Autoantibodies' titre modulation by anti-BlyS treatment in systemic lupus erythematosus.

OBJECTIVE: The objective of this study was to analyse autoantibodies' titres modulation during belimumab treatment in 50 patients with systemic lupus erythematosus (SLE). METHODS: Sera were collected at belimumab start (T0) and every six months until the 24th month. Disease activity index (SLEDAI-2K) was analysed at every timepoint. High avidity anti-dsDNA was detected by radioimmunological method, anti-ENA, anti-cardiolipin antibodies (aCL), anti-ß2 glycoprotein I (anti-ß2GPI) were analysed by ELISA. RESULTS: Fifty patients with SLE (mean SLEDAI-2K: 7.18 ± :3), mean age of 39 ± 11 years and mean follow-up of 13 ± 7.8 years were enrolled. A significant decrease of anti-dsDNA and anti-ß2GPI IgM titres was observed at all timepoints. IgG aCL titre showed significant decrease only at T18. Anti-dsDNA negativization was detected in 21%, anti-ß2GPI IgG in 33% and aCL IgG in 30% of sera, mostly at T6. Anti-ribosomal showed a significant titre decrease at T6 and T12, with negative seroconversion at T18. Anti-Sm titre significantly dropped down at T6, then remained stable during the time. Significant correlations were found between anti-dsDNA and anti-ribosomal titre and between SLEDAI ratio (SLEDAI value/SLEDAI T0) and anti-ribosomal titre ratio (value/value T0). CONCLUSIONS: Belimumab treatment induced a significant reduction of SLE-specific autoantibodies titre and IgM anti-ß2GPI. Anti-ribosomal titre decrease correlates with anti-dsDNA titre and disease activity improvement.

Relationship between endothelial dysfunction, videocapillaroscopy and circulating CD3+CD31+CXCR4+ lymphocytes in systemic lupus erythematosus without cardiovascular risk factors.

OBJECTIVE: The objective of this paper is to analyse whether digital capillary morphology, analysed by nailfold videocapillaroscopy (NVC), and the number of circulating CD3 + CD31 + CXCR4 + lymphocytes (angiogenic T cells) could be markers of endothelial dysfunction (ED) in systemic lupus erythematosus (SLE) without cardiovascular disease (CVD) and CV risk factors. METHODS: Nineteen consecutive SLE patients, according to Systemic Lupus International Collaborating Clinics Classification Criteria, with a disease duration less than five years, low disease activity, without CVD and CV risk factors (diabetes, chronic renal disease, uncontrolled systemic arterial hypertension, smoking, hypercholesterolemia, obesity), statin or beta-blocker use were enrolled. Each patient and sex- and age-matched healthy control (HC) underwent Doppler echocardiogram, an endothelial function study by peripheral arterial tonometry technique, NVC and peripheral blood immunophenotyping. RESULTS: SLE ED+ more frequently showed NVC abnormalities compared with HCs ( p < 0.0001) in terms of minor alterations ( p = 0.017), lower capillary numbers ( p = 0.0035) and major alterations. SLE ED + showed a higher rate of CD3 + CD31 + CXCR4 + lymphocytes compared with SLE ED- and with HCs. NVC + SLE showed a significantly reduced rate of total CD3 + cells, but a higher rate and absolute number of CD3 + CD31 + CXCR4 + , compared with NVC- SLE. CONCLUSION: NVC alterations are frequent in SLE without any CV risk factors and CVD. They are associated with ED and increased circulating CD3 + CD31 + CXCR4 + lymphocytes. These findings demonstrate a clear microvascular perturbation in patients with short disease duration, low disease activity and no CV risk factors.

Macrophage activation syndrome in adult systemic lupus erythematosus: report of seven adult cases from a single Italian rheumatology center.

