•The clinical characteristics of obese patients with AOSD were assessed.•Obese patients with AOSD did not differ in main clinical features than others.•Obese patients with AOSD showed higher ferritin ...and CRP, which correlated with BMI.•Obese patients with AOSD showed higher CRP values than obese patients without IMID.•Obesity was a predictive factor for a chronic disease course and bDMARD failure.
To evaluate the impact of obesity in patients with adult-onset Still's disease (AOSD) and to assess their clinical characteristics and disease outcomes.
The clinical features of AOSD patients with a body mass index (BMI)≥30 were assessed among those included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort.
Out of 139 AOSD patients, who had BMI registered in our database, 26 (18.7%) had a BMI≥30. A lower rate of sore throat (P<0.05), pericarditis (P<0.05), and pleuritis (P<0.05) was shown in obese patients. Additionally, obese patients showed higher values of C-reactive protein (CRP) (P<0.05) and ferritin (P<0.05) than others. Furthermore, obese patients were characterised by biologic disease-modifying antirheumatic drug (bDMARD) failure in subsequent follow-up (P<0.05). They also presented higher rate of comorbidity than non-obese patients (P<0.05). Finally, obesity predicted the presence of a chronic disease course in both univariate (HR: 1.72, 95%CI: 1.03–2.51, P<0.05) and multivariate analyses (HR: 1.85, 95%CI: 1.45–2.89, P<0.05). Obesity was also a significant predictor of bDMARD failure in AOSD patients in both univariate (HR: 3.03, 95%CI: 1.42–6.45, P<0.01) and multivariate analyses (HR: 3.59, 95%CI: 1.55–8.27, P<0.01).
Obese patients at the time of diagnosis of the disease were characterised by a lower prevalence of sore throat, serositis, as well as by higher values of CRP and ferritin. Obesity was also a predictive factor for a chronic disease course and bDMARD failure, thus highlighting a subset of patients with AOSD to be carefully managed.
Several studies have pointed out a significant association between rheumatoid arthritis (RA) and accelerated atherosclerosis. At the best of our knowledge, no such study has been carried out in a ...large Italian series and, in this study, we aimed to investigate the prevalence of both subclinical atherosclerosis and history of cardiovascular events (CVEs), in patients consecutively admitted from January 1, 2015 to December 31, 2015 to Rheumatology Units throughout the whole Italy.Centers members of GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) were invited to enrol patients consecutively admitted from January 1, 2015 to December 31, 2015 and satisfying American College of Rheumatology/ European League Against Rheumatism criteria for RA and to investigate each of them for: traditional cardiovascular risk factors: sex, age, smoking habit, total cholesterol, triglycerides, glycaemia, high blood pressure, metabolic syndrome (MS), type 2 diabetes (T2D); RA features: disease duration as assessed from the first symptom, disease activity as evaluated by DAS28, radiographic damage as assessed by hands and feet x-ray, and previous joint surgery; prevalence of both subclinical atherosclerosis and history of CVEs.Eight centers participated to the study. From January 1, 2015 to December 31, 2015, the 1176 patients, who had been investigated for all the items, were enrolled in the study. They were mostly women (80.52%), with a median age of 60 years (range, 18-91 years), a median disease duration of 12 years (range, 0.8-25 years), seropositive in 69.21%. Nineteen percent were in remission; 17.51% presented low disease activity; 39.45% moderate disease activity; 22.61% high disease activity.Eighty-two patients (6.9%) had a history for CVEs (58 myocardial infarction, 38 heart failure, 10 ischemic transitory attack, and 7 stroke). This figure appears to be lower than that reported worldwide (8.5%). After excluding the 82 patients with a history of CV events, subclinical atherosclerosis was detected in 16% of our patients, (176 patients), a figure lower than that reported worldwide (32.7%) and in previous Italian studies.This is the first Italian multicenter study on subclinical and clinical atherosclerosis in patients with RA. We pointed out a low prevalence of both subclinical atherosclerosis and history of CV events.
