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Found 9 results

  1. Pathogenic and Therapeutic Role of Vitamin D in Antiphospholipid Syndrome Patients By Svetlana Jelic, Dejan Nikolic, Dragomir Marisavljević and Ljudmila Stojanovich Submitted: November 5th 2015Reviewed: August 2nd 2016 Published: April 26th 2017 DOI: 10.5772/65071 Abstract In this chapter, the novel findings on interrelationship between vitamin D status and two well‐known prothrombotic states, antiphospholipid syndrome, particularly its thrombotic phenotype, and metabolic syndrome will be reviewed. We shall present the results obtained from patients included in Serbian National Antiphospholipid Syndrome Registry, 68 patients with primary antiphospholipid syndrome (PAPS) and 69 patients with antiphospholipid syndrome associated with certain autoimmune rheumatic disease (sAPS), as well as 50 patients with pure metabolic syndrome (MetS). These results will be analysed and compared with the novel literature data. Prevalence of MetS in APS is high, with the atherogenic dyslipidaemia as its most prevalent characteristic. Prevalence of thrombotic events was significantly higher in APS patients with coexisting MetS, compared with those without MetS. Among APS patients, prevalence of VitD deficiency was significantly higher than in patients with pure MetS. VitD level was also significantly lower in APS patients with coexisting MetS or previous thrombotic events than in those without them. Elucidating interrelationships between VitD deficiency, MetS and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of modifiable risk factors and VitD supplementation. Keywords vitamin D antiphospholipid syndrome metabolic syndrome classification criteria thrombosis Chapter and author info Show + 1. Introduction The antiphospholipid syndrome (APS), primary or associated with certain autoimmune rheumatic diseases, especially systemic lupus erythematosus, represents prothrombotic state. Coexistence of metabolic syndrome (MetS) and autoimmune rheumatic diseases is already recognized [1, 2], while clinical significance of MetS in patients with APS has not been systematically studied [3]. Recent recognition of certain pleiotropic functions of vitamin D (VitD) has enabled us to hypothesize on its role in the pathogenesis of obesity, MetS, APS, autoimmunity and thrombosis. Therefore, the aim of this review will be: (1) to clarify the possible linking role of VitD between APS and MetS, (2) to critically assess the need for estimation of VitD status in APS patients, depending on the coexistence of MetS and (3) to explore the potential therapeutic role which VitD, as an immunomodulator and anti‐thrombotic agent, could have in these patients. 2. Basic definitions Metabolic syndrome (MetS) and antiphospholipid syndrome (APS) are among most prevalent and still highly controversial syndromes. While clinical relevance of antiphospholipid antibodies (aPL) was recognized more than 30 years ago, definite classification criteria for antiphospholipid syndrome were given at the International Workshop in Sapporo, Japan 1998 [4] and revised 2006 in Sidney, Australia [5]. Very interesting proposal of APS criteria based on biological mechanisms is presented lately aiming at simplicity and greater accuracy and, at the same time, avoiding non‐specific formulations [6] (Table 1). Recent investigations have also shown that, beside characteristic thrombotic or obstetric symptoms, there is growing number of systemic non‐criteria manifestations (for example, thrombocytopenia, livedo reticularis, skin ulcerations, pseudovasculitis, migraine and epilepsy) correlating with certain type of aPL and with important predictive role [7, 8]. It is likely that a prominent place among these manifestations belongs to components of MetS, but it is still to be proved. The prevalence of APS in the general population is estimated to be around 2–4%. Initial Reaven's postulate in 1988, which draw attention to the causal association between insulin resistance with ensuing hyperinsulinemia and cardiovascular diseases [9], was followed by numerous definitions of MetS. Three of them, i.e. definitions given by World Health Organization (WHO) [10], the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) [11] and International Diabetes Federation (IDF) [12], were most frequently used and still neither of them is obsolete. While all three definitions share central obesity, atherogenic dyslipidaemia and arterial hypertension as common criteria, WHO definition put the insulin resistance in focus of metabolic syndrome while an obligatory criterion requested by IDF definition is elevated