Response to treatment of rheumatoid arthritis shows large inter-individual variability. This heterogeneity is observed with all the anti-rheumatic drugs, including the commonly used TNF inhibitors. ...It seems that drug-specific and target-specific factors lead individual patients to respond or not to a given drug, although this point has been challenged. The search of biomarkers distinguishing responders from non-responders has included shotgun proteomics of serum, as a previous study of response to infliximab, an anti-TNF antibody. Here, we have used the same study design and technology to search biomarkers of response to a different anti-TNF antibody, adalimumab, and we have compared the results obtained for the two anti-TNF drugs. Search of biomarkers of response to adalimumab included depletion of the most abundant serum proteins, 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) labeling, two-dimensional liquid chromatography fractionation and relative quantification with a hybrid Orbitrap mass spectrometer. With this approach, 264 proteins were identified in all the samples with at least 2 peptides and 95% confidence. Nine proteins showed differences between non-responders and responders (P < 0.05), representing putative biomarkers of response to adalimumab. These results were compared with the previous study of infliximab. Surprisingly, the non-responder/responder differences in the two studies were not correlated (rs = 0.07; P = 0.40). This overall independence with all the proteins showed two identifiable components. On one side, the putative biomarkers of response to either adalimumab or infliximab, which were not shared and showed an inverse correlation (rs = -0.69; P = 0.0023). On the other, eight proteins showing significant non-responder/responder differences in the analysis combining data of response to the two drugs. These results identify new putative biomarkers of response to treatment of rheumatoid arthritis and indicate that they are notably drug-specific.
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the generation of anti-DNA autoantibodies due to exposure of immune cells to excessive amounts of extracellular DNA. Lack ...of P-selectin in mice induces the development of a lupus-like syndrome and patients with cutaneous lupus have reduced P-selectin expression in skin vessels. Using flow cytometry we analyzed in healthy donors and patients the expression of P-selectin Glycoprotein Ligand-1 (PSGL-1) in circulating neutrophils and the implication of PSGL-1/P-selectin interaction in neutrophil extracellular traps (NETs) generation. We found a statistical significance that neutrophils from active SLE patients have a reduced expression of PSGL-1 and low levels of PSGL-1 in neutrophils from SLE patients associated with the presence of anti-dsDNA antibodies, clinical lung involvement, Raynaud's phenomenon, and positive lupus anticoagulant. PSGL-1 is present along the DNA in the NET. In healthy donors, neutrophil interaction with immobilized P-selectin triggers Syk activation, increases the NETs percentage and reduces the amount of DNA extruded in the NETs. In active SLE patients, neutrophil interaction with P-selectin does not activate Syk or reduce the amount of DNA extruded in the NETs, that might contribute to increase the extracellular level of DNA and hence, to disease pathogenesis.
Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not ...in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA).
Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient 95% confidence interval: 0.12 0.06-0.18; p<0.001) or ACPA (0.34 0.01-0.67; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007).
Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatment.
The present study was undertaken to assess mortality, causes of death, and associated prognostic factors in a large cohort of patients diagnosed with idiopathic inflammatory myositis (IIM) from ...Spain. A retrospective longitudinal study was carried out in 467 consecutive patients with IIM, identified from 12 medical centers. Patients were classified as primary polymyositis, primary dermatomyositis (DM), overlap myositis, cancer-associated myositis (CAM), and juvenile idiopathic inflammatory myopathies. A total of 113 deaths occurred (24%) after a median follow-up time of 9.7 years. In the overall cohort, the 2-, 5-, and 10-year survival probabilities were 91.9, 86.7, and 77%, respectively. Main causes of death were infections and cancer (24% each). Multivariate model revealed that CAM (HR = 24.06), OM (HR = 12.00), DM (HR = 7.26), higher age at diagnosis (HR = 1.02), severe infections (HR = 3.66), interstitial lung disease (HR = 1.61), and baseline elevation of acute phase reactants (HR = 3.03) were associated with a worse prognosis, while edema of the hands (HR = 0.39), female gender (HR = 0.39), and longer disease duration (HR = 0.73) were associated with a better prognosis. The standardized mortality ratio was 1.56 (95% CI 1.28–1.87) compared to the Spanish general population. Our findings indicate that IIM has a high long-term mortality, with an excess of mortality compared to the Spanish population. A more aggressive therapy may be required in IIM patients presenting with poor predictive factors.