The aim was to describe the macrophage activation syndrome (MAS), a life-threatening syndrome characterized by excessive immune activation that can be triggered by conditions affecting immune homeostasis, in a cohort of adult Italian patients with systemic lupus erythematosus (SLE). This was a monocentric retrospective evaluation. The utility of the H-score, developed to estimate the individual risk of having reactive MAS in adult patients, was assessed. Among 511 patients with SLE, 7 cases (1.4%) of MAS (all females) were identified and their medical records reviewed. In all cases, MAS was simultaneous to the onset of SLE. All patients had fever, lymphadenopathy, hematological involvement, and high titer of anti-dsDNA antibodies. Workup for infections and malignancies was negative. In all cases, the H-score was higher than the cut-off suggested for the classification of reactive MAS. All cases required hospital admission, and 2 patients were admitted to the intensive care unit. Most patients were treated successfully with high doses of corticosteroids and with immunosuppressive drugs, whereas the full therapeutic regimen developed for primary hemophagocytic lymphohistiocytosis HLH was used only in one case. No death from MAS was observed. MAS is a rare and severe disorder that complicated the onset of SLE in our cohort. The H-score may be useful in the classification of these patients.

Organ damage accrual and distribution in systemic lupus erythematosus patients followed-up for more than 10 years.

Objective The aim of this study was to determine the prevalence, predictors and progression of organ damage in a monocentric cohort of systemic lupus erythematosus patients with a long follow-up. Organ damage was assessed by the Systemic Lupus International Collaborating Clinics Damage Index one year after diagnosis and every five years. Disease activity was measured by the systemic lupus erythematosus disease activity index (SLEDAI)-2K at the beginning of the follow-up. Univariate and multivariable analyses were used to detect items associated with damage. A total of 511 systemic lupus erythematosus patients (92% females, 95% Caucasian), prospectively followed from 1972 to 2014, were included. Results After a mean disease duration of 16 years (SD: 9.5) and a mean follow-up of 12.9 years (SD: 8.8), 354 patients (69.3%) had accrued some damage: 49.7% developed mild/moderate damage, while 19.5% showed severe damage. Damage was evident in 40% of 511 patients one year after diagnosis, and its prevalence linearly increased over time. Longer disease duration, higher SLEDAI, severe Raynaud's, chronic alopecia and cerebral ischaemia were significantly associated with organ damage. No associations between damage and autoantibodies, including anti-dsDNA, anti-Sm or antiphospholipid antibodies, were observed. Anyway, antiphospholipid syndrome and anticardiolipin antibodies predicted the development of neuropsychiatric damage. The ocular, musculoskeletal and neuropsychiatric systems were the most frequently damaged organs, with a linear increase during follow-up. Conclusion A high rate of moderate and severe damage has been detected early in a wide cohort of young lupus patients, with a linear trend of increase over time. Disease activity and long duration of disease predict damage, while antiphospholipid antibodies play a role in determining neuropsychiatric damage.

The role of clinically significant antiphospholipid antibodies in systemic lupus erythematosus.

The objective is to investigate the role of clinically significant antiphospholipid antibodies (aPL) in a cohort of systemic lupus erythematosus (SLE) patients. All SLE patients followed for at least 5 years and with available aPL profile at the beginning of the follow-up in our center were studied. Clinically significant aPL were defined as: positive lupus anticoagulant test, anti-cardiolipin and/or anti- ß2Glycoprotein I IgG/IgM >99th percentile on two or more occasions at least 12 weeks apart. Patients with and without clinically significant aPL were compared by univariate (Chi square or Fisher's exact test for categorical variables and Student's t or Mann-Whitney test for continuous variables) and multivariate analysis (logistic regression analysis). P values <0.05 were considered significant. Among 317 SLE patients studied, 117 (37%) had a clinically significant aPL profile at baseline. Such patients showed at univariate analysis an increased prevalence of deep venous thrombosis, pulmonary embolism, cardiac valvular disease, cognitive dysfunction and antiphospholipid syndrome (APS), but a reduced prevalence of acute cutaneous lupus and anti-extractable nuclear antigens (ENA) when compared with patients without clinically significant aPL. Multivariate analysis confirmed the association between clinically significant aPL and reduced risk of acute cutaneous lupus [p=0.003, odds ratio (OR) 0.43] and ENA positivity (p<0.001, OR 0.37), with increased risk of cardiac valvular disease (p=0.024, OR 3.1) and APS (p<0.0001, OR 51.12). Triple positivity was the most frequent profile and was significantly associated to APS (p<0.0001, OR 28.43). Our study showed that one third of SLE patients had clinically significant aPL, and that this is associated with an increased risk, especially for triple positive, of APS, and to a different clinical and serological pattern of disease even in the absence of APS.

Rare autoantibodies to cellular antigens in systemic lupus erythematosus.