waist circumference (WC) with population‐ and country‐specific cut‐offs (Table 2). All of these three definitions are very similar but different enough, especially when used for the assessment of prevalence of MetS in some other entities, in this case, among patients with APS. Even the latest joint attempt of several major professional organizations (the IDF Task Force on Epidemiology and Prevention, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity) to unify interconnected cardio‐metabolic risk factors into a universal definition of metabolic syndrome did not seem to be final [13]. Table 1. Antiphospholipid syndrome definitions. Similar ambiguity exists concerning the definition of adequate circulating VitD level, as well as of its deficiency and insufficiency. Earlier definition of VitD insufficiency by its blood level of <20 ng/mL (50 nmol/L), given by the World Health Organization (WHO) [14], has been recently accepted by most researchers as a definition of the deficiency of this vitamin [15, 16]. Its insufficiency is defined as a VitD concentration between 20 and 30 ng/mL (50 and 75 nmol/L), while its concentrations >30 ng/mL (75 nmol/L) are regarded as sufficient [17, 18]. The WHO definition10 NCEP ATP III definition11 IDF definition12 Insulin resistance plus ≥ 2 of: ≥ 3 of: Central obesity plus 2 of: Atherogenic dyslipidaemia Hypertension Microalbuminuria Impaired fasting glucose/Glucose intolerance/Diabetes Table 2. Metabolic syndrome definitions—similar but different enough. 3. Experience from Serbian National APS Registry 3.1. Patients and methods Study included a total of 137 APS patients, attending outpatient clinic of the University Medical Center Bezanijska kosa, all Caucasians, who were previously enrolled in Serbian National APS Registry. These patients represented only the part of those so far included in this Registry, which is still growing and is still unable to appraise the prevalence of APS among general population in Serbia. Among studied patients, 68 were PAPS patients (59 females, nine males, mean age 43.51+10.58 years) and 69 sAPS patients (61 females, eight males; mean age 47.83+15.67 years). All studied APS patients have met 2006 updated Sydney criteria [5] which requested the presence of at least one clinical criteria (i.e. vascular thrombosis or multiple and recurrent foetal losses) and at least one of antiphospholipid antibodies (aPL), i.e. lupus anticoagulant (LA), anticardiolipin (aCL) and/or anti‐β2‐glycoprotein 1 (β2GP1) antibodies. Most of our sAPS patients had APS associated with systemic lupus erythematosus (SLE) (n=60; 87%), while the rest had Sjögren's syndrome (n=8; 11.5%) and ankylosing spondylitis (n=1; 1.5%). Mean duration of these rheumatic diseases in sAPS patients was 5.69+2.87 years, ranging from 1 to 13 years. Characteristics of two subgroups of APS patients were compared with 50 MetS patients (35 females, 15 males; mean age 47.68+11.66 years). The presence of metabolic syndrome among studied patients was determined according to the International Diabetes Federation (IDF) clinical definition [12]. An obligatory criterion for MetS requested by this definition is abdominal obesity defined by elevated waist circumference (WC) with gender‐ and ethnic‐specific cut‐offs, meaning 94 cm for males, and 80 cm for females belonging to European population. Besides abdominal obesity, two or more of the four additional criteria (a) hypertriglyceridemia >150 mg/L, confirmed or already treated; (b) high density lipoprotein (HDL) cholesterol <40 mg/dL in males or <50 mg/dL in females; (c) blood pressure >130/85 mmHg, newly diagnosed or already treated; (d) impaired fasting glycaemia, >100 mg/dL or previously diagnosed diabetes) are necessary for the diagnosis. For every participant, clinical data concerning thrombotic events, their appearance, management and follow‐up were obtained from medical charts review. As thrombotic events, the following were recorded: superficial and deep venous thrombosis, pulmonary embolism, peripheral arterial occlusion, cerebral vascular accident and myocardial infarction. After an overnight fast, height (m), weight (kg) and waist circumference (cm) were measured in every participant with underwear and without shoes. Waist circumference (WC) was measured at the level of the umbilicus while the participant was standing and breathing normally. Body mass index (BMI) was calculated according to the widely accepted formula dividing body weight by the square of individual's height. Morning samples of venous blood (3–5 mL) were withdrawn from every participant for the analysis of serum glucose and lipids. Serum vitamin D