**4. Relationship between antiphospholipid syndrome and metabolic syndrome**

Estimation of prevalence of MetS in general population seems to depend to a substantial degree on the used definition, at least in certain countries or in certain ethnic groups [19–22]. Its prevalence varies between <10% in China and as much as 60% among women of Samoa [23]. Different prevalences of MetS, ranging between 18 and 48%, were also recorded among populations of different European countries and regions [20–22, 24–26]. It is interesting to emphasize that even in populations in which comparable prevalence of MetS was found using each of three already mentioned definitions, level of agreement between them was not good. As could be expected, worse agreement was found between WHO‐NCEP ATP III and WHO‐ IDF than between NCEP ATP III‐IDF definitions because of the central obesity as common denominator of the last two definitions [20, 21, 23]. This observation raised the possibility that in fact different individuals were identified as having MetS by different definitions of this syndrome [23].

In a search for factors that contribute to the manifestations of APS, MetS came into a focus surprisingly late. Data on coexistence of these two syndromes are still relatively scarce, particularly considering that of MetS and primary APS (PAPS).

#### **4.1. Metabolic syndrome in primary antiphospholipid syndrome patients**

Recently, prevalence of MetS among PAPS patients has been assessed by Medina et al. [3] and Rodrigues et al. [27]. Both surveys were performed in Hispanics among whom MetS has the

highest prevalence [28]. Defined by the IDF criteria, the prevalence of MetS among 71 Brazilian PAPS patients was 33.8% [27]. Comparable prevalences of MetS were recorded among 58 Mexican PAPS patients, using NCEP ATP III (34.5%) or IDF definitions (37.9%), while it was only 17.2% when WHO definition was applied [3]. It has been hypothesized that these cases, identified by WHO definition, were insulin resistant and with more severe forms of MetS [3, 29]. However, in investigation conducted by Medina et al., prevalence of MetS among PAPS patients was higher than in corresponding general population (17.2% vs. 13.6%) when WHO definition was used [3]. Same as in general population without APS [20, 21, 23], among PAPS patients agreement between WHO and NCEP ATP III definitions of MetS was low (κ value 0.394), moderate between WHO and IDF definitions (κ value 0.427), while only between NCEP ATP III and IDF definitions agreement was good (κ value 0.851) [3].

Regarding individual components of MetS, atherogenic dyslipidaemia was most prevalent among Mexican PAPS patients, being present in approximately half of them [3]. Significantly higher mean triglyceride levels and significantly lower mean HDL levels were previously reported among PAPS patients in comparison with controls [30–33]. Some specific autoanti‐ bodies could influence lipoprotein levels and effects in these patients. These antibodies may interfere with paraoxonase (PON) activity of HDL and, indirectly, beta‐2‐glycoprotein I (beta‐ 2‐GPI) [32, 33], thus promoting LDL oxidation. Relationships between lipid profile, certain anti‐lipoprotein antibodies, inflammatory markers and clinical manifestations of PAPS were meticulously investigated [31–33], but on relatively small number of patients and with inconsistent results. Delgado Aves et al. have not demonstrated any correlation between the observed decrease in PON activity and either aPL nor antibodies against HDL (anti‐HDL) in PAPS patients [33]. However, pro‐inflammatory and prothrombotic roles were proposed for anti‐HDL, being present in higher titre among asymptomatic persistently aPL positive subjects, as well as in PAPS patients with thrombotic events, when compared with patients with inherited thrombophilia and healthy controls [32]. It has been also hypothesized that hypertriglyceridemia could be the result of decreased degradation as a consequence of an inhibition of lipoprotein lipase (LPL) by aPL [3]. Currently, there are only scarce data on prevalence of antibodies against LPL (anti‐LPL) in PAPS patients, speaking against their existence and influence [31].

Different authors have observed similar prevalences of hypertension among PAPS patients (22.4 and 26.3%) [3, 31], not differing significantly from that in controls (20%). Nevertheless, among PAPS patients, hypertension was significantly more frequent in those with arterial thrombosis, with which it was independently associated [31]. It is interesting that in spite of highly prevalent insulin resistance (32.8%), hyperglycaemic disorders were present in only 5% of PAPS patients [3].

#### **4.2. Metabolic syndrome in patients with antiphospholipid syndrome associated with autoimmune rheumatic diseases.**

The literature data on coexistence of MetS and numerous rheumatic diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, osteoarthritis, gout) are fairly extensive [1, 34–42]. The prevalence of MetS among patients with these disorders ranges between 14 and 62.8% [1, 3]. Qualifier "antiphospholipid syndrome associated with certain autoimmune rheumatic disease" (sAPS), which replace currently obsolete term "secondary APS", refers mainly to the systemic lupus erythematosus (SLE) despite the still unscrambled puzzle of their relations [5].

It has been speculated that high prevalence of MetS among these patients might be the consequence of certain pharmacologic interventions, particularly of chronic corticosteroid therapy [43]. However, the presence of MetS in as much as 16% of 1494 young (35.2+13.4 years) SLE patients with rather short disease duration (24.1+18.0 weeks) seems to be enough to reject this relationship as causal [2]. Nevertheless, it should be kept in mind that duration and magnitude of corticosteroid exposure could aggravate well‐known cardiovascular risk factors clustering as characteristics of MetS.

On the other hand, other pharmacological interventions, primarily methotrexate (MTX) use in patients with rheumatoid arthritis, have been depicted as independent factors for reduced prevalence of MetS in these patients, especially those older than 60 years [44, 45]. This beneficial effect of MTX was attributed to its anti‐inflammatory, as well as to some still unclear drug‐ specific effects, i.e. affecting adenosine levels and, concomitantly, glucose and lipid metabo‐ lism, or decreasing homocysteine levels as an indirect effect of simultaneous use of folic acid [44]. However, other authors reported somewhat conflicting results not being able to confirm decreasing prevalence of MetS in subjects treated with MTX, among total of 353 patients with rheumatoid arthritis [46].