Few studies have considered immune-mediated inflammatory disorders (IMID) together, which is necessary to adequately understand them given they share common mechanisms. Our goal was to investigate ...the expression of vasoactive intestinal peptide (VIP) and its receptors VPAC1 and VPAC2 in selected IMID, analyze the effect of biological therapies on them, and identify miRNA signatures associated with their expression. Serum VIP levels and mRNA of VPAC and miRNA expression in peripheral blood mononuclear cells were analyzed from 52 patients with psoriasis, rheumatoid arthritis, Graves’ disease, or spondyloarthritis and from 38 healthy subjects. IMID patients showed higher levels of VIP and increased expression of VPAC2 compared to controls (p < 0.0001 and p < 0.0192, respectively). Receiver operating characteristic curve analysis showed that the levels of VIP or VPAC2 expression were adequate discriminators capable of identifying IMID. Treatment of IMID patients with anti-TNFα and anti-IL12/23 significantly affected serum VIP levels. We identified miRNA signatures associated with levels of serum VIP and VPAC2 expression, which correlated with IMID diagnosis of the patients. The results indicate that the expression of VIP/VPAC2 is able of identify IMIDs and open up a line of research based on the association between the VIP/VPAC axis and miRNA signatures in immune-mediated diseases.
BackgroundNo data on agreement between patient perception, DORIS 2021 remission, LLDAS, or physician assessment is currently available.The aim is to compare the SLE activity perceived by the patient ...using the Patient Acceptable Symptom State (PASS) question with the global assessment of activity by the physician, and the definitions of LLDAS/DORIS2021.MethodsA cross-sectional multicenter study involving SLE patients from seven Spanish Rheumatology Departments was conducted. The study applied DORIS 2021 remission criteria and LLDAS. Rheumatologists classified disease activity into five categories: remission, SACQ, low, moderate, or high. The patients were asked about their clinical SLE condition through the PASS question: ‘Considering all the different ways your disease is affecting you, if you were to stay in this state for the next few months, do you consider your current state satisfactory?’: PASS yes/PASS no. Statistical analysis included descriptive cross-sectional analysis and Cohen’s kappa for agreement analysis.ResultsAmong the 503 patients in the study (table 1), 386 (77.4%) reported an acceptable symptom state according to the PASS question. Mean patient global assessment (PtGA) was 29.62 (±24.38) on a scale of 0–100, while mean physician global assessment (PGA) was 0.46 (±0.59) on a scale of 0–3. A total of 236 (47.6%) patients met DORIS 2021 remission criteria, and 289 (59%) met LLDAS. According to the rheumatologists’ categorical classification, 435 (86.8%) patients were in remission or low disease activity (table 2).Among PASS-affirmative patients, 65.5% met LLDAS and 57.9% met DORIS 2021 remission criteria, with lower PtGA (19.7) and PGA (0.29) scores. In the non-PASS group, 62.8% were not in LLDAS, and 87.6% did not meet DORIS 2021 remission criteria, with higher PtGA (58) and PGA (1) scores (table 3). The overall agreement between PASS and categorical classification was 82% with a Cohen’s kappa of 0.43.ConclusionsThe majority of SLE patients reported an acceptable symptom state according to the PASS question, which aligns with the PtGA scale. Physicians’ assessments also showed similarities with patient perspectives. However, notable differences were observed regarding remission/LLDAS criteria, indicating that while patient and physician perspectives align on subjective classification, variations exist concerning LLDAS and DORIS.Abstract P129 Table 1Patient demographics and disease characteristics Number (%) or mean (± SD)(n = 503 patients) Female gender 463 (92%) Age at diagnosis (years) 40.7 (±21) Disease duration at enrollment (years) 10,8 (± 9.9) Age at enrollment (years) 50.4 (± 13.71) ACR criteria (a) ANA 495 (96.5%) Immunologic 398 (77.6%) Arthritis 382 (74.5%) Haematologic 291 (56.7%) Malar rash 231 (45.0%) Photosensitivity 229 (44.6%) Mouth ulcers 178 (34.7%) Renal 168 (32.7%) Serositis 100 (19.5%) Discoid rash 69 (13.5%) Neurologic 28 (5.5%) SLE activity SLEDAI-2K score at enrollment 2.8 (± 3.3) SLICC/ACR-DI score at enrollment 0.96 (± 1.4) Damage present at enrollment, n (%) 253 (49.8%) Clinical SLEDAI-2 K (no complement or a-sDNA) 1.6 (±2.7) PGA at enrollment 0.46 (± 0.59) Treatment Prednisone 200 (39.7%) Prednisone dose (mean ± SD) 5 (±6.27) Antimalarials 366 (72.5%) Inmunosupresants and/or biologic 219 (44%) Abbreviations: SLE, systemic lupus erythematosus; ACR, American College of Rheumatology; SLEDAI, SLE disease activity index; PGA, physician global assessment; ANA, antinuclear antibody; ds DNA, double stranded DNA. SLICC/ACR-DI: Systemic Lupus International Collaborating Clinics (SLICC/American College of Rheumatology (ACR) damage index (SDI) (a) Ever present based on ACR criteria, LLDAS: Lupus Low Disease Activity State Abstract P129 Table 2SLE activity: patient and expert’s perspective Number (%) or mean (± SD) (n = 503 patients) SLE disease state classification by expert Remission of SLE 205 (40.9%) Serologically active, clinically inactive 74 (14.8%) Low SLE activity 156 (31.1%) Moderate SLE activity 56 (11.2%) Severe SLE activity 10 (2%) PGA at enrolment 0.46 (± 0.59) Positive PASS question 386 (77.4%) PtGA at enrolment 29.62 (±24.38) Abbreviations: SLE, systemic lupus erythematosus; PGA, physician global assessment; PASS: Patient acceptable symptoms state; PtGA: patient global assessment.Abstract P129 Table 3LLDAS and DORIS 2021 remission states according to PASS yes/no perspective by patient PASS (n,%) non-PASS (n,%) LLDAS DORIS LLDAS DORIS YES NO YES NO YES NO YES NO 245 (65.5%) 129 (34.5%) 220 (57.9%) 160 (42.1%) 42(37.2%) 71(62.8%) 14(12.4%) 99(87.6%) PtGA, mean, SD 19.76 (±18) PtGA, mean, SD 58.04 (±19) PGA, mean, SD 0.29 (±0.4) PGA, mean, SD 1.01 (±0.72) Abbreviations: PASS: Patient acceptable symptoms state; LLDAS: lupus low disease activity state; PGA: physician global assessment; PtGA: patient global assessment.
Objectives. To assess the retention rate of TNF antagonists in elderly patients suffering from chronic arthropathies and to identify predictive variables of discontinuation by inefficacy or by ...adverse events (AEs).
Methods. All patients treated with TNF antagonists in BIOBADASER 2.0, with a diagnosis of either RA or spondyloarthritis (SpA: AS and PsA) were included and classified as <65 (younger) or 65 years of age (older) at start of the treatment. Cumulative incidence function for discontinuation (inefficacy or AE) was estimated as being the alternative reason for a competing risk. Competing-risks regression models were used to measure the association between study groups, covariates and reason for discontinuation.
Results. A total of 4851 patients were studied; 2957 RA (2291 in the younger group and 666 in the older group) and 1894 SpA (1795 in the younger group and 99 in the older group). Retention curves were statistically differently stratified by age groups, with the SpA younger group having the largest retention rate. Competing-risks regression models showed that in the older group, AEs were the most common reason for discontinuation regardless of the diagnosis of the patient and TNF antagonist molecule, whereas in the younger group, the most common cause of discontinuation was inefficacy.
Conclusion. In conclusion, factors predicting discontinuation of TNF antagonists due to AEs are older age and diagnosis of RA. On the other hand, younger age predicts discontinuation due to lack of efficacy.