The objective of this study is to describe the possible prognostic impact of smoking habit on adult-onset Still’s disease (AOSD) patients, by the assessment of clinical characteristics, ...life-threatening complications occurrence, and mortality in smokers than non-smokers. A multicentre retrospective study of prospectively followed-up AOSD patients included in
Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale
(GIRRCS) cohort was conducted. Out of 185 AOSD assessed patients, 45 smokers were identified. These showed a higher frequency of pericarditis (35.5% vs 16.4%,
p
= 0.011), pleuritis (33.3% vs 14.3%,
p
= 0.008), and abdominal pain (17.7% vs 6.4%,
p
= 0.035). Furthermore, smokers showed higher values of systemic score (6.4 ± 2.2 vs 5.4 ± 1.8,
p
= 0.004), an increased rate of macrophage activation syndrome (MAS) (28.9% vs 6.4%,
p
< 0.0001) and of parenchymal lung disease (17.7% vs 12.6%,
p
= 0.035). Although not significant, these patients more frequently experienced a poor prognosis (13.3% vs 4.3%,
p
= 0.074). Smoking habit predicted MAS occurrence in both univariate (HR: 5.98, 95% CI: 2.45–14.57,
p
< 0.0001) and multivariate regression models (HR: 6.21, 95% CI: 2.46–15.70,
p
< 0.0001). Smokers had a significant higher risk of parenchymal lung disease in both univariate (HR: 3.97, 95% CI: 1.43–11.02,
p
= 0.008) and multivariate regression models (HR: 3.90, 95% CI: 1.36–11.23,
p
= 0.012). Smoking habit also increased the risk of mortality in univariate regression model (HR: 4.25, 95% CI: 1.33–13.55,
p
= 0.015). Smoking habit resulted to be a negative prognostic factor on AOSD patients. Smokers were characterised by a higher frequency of serositis and higher values of systemic score. Additionally, these patients were more frequently burdened by MAS and parenchymal lung disease associated with a poor prognosis.
Key points
•
Smoking habit resulted to be a negative prognostic factor on AOSD.
•
Smokers were characterised by an increased frequency of serositis and higher values of systemic score.
•
Cigarette exposure was associated with MAS and parenchymal lung disease in AOSD.
Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage ...adjustment or switch to different drugs, enabling a personalized medicine approach.
We report a multicenter cross-sectional study on different methods ELISA and a cell based functional assay (reporter gene assay – RGA) for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria.
The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.
•Commercial ELISA and RGA perform comparably in detecting drug/ADAb levels.•ADAb inversely correlated with drug levels.•ETA displays the lowest immunogenicity.•Measurements of drug and anti-drug antibody levels are useful for monitoring treatment in RA.•TNF inhibitor pharmacology is better defined by the combination of the two assays.
Severe pulmonary arterial hypertension (PAH) is rarely observed as the initial manifestation of systemic lupus erythematosus (SLE), and the diagnosis is often delayed. Here we present the case of a ...32-year-old woman with severe PAH as the initial manifestation of SLE, who was successfully treated with mycophenolate mofetil and cyclosporine. This case offered the opportunity to critically review the epidemiology data, predictive markers, and pathogenic pathways of SLE-associated PAH (SLE-PAH) in relation to the currently available therapeutic options and to the main clinical trials of the last 10 years focused on the treatment of SLE-PAH. Mycophenolate mofetil and cyclosporine - currently used in the maintenance phase of the disease in certain clinical settings - should be considered, as an alternative to cyclophosphamide, in future clinical trials aimed at evaluating the most effective treatment of SLE-PAH at presentation.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which any organs can be potential targets of autoimmune aggression. Although the pathogenic auto-antibodies have been well ...characterized, the role of B cells goes far beyond that of antibodies production, and B cell-targeted therapy may be an interesting therapeutic approach. The anti-CD20 monoclonal antibody rituximab has been successfully used to control the most severe form of SLE, and even if two controlled clinical trials failed to demonstrate its superiority compared to conventional immunosuppressants, off-label use of rituximab is still commonly adopted in clinical practice in SLE nephritis resistant to immunosuppressants. Different protocols have stipulated heterogeneous dosages but all of them included repeated injections of the drug, exposing the patient to the risk of adverse reactions and to tachyphylaxis (loss of the therapeutic effect). Stimulation of the host’s immune system to develop a CD20 antigen-specific immune response by means of CD20-mimotope molecules may offer an approach that can overcome these drawbacks. This study provides a critical overview of vaccination therapy in rheumatic diseases and reports the design of a vaccination strategy in (New Zealand Black/New Zealand White) F1 SLE-prone mice using CD20-mimotope peptides. By week 47, this vaccine induces a B- cell depletion by 74 % (cell number, mean ± SD, 0.57 ± 0.38) as compared to week 29 (2.19 ± 0.55) (
p
= 0.005) and prolongs survival in peptide-treated mice (median, 46.71 weeks; 95 % CI, 39.78–53.64) as compared to the control group (median 39.85; 95 % CI, 37.41–42.30) (Kaplan-Meier
p
= 0.002), although no differences between the peptide group and control group were detected in terms of proteinuria and auto-antibodies titers. These data indicate the feasibility of this approach, and the mouse model described here may be useful to optimize vaccination protocol and to define the mechanism(s) underlying B- cell depletion.
