Fulvia Ceccarelli

An overview on the genetic of rheumatoid arthritis: A never-ending story

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, multi-factorial disease sustained by environmental and genetic factors. These seem to be necessary but not sufficient in the disease development, nonetheless they can be responsible of different clinical pictures and response to therapy, and they can represent potential therapeutic targets. Several genes have been indicated so far in the pathogenesis of RA. The most important region is the Human Leukocyte Antigen (HLA) that contributes to approximately half of the genetic susceptibility for RA. The association seems to be stronger or specific for anti-citrullinated protein antibodies positive disease. Several alleles in the epitope-recognition part of the HLA molecule that show the highest association with RA susceptibility, also share a common string of amminoacid residues (the so-called shared-epitope hypothesis). Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4. Other polymorphisms seem to be responsible for more aggressive disease phenotype such as those located at TNF, IL-1, IL-6, IL-4, IL-5, OPN, PRF1. However, still nowadays, the genetic background of RA remains to be clearly depicted, and the efforts in the post-genomic era can bring to an estimation of the real likelihood of the genetic effect on RA. Finally, the discovery of new genes associated with the disease can be relevant in finding potential biomarkers, potentially useful in disease diagnosis and treatment.

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.

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.

Smoke and autoimmunity: The fire behind the disease.

The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases.

The 6-joint ultrasonographic assessment: a valid, sensitive-to-change and feasible method for evaluating joint inflammation in RA

OBJECTIVE Musculoskeletal US can be useful in monitoring RA. It can be time-consuming and there is no consensus in defining the joints to evaluate. We assessed the validity, sensitivity to change and feasibility of a reduced 6-joint US score in patients with RA starting therapy with an anti-TNF agent. METHODS A group of consecutive RA patients starting etanercept were investigated. The patients underwent clinical evaluation, laboratory tests and US assessment at baseline and 3 months. A semi-quantitative score (0-3) was used to evaluate synovial effusion (SE), synovial proliferation (SP) and power Doppler (PD) signal in 12 joints. A process of data reduction, based on the frequency of synovial site involvement by US-SE, US-SP and US-PD signal, was conducted to investigate the validity of a 6-joint US assessment. RESULTS Forty-five RA patients were evaluated. A significant decrease in all clinical, serological and 12-joint US parameters was found at follow-up. A significant correlation between changes in the DAS-28 and changes in the US scores in the 12-joint assessment was observed at follow-up (P < 0.001). A reduced 6-joint US score was obtained, including wrist, second MCP and knee joints of both sides, detecting US-SE in 97.78% of patients, US-SP in 100% of patients and positive US-PD in 100% of patients. The 6-joint US score showed a highly significant correlation with changes in DAS-28 (P < 0.001). The 6-joint evaluation was quick and easy to do. CONCLUSION A 6-joint US assessment may be a valid, sensitive-to-change and feasible method for evaluating joint inflammation in RA.

Nailfold capillaroscopy changes in systemic lupus erythematosus : correlations with disease activity and autoantibody profile

In systemic lupus erythematosus (SLE) nailfold capillaroscopy (NC) studies have described many different nonspecific patterns. We decided to evaluate NC changes in 44 SLE patients, comparing them with the main clinical, demographic and laboratory parameters, thus to define the real role for NC and its abnormalities in the management of this disease. Fifteen patients (34%) complained of Raynaud’s phenomenon; nine of them (20%) showed relevant capillaroscopic changes (capillaroscopic score >1). In details: three patients (6.8%) had loss of capillaries, while 18 (41%) had a capillary length variability, 16 (36.5%) showing shorter and two (4.5%) longer capillaries; tortuous, meandering, bizarre, ramified and/or bushy capillaries were found in 26 (59%), seven (16%), two (4.5%), three (7%) cases, respectively. An irregular distribution of the capillary array was present in six cases (14%) while microhaemorrhages were found in four cases (9%). 4 patients (9%) showed enlarged capillaries and changes of blood flow. A capillaroscopic score >1 was more frequently associated with higher ECLAM (P < 0.005) and SLEDAI (P < 0.01) activity scores, with the presence of anti-cardiolipin (P < 0.04) and anti-Sm (P < 0.04) antibodies, and also with the presence (P < 0.04) and higher titer (P < 0.001) of anti-dsDNA antibodies. No statistically significant correlation was found among the different capillaroscopy findings, age, disease duration, or treatment, nor with any clinical manifestation of the disease, such as cutaneous, renal or neurological. Our findings confirm the importance of the microvascular involvement in SLE. The NC abnormalities seem to be related to the disease activity and to the presence of many different antibodies, highly involved in the expression of SLE. NC proved to be an easy-to-perform noninvasive technique, able to achieve useful data to better evaluate such a pleomorphic disease as SLE.

