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A systematic review and meta-analysis were conducted, according to the PRISMA methodology, to summarize current evidence on the prevalence and predictors of long-term glucocorticoid (GC) treatment and disease relapses in the real-life management of polymyalgia rheumatica (PMR). Out of 5442 retrieved studies, 21 were eligible for meta-analysis and 24 for qualitative analysis. The pooled proportions of patients still taking GCs at 1, 2, and 5 years were respectively 77% (95%CI 71–83%), 51% (95%CI 41–61%), and 25% (95CI% 15–36%). No significant difference was recorded by distinguishing study cohorts recruited before and after the issue of the international recommendations in 2010. The pooled proportion of patients experiencing at least one relapse at 1 year from treatment initiation was 43% (95%CI 29–56%). Female gender, acute-phase reactants levels, peripheral arthritis, starting GCs dosage, and tapering speed were the most frequently investigated potential predictors of prolonged GC treatment and relapse, but with inconsistent results. Only a few studies and with conflicting results evaluated the potential role of early treatment with methotrexate in reducing the GC exposure and the risk of relapse in PMR. This study showed that a high rate of prolonged GC treatment is still recorded in the management of PMR. The relapse rate, even remarkable, can only partially explain the long-term GC treatment, suggesting that other and not yet identified factors may be involved. Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies. Key Points: • High rate of long-term glucocorticoid (GC) treatment is recorded in polymyalgia rheumatica (PMR), being 77%, 51%, and 25% of patients still on GCs after respectively 1, 2, and 5 years. • A pooled relapse rate of 43% at 1 year, even remarkable, can only partially explain the long-term GC treatment in PMR. • Several studies have attempted to identify potential predictors of prolonged treatment with GCs and relapse, but with inconsistent results. • Additional research is needed to profile patients with a higher risk of long-term GC treatment and relapse and identify more effective steroid-sparing strategies.

Background The aim was to assess the attainability and outcome of the lupus low disease activity state (LLDAS) in the early stages of systemic lupus erythematosus (SLE). Methods LLDAS prevalence was evaluated at 6 (T1) and 18 (T2) months after diagnosis and treatment initiation (T0) in a monocentric cohort of 107 (median disease duration 9.7 months) prospectively followed Caucasian patients with SLE. Reasons for failure to achieve LLDAS were also investigated. Multivariate models were built to identify factors associated with lack of LLDAS achievement and to investigate the relationship between LLDAS and Systemic Lupus International Collaboration Clinics (SLICC)/Damage Index (SDI) accrual. Results There were 47 (43.9%) patients in LLDAS at T1 and 48 (44.9%) at T2. The most frequent unmet LLDAS criterion was prednisolone dose >7.5 mg/day (83% of patients with no LLDAS at T1). Disease manifestations with the lowest remission rate during follow up were increased anti-double-stranded DNA (persistently present in 85.7% and 67.5% of cases at T1 and T2, respectively), low serum complement fractions (73.2% and 66.3%) and renal abnormalities (46.4% and 28.6%). Renal involvement at T0 was significantly associated with failure to achieve LLDAS both at T1 (OR 7.8, 95% CI 1.4–43.4; p  = 0.019) and T2 (OR 3.9, 95% CI 1.4–10.6; p  = 0.008). Presence of any organ damage (SDI ≥1) at T2 was significantly associated with lack of LLDAS at T1 (OR 5.0, 95% CI 1.5–16.6; p  = 0.009) and older age at diagnosis (OR 1.05 per year, 95% CI 1.01–1.09; p  = 0.020). Conclusion LLDAS is a promising treatment target in the early stages of SLE, being attainable and negatively associated with damage accrual, but it fit poorly to patients with renal involvement.

Steri, M.; Orru, V.; Idda, M. L.; Pitzalis, M.; Pala, M.; Zara, I.; Sidore, C.; Faa, V.; Floris, M.; Deiana, M.; Asunis, I.; Porcu, E.; Mulas, A.; Piras, M. G.; Lobina, M.; Lai, S.; Marongiu, M.; Serra, V.; Marongiu, M.; Sole, G.; Busonero, F.; Maschio, A.; Cusano, R.; Cuccuru, G.; Deidda, F.; Poddie, F.; Farina, G.; Dei, M.; Virdis, F.; Olla, S.; Satta, M. A.; Pani, M.; Delitala, A.; Cocco, E.; Frau, J.; Coghe, G.; Lorefice, L.; Fenu, G.; Ferrigno, P.; Ban, M.; Barizzone, N.; Leone, M.; Guerini, F. R.; Piga, M.; Firinu, D.; Kockum, I.; Bomfim, I. Lima; Olsson, T.; Alfredsson, L.; Suarez, A.; Carreira, P. E.; Castillo-Palma, M. J.; Marcus, J. H.; Congia, M.; Angius, A.; Melis, M.; Gonzalez, A.; Riquelme, M. E. A.; da Silva, B. M.; Marchini, M.; Danieli, M. G.; Del Giacco, S.; Mathieu, A.; Pani, A.; Montgomery, S. B.; Rosati, G.; Hillert, J.; Sawcer, S.; D'Alfonso, S.; Todd, J. A.; Novembre, J.; Abecasis, G. R.; Whalen, M. B.; Marrosu, M. G.; Meloni, A.; Sanna, S.; Gorospe, M.; Schlessinger, D.; Fiorillo, E.; Zoledziewska, M.; Cucca, F.

The pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined. To identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s). We enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients' sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients' sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies. In conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.

Background This study aimed to investigate the trajectory of damage accrual, associated factors, and impact on health-related quality of life (HR-QoL) in a multicenter cohort of patients with Behçet’s syndrome (BS) over 2 years of follow-up. Methods Patients recruited in the BS Overall Damage Index (BODI) validation study were prospectively monitored for 2 years and assessed for damage accrual, defined as an increase ≥1 in the BODI score, and HR-QoL was evaluated by the SF-36 questionnaire. Logistic and multiple linear regression models were built to determine factors associated with damage accrual and impairment in the different SF-36 domains. Results During follow-up, 36 out of 189 (19.0%) patients had an increase ≥1 in the BODI score with a mean (SD) difference of 1.7 (0.8) ( p <0.001). The incidence rate of damage accrual was stable over time, regardless of the disease duration. Out of 61 new BODI items, 25 (41.0%) were considered related to glucocorticoid (GC) use. In multivariate analysis, duration of GC therapy (OR per 1-year 1.15, 95% CI 1.07–1.23; p <0.001) and occurrence of ≥1 disease relapse (OR 3.15, 95% CI 1.09–9.12; p 0.038) were identified as predictors of damage accrual, whereas the use of immunosuppressants showed a protective effect (OR 0.20, 95% CI 0.08–0.54, p <0.001). Damage accrual was independently associated with the impairment of different physical domains and, to a greater extent, in emotional domains of the SF-36 questionnaire. Female sex, higher disease activity, and fibromyalgia were also significantly associated with impairment in HR-QoL. Conclusion In BS, organ damage accrues over time, also in long-standing disease, resulting in an impairment of the perceived physical and mental health. Adequate immunosuppressive treatment, preventing disease flares and minimizing exposure to GCs have a crucial role in lowering the risk of damage accrual.

The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B 2706 in Asia and the HLA-B 2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes. In Sardinia, the prevalence of HLA-B 2709, which differs from the strongly AS-associated B 2705 prototype for one amino acid (His/Asp116) in the F pocket of the peptide binding groove, is around 20% of all HLA-B27 alleles. We have previously hypothesized that malaria could have contributed to the establishment of this allele in Sardinia. Based on our recent findings, in this perspective article we speculate that the ndoplasmic eticulum mino eptidases, ERAP1 and 2, associated with AS and involved in antigen presentation, underwent co-selection by malaria. These genes, besides shaping the immunopeptidome of HLA-class I molecules, have other biological functions that could also be involved in the immunosurveillance against malaria.

Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD). To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity. One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations ( < 0.0001), and Pouchot's score was found to be significantly reduced at all time points ( < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points ( < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

Objectives. To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events. Materials and Methods. Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis—ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED. Results. Peripheral microvascular ED was documented in one-third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218–2.396), p<0.01 and OR (95% CI) = 1.005 (1.002–1.009), p<0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values. Conclusions. This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration.

ObjectivesTo explore the effects of anti-ribosomal P protein (anti-P) and anti-N-methyl-D-aspartic acid receptor subunit 2 (anti-NR2) autoantibodies on depression and cognitive dysfunction and their relationships with functional brain connectivity in SLE.MethodsThis cross-sectional study included adult patients who fulfilled the American College of Rheumatology/European Alliance of Associations for Rheumatology 2019 SLE criteria. Anti-P and anti-NR2 were quantified using ELISA. A 1-hour battery of neuropsychological testing interpreted by a neuropsychologist explored depressive symptoms (Center for Epidemiologic Studies Depression Scale, CES-D), cognitive domains and quality of life (SF-12). Resting-state functional connectivity (rs-fc) MRI analysis was performed within 1 month, and region-of-interest to region-of-interest (ROI-to-ROI) analyses with the graph theory were performed.ResultsThirty-three patients with SLE (9% male) were enrolled, mean age (SD) of 43.5 (14) years and median disease duration of 10.4 years (2.9–25.4). Anti-P was positive in 6 (18.2%) and anti-NR2 in 14 (42.4%) patients. Depressive symptoms were found in 14 (42.4%) patients using the CES-D (range 0–51). After correction for age, disease duration, disease activity and white matter lesion load, the CES-D score was independently associated with anti-P serum level (β=0.32; p=0.049) and prednisone daily dose (β=0.38; p=0.023). Nineteen patients (57.6%) showed at least a cognitive test alteration, but no significant association with autoantibodies was found. The rs-fc MRI analysis revealed an independent association between the anti-P serum levels and many altered brain ROI properties but no anti-NR2 and prednisone effects on the cerebral network.ConclusionsAnti-P was associated with brain network perturbation, which may be responsible for depressive symptoms in patients with SLE.

Behçet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B*51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B*51. In fact, the HLA-B*51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B*51. Overall, 64 BD patients, 43 HLA-B*51 positive healthy controls (HC) and 70 random HC were enrolled in the study. HLA-B*51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571T AIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B*51 and rs2259571G (pc = 9E-5), even though the rs2259571G distribution did not significantly differ between BD patients and HC. No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B*51 positive BD patients and HLA-B*51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia.