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Background and Aims

Antiphospholipid syndrome (APS) is an autoimmune disorder, manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack.

Although the major antigen of APS is β₂ glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease.

Methods

Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups.

Results

Results - Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9±3.3 mm³ and control 113.7±7.4 mm³; p=0.017) and a more severe neurological outcome (iANXA2 2.2±0.2, and control 1.5±0.18; p=0.03).

Conclusions

Conclusions - This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.

Background and Aims

Humoral immune reaction, including complement activation plays important role in mechanisms of stress.

Methods

Quantification of complement levels is based on titration of 50% hemolysis. The phenomenon of complement dependent lysis of sheep erythrocytes loaded with antibodies arises. In accordance with the international standard, such an amount is taken as a unit of complement activity that causes hemolysis of 50% of sensitized red blood cells under standard conditions. In the presence of a constant dose of antigen, a reverse serum titer is determined, i.e., a serum dilution is selected at which such an amount of complement is bound that 50% inhibition of hemolysis occurs.

Results

A study of the effect of antidepressants on the immune responses of stressed animals showed that intraperitoneal administration of amitriptyline and paroxetine in the form of monotherapy under stress is accompanied by even greater changess of immunological parameters of blood mice than with saline. At the same time, despite unidirectional changes in immune responses, amitriptyline caused more pronounced dysfunctional immune disorders than paroxetine: it significantly suppressed the phagocytic and metabolic activity of neutrophils, contributed to the accumulation of large, medium and small fractions of circulating immune complexes (up to 12.4 + 0.5, 37.5 + 5.3, 143.4 + 9.2, respectively). The disturbed ratio of leukocyte subpopulations in the leukoformula, caused by stress, persisted with amitriptyline monotherapy - there was an increase of segmented neutrophils, lymphopenia.

Conclusions

Use of psychoactive drugs such as amitriptyline and paroxetine seems plays significant role in stress inducted changes of innate immune responses.

Background and Aims

To analyse complement variations during SLE pregnancies, focusing on disease flares and adverse pregnancy outcome (APO).

Methods

Retrospective analysis of 246 SLE pregnancies (172 patients, table 1) prospectively-followed in 2 Italian Centers (1987-2018). C3 and C4 normal levels were calculated in general obstetric population (GOP) as previously described¹, and related to maternal and fetal outcome.

Results

Pregnancies with flare (30) showed higher frequency of low C3 and C4 at preconception visit(T0) and of low C4 in every trimester(T1-T2-T3), as compared with pregnancies without flare. At multivariate analysis, low C4 at T0 was associated with flare (OR[95%CI]: 10.34 [2.52-42.39]; p=0.001). Fig.1 shows the variation of complement in SLE pregnancies with and without flare and in GOP. APO were recorded in 47 pregnancies (27 fetal loss: 20 early miscarriage, 7 late pregnancy loss; 11 severe preterm birth; 15 hypertensive disorder: 11 pre-eclampsia and 4 pre-eclampsia+HELLP syndrome). In pregnancies without APO, C3 increased from T0 to T3 and C4 increased from T0 to T2; in fetal death and severe preterm birth C3 and C4 did not increase; in hypertensive disorders C3 and C4 increased only between T0 and T1 (Fig.2).

Conclusions

In SLE pregnancies, monitoring of C3 and C4 is important: its failure to increase can be useful to recognize potential risk situations which deserve particular monitoring.

References ¹Reggia R. et al. Rheumatology 2012;51:2186-2190

Background and Aims

Prognosis of pregnancies in women with antiphospholipid syndrome has dramatically improved over the past two decades using conventional treatment with low molecular weight heparin and low-dose aspirin. However, despite this regimen, 10–15% of antiphospholipid syndrome patients experience pregnancy losses.

Methods

Several studies have been performed in order to identify risk factors predictive of complications. Thrombosis has been generally accepted as the key pathogenetic mechanism underlying pregnancy morbidity. However, the thrombogenic state alone is not able to explain all the different mechanisms leading to pregnancy failure.

Results

Low complement levels (C3 and C4) are associated with poor pregnancy outcome in women with antiphospholipid syndrome in different studies. In fact, emerging evidence shows that complement pathway could play an important role in mediating clinical events in antiphospholipid syndrome. However, the exact mechanism through which complement mediates antiphospholipid syndrome complications remains unknown.

Conclusions

Hypocomplementemia could be indicated as an early predictor of adverse pregnancy outcome, available at the beginning of pregnancy for starting, if necessary, additional treatment to conventional therapy. However, future studies need to better understand the impact of low complement level on antiphospholipid syndrome pregnancy outcome.

Background and Aims

Hypocomplementemia in rheumatoid arthritis (RA) has been associated to higher inflammatory disease activity, more erosive disease and most frequent extra-articular involvement (such as pleuropulmonary complications, vasculitis, rheumatoid nodules or infection), being all of the above associations also related to seropositivity for rheumatoid factor (RF) or anti-CCP antibodies. Our objective is to explore if hypocomplementemia in RA independently of seropositivity is associated with a more aggressive disease.

Methods

We searched for patients with RA diagnosis and RF+ (>15 UI/mL) and hypocomplementemia C3 (<84 mg/dL) in 2017, as well as patients with RF+ but normal levels of C3 (>84 mg/dL) and C4 (>14 mg/dL) in the same period as controls. Demographic, biochemical, clinical ( and therapeutic were obtained from medical records. Differences between variables were analysed using Student-t or Chi-square tests.

Results

25 RA patients with RF+ and hypocomplementemia C3 (+/-C4) and 50 RA controls with RF+ and normal complement levels were identified. Basal characteristics (sex, age, disease duration) were similar in both groups. All biochemical, clinical and therapeutic variables were comparable between both groups except for higher levels of CRP in patients with hypocomplementemia (Table 1).

Conclusions

The present study does not find differences between patients with seropositive RA with low complement levels and those with normocomplementemia in terms of a more aggressive disease, cardiovascular comorbidity or inflammatory burden, except for higher CRP levels. This findings support that clinical associations of hypocomplementemia in RA are the same as those of RF seropositivity (to which it is associated).