5 after LPS stimulation. In conclusion, VIP acts as a negative modulator of the TLR4-signaling by overturning the production of several checkpoints molecules of the cascade and thus, widening its potential therapeutic effects.

Immunoregulatory properties of vasoactive intestinal peptide in human T cell subsets: implications for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease whose pathogenesis is not completely understood. Unbalanced Th1/Th2 T-cell polarization has been suggested to play a pathogenetic role and therefore, modulation of T-cell polarization is a potential therapeutic target. Vasoactive intestinal peptide (VIP) is a broadly distributed peptide that exerts anti-inflammatory and immunomodulatory effects, in the collagen-induced arthritis (CIA) murine model of RA, and ex vivo, in synovial cells from RA patients. In the present study, we have found that polyclonal stimulation of peripheral blood lymphocytes (PBL) from RA patients produces higher levels of inflammatory mediators and lower levels of Th1 cytokines than PBL from healthy controls; moreover, VIP has negligible effects on inflammatory mediators and Th1 cytokines produced by PBL from healthy controls but favours Th2 profile and enhanced IL-10 production after stimulation. VIP increases the levels of IL-10 and IL-4 in the supernatant of human CD4(+)CD45RA(+) cells cultured in a non-conditioned or a Th2-conditioned situation. In contrast, VIP does not modify the production of these cytokines in a Th1-conditioned medium. In summary, VIP can differentially modify the functional capacity of human lymphocytes by inducing Th2/Treg differentiation depending on their previous phenotype.