Primary anti-phospholipid syndrome: any role for serum complement levels in predicting pregnancy complications?

OBJECTIVE: To evaluate the association between serum complement levels (C3 and C4) and obstetric complications. METHODS: Fifty-seven pregnancies in primary APS (PAPS) patients were compared with 49 pregnancies in patients with UCTD and SS. A group of 175 healthy pregnant women were studied to calculate a normality range for C3 and C4 during pregnancy. Such a range was applied to define hypocomplementaemia in PAPS and UCTD/SS. RESULTS: Both groups of patients (PAPS and UCTD/SS) showed significantly lower levels of C3 and C4 in each trimester as compared with healthy women; conversely, no significant difference was found between PAPS and UCTD/SS. Comparing PAPS pregnancies with and without complications, no difference was found in the prevalence of low C3 or low C4. CONCLUSION: No association was found between hypocomplementaemia and obstetric complications in PAPS. However, both cases of pre-eclampsia were characterized by low C3 throughout pregnancy. There is evidence that the complement system is a contributor to the mechanisms of aPL-mediated damage, but its predictive role on the final pregnancy outcome does not seem to be of major impact.

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: comparison of adalimumab, etanercept and infliximab in the GISEA registry.

OBJECTIVE: To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS: The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS: 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS: Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

Longterm retention of tumor necrosis factor-α inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors.

OBJECTIVE: To evaluate 4-year retention rates of tumor necrosis factor-α (TNF-α) inhibitors adalimumab, etanercept, and infliximab among patients with longstanding rheumatoid arthritis (RA), as derived from an Italian national registry. METHODS: The clinical records of 853 adult patients with RA in the GISEA (Gruppo Italiano Studio Early Arthritis) registry were prospectively analyzed to compare drug survival rates and the baseline factors that may predict adherence to therapy. RESULTS: In 2003 and 2004, 324 patients started treatment with adalimumab, 311 with etanercept, and 218 with infliximab. After 4 years, the global retention rate of anti-TNF-α therapy was 42%. Etanercept survival (51.4%) was significantly better than that of infliximab (37.6%) or adalimumab (36.4%; p < 0.0001). Accordingly, the mean duration of therapy was significantly longer for etanercept (3.1 ± 2 yrs) than for adalimumab (2.6 ± 2 yrs) or infliximab (2.7 ± 2 yrs; p < 0.05). The use of concomitant disease-modifying antirheumatic drugs, mainly methotrexate, and the presence of comorbidities significantly predicted drug continuation (p < 0.01), whereas a high Disease Activity Score did not. CONCLUSION: The 4-year global drug survival of adalimumab, etanercept, and infliximab was lower than 50%, with etanercept having the best retention rate. The main positive predictor of adherence to anti-TNF-α therapy was the concomitant use of methotrexate. Our study provides further evidence that the real-life treatment of patients with RA may be different from that of randomized clinical trials.

Baseline numbers of circulating CD28-negative T cells may predict clinical response to abatacept in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the number of circulating CD28-negative (CD28-) T cells as a predictor of clinical response to abatacept in patients with rheumatoid arthritis (RA). METHODS: Peripheral blood CD28- T cell subsets were evaluated by flow cytometry at baseline in 32 patients with RA treated with abatacept. Receiver-operator curves were applied to examine the predictive value of T cell populations and to choose the cutoff for the best performance of the test. Remission was defined using the Disease Activity Score 28 based on C-reactive protein. RESULTS: The overall predictive values of the CD8+CD28- and CD4+CD28- cells for remission after 6 months of abatacept therapy were 0.802 (SE 0.078) and 0.743 (SE 0.089), respectively. Cutoff values of < 87 CD8+CD28- cells/µl and < 28 CD4+CD28- cells/µl had 80.0% sensitivity and 81.8% specificity (Fisher test: p = 0.001), and 60.0% sensitivity and 77.3% specificity (p = 0.043), respectively, for prediction of remission at 6 months. Patients having low baseline numbers of CD8+CD28- T cells had a more than 4-fold higher probability of achieving remission within 6 months than patients with higher levels of these cells. CONCLUSION: A simple laboratory measure, the baseline number of circulating CD28- T cells, predicted remission after 6 months of abatacept treatment in patients with RA.

Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response.

OBJECTIVE: To verify the hypothesis that blockade of CD28 costimulation by treatment with abatacept in patients with rheumatoid arthritis (RA) might induce a reduction in the number of CD28- T cells, as well as other effector T cell populations. We evaluated whether these variations correlate with clinical response. METHODS: Peripheral blood T cell subsets were longitudinally evaluated by flow cytometry through the analysis of CD28, CD45RA, and CCR7 expression in 16 patients with RA who were treated with abatacept. RESULTS: After 48 weeks of treatment, the proportion and the absolute number of circulating CD8+CD28- T cells decreased (p = 0.008, p = 0.055, respectively, compared with baseline), as well as the proportion of the CD8+CD45RA+CCR7- cells, thought to represent terminally differentiated effector T cells (p = 0.03). Reductions of percentages of circulating CD4+CD28- and CD8+CD28- T cells, and (CCR7-) CD8+ total effector T cells were directly correlated with the reduction of Disease Activity Score 28 C-reactive protein (r = 0.58, p = 0.014; r = 0.47, p = 0.059; r = 0.59, p = 0.012, respectively). CONCLUSION: After therapy with abatacept, circulating CD28- T cells and other effector populations decrease in patients with RA. This decrease is correlated with clinical response.

Complement activation and pregnancy failure.

Pregnancy represents a physiologic condition where maternal immune system tolerates the semi-allogenic fetus. The fetal tissues are directly exposed to the maternal blood with potential attacks from maternal immune system, including the activation of complement cascade. Small amounts, of both early and late components, of complement are physiologically found in the placenta, maybe in relation to the vascular remodeling process. A significant increase of complement activation was associated with different pathologic pregnancy outcomes, namely pre-eclampsia, recurrent spontaneous abortions, intra-uterine growth retardation, and anti-phospholipid syndrome (APS). In some, but not in all, mice models of APS, complement activation plays a major role in pregnancy loss, with a massive accumulation of C3 in the placenta, while C3 deficient mice didn't show fetal resorption. Basing on these findings, anti-phospholipid antibodies and complement activation (via C3a, C5a, and MAC) may cooperate in triggering a local inflammatory process, eventually leading to placental thrombosis, hypoxia, and neutrophil infiltration. However, histological analysis of human placenta tissues from APS women shows small rather than widespread inflammation. In a similar manner, complement activation can be detected in human APS placentas but without any relationship with pregnancy outcome and therapy. Further studies are necessary to investigate whether complement activation and inflammatory processes found in animal models are really taking place in APS.