levels were determined in every participant . The study was approved by the Institutional Ethics Committee. All examinations were conducted according to the most recent amendment of Declaration of Helsinki (Edinburgh, 2000), only after obtaining an informed consent for participation in the study from every subject. Statistical analysis was performed using the STATISTICA 10 software program. Descriptive statistics was used. Prevalence of MetS as well as of its individual components, within studied groups of patients was expressed as percentage. Testing significance of their differences, the Student's t‐test and Fisher's exact test were used, considering p value <0.05 statistically significant. 3.2. Results 3.2.1. Prevalence of MetS among patients with APS Metabolic syndrome was observed in high percentage of patients with APS. Its prevalence did not differ significantly between PAPS (36.76%) and sAPS (42.03%) patients (p=0.53). Anthropometric and metabolic syndrome characteristics among studied groups are given in Table 3. Borderline statistical significance of the difference in WC value was observed when two subgroups of APS patients were compared with MetS patients (F=2.77, p=0.065), while BMI has differed highly significantly between these groups (F=9.765, p=0.0001). In spite of slightly lower BMI and slightly higher WC in PAPS patients, neither BMI (p=0.434) nor WC (p=0.275) did differ significantly between two subgroups of APS patients. Atherogenic dyslipidaemia, represented by hypertriglyceridemia and low HDL cholesterol, was the most prevalent characteristic of metabolic syndrome among PAPS patients. In spite of this, prevalence of low HDL cholesterol among PAPS patients were significantly lower than in MetS patients (48.3% vs. 70%, p=0.02). Prevalence of hypertriglyceridemia (45.59% vs. 42.03%, p=0.67) and low HDL cholesterol (48.53% vs. 53.62%, p=0.55) did not differ significantly between PAPS and sAPS patients. Hypertension was significantly less prevalent among these patients compared with MetS (23.53% vs. 58%, p=0.0002) and even with sAPS (23.53% vs. 52.17%, p=0.0007) patients. The least prevalent characteristic of metabolic syndrome among patients with APS was hyperglycaemic disorder. Compared with MetS patients in whom impaired fasting glycaemia, glucose intolerance or diabetes were present in as much as 36%, these disorders were observed in only 5.88% of PAPS patients (p=0.0001) and 4.35% of sAPS patients (p<0.0001). MetS PAPS sAPS BMI (kg/m2) 32.09+6.14 27.81+5.98 28.54+4.22 WC (cm) 93.67+14.36 90.73+9.18 88.53+11.91 TG > 150 mg/dL (%) 58 45.59 42.03 HDL < 40/50 mg/dL (%) 70 48.53** 53.62 Hypertension (%) 58 23.53**** 52.17§§ IFG, IGT, DM (%) 36## 5.88**** 4.35 Table 3. Anthropometric and metabolic syndrome characteristics among studied groups. *p < 0.05, PAPS vs. MetS. **p < 0.01, PAPS vs. MetS. #p < 0.01, sAPS vs. MetS. §p < 0.01, PAPS vs. sAPS. 3.2.2. Prevalence of thrombotic events among APS patients with or without MetS Compared with patients with metabolic syndrome, prevalence of thrombotic events was significantly higher among patients with PAPS (52.94% vs. 22%, p=0.0009) and sAPS (56.52% vs. 22%, p=0.0003). Thrombotic events were reported with similar prevalence in PAPS and sAPS patients (p=0.674). When compared with APS patients without characteristics of MetS, thrombotic events were significantly more frequent among MetS positive patients with sAPS (75.86% vs. 42.5%, p=0.0075). Although higher among MetS positive, compared with MetS negative patients with PAPS, difference of prevalence of thrombotic events among these two subgroups of PAPS patients did not reach statistical significance (68% vs. 44.19%, p=0.0622). 3.2.3. Vitamin D status among APS patients depending on MetS and/or thrombotic events Low VitD status (insufficiency or deficiency) was highly prevalent among PAPS (insufficiency in 27.94% and deficiency in 36.76%) and sAPS patients (insufficiency in 30.43% and deficiency in 40.58%), as well as among patients with pure MetS (insufficiency in 20% and deficiency in 32%). In comparison with patients with pure MetS (28.58+14.32 ng/mL), VitD concentrations were lower in PAPS (25.76+12.18 ng/mL) and sAPS patients (23.81+11.22 ng/mL), but with statistically significant difference only between these concentrations in sAPS patients and patients only with MetS (p=0.04). Significantly lower VitD level was observed in those with coexisting MetS (MetS +), compared with those without it (MetS -) both in PAPS (MetS +: 22.0+8.52 vs. MetS -: 27.0+13.49 ng/mL, p=0.05 ) and sAPS patients (MetS +: 18.83+9.16 vs. MetS -: 27.42+11.28 ng/mL, p=0.0012). Also, significantly lower VitD level was observed in APS patients with thrombotic events (TE+), compared with those without these events (TE -), both in PAPS (TE +: 20.61+12.18 vs. TE -: 31.56+12.72 ng/mL, p=0.0001 ) and sAPS patients (TE +: 20.67+10.43 vs. TE -: 27.9+11.04 ng/mL, p=0.007). In 11 (22%) of patients with MetS, but without APS, some thrombotic event was confirmed. In those patients, VitD levels were also significantly lower than in those without these events (TE +: 18.45+10.66 vs. TE -: 31.43+13.63 ng/mL, p=0.003). However, both in PAPS and sAPS patients, with coexisting MetS, previous thrombotic events did not influence serum VitD levels (PAPS: p=0.12; SAPS: p=0.93). 