Silvano Todesco

Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus.

Objective: To evaluate traditional and non-traditional risk factors for subclinical atherosclerosis in systemic lupus erythematosus (SLE). Methods: A prospective cohort of 78 patients with SLE without overt atherosclerotic disease was studied. SLE clinical and laboratory parameters, disease activity and damage, treatment and traditional risk factors for atherosclerosis were evaluated. At baseline (T1) and after five years’ follow up (T2), the serum levels of anti-oxidised palmitoyl arachidonoyl phosphocholine (oxPAPC), anti-heat shock protein 65, and anti-β2-glycoprotein I antibodies and C reactive protein were tested. At T2, intima-media thickness (IMT) was measured using duplex carotid sonography. Thickened intima, plaque, mean IMT (m-IMT), and maximum IMT (M-IMT) were assessed. Results: A thickened intima was seen in 22/78 (28%) patients and plaque in 13/78 (17%). M-IMT and m-IMT were (mean (SD)) 0.77 (0.34) mm and 0.55 (0.15) mm, respectively. Patients with carotid abnormalities were significantly older, had higher blood pressure and total serum cholesterol levels, and had taken a higher prednisone cumulative dosage than those without any lesions. The carotid abnormalities were associated with renal disease and ECLAM >2 at T1, and with azathioprine treatment. In multivariate analysis, age and cumulative prednisone dose were associated with carotid abnormalities; age, hypertension, and anti-oxPAPC at T2 were correlated with higher M-IMT and m-IMT. Conclusions: In patients with SLE some non-traditional risk factors for atherosclerosis were identified, the most important of which was the cumulative prednisone dose. The role of some traditional risk factors, such as age and hypertension, was also confirmed. The predictive value of the new immunological and inflammatory markers of atherosclerosis seems to be masked by some disease related features.

Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate

Infliximab, a humanised, mouse derived, genetically engineered, monoclonal antibody to tumour necrosis factor α (TNFα), is successfully used in association with low dose methotrexate in the treatment of rheumatoid arthritis (RA).1 Serious infections have been reported to be associated with infliximab treatment.1,2 However, the safety of infliximab is unknown or has not been yet established in chronic viral infections, including human immunodeficiency virus, hepatitis B virus (HBV) or hepatitis C virus infections. We describe a case, from our cohort of 102 patients treated with infliximab plus methotrexate, who carried hepatitis B surface antigen (HBsAg) and subsequently developed acute hepatitis due to HBV reactivation after 16 months of treatment with infliximab. A 49 year old man was diagnosed as having RA in January 1990. HBsAg, and HBe and HBc antibodies were positive, while HBe antigen and HBs …

Clinical implications of autoantibody screening in patients with autoimmune myositis

Objective: To evaluate the clinical usefulness of serum autoantibody profiling in patients with autoimmune myositis. Methods: We retrospectively studied 74 consecutive patients: 68 had definite or probable myositis according to Bohan–Peter criteria, six suffered from antisynthetase syndrome with subclinical myopathy. Myositis specific antibodies (MSA) (anti-ARS, -SRP, -Mi-2) were determined by RNA immunoprecipitation or immunoblot, myositis associated antibodies (MAA) (anti-RoRNP, -U1RNP, -PM/Scl, -Ku) by immunoblot. Results: Forty-three patients (58%) were positive for MSA: anti-Jo-1 in 15/27 polymyositis (PM) (55%), 4/33 dermatomyositis (DM) (12%), 1/8 overlap (12%) and 2/6 antisynthetase syndrome (33%); anti-ARS non-Jo-1 in 1/27 PM (4%), 2/33 DM (6%) and 4/6 antisynthetase syndrome (67%); anti-Mi-2 in 1/27 PM (4%) and 11/33 DM (33%); anti-SRP in 3/27 PM (11%) and 1/33 DM (3%). One patient was anti-Jo-1/Mi-2 positive, one anti-Jo-1/SRP positive. Moreover, 27 patients (36%) were positive for MAA: anti-Ro/SSA in 8/27 PM (30%), 7/33 DM (21%), 1/8 overlap (12%), and 3/6 antisynthetase syndrome (50%); anti-U1RNP in 1/27 PM (3.7%), 1/33 DM (3%), and 2/8 overlap (25%); anti-PM/Scl in 2/8 overlap (25%), anti-Ku in 2/8 overlap (25%). Anti-Jo-1 was predominantly associated with PM, anti-Mi-2 was almost exclusively found in DM patients. Anti-ARS antibodies were closely associated with interstitial lung disease and polyarthritis; notably, anti-ARS non-Jo-1 was more frequent in patients without overt muscle alterations. Anti-Ro/SSA antibody was not associated with any disease subset, but significantly more frequent in antisynthetase syndrome. Conclusions: Searching for MSA and MAA in patients with autoimmmune myositis is recommended because of its diagnostic and clinical value. Anti-ARS non-Jo-1 antibodies seem to preferentially target patients with pulmonary fibrosis without overt myopathy.