OBJECTIVE: A high number of antinuclear antibody specificities can be detected in systemic lupus erythematosus (SLE). Some of them are related to a distinct clinical subset of disease, independently of their frequency. The aim of our study was to investigate, in a cohort of SLE patients, the prevalence and the clinical relevance of autoantibodies to cellular antigens less frequently found in SLE. METHODS: Antinuclear antibodies were detected by indirect immunofluorescence on HEp-2 cells while counterimmunoelectrophoresis was used to detect anti-ENA antibodies in 540 patients with SLE, classified according to ACR and SLICC criteria. Clinical and serological features were collected from clinical charts. RESULTS: A total of 319 (58.9%) out of 540 sera were positive for anti-ENA antibodies. Anti-Ro/SSA was found in 235 sera, 50 of which also contained anti-La/SSB. Anti-U1RNP were detected in 67, anti-Sm in 46 and anti-ribosomal P protein in 13 sera. In a multivariate analysis anti-Sm was associated with discoid lupus (p = 0.045) and photosensitivity (p = 0.037), anti-U1RNP with malar rash and Raynaud's phenomenon (p = 0.01 and p = 0.0004, respectively) and anti-Ro/SSA with malar rash, oral ulcers, xerostomia, xerophthalmia and rheumatoid factor (p = 0.029, p = 0.01, p = 0.031, p = 0.002 and p = 0.028, respectively). Other anti-ENA antibodies were found in 50 positive sera (15.6%). Anti-Ki antibodies were detected in 31, anti-Ku in 8, anti-centromere in 5, isolated anti-La/SSB, anti-PCNA and anti-Topo I in 3 each and anti-Jo-1 in 2 sera. About half of these antibodies (27 out of 50) were detected as the single anti-ENA specificity in serum. At multivariate analysis anti-Ki was significantly associated with male gender while anti-Ku with African ethnicity (p = 0.017 and p < 0.0001, respectively). No sign of muscular or pulmonary involvement was found in anti-Jo-1-positive patients whilst features of systemic sclerosis were detectable in two out of three anti-Topo I. CONCLUSIONS: Our study shows that antibodies to cellular antigens more rarely found in SLE are detectable in more than 15% of patients with anti-ENA antibodies. Most of them are found as single anti-ENA specificity. Anti-Ki and anti-Ku are found in a subset of disease, characterized by male gender and African origin, respectively. Clinical features of scleroderma were found only in patients with anti-Topo I.

Anti-cyclic citrullinated peptide antibodies in systemic lupus erythematosus patients with articular involvement: a predictive marker for erosive disease?

A small number of systemic lupus erythematosus (SLE) patients develop an erosive disease. Some studies have suggested an association between anti-cyclic citrullinated (anti-CCP) antibodies and this pattern of arthritis, but their exact significance in SLE patients remains unclear. The aim of this study was to evaluate the prevalence of anti-CCP antibodies in SLE patients with different subsets of articular disease. Among 521 SLE patients followed in this center from 1976 to 2011, those with articular involvement (n=298) were selected to take part in the study. We searched for anti-CCP2 IgG antibodies in 198 patients using a commercial enzyme linked immunosorbent assay (Immunoscan RA, Eurodiagnostica). In 174 patients the results for rheumatoid factor (RF) by nephelometry were retrospectively collected. C reactive protein (CRP) was obtained from clinical records. Patients were classified into 3 groups: erosive, non-erosive deforming, non-erosive non-deforming arthritis. Results of the different tests were compared among the groups. P<0.05 was considered statistically significant. Anti-CCP antibodies were significantly associated with erosive disease. We also found that RF positivity and increased CRP were more frequent in erosive arthritis and erosive or non-deforming arthritis, respectively, than in non-erosive non-deforming arthritis. This study supports the evidence that anti-CCP antibodies could be a useful marker of erosive disease in SLE patients. Increase in RF and CRP could be an additional means of identifying lupus patients with arthritis at risk of a worse prognosis.

Systematic Review and Meta-analysis on the Association of Occupational Exposure to Free Crystalline Silica and Rheumatoid Arthritis.

