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Objective: The aims of this study were to describe the clinical presentation of primary SS (pSS) in a large cohort of patients by assessing the prevalence of the patient subgroups at high risk for severe extraglandular manifestations and to explore the influence of the patients' serological profile on disease severity and on immunosuppressive drug utilization., Methods: Cumulative demographic, clinical, serological, histological and therapeutic data of 1115 pSS patients were retrospectively evaluated. Independent serological markers for glandular and extraglandular disease manifestations were identified by logistic regression., Results: The cohort included 1115 (1067 female, 48 male) pSS patients. Severe extraglandular manifestations were detectable in 15% of the patients and were represented by active synovitis (11%), axonal sensory-motor neuropathy (2%), severe leucocytopenia (14%), cutaneous vasculitis (6%) and non-Hodgkin's lymphoma (4.5%). We found that low C3/C4, hypergammaglobulinaemia, RF and cryoglobulinaemia were markers of severity for pSS. According to the number of serological variables, the patients were subdivided into three distinct groups: favourable (no serological markers), intermediate (one serological marker) and poor (two or more serological markers). In comparison with the other two patient groups, pSS patients presenting with two or more adverse determinants had a higher frequency of severe visceral disease complications and required more aggressive therapeutic interventions., Conclusion: This study confirmed that the prevalence of the pSS high-risk subset for severe systemic manifestations is ∼15%. Serological markers might help in the early identification of patients who are candidates to receive more aggressive treatments.

Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies, ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20 U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9±26.5 vs 110±25 mg/dl, P=0.0012; C4 29.7±10.2 vs 22.7±8.3mg/dl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA- (n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (X2=22.793, P<0.001). RF levels seem to correlate with complement CH50. The presence of high levels of C3 in RA patients may reflect a pro-inflammatory status and represent a negative prognostic factor for anti-TNF therapy.

There is not agreement about the best maintenance treatment for patients with diffuse lupus nephritis. This multicenter, randomized trial compared the safety and efficacy of cyclosporine and azathioprine. Seventy-five patients with diffuse proliferative lupus were given three intravenous methylprednisolone pulses followed by prednisone and oral cyclophosphamide for a median of 90 d. Subsequently, patients were randomly assigned either to cyclosporine or to azathioprine for 2 yr (core study). Treatment continued for up to 4 yr (follow-up study). The primary outcome measure was the incidence of disease flares. Secondary end points were proteinuria per day, creatinine clearance, and adverse effects. Seven flares occurred in the cyclosporine group, and eight occurred in the azathioprine group. At the end of the core study, mean proteinuria decreased from 2.8 +/- 3.57 to 0.4 +/- 0.85 g/d (P < 0.0001) in the cyclosporine group and from 2.2 +/- 1.94 to 0.5 +/- 0.78 g/d (P < 0.0002) in the azathioprine group. After 4 yr, mean proteinuria was 0.2 +/- 0.24 and 0.3 +/- 0.33 g/d, respectively. At the core study end and at the follow-up completion, creatinine clearance and BP levels did not change significantly from baseline in either group. Five of 36 patients who were receiving cyclosporine and four of the 33 who were receiving azathioprine stopped the treatment because of adverse effects. For patients with diffuse proliferative lupus nephritis, azathioprine or cyclosporine combined with corticosteroids demonstrated equal efficacy in the prevention of flares.

Aim: The aim of this study was to assess the association between the third component of the complement (C3) and other risk factors of coronary heart disease., Methods and Results: We evaluated 1200 individuals aged 25-74 years (600 men and 600 women). A strong relationship was shown between serum C3 and both body mass index (BMI, P<0.01) and fibrinogen (P<0.01). We found a significant, independent correlation with: platelet count (P<0.01), insulin level (P<0.01), triglycerides (P<0.01), low-density lipoprotein (LDL) cholesterol (P<0.01), and an inverse correlation with cigarette smoking (P<0.01)., Conclusions: A high concentration of C3 is a marker of a profile at risk of atherogenesis.

Background: The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown., Methods: We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups., Results: Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS. For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups., Conclusion: FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.

Background: Some acute phase proteins are associated with both ischemic events and traditional risk factors. Since they are strongly interrelated, each of them partly reflects the characteristics of other proteins. This study was carried out to ascertain the specific preferential associations of some acute phase proteins with traditional risk factors for atherosclerotic disease., Methods: High-sensitivity C-reactive protein, fibrinogen and C3-complement were assessed in 288 unselected men aged 55-64 years. Three multiple linear regression analyses were performed, in which each of the three acute phase proteins was considered the dependent variable of both traditional risk factors and the other two proteins., Results: The three acute phase proteins strongly correlated with each other. Moreover, C-reactive protein was independently associated with triglycerides (P<0.0001), age (P=0.0130), body mass index (P=0.0179), and acute (P=0.0280) and chronic (P=0.0582) inflammations (R2=0.17). Fibrinogen was associated with alcohol consumption (inversely, P=0.0001) and smoking (P=0.0598) (R2=0.06). Finally, C3 was associated with insulin (P<0.0001), cholesterol (P=0.0001), sedentarity (P=0.0028), glucose (P=0.0077), and systolic blood pressure (P=0.0124) (R2=0.28)., Conclusions: When simultaneously studied in multivariate analysis, acute phase proteins have different preferential associations with traditional risk factors, a probable consequence of their involvement in different cellular activations and metabolic processes.

Objective: Serum C3, a complement component produced by macrophages, the liver and the adipose tissue, is associated with the risk of myocardial infarction in men. This study was performed to ascertain the relationships between serum C3 and traditional risk factors in an unselected population sample., Methods and Results: A random population of 1,068 subjects (537 men and 531 women, 23 to 90 years old) was examined for risk factor assessment. Serum C3 was measured by nephelometry. C3 was independently associated with body mass index (P < 0.0005, especially in women), LDL-cholesterol (P = 0.0014 in men and 0.0215 in women), systolic blood pressure (P < 0.05) and, in women, with triglycerides (P = 0.0133) and blood glucose (P = 0.0383), as assessed by multivariate analysis (multiple linear regression). The overall R2 were 0.07 and 0.21 for men and women, respectively. Women over 50 years of age had significantly higher C3 levels, LDL-cholesterol and body mass index than younger women. The correlation of C3 with LDL-cholesterol was present after the age of 40 in men, and 2 decades later in women., Conclusions: These data show that serum C3 correlates with a cluster of conventional risk factors for myocardial infarction resembling insulin resistance. Such correlations may be either independent of, or mediated by the development of coronary atherosclerosis.