Alessandra Vacca

Prevalence of Pulmonary Hypertension in Systemic Sclerosis in European Caucasians and Metaanalysis of 5 Studies

Objective. To measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a multicenter European sample, with a metaanalysis of relevant studies. Methods. Consecutive patients with SSc recruited at 11 French and Italian centers underwent detailed evaluations, including Doppler echocardiography, chest computed tomography, pulmonary function tests, and right-heart catheterization (RHC), to detect the presence and causes of PH. A metaanalysis was performed, including data from 4 other studies. Results. Among 206 patients in whom it was suspected, PH was confirmed by RHC in 83 patients (7%). Precapillary PH was found in 64 patients (5%), of whom 42 had pulmonary arterial hypertension (PAH) and 22 had PH secondary to interstitial lung disease (ILD). RHC identified 17 patients (1%) with postcapillary PH secondary to left-heart disease. Patients with DLCO/alveolar volume < 70% were more likely to have precapillary PH (87.5% vs 42%; p < 0.0001). Precapillary and postcapillary PH were associated with advanced age (68 ± 14 vs 59 ± 12 yrs, p < 0.0001, and 74 ± 16 vs 61.5 ± 10 yrs, p < 0.0001, respectively). The metaanalysis of 3818 patients showed a prevalence of precapillary PH of 9% (95% CI 6%–12%) and identified advanced age, longer disease duration, and limited cutaneous disease subset as risk factors for this condition. Conclusion. The prevalence of precapillary PH in our multicenter study of SSc was 5%, and in the metaanalysis 9%. Our observations support use of RHC to confirm the presence of precapillary PH suspected by noninvasive testing. We also identified patients at high risk who should be carefully monitored.

Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study

Objective To evaluate the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-polyarthritis or SSc-myopathy. Methods 20 patients with SSc with refractory polyarthritis and seven with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab and 12 patients abatacept. All patients with SSc-myopathy received abatacept. Clinical and biological assessments were made at the start of treatment and at the last infusion. Results After 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response. Treatment was stopped in two patients because of inefficacy. After 11 months’ treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria. Abatacept did not improve muscle outcome measures in SSc-myopathy. No significant change was seen for skin or lung fibrosis in the different groups. Both treatments were well tolerated. Conclusions In this observational study, tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc. No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria. Larger studies with longer follow-up are warranted to further determine the safety and effectiveness of these drugs in SSc.

The interplay between the geographic distribution of HLA-B27 alleles and their role in infectious and autoimmune diseases: A unifying hypothesis

Due to its strong association with Ankylosing Spondylitis and the other Spondyloarthropathies, the HLA-B27 family of alleles and, in particular, the ancestral HLA-B*2705, has been the object of numerous studies. More recently, some novel interesting features have emerged such as the ability of HLA-B27 to confer resistance to the progression of HIV infection and to promote a spontaneous CD8+ T cell-mediated viral clearance of HCV. The co-occurrence of these protective and pathogenic features suggests a common ground, i.e. to promote a more pronounced immune/inflammatory response leading to an effective clearance of some pathogens on one side and to autoimmunity on the other. This might be due to the antigen presenting properties and/or to the co-inheritance of gene variants that contribute to an altered homeostasis in case of microbial infections or tissue injury. The existence of conserved HLA haplotypes have since long been thought to result from a selective pressure by some pathogens that have edited the immune response genes. The peculiar distribution of the ancestor HLA-B*2705 along a latitude-dependent gradient and the opposite distribution of their variants have suggested a correlation with endemic malaria. In this respect, Sardinia, a small Mediterranean island plagued by malaria, represents an interesting laboratory since its population is enriched in conserved HLA haplotypes and several genetic studies have disclosed their correlation with infectious and autoimmune diseases.

Vitamin D Deficiency and Insufficiency in 2 Independent Cohorts of Patients with Systemic Sclerosis