KEY MESSAGES: • Occupational exposure to free crystalline silica and tobacco smoking are associated with an increased risk rheumatoid arthritis, with the evidence of an interaction in seropositive subjects. • Further studies in the field are needed to support such association We carried out a systematic search for all published epidemiological studies concerning the association between occupational exposure to free crystalline silica (FCS) and subsequent development of rheumatoid arthritis (RA). A meta-analysis was conducted on relevant studies. We searched PubMed and Embase, search engines, for original articles published (from 1960 to November 2019) in any language. In addition, we also searched reference lists of included studies manually for additional relevant articles. Finally, twelve studies were included in the meta-analysis (seven case-control cases and five cohort studies). The odds risks and 95% confidence interval (CI) were calculated using a random effect meta-analysis. A primary meta-analysis (using a random effect model)-regarding RA risk in subjects exposed to FCS-yelled to an overall OR of 1.94 (95% CI 1.46-2.58). We also conducted three further meta-analysis, taking into account the presence of autoantibodies (anti-RF or anti-ACPA) and smoking habits and found a significant association between FCS and RA in both seropositive and seronegative subjects (OR 1.74, 95% CI 1.35-2.25 and OR 1.23, 95% CI 1.06-1.4, respectively) and in seropositive subjects which were smokers (OR 3.30, 95% CI 2.40-4.54). The studies that have investigated the association between RA and occupatational exposure to FCS are still scarce and the heterogeneity between the studies remains high. Some critical limitations have been identified within studies, among which, the methods for assessing exposure stand out. Although with due caution, our results confirm the hypothesis of an association between occupational exposure to FCS and RA development. There was an interaction between FCS and tobacco smoking in RA seropositive workers.

Evaluation of a novel particle-based assay for detection of autoantibodies in idiopathic inflammatory myopathies.

BACKGROUND: Myositis specific antibodies (MSA) represent not only important diagnostic tools for idiopathic inflammatory myopathies (IIM), but also help to stratify patients into subsets with particular clinical features, treatment responses, and disease outcome. Consequently, standardization of MSA is of high importance. Although many laboratories rely on protein immunoprecipitation (IP) for the detection of MSA, IP standardization is challenging and therefore reliable alternatives are mandatory. Recently, we identified significant variation between IP and line immunoassay (LIA) for the detection of MSA and myositis associated antibodies. In this study we aimed to compare the results from our previous study to the results obtained with a novel fully automated particle-based technology for the detection of MSA and MAA. METHODS: A total of 54 sera from patients with idiopathic inflammatory myopathy (IIM) were tested using three methods: IP, LIA (Euroimmun, Germany) and a novel particle-based multi-analyte technology (PMAT, Inova Diagnostics, US, research use only). The analysis focused on antibodies to EJ, SRP, Jo-1, NXP-2, MDA5, TIF1-γ, and Mi-2. RESULTS: Significant variations were observed among all methods. Overall, the novel PMAT assays showed slightly better correlation with IP, but the kappa agreement was strongly dependent on the antibody tested. When the results obtained from IP were used as reference for receiver operating characteristic (ROC) curve analysis, good discrimination and a high area under the curve (AUC) value were found for PMAT (AUC = 0.83, 95% confidence interval, CI 0.70-0.95) which was significantly higher (p = .0332) than the LIA method (AUC = 0.70, 95% CI 0.56-0.84). CONCLUSION: The novel PMAT used to detect a spectrum of MSA in IIM represents a potential alternative to IP and other diagnostic assays. Additional studies based on larger cohorts are needed to fully assess the performance of the novel PMAT system for the detection of autoantibodies in myositis.

Isotype switching and titer variation of anti-Ro/SSA antibodies over time in 100 patients with undifferentiated connective tissue disease (UCTD).

OBJECTIVE: To correlate the clinical course of the disease with the titer, the isotype profile and the switch of the anti-Ro/SSA antibodies in a cohort of patients affected by UCTD. METHODS: One hundred selected patients with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis (CIE), and affected by UCTD with a mean follow-up of 7.6 years (SD 4.8 yrs.), were studied. The titer of IgA, IgG and IgM anti-Ro/SSA antibodies was determined in two different sera, obtained at the time of diagnosis and at the last visit, by ELISA with Ro/SSA recombinant proteins as substrate. RESULTS: Thirty-five patients evolved from UCTD to a different connective tissue disease, while 65 showed a stable disease. Anti-Ro/SSA antibodies were detected in 91% and 97% of the patients, at baseline and during follow-up, respectively. IgG dominates the anti-Ro response. The titer of IgA, IgM and IgG anti-Ro/SSA did not differ significantly between the two groups of patients with UCTD. An increasing trend of IgG and IgA anti-Ro/SSA titer could be detected in patients evolving in primary Sjögren's Syndrome (pSS), but only the increase of IgG anti-Ro/SSA was significant (p=0.0235). CONCLUSION: IgG dominates the anti-Ro/SSA response in patients with UCTD. No substantial change of the antibody isotype against Ro/SSA peptides could be observed during follow-up. The titer of IgG anti-Ro/SSA significantly raised in the group of patients evolving in pSS.

