Francesca Romana Spinelli

Switching tumour necrosis factor α antagonists in patients with ankylosing spondylitis and psoriatic arthritis: an observational study over a 5-year period

Objective: To evaluate the clinical response after switching from one tumour necrosis factor (TNF)α antagonist to another in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods: In this ongoing, longitudinal, observational study, data were prospectively collected on efficacy and safety since 2000 for patients starting biological treatments. The present analysis was restricted to patients with a diagnosis of spondyloarthropathy (SpA) who switched from one TNFα antagonist to another because of inadequate efficacy or adverse events. Results: In total, 589 anti-TNFα-naive patients were registered, of whom 165 had a diagnosis of SpA; 7 patients with AS and 15 with PsA received >1 TNFα antagonist. Two patients with PsA were treated with all the drugs. In all, 16 subjects switched from infliximab to etanercept, 7 from etanercept to adalimumab and 1 from etanercept to infliximab. Overall, a clinical response was seen in 75% of patients who changed from infliximab to etanercept, and in 57.1% who switched from etanercept to adalimumab. Conclusions: The findings of this study on a selected population of patients with SpA indicate that the failure of an initial TNFα antagonist does not preclude the response to another one. Further trials are needed to confirm this preliminary observation.

Autoantibody profile in systemic lupus erythematosus with psychiatric manifestations: a role for anti-endothelial-cell antibodies

This study was performed to determine the correlation between psychiatric manifestations and several autoantibodies that might participate in the pathogenesis of psychiatric disorders in the course of systemic lupus erythematosus (SLE). Fifty-one unselected outpatients with SLE were enrolled. Psychiatric evaluation was performed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The prevalence of antibodies against endothelial cells (AECA), cardiolipin, β2 glycoprotein I, Ro, Ro52, La, glial fibrillary acidic protein, ribosomal P protein, dsDNA, and nucleosomes was assessed by experimental and commercial enzyme-linked immunosorbent assays. According to the cutoff value, AECA were present in 11 of 17 (64.7%) SLE patients with psychosis and mood disorders and in 10 of 34 (29.4%) patients without psychiatric manifestations other than anxiety (P = 0.03). Moreover, the AECA binding index was significantly higher in the first group (P = 0.03). Conversely, no significant correlation was found between the presence of the other autoantibodies studied and psychiatric involvement. The results of this study suggest a relationship between AECA and psychosis and mood disorders in SLE, supporting the hypothesis of a biological origin of these disturbances.

Anti-tumour necrosis factor (TNF) α treatment of rheumatoid arthritis (infliximab) selectively down regulates the production of interleukin (IL) 18 but not of IL12 and IL13

Objective: To measure interleukin (IL)18 serum concentrations in patients with rheumatoid arthritis (RA) undergoing infliximab treatment (tumour necrosis factor (TNF) α blockade) and to evaluate the concomitant modification of IL12 and IL13 serum concentrations, two cytokines belonging to the Th1 and Th2 profile respectively and biologically related to IL18. Methods: Ten patients with RA not responding to disease modifying antirheumatic drugs (DMARDs) received intravenous infliximab at a dose of 3 mg/kg at baseline and after two and six weeks. Serum samples were collected from all patients before each infusion and assayed for IL18, IL12, and IL13 by enzyme linked immunosorbent assay (ELISA); IL18 was also measured eight weeks after the last infusion. Results: Serum concentrations of IL18 in all patients were already markedly reduced from baseline after two weeks (p<0.005). Serum IL18 was also decreased in a stable manner after six (p<0.01) and 14 weeks (p<0.01) compared with baseline concentrations. No significant modifications were found in serum concentrations of IL12 and IL13 at any time point. Conclusion: There was a rapid and persistent decrease in serum concentrations of IL18 in all the patients studied. This result provides evidence of an in vivo regulation of IL18 by TNFα and suggests that anti-TNFα therapy is likely to interrupt the synergistic effect between these two cytokines.

Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

Introduction Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs). Results Nineteen percent of patients had mild GCDs impairment (GCDs 2–3), 7% moderate (GCDs 4–5) and 5% severe (GCDs≥6). The visuospatial domain was the most compromised (MDZs = −0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment. Conclusions Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients.

Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis.

Endothelial dysfunction has been detected in RA patients and seems to be reversed by control of inflammation. Low circulating endothelial progenitor cells (EPCs) have been described in many conditions associated with increased cardiovascular risk, including RA. The aim of this study was to investigate the effect of inhibition of TNF on EPCs in RA patients. Seventeen patients with moderate-severe RA and 12 sex and age-matched controls were evaluated. Endothelial biomarkers were tested at baseline and after 3 months. EPCs were identified from peripheral blood mononuclear cells by cytofluorimetry using anti-CD34 and anti-vascular endothelial growth factor-receptor 2. Asymmetric dimethylarginine (ADMA) was tested by ELISA and flow-mediated dilatation (FMD) by ultrasonography. Circulating EPCs were significantly lower in RA patients than in controls (P = 0.001). After 3 months EPCs increased significantly (P = 0.0006) while ADMA levels significantly decreased (P = 0.001). An inverse correlation between mean increase in EPCs number and mean decrease of DAS28 after treatment was observed (r = −0.56, P = 0.04). EPCs inversely correlated with ADMA (r = −0.41, P = 0.022). No improvement of FMD was detected. Short-term treatment with anti-TNF was able to increase circulating EPCs concurrently with a proportional decrease of disease activity suggesting that therapeutic intervention aimed at suppressing the inflammatory process might positively affect the endothelial function.