Heterogeneity of the effector functions displayed by rituximab and other anti-CD20 monoclonal antibodies (mAbs) apparently recognizing the same CD20 epitope suggests that additional mechanisms, ...probably related to mAb fine specificity, are responsible for B-cell depletion. To improve our understanding of rituximab's function, its fine specificity was investigated by means of phage display peptide library (PDPL)-expressing 7-mer cyclic (c7c) or 7-/12-mer linear peptides. Rituximab-specific c7c PDPL-derived clone insert sequences expressed the motif A(S)NPS overlapping the human CD20 170ANPS173. P172 was the most critical for rituximab binding, since its replacement with S172 (of mouse CD20) abolished the reactivity. The WPXWLE motif expressed by the linear PDPL-derived clone insert sequences could only be aligned to the reverse-oriented 161WPXWLE156 of acid sphingomyelinase-like phosphodiesterase 3b precursor (ASMLPD), though linear peptides bearing WPXWLE competed with cyclic ones for rituximab-paratope binding. Anti-CD20 mAb 1F5 only displayed a reactivity profile similar to that of rituximab, which also reacted with ASMLPD-derived peptides. Peptides induced antibodies with specificity and effector functions similar to those of rituximab. Our results show a unique fine specificity of rituximab, define the molecular basis for the lack of rituximab reactivity with mouse CD20 (mCD20), and the potential of targeting CD20 in an active immunotherapy setting. A possible rituximab interaction with ASMLPD is suggested.
Despite the production of neutralizing antibodies to hepatitis C virus (HCV), many patients fail to clear the virus and instead develop chronic infection and long-term complications. To understand ...how HCV infection perturbs the antibody repertoire and to identify molecular features of antibody genes associated with either viral clearance or chronic infection, we sequenced the V(D)J region of naïve and memory B cells of 6 persons who spontaneously resolved an HCV infection (SR), 9 patients with a newly diagnosed chronically evolving infection (CE), and 7 healthy donors. In both naïve and memory B cells, the frequency of use of particular antibody gene subfamilies and segments varied among the three clinical groups, especially between SR and CE. Compared to CE, SR antibody genes used fewer VH, D and JH gene segments in naïve B cells and fewer VH segments in memory B cells. SR and CE groups significantly differed in the frequency of use of 7 gene segments in naïve B cell clones and 3 gene segments in memory clones. The nucleotide mutation rates were similar among groups, but the pattern of replacement and silent mutations in memory B cell clones indicated greater antigen selection in SR than CE. Greater clonal evolution of SR than CE memory B cells was revealed by analysis of phylogenetic trees and CDR3 lengths. Pauciclonality of the peripheral memory B cell population is a distinguishing feature of persons who spontaneously resolved an HCV infection. This finding, previously considered characteristic only of patients with HCV-associated lymphoproliferative disorders, suggests that the B cell clones potentially involved in clearance of the virus may also be those susceptible to abnormal expansion.
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