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 autoantibodies 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 metabolism, 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]. 5. Vitamin D and thrombosis Prothrombotic state is one of the well‐known characteristics of both antiphospholipid and metabolic syndrome. It has rather complex pathogenesis in which VitD status has an important role affecting primarily immune‐mediated thrombosis. Indirect proofs for this relationship are as follows: (a) existence of nuclear VitD receptors in vascular smooth muscle cells, endothelial cells, cardiomyocytes, platelets, as well as in most types of the immune cells [47–51], and (b) expression of cytochrome P450 enzyme, CYP27B1 activity by the same cell types, enabling local synthesis of biologically active form of VitD, 1,25(OH)2D [52]. There is substantial experimental data indicating that VitD plays significant role in maintenance of physiological balance between thrombosis and haemostasis [47]. It has been demonstrated that VitD exerts following actions: in monocytes, expression of tissue factor (TF) is downregulated, while the expression of thrombomodulin (TM) is upregulated [53]; in vascular smooth muscle cells, the expression of TM is upregulated, but there is also downregulation of plasminogen activator inhibitor‐1 (PAI‐1) and thrombospondin‐1 (THSP‐1) [54]; in endothelial cells, platelet activation is attenuated as well as the expression of vascular cell adhesion molecule‐1 (VCAM‐1) [55]. Net result of numerous effects of this vitamin on different haemostatic factors is its antithrombotic role. Prothrombotic state that exists in VitD receptor knockout animal models proves the importance of these extra‐skeletal effects of VitD as well as the observation that all of them are VitD receptor‐mediated [47, 56]. However, there are still relatively few indirect and even less direct clinical evidences for the association between VitD status and thrombotic events in humans. First of them came from the epidemiological studies in which have been observed that cardiovascular morbidity and mortality depended on season of the year and latitude [47, 57, 58]. Seasonal variations were also demonstrated for tissue plasminogen activator (tPA) antigen, fibrinogen, D‐dimer and von Willebrand factor (vWF) concentrations in 6538 British subjects without significant cardiovascular disorders, aged 45 years [59]. In this population, negative correlation between VitD level and tPA, fibrinogen and D‐dimer concentrations was observed indicating that at least some of the seasonal variations of these thrombotic markers could be attributed to the VitD status. More direct proof for the association between VitD status and thrombosis came from the research conducted in huge population of 18 791 subjects from general population of Copenhagen [60]. Authors have observed that every quartile of a decrease in VitD concentrations was accompanied by an increase in risk of venous thromboembolism (VTE), resulting in a 37% increased VTE risk between subjects with the VitD concentrations, in the lowest quartile and those in highest quartile. Recent publication which retested the seasonality of different cardiovascular events in regard to VitD levels, in the Scottish Heart Health Extended Cohort (SHHEC), brings a dose of confusion in previously proposed relations. Namely, it failed to prove that seasonal appearance of cardiovascular events resembled seasonal variations in serum VitD concentrations nor that these events expressed more pronounced seasonality in those with lower VitD concentrations, compared with those with its higher concentrations [61]. But, during follow‐up, significant correlations were observed between lower baseline concentrations of VitD and subsequent incident cardiovascular morbidity and incident cardiovascular and all‐cause mortality [61]. Results of recent trials assessing the effects of VitD supplementation on the risk of thromboembolism