Flare, Persistently Active Disease, and Serologically Active Clinically Quiescent Disease in Systemic Lupus Erythematosus: A 2-Year Follow-Up Study

Objective Several indices have been proposed to assess disease activity in patients with Systemic Lupus Erythematosus (SLE). Recent studies have showed a prevalence of flare between 28–35.3%, persistently active disease (PAD) between 46%–52% and serologically active clinically quiescent (SACQ) disease ranging from 6 to 15%. Our goal was to evaluate the flare, PAD and SACQ rate incidence in a cohort of SLE patients over a 2-year follow-up. Methods We evaluated 394 SLE patients. Flare was defined as an increase in SLEDAI-2K score of ≥4 from the previous visit; PAD was defined as a SLEDAI-2K score of ≥4, on >2 consecutive visits; SACQ was defined as at least a 2-year period without clinical activity and with persistent serologic activity. Results Among the 95 patients eligible for the analysis in 2009, 7 (7.3%) had ≥1 flare episode, whereas 9 (9.4%) had PAD. Similarly, among the 118 patients selected for the analysis in 2010, 6 (5%) had ≥1 flare episode, whereas 16 (13.5%) had PAD. Only 1/45 patient (2.2%) showed SACQ during the follow-up. Conclusion We showed a low incidence of flare, PAD and SACQ in Italian SLE patients compared with previous studies which could be partly explained by ethnic differences.

Ultrasound evaluation of hand, wrist and foot joint synovitis in systemic lupus erythematosus

OBJECTIVES To assess the prevalence and severity of inflammatory abnormalities of the hand, wrist and foot joints in SLE patients by US and to correlate them with clinical, laboratory and disease activity score parameters. METHODS Sixty-two consecutive SLE patients were enrolled in the present study and underwent clinical evaluation, laboratory tests and bilateral high-resolution US of the hand, wrist and foot joints. Joint effusion (JE), synovial hypertrophy (SH) and local pathological vascularization [power Doppler (PD)] were evaluated according to both a dichotomous score and a semi-quantitative (0-3) grading system. In addition, a global US score was calculated by summing the values given to each elementary lesion for every single joint and every joint group. US findings were correlated with physical examination, serological parameters (CRP, ANA, anti-dsDNA, ENA, aPL, C3 and C4 serum levels) and disease activity indexes (SLEDAI-2K, ECLAM). RESULTS US detected inflammatory joint abnormalities in 54/62 patients (87.1%); 72.6% presented involvement of the MTP joints, 46.7% the MCP joints, 19.3% the PIP joints and 53% the wrists. A total of 1984 joints were examined highlighting JE in 19.1% of cases, SH in 6.9% and positive PD in 1.1%. The global US inflammatory score had a mean value of 10.9 (s.d. 15.2). No correlations were found between US findings and SLE disease activity parameters. CONCLUSION US demonstrated a high prevalence of inflammatory joint abnormalities in SLE that were also present in asymptomatic patients. Interestingly, the foot joints were the most frequently involved. US is a valuable tool for detecting subclinical synovitis in SLE.

International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.

A multilocus genetic study in a cohort of Italian SLE patients confirms the association with STAT4 gene and describes a new association with HCP5 gene.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease with complex pathogenesis in which genes and environmental factors are involved. We aimed at analyzing previously identified loci associated with SLE or with other autoimmune and/or inflammatory disorders (STAT4, IL10, IL23R, IRAK1, PSORS1C1, HCP5, MIR146a, PTPN2, ERAP1, ATG16L1, IRGM) in a sample of Italian SLE patients in order to verify or confirm their possible involvement and relative contribution in the disease. Materials and methods Two hundred thirty-nine consecutive SLE patients and 278 matched healthy controls were enrolled. Study protocol included complete physical examination, and clinical and laboratory data collection. Nineteen polymorphisms were genotyped by allelic discrimination assays. A case-control association study and a genotype-phenotype correlation were performed. Results STAT4 was the most associated gene [P = 3×10−7, OR = 2.13 (95% CI: 1.59–2.85)]. IL10 confirmed its association with SLE [rs3024505: P = 0.02, OR = 1.52 (95% CI: 1.07–2.16)]. We describe a novel significant association between HCP5 locus and SLE susceptibility [rs3099844: P = 0.01, OR = 2.06 (95% CI: 1.18–3.6)]. The genotype/phenotype correlation analysis showed several associations including a higher risk to develop pericarditis with STAT4, and an association between HCP5 rs3099844 and anti-Ro/SSA antibodies. Conclusions STAT4 and IL10 confirm their association with SLE. We found that some SNPs in PSORS1C1, ATG16L1, IL23R, PTPN2 and MIR146a genes can determine particular disease phenotypes. HCP5 rs3099844 is associated with SLE and with anti-Ro/SSA. This polymorphism has been previously found associated with cardiac manifestations of SLE, a condition related with anti-Ro/SSA antibodies. Thus, our results may provide new insights into SLE pathogenesis.

Genetic factors in systemic lupus erythematosus: Contribution to disease phenotype

Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association.