Sonographic-detected joint effusion compared with physical examination in the assessment of sacroiliac joints in spondyloarthritis

Objective: An observational case–control study was designed to analyse the discriminative value of ultrasound (US)-detected joint effusion compared with physical examination in the assessment of sacroiliac joints (SIJ) in patients with spondyloarthropathy (SpA) with or without inflammatory back pain (IBP). Methods: 45 patients with SpA, classified according to European Spondylarthropathy Study Group criteria, and 30 healthy volunteers were studied. All patients had clinical evaluation of the SIJ, Bath ankylosing spondylitis (AS) metrology index, Bath AS disease activity index, Bath AS functional index, health assessment questionnaire, patient’s and physician’s visual analogue scale on global disease activity. Results: Ultrasound showed joint effusion in 38.9% of SIJ of patients with SpA and in 1.7% of SIJ of controls (p<0.001). The presence of IBP was significantly associated with SIJ effusion assessed by US alone or plus at least one SIJ test. SIJ effusion assessed by US alone or plus at least one SIJ test had a positive likelihood ratio (LR) (2.67 and 4.04, respectively) for the presence of IBP higher than LR of single clinical tests. Positive sacral sulcus test, iliac gapping and midline sacral thrust test were associated with SIJ effusion assessed by US, but all clinical tests, singly and in various combinations, had a low LR for the presence of SIJ effusion assessed by US. Conclusions: The study suggests that high resolution sonography is useful in the assessment of SIJ involvement in SpA, resulting in images that are fast and inexpensive and may locate, complementing the physical examination, the origin of IBP.

Life-table analysis of etanercept with or without methotrexate in patients with psoriatic arthritis

The recent analysis of data included in the Stockholm TNFα Follow- Up (STURE) registry showed that the concomitant use of methotrexate (MTX) with etanercept (ETN), adalimumab or infliximab was associated with long-term drug survival of anti-tumour necrosis factor (TNF) agents in patients with psoriatic arthritis (PsA).1 The positive effect of MTX was primarily linked to fewer drop-outs due to adverse events.1 This analysis did not consider each anti-TNF drug subgroup. For this reason we determined the cumulative probability of taking ETN with or without MTX in a large cohort of patients. We prospectively studied 82 patients, admitted to our rheumatological unit since 2001, affected by PsA, classified …

The interobserver reliability of ultrasound in knee osteoarthritis

OBJECTIVE To assess the interobserver reliability between sonographers with different levels of experience in detecting inflammatory and structural damage abnormalities in patients with knee OA. METHODS After achieving consensus on definitions and scanning protocols, three ultrasonographers with different levels of experience in musculoskeletal US examined the knees of nine patients with OA. US examinations were conducted with independent blinded evaluations of inflammatory (joint effusion, synovial hypertrophy, power Doppler signal, Bakers cysts) and structural (osteophytes, cortical bone irregularities, femoral hyaline cartilage abnormalities, protrusion of the medial meniscus) lesions. All abnormalities were scored by applying a dichotomous scale (0-1). In addition, at each knee joint site global scores for joint inflammation, cortical bone abnormalities and cartilage damage were calculated by summing the single-lesion scores. Reliability was assessed using kappa (κ) coefficients. RESULTS Seventeen knees were examined. Inflammatory abnormalities were observed with moderate to very good agreement (κ = 0.55-0.88) between the observers. From fair to very good agreement (κ = 0.31-0.82) was registered between sonographers for structural damage lesions. The overall κ was 0.716 for junior and 0.571 for beginner sonographers comparing their findings with those of senior sonographers. CONCLUSION This represents the first ultrasonographic study focusing on the analysis of interobserver reliability between sonographers with different levels of experience in demonstrating inflammatory and structural abnormalities in knee OA. Globally, even considering some variable results that were mainly obtained by the evaluation of single components of bone involvement, US offered a reliable assessment of a wide set of abnormalities in knee OA.

Intra-articular infliximab in patients with rheumatoid arthritis and psoriatic arthritis with monoarthritis resistant to local glucocorticoids. Clinical efficacy extended to patients on systemic anti-tumour necrosis factor α

Some experiences with intra-articular (IA) infliximab treatment in patients with refractory monoarthritis have been reported, even though these studies have important limitations including small sample size and short trial duration.1–4 Aim of this study was to evaluate the efficacy and safety of IA infliximab administration in a larger cohort of patients. We studied 10 patients with rheumatoid arthritis (RA) and seven with psoriatic arthritis (PsA) with active monoarthritis lasting at least 3 months, refractory to disease-modifying antirheumatic drugs (DMARDs) and to IA glucocorticoids.5 6 DMARDs dose had to be stable for at least 6 weeks before IA injection of infliximab, …