Objective. To investigate 25-OH vitamin D concentrations in 2 independent systemic sclerosis (SSc) populations from France and Italy. Methods. We studied 156 consecutive SSc patients comparable for demographic characteristics: 90 from Northern France and 66 from Southern Italy. 25-OH vitamin D, intact parathyroid hormone, and serum total calcium and phosphorus were measured in all patients. Vitamin D concentrations < 30 ng/ml were considered insufficiency, while values < 10 ng/ml were classified as deficiency. Results. Vitamin D insufficiency and deficiency rates were very high and comparable between the 2 populations: 74/90 (82%) versus 57/66 (86%) for insufficiency and 29/90 (32%) versus 15/66 (23%) for deficiency, respectively, in the French and Italian patients. They were not influenced by vitamin D supplementation, which was not statistically different in the 2 groups. In the combined populations, a significant negative correlation was found between low vitamin D levels and European Disease Activity Score (p = 0.04, r = −0.17) and an even more significant correlation was found with acute-phase reactants (p = 0.004, r = −0.23 for erythrocyte sedimentation rate), and low levels of vitamin D were associated with the systolic pulmonary artery pressure (sPAP) estimated by echocardiography (p = 0.004). In multivariate analysis, vitamin D deficiency was associated with sPAP (p = 0.02). Conclusion. Vitamin D deficiency was very common in the 2 SSc populations, independent of geographic origin and vitamin D supplementation. This suggests that common vitamin D supplementation does not correct the deficiency in SSc patients, and that a higher dose is probably needed, especially in those with high inflammatory activity or severe disease.

Patient Global Assessment in Psoriatic Arthritis: A Multicenter GRAPPA and OMERACT Study

Objective. During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0–100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). Methods. In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. Results. Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). Conclusion. PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.

Joint and tendon involvement in systemic lupus erythematosus: an ultrasound study of hands and wrists in 108 patients

OBJECTIVE To estimate the prevalence of, and identify factors associated with, hand and wrist US alterations in a large cohort of SLE patients. METHODS One hundred and eight consecutive SLE patients were recruited and classified according to arthropathy type and the musculoskeletal item of the British Isles Lupus Assessment Group (BILAG) 2004 score. US examinations were performed on hand and wrist flexor tendons, wrist extensor tendons, second and third MCP and wrist joints bilaterally using a multi-planar scanning technique. RESULTS US examination showed joint involvement in 42/108 (38.8%) subjects, tendon involvement in 44/108 (40.7%) and both in 22/108 (20.3%). Patients with rhupus syndrome (n = 8) carried a higher incidence of inflammatory changes (87%) and erosions (87%) compared with the six with Jaccouds arthropathy (50% and 17%, respectively) and the 94 with non-deforming X-ray non-erosive arthropathy (37% and 21%, respectively). Power Doppler signal was prevalent in patients scoring A (n = 4) or B (n = 9) on the musculoskeletal item of the BILAG 2004, and was significantly more frequent at the joint (92%) and tendon (54%) level than in the 26 patients scoring C (19%, P = 0.0007 and 15%, P = 0.016, respectively) and in the 69 scoring D (3%, P < 0.0001 and 3%, P < 0.0001). US changes in patients who scored C or D were more expressed at the tendon level (50% and 29%, respectively) than at the joint level (35% and 9%, respectively). CONCLUSION The picture of musculoskeletal US in SLE depends on arthropathy subtype and disease activity. US examination could be a valid and reliable tool to monitor musculoskeletal features and therapeutic outcomes in SLE patients.

Associated Autoimmune Diseases in Systemic Sclerosis Define a Subset of Patients with Milder Disease: Results from 2 Large Cohorts of European Caucasian Patients

Objective. To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID). Methods. A multicenter study was performed in France and Italy to recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases. Results. We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren’s syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren’s syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers. Conclusion. Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.

Cardiac arrhythmias and conduction defects in systemic sclerosis

Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e., related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations.

A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B * 2705 in Sardinia

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B *2705 strongly associated with AS and B *2709 which is not, and show the co-occurrence of the B *2705 allele with a single nucleotide polymorphism (SNP) mapping at 3′-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B *2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a ‘danger’ signal might influence susceptibility to AS.

Absence of epicardial coronary stenosis in patients with systemic sclerosis with severe impairment of coronary flow reserve

Systemic sclerosis (SSc) is known to be characterised by a diffuse microvascular pathological process leading to cutaneous and visceral changes and to related clinical manifestations. Both necropsy studies1,2 and in vivo investigations3–5 have shown that in a number of patients with SSc there is evidence of a coronary microvascular disease, while coronary artery disease does not exceed that seen in a control group. In particular, myocardial perfusion defects on thallium-201 scintigraphy usually occur in the absence of angiographic evidence of coronary stenosis.3 Recently, we used a new and non-invasive method of contrast enhanced, transthoracic, second harmonic echo Doppler in patients with SSc to evaluate the coronary flow reserve (CFR), a functional variable measuring the ability of the coronary microvasculature to adapt its lumen to a vasodilating stimulus.6 We detected a significant reduction of the CFR …