Antinuclear antibodies in Frontotemporal Dementia: the tip's of autoimmunity iceberg?

Recent studies suggest a role of the autoimmune system dysregulation in Frontotemporal dementia (FTD). In the present study, we performed a broad immunological screening in a large sample of sporadic FTD patients. We reported a significant increase of antinuclear autoantibodies (ANA) positivity in 100 FTD patients as compared to 100 healthy controls (HC) (60% vs. 13%, p < .001). In FTD, ANA-positive and ANA-negative patients did not differ for any clinical feature. These data extend and further confirm autoimmune dysregulation in FTD. However, it still remains to be clarified whether these antibodies have a potential pathogenic role or represent simply an epiphenomenon.

Unusual association between pure red cell aplasia and primary Sjögren's syndrome: a case report.

Pure red cell aplasia (PRCA) is an acute anemia due to selective suppression of erythropoiesis. We report a case of PRCA diagnosed before the onset of primary Sjögren's syndrome (SS). A young woman, with autoimmune thyroiditis, developed polyarthritis with ANA and Rheumatoid factor positivity, diagnosed as Rheumatoid arthritis. During the time she developed anti-Ro and anti-La antibodies and deformities at proximal interphalangeal joints. After 4 years, she developed severe acute anemia, without reticolocytes: a bone marrow biopsy indicated a PRCA and she started transfusions, steroids, cyclosporin. A steroid-dependent anemia persisted. After 2 years she developed sicca, parotid swelling, fatigue, mild leukopenia, elevated serum creatinine, hypokalemia, hyposthenuria and tubular proteinuria. Lip biopsy and dacriologic tests confirmed a diagnosis of SS, while X-ray revealed a deforming non-erosive arthropathy (Jaccoud type). In present case, PRCA could be considered an autoimmune bone marrow disease within SS, whose extra-glandular manifestations onset before the sicca symptoms.

Intravenous cyclophosphamide for interstitial lung disease associated to systemic sclerosis: results with an 18-month long protocol including a maintenance phase.

OBJECTIVE: Cyclophosphamide (CYC) is generally considered the most promising agent available today for systemic sclerosis (SSc)-related interstitial lung disease (ILD). However, the optimal dosage and length of treatment are still undetermined. Our objective was to evaluate the effect of an 18-month long protocol with intravenous (iv) CYC. METHODS: In a single-centre, prospective, observational study, 13 patients with SSc and active alveolitis were given 8 iv pulses in a 6-months period (CYC 750 mg + 6-methylprednisolone 125 mg every three weeks), as an induction therapy. Patients received maintenance therapy with further cycles at 4 (3 pulses), 6 (3 pulses) and 9 weeks (3 pulses) interval. Total CYC dosage was 12.75 g in an 18-month period. End-points were modifications of lung function test (LFT). RESULTS: During the first 6 months of treatment with CYC an increase in Forced Vital Capacity (FVC; p = 0.005) and in diffusion lung capacity for carbon monoxide (DLCO; p = 0.10) was observed; during the maintenance therapy, there was a stabilization in FVC and a mild, non significant decline in DLCO. Treatment was well tolerated. CONCLUSION: iv CYC can induce an initial improvement in LFT (particularly, in FVC) in the first six months, but no further improvement was observed during the maintenance phase.

Anti-TNF-alpha treatment in rheumatoid arthritis with anti-Ro/SSA antibodies. Analysis of 17 cases among a cohort of 322 treated patients.

OBJECTIVE: To compare the efficacy and safety of anti-TNF-alpha treatment in RA patients with and without anti-Ro antibodies, in order to detect any change in their immunological or clinical profile. METHODS: Autoantibodies in 322 patients being treated with anti-TNF-alpha drugs were studied; 17 were found to be anti-Ro positive, while 305 were anti-Ro negative. RESULTS: Two groups, comparable in terms of sex distribution, RA duration and anti-TNF-alpha drug employed, showed symmetrical, erosive polyarticular RA with high disease activity. Anti-TNF-alpha led to significant improvement in both groups. At baseline rheumatoid factor and ANA, globally positive in 68.6% and 40%, were more frequent in anti-Ro positive sera. ANA showed a rising trend beginning in the 6th month of treatment in both groups, which was always statistically significant compared to baseline. Anti-dsDNA antibodies, measured using either CLIFT and ELISA or the Farr assay, remained stable in the first 6 months, then increased at 12th and 18th month, and subsequently declined. No difference was detected between the two groups regarding the number or cause of dropouts, but lupus-like disease was more frequent in anti-Ro positive subjects (p = 0.012). In addition, two cases of NHL were detected. CONCLUSION: Anti-TNF-alpha treatment was shown to be effective in patients with anti-Ro antibodies. Although anti-dsDNA and lupus-like disease were more frequent in anti-Ro positive patients, severe manifestations of systemic involvement were not observed. A longer follow-up is warranted to evaluate the risk of NHL in these patients.

[Renal involvement in systemic sclerosis]. / Sclerosi sistemica e coinvolgimento renale.

Systemic sclerosis is an autoimmune disease characterized by fibrosis of the skin and internal organs. Raynaud's phenomenon generally precedes other disease manifestations. The distribution of skin lesions and the internal organ involvement are the basis for the classification into limited and diffuse forms of the disease. Clinically evident renal disease is observed in 10-40% of patients. The most common renal presentation is renal crisis, characterized by acute onset of renal failure and severe hypertension; some patients remain normotensive, showing microangiopathic hemolytic anemia. Renal complications due to penicillamine may occur in some patients. Finally, ANCA-associated glomerulonephritis is a rare complication of the disorder. In spite of treatment with ACE inhibitors, 20-50% of patients with renal crisis progress to end-stage renal disease. In the absence of a specific therapy, there is accumulating evidence supporting the effectiveness of prostacyclin derivatives, antifibrotic and immunosuppressive drugs. The evidence is strong that the ACE inhibitors that are used in renal crisis are disease modifying. In our series including 193 patients with systemic sclerosis, renal involvement was observed in 19 patients; 11 presented renal crisis (hypertensive in 8; normotensive in 3); 5 had chronic nephropathy; 2 developed penicillamine-induced nephrotic syndrome, and 1 ANCA-associated glomerulonephritis. Renal disease occurs in a minority of patients with systemic sclerosis, and may have a variable clinicopathological picture. As renal involvement is associated with a worse prognosis, careful monitoring of blood pressure, urine chemistry and renal function is required, particularly in patients with diffuse skin disease.

The inter-observer reading variability in anti-nuclear antibodies indirect (ANA) immunofluorescence test: A multicenter evaluation and a review of the literature.

Recently there has been an increase demand for Computer-Aided Diagnosis (CAD) tools to support clinicians in the field of Indirect ImmunoFluorescence (IIF), as the novel digital imaging reading approach can help to overcome the reader subjectivity. Nevertheless, a large multicenter evaluation of the inter-observer reading variability in this field is still missing. This work fills this gap as we evaluated 556 consecutive samples, for a total of 1679 images, collected in three laboratories with IIF expertise using HEp-2 cell substrate (MBL) at 1:80 screening dilution according to conventional procedures. In each laboratory, the images were blindly classified by two experts into three intensity classes: positive, negative, and weak positive. Positive and weak positive ANA-IIF results were categorized by the predominant fluorescence pattern among six main classes. Data were pairwise analyzed and the inter-observer reading variability was measured by Cohen's kappa test, revealing a pairwise agreement little further away than substantial both for fluorescence intensity and for staining pattern recognition (k=0.602 and k=0.627, respectively). We also noticed that the inter-observer reading variability decreases when it is measured with respect to a gold standard classification computed on the basis of labels assigned by the three laboratories. These data show that laboratory agreement improves using digital images and comparing each single human evaluation to potential reference data, suggesting that a solid gold standard is essential to properly make use of CAD systems in routine work lab.