Esophageal motor function in primary Sjögren's syndrome : Correlation with dysphagia and xerostomia

The incidence of dysphagia in patients withprimary Sjögrens syndrome (pSS) has beenunderestimated and all too often ascribed to xerostomia,without considering the possible presence of esophagealmotor abnormalities affecting other nonsclerodermaconnective tissue diseases. Esophageal and salivaryfunctions were prospectively evaluated in 27 females whomet the four criteria proposed by Fox for the diagnosis of pSS, using esophageal manometry after wetswallows and Saxons test, respectively. Dysphagia wasgraded using a standard symptoms questionnaire andresults were compared with those obtained in a group of 21 healthy controls. Seven patients with pSS(26%) had no swallowing discomfort, 2 (7.4%) had milddysphagia, 7 (26%) had moderate dysphagia, and 11(40.6%) had severe dysphagia. Saxons test revealed an overall decrease in the salivary flow ratecompared to controls, with no difference betweenpatients with or without dysphagia. Esophageal manometrydemonstrated the absence of any lower or upperesophageal sphincter function abnormalities in allpatients. In the patients with pSS as a whole,manometric study of the esophageal body showed a motorpattern comparable with that of controls, with nodifference between patients with and without dysphagia.Defective peristalsis, ie, the presence of simultaneouscontractions in more than 30% of wet swallows wasdetected, however, in the distal tract of the esophagus of six patients (22.2%) and in the proximaltract of three (11.1%). All these patients had severedysphagia and the modified Saxons test revealed asalivary secretion comparable with that of patients with a normal peristalsis. Dysphagia is a verycommon complaint in patients with pSS and does not seemto correlate with xerostomia, which is a constant andtypical finding of the disease. About one third of patients with pSS have an abnormal esophagealperistalsis that is responsible for severe dysphagia,whereas decreased salivary outflow exacerbates theswallowing discomfort. This has to be taken into account and justifies the routine use of esophagealmanometry in patients with pSS. The cause of dysphagiain pSS patients without peristaltic disorders of theesophagus has to be investigated.

Early phenotypic activation of circulating helper memory T cells in scleroderma: correlation with disease activity.

OBJECTIVES--The differential expression of several accessory/activation molecules (CD26, CD29, CD45RA, CD25, MLR4, HLA-DR) on peripheral blood CD4+ and CD8+ T lymphocytes in patients with scleroderma was compared with that in controls and patients with other connective systemic diseases to look for evidence of the involvement of T cells in the disease process of scleroderma. METHODS--The two colour expression of surface molecules by circulating T cells was analysed with a panel of monoclonal antibodies and flow cytometry in 17 patients with scleroderma, 10 patients with systemic lupus erythematosus, and five patients with rheumatoid arthritis, and the results compared with those for 10 normal controls. The two colour T CD4+ phenotype was further compared between patients with active and quiescent disease in these patients with scleroderma. The coexpression of surface molecules by CD4+ T cells was also analysed by three colour flow cytometry in eight patients with scleroderma. RESULTS--Patients with scleroderma showed increased CD4+CD26+ and CD4+CD25+ percentages and absolute numbers and decreased CD8+CD29+ percentages compared with controls. Moreover, a significant correlation between the higher CD4+CD26+ T cell percentage and absolute cell numbers with disease activity was observed. Most of the CD4+ peripheral blood T cells from patients with scleroderma showed the CD26+CD45RA- phenotype by three colour flow cytometry analysis. CONCLUSIONS--The distinctive pattern of early helper memory T cell activation in these patients with rapidly evolving scleroderma supports the role of a T cell mediated mechanism in the progression of scleroderma.

Estrogens in pregnancy and systemic lupus erythematosus.