Aims:The objective of this study was to investigate whether baseline receptor activator for nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) serum (s) levels can predict the therapeutic ...response to TNF antagonists (a-TNF).Methods:We studied 75 rheumatoid arthritis patients (81% female) with a longstanding refractory disease. The variables of disease activity, physical function and sRANKL and sOPG levels were determined before and after both 12–14 and 28–30 weeks of a-TNF therapy (65 adalimumab, 10 infliximab). Remission was defined by a 28 joint count disease activity score (DAS28) ⩽2.6 and clinical response by a reduction in DAS28⩾1.2 at both 3- and 7-month follow-up visits.Results:In most patients, disease activity was severe, as reflected by a baseline DAS28 score of 5.9±1 (mean±SD), an HAQ of 1.6 (1.1 to 2.1) (median (interquartile range (IQR))) and a CRP 15 mg/l (IQR: 9 to 24). The sRANKL levels and RANKL/OPG ratio in patients that achieved remission were significantly lower at baseline than in the remaining patients at both 3 and 7 months of follow-up. The sOPG levels correlated with the HAQ and the physician’s disease assessment and diminished significantly after a-TNF treatment. However, no significant association was detected between the therapeutic response profile and sOPG levels.Conclusions:These data suggest that in patients receiving a-TNF treatment, lower serum levels of RANKL and RANKL/OPG ratio may serve to predict remission.
Objective
To study prognostic factors in different types of idiopathic inflammatory myopathies (IIM) associated with interstitial lung disease (ILD).
Patients and methods
Multicenter retrospective ...study of a Spanish cohort of patients diagnosed with IIM. Patients were classified into four categories: polymyositis (PM), dermatomyositis (DM), antisynthetase syndrome (ASS), and overlap myositis (OM). Sociodemographic data, clinical characteristics, antibodies, and treatments were collected. Cox regression models were calculated to identify factors associated with mortality, the necessity for long-term oxygen therapy (LTOT), and deterioration in respiratory function tests (RFT).
Results
The number of patients included was 478, of whom 112 (23.4%) suffered from ILD: 17% PM, 16% DM, 45% ASS, and 22% OM. Factors associated with mortality in the multivariate analysis were clinically meaningful progression of ILD after 3 months (CMP 3m) (hazard ratio (HR) 9.48,
p
= 0.005), severe infections (HR 6.41,
p
= 0.016), heliotrope erythema (HR 31.1,
p
= 0.002), delay in diagnosis (HR 1.29;
p
= 0.011), and Raynaud’s phenomenon (HR 11.9,
p
= 0.007). However, being female (HR 0.19,
p
= 0.044) and positivity solely for ANAs (HR 0.08,
p
= 0.008) presented a protective effect. CMP 3m (HR 22.7,
p
= 0.027) was associated with the need for LTOT, while basal aldolase (HR 0.90;
p
= 0.049) had a protective effect. Likewise, joint manifestations (HR 0.04,
p
= 0.034) were shown to reduce risk of deterioration in RFT.
Conclusions
CMP 3m, severe infections, delay in diagnosis, heliotrope erythema, and Raynaud’s phenomenon were identified as factors of poor prognosis in different IIM associated with ILD.
Pro-inflammatory CD4
CD28
T cells are characteristic of immunosenescence, but also of several autoimmune/inflammatory diseases. Vasoactive intestinal peptide (VIP) acts as an anti-inflammatory and ...immunomodulatory mediator on these cells. Our objective was to study the mutual influence between senescent Th cells and VIP axis in early arthritis (EA), comparing with non-EA donors. We characterized the correlation between senescent Th cells and clinic parameters of EA as well as the behavior of senescent Th biomarkers by real-time PCR. Clinical data were systematically recorded at baseline and after 6 months of follow-up. The number of CD4
CD28
T cells measured by sorting is higher in patients who initially meet ACR classification criteria for rheumatoid arthritis (RA) compared to those who were classified as undifferentiated arthritis (UA). A slight positive correlation between EA CD4
CD28
T cells and CRP or ESR and a negative correlation with bone mineral density were found. Th senescent biomarkers in EA CD4
CD28
T cells were similar to donors, however some of them increased after 6 months of follow-up. VPAC receptors were analyzed by real-time PCR and immunofluorescence, and CD4
CD28
T cells showed higher expression of VPAC
and lower of VPAC
, VPAC
showing a significant increased expression in EA cells. Sorted CD4
CD28
T cells were in vitro expanded in presence of VIP, wherein VIP increased senescent biomarker CD27, while it diminished CD57 or NKG2 senescent biomarkers. Our study demonstrates for the first time the existence of a link between senescent Th cells and the VIP axis.
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