Are the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and the undifferentiated connective tissue disease (UCTD) related to each other? A case-control study of environmental exposures.

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is an entity that includes different autoimmune conditions observed after exposure to an adjuvant. Patients with undifferentiated connective tissue disease (UCTD) present many signs and symptoms of ASIA, alluding to the idea that an exposure to adjuvants can be a trigger also for UCTD. The aim of this case-control study was to investigate exposure to adjuvants prior to disease onset in patients affected by UCTD. Ninety-two UCTD patients and 92 age- and sex-matched controls with no malignancy, chronic infections, autoimmune disease nor family history of autoimmune diseases were investigated for exposure to adjuvants. An ad hoc-created questionnaire exploring the exposure to vaccinations, foreign materials and environmental and occupational exposures was administered to both cases and controls. Autoantibodies were also analyzed (anti-nuclear, anti-extractable nuclear antigens, anti-double-stranded DNA, anti-cardiolipin, anti-ß2 glycoprotein I). UCTD patients displayed a greater exposure to HBV (p = 0.018) and tetanus toxoid (p < 0.001) vaccinations, metal implants (p < 0.001), cigarette smoking (p = 0.006) and pollution due to metallurgic factories and foundries (p = 0.048) as compared to controls. UCTD patients exposed to major ASIA triggers (vaccinations, silicone implants) (n = 49) presented more frequently with chronic fatigue (p < 0.001), general weakness (p = 0.011), irritable bowel syndrome (p = 0.033) and a family history for autoimmunity (p = 0.018) in comparison to non-exposed UCTDs. ASIA and UCTD can be considered as related entities in the "mosaic of autoimmunity": the genetic predisposition and the environmental exposure to adjuvants elicit a common clinical phenotype characterized by signs and symptoms of systemic autoimmunity.

Mechanisms of immune-mediated skin diseases: an overview.

The skin is a frequent site of pathological immune responses that can take place in the dermal and/or the epidermal compartments.These immunopathological reactions often occur towards innocuous antigens and may be the result of T cell-dependent and/or autoantibody dependent mechanisms. Defective immune regulation is increasingly recognized as very relevant in many skin and systemic immune-mediated disorders. In some instances (e.g., psoriasis and atopic dermatitis) genetic predisposition can affect also the capacity of keratinocytes to initiate or perpetuate inflammatory responses. A more precise understanding of the molecular and cellular mechanisms underlying each disorder may allow the identification of novel targets for more effective therapeutic strategies.

Anti-Ro/SSA antibodies in rheumatoid arthritis: clinical and immunologic associations.

OBJECTIVE: To assess the prevalence of anti-Ro/SSA in RA and to analyse clinical and serological features of anti-Ro/SSA positive patients with RA. METHODS: 195 consecutive patients affected by RA were studied by counterimmunoelectrophoresis and ELISA for the detection of anti-Ro/SSA antibodies. Anti-Ro were found in 12 patients, with a prevalence of 6%. These 12 patients were pooled with other 15 patients known to have anti-Ro/SSA antibodies and RA, in order to evaluate their clinical and laboratory features. RESULTS: Anti-Ro positive patients showed a common pattern of joint involvement at onset and a comparable progression of disease compared to anti-Ro negative subjects. In addition, extra-articular manifestations (such as xerophthalmia, xerostomia, scleritis, oral ulcers and amyloidosis) and peculiar autoantibody profile (hypergammaglobulinemia, anti-dsDNA and AMA) were found significantly associated to anti-Ro/SSA positivity. Even though DMARDs withdrawals were more frequently detected in anti-Ro/SSA patients, especially when using gold salts, no statistical difference between the two groups was detected. In addition, anti-TNFalpha treatment did not cause further progression of autoimmunity neither on laboratory nor on clinical ground. CONCLUSION: Anti-Ro/SSA can be detected in about 6% of patients affected by RA. These patients presented a peculiar clinical picture characterised by extra-articular manifestations some of which are known to be anti-Ro/SSA correlated, while others are more disease-specific (amyloidosis, episcleritis). Anti-Ro/SSA are significantly associated with other autoantibodies not specific for RA such as anti-dsDNA and AMA. Treatment with anti-TNF drugs did not cause further progression of autoimmunity neither on laboratory nor on clinical ground.