Abstract:  Successful pregnancy depends on an adaptation of the maternal immune system that becomes tolerant to fetal antigens of paternal origin. The altered immune regulation induced by pregnancy occurs predominantly at the maternal–fetal interface, but it has also been observed in the maternal circulation. Th1/Th2 shift is one of the most important immunologic changes during gestation. It is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1‐mediated responses and stimulate Th2‐mediated immunologic responses. For this reason Th1‐mediated diseases, such as rheumatoid arthritis, tend to improve, while Th2‐mediated diseases, such as systemic lupus erythematosus (SLE) tend to worsen during pregnancy. However, in some recent studies SLE flare‐ups were less frequently observed in the third trimester of gestation in comparison to the second trimester and postpartum period. These data are apparently in contrast to the Th2 immune‐response polarization expected during pregnancy due to the progressive increase of estrogens. Some further data suggest that in SLE patients estradiol serum levels are surprisingly lower than expected during the third trimester of pregnancy, probably due to a placental compromise. This occurrence could lead to a lower‐than‐expected increase of IL‐6, accounting for the low humoral immune response and the low disease activity observed in the third trimester of pregnancy in such patients.

Interrelationships between interleukin (IL)-1, IL-6 and IL-8 in synovial fluid of various arthropathies

High levels of many cytokines, including interleukin (IL)-1, IL-6 and IL-8, were found in various arthropathies suggesting that they play a role in the pathogenesis of disease, although their relationship with the type and activity of disease is still not clear. The synovial fluid (SF) of 24 patients with rheumatoid arthritis (RA), 19 with psoriatic arthritis (PA) and 33 with osteoarthritis (OA) was analyzed for IL-1β, IL-6 and IL-8. The highest concentration of the three cytokines was found in the SF of RA. IL-β detectable levels (>-20 pg/ml) were observed in 8/24 (33.3%) patients with RA, in one patient with PA but in no patient with OA.IL-6 (mean±SD) (1610.37±1781.65 pg/ml) was higher in RA than in PA (672.47±867.40 pg/ml,p=0.043) and OA (89.45±120.52 pg/ml,p=0.0001). IL-8 (1042.72±698.64 pg/ml) was higher in RA than in PA (660.36±625.11 pg/ml,p=0.03) and OA (89.9±45.88 pg/ml,p=0.0001). A correlation between IL-1β, IL-6 and IL-8 was found in RA. In all patients a correlation between IL-6 and IL-8 levels was found; moreover, these two cytokines were associated with SF indices of inflammation, such as white blood cells (WBC) count and total protein (TP) concentration.Out findings suggest that these interrelationships play a role in the evolution of more severe erosive arthropathy such as RA.

Nuclear membrane-staining antinuclear antibody in patients with primary biliary cirrhosis.

An antinuclear antibody specific for nuclear membrane (ANMA) was observed by the immunofluorescence method in sera from patients with primary biliary cirrhosis (PBC). ANMA was present in 18 of 63 PBC sera (28.5) and in 1 of 431 control sera (0.2%). Its reaction appeared as a thin fluorescent ring confined to the nuclear envelope and was more evident when the sera were highly diluted and the fluorescence, due to frequently associated antimitochondrial antibody, faded. The ANMA fluorescent pattern was confirmed by indirect immunoperoxidase staining. ANMA was seen on both tissue cryostat sections and HEp-2 cells. It was a poorly or non-complement-fixing IgG, specific for an antigen resistant to DNase I, RNase, and trypsin. The significance of its presence in PBC in unknown at present. Identification of its antigen with one of the centromeric antigens is suggested.

Autoantibodies of systemic rheumatic diseases in the healthy elderly

Antinuclear antibodies, anticardiolipin antibodies and IgM rheumatoid factor were determined in 300 healthy aged subjects, comparing their prevalence to that in 100 healthy subjects aged between 19 and 44 years and 352 patients under 65 years of age, affected by various systemic rheumatic diseases. Increased production of IgM rheumatoid factor and antinuclear and anticardiolipin antibodies was found as characteristic of aged humans, and suggested that a correction for age should be considered in evaluating the clinical significance of autoantibody profiles in elderly patients.

Anticentromere antibody in localized scleroderma

Using metaphase chromosome spreads as substrate for indirect immunofluorescence technic, we observed anticentromere antibody in three of twenty-five patients affected with various clinical forms of localized scleroderma. Anticentromere antibody is generally considered a serologic marker of the CREST syndrome, a more benign subset of systemic sclerosis. However, none of the three anticentromere antibody-positive patients with localized scleroderma had Raynauds phenomenon, acrosclerosis, or any signs or symptoms of systemic disease; on physical and laboratory examination, they showed only typical cutaneous features of localized scleroderma: two showed linear scleroderma, and one showed localized morphea. A 2-year 8-month follow-up of two patients did not disclose any clinical evidence of systemic sclerosis. The occurrence of anticentromere antibody in patients with localized scleroderma seems to offer supportive evidence that a relationship exists between localized scleroderma and systemic sclerosis.