were inconclusive [62–64]. In the Multiple Environmental and Genetic Assessment (MEGA) case‐control study which included 2506 patients with venous thrombosis, thrombotic risk was 37% lower in those supplemented with various vitamins including VitD [62]. However, in a large cohort of postmenopausal women (n=36282) from the Women's Health Initiative, daily supplementation with calcium and VitD failed to reduce the overall risk of thromboembolism [63]. Even when high doses (300,000 IU) of VitD were given intramuscularly, in a small group of patients with proven deep vein thrombosis and pulmonary embolism, observed reduction in plasma concentrations of P‐selectin and high‐sensitive C‐reactive protein (hs‐CRP) did not reached statistical significance [64]. Additional information could be expected from the ongoing Vitamin D and OmegA‐3 Trial (VITAL) and that is why the results of this investigation are eagerly awaited [65]. 6. Role of vitamin D in metabolic syndrome Currently, increasing prevalence and co‐existence of obesity, MetS and hypovitaminosis D represent serious public health concern [66, 67]. New data have considerably changed hierarchy of MetS components, with the shift of the focus from obesity and insulin resistance, firstly toward fatty liver and now toward VitD deficiency [68]. It is still questionable if relationship between VitD status and obesity is unidirectional or bidirectional, with the accumulating evidence favouring the influence of VitD on body composition and not vice versa. Namely, few years ago tempting hypothesis on essential role of VitD in evolvement of obesity has been postulated [68]. It started from a situation that is completely opposite to the “thrifty genotype hypothesis” proposed long ago [69] and gave the feasible explanation not only for obesity and MetS epidemic in adults but also for their growing prevalence among children [70]. According to this hypothesis, we are living in “obesogenic” environment, loaded with energy resources and unsuitable for efficient metabolism. It has been proposed that VitD as an ultraviolet (UV)‐B radiation sensor (i.e. decline in its concentrations) could induce shift toward “winter metabolism”, characteristic for MetS [68]. If this is true, then it could be expected that VitD supplementation may be efficient in prevention and treatment of obesity and MetS. Significant decrease in body fat mass after 12 week of VitD repletion (25 μg of cholecalciferol daily), compared to placebo (−2.7+2.0 kg vs. −0.4+2.0 kg, p<0.001), could be the proof for this presumption [71]. It was also speculated that VitD deficiency during pregnancy could lead to the epigenetic changes predisposing, in that manner, new‐born children to obesity and MetS later in life [68, 70]. Experimental support for these assumptions is the expression of VitD receptors on adipocytes and its involvement in adipogenesis which is regulated by the intracellular concentrations of VitD [72], as well as inhibition of lipid accumulation in adipocytes and their atrophy achieved by the knock‐down of VitD receptors [72, 73]. Nowadays, VitD deficiency is common even in general population (49%), but significantly more prevalent (p=0.006) and quite similar in overweight/obese patients with MetS (72%) and without MetS (69%) [74]. Premise that exaggerated adiposity could lead to VitD insufficiency or deficiency by its seclusion within adipose tissue could not be confirmed. It has been shown that VitD concentrations varied considerably (range 4–2470 ng/g) in the subcutaneous abdominal fat of 17 severely obese patients (BMI=48.7+8.1 kg/m2) undergoing bariatric surgery [75]. In spite of the average weight loss of 54.8 kg after one year and continuous VitD supplementation with more than 2500 IU/day, mean serum VitD concentrations did not change significantly during this period (23.1+12.6 vs. 26.2+5.36, p=0.58) [75]. Most of the studies have confirmed that serum VitD concentrations significantly inversely correlated with obesity parameters, BMI (r=-0.159, p=0.007) [74], or waist circumference (p<0.001) [76] as well as with serum triglycerides (r=-0.149, p=0.012) [76]. In the lowest quartiles of VitD concentrations corresponding to its severe deficiency, odds ratio (OR) for hypertriglyceridemia was 2.74 (95% CI: 1.64–4.57) [77]. This association between serum concentrations of VitD and triglycerides could be explained by the activation of lipoprotein lipase by VitD in adipocytes [76]. No significant relation could be demonstrated between VitD status and total‐ (r=-0.044, p=0.461) [74], low density lipoprotein (LDL)‐ (r=-0.005, p=0.932) and high density lipoprotein (HDL)‐cholesterol (r=0.065, p=0.276) [74]. Interestingly, hypothesis was proposed ten years ago stating the possibility that statins could be the analogues of VitD, acting via same receptors, particularly when we are talking about their mutual effect of enhancement of immune competence [78]. So, it seems that this absence of association between VitD status and parameters of cholesterol metabolism made this hypothesis shaky to some extent. Another component of MetS for which association with VitD status has not been unequivocally confirmed is hypertension. Variability of blood pressure driven by the seasons or latitude speaks for the existence of this association, as well as the results of experimental studies pointing to VitD as an inhibitor of the renin‐angiotensin‐aldosterone axis [79, 80]. Negative correlation between VitD concentrations and blood pressure was demonstrated in most but not all of the surveys. This negative association was stronger in subjects younger than 50 years [81–83], while the absence of any relationship between VitD status and hypertension was also registered in some of the trials [74, 76, 84, 85], particularly those conducted in older subjects [84, 85]. However, in postmenopausal women with the VitD concentrations in the lowest quartiles corresponding to its severe deficiency, odds ratio (OR) for hypertension was 1.81 (95% CI: 1.15–2.85) [77]. 7. Role of vitamin D in antiphospholipid syndrome Although APS represents acquired, autoimmune condition, its pathophysiology and, especially pathophysiology of thrombosis in APS is highly heterogeneous, involving different genes and acquired factors [86], VitD insufficiency/deficiency being among them. Same as for relationship between MetS and APS, much more is known about the impact of VitD status on antiphospholipid syndrome, associated with autoimmune rheumatic diseases, than on primary antiphospholipid syndrome. Patients with PAPS represent the population of particular interest for the investigation of interrelations with components of MetS and/or VitD status since these patients, unlike those with sAPS, were not treated with drugs (i.e. corticosteroids, immunosuppressants) which may affect expression of most of the MetS characteristics as well as VitD level. One of the first announcements on the prevalence of VitD insufficiency or deficiency in PAPS and their impact on its manifestations dated from 2010 [87]. This letter to the editor presented the results of research conducted by Brazilian investigators in the group of forty‐six PAPS patients, younger than 60 years, in whom the VitD levels were assessed in the autumn, when it was expected to be highest. VitD deficiency was found in 11% and insufficiency in 74% of these PAPS patients, resembling the findings of Italian authors [88] which have reported the prevalence of VitD deficiency in 17% and insufficiency in 60% of PAPS patients. It is interesting that Brazilian authors have noticed that VitD insufficient PAPS patients tended to be more overweighed than those with adequate VitD level [87]. Also, it seems that thrombotic APS is characterized with significantly lower concentrations of VitD than purely obstetric clinical syndrome (20.8 vs. 33.3 ng/ml, p<0.01) [88] highlighting once again the role of this vitamin in thrombosis. High prevalence of VitD deficiency among patients with APS (49.5%) and its significant correlation with thrombotic events were confirmed by Israeli authors [68]. In vitro, they have also demonstrated VitD ability to inhibit anti‐β2‐glycoprotein I autoantibody (anti‐β2‐GPI Ab)‐mediated TF expression [89]. Seasonal variations in VitD concentrations were demonstrated in PAPS patients same as in healthy controls, with preserved differences in its level between these two groups through all seasons [88, 90]. These differences were most pronounced during summer, while they were not statistically significant only during the spring. This observation was somewhat surprising, given the lack of banning from sun exposure in these patients. That sun avoidance is not a cause of highly prevalent VitD deficiency and insufficiency in PAPS patients was indirectly demonstrated in previous Italian studies [88, 90] by observed absence of any difference in VitD levels between antinuclear antibodies (ANA)‐positive and negative PAPS patients. Until now, there is no valid explanation for the probable cause‐and‐effect relationship between insufficient VitD level, on one side, and PAPS or sAPS, on the other. There are only assumptions, and even they are much better clarified for sAPS [91–93], especially that accompanying SLE [91, 94, 95]. It is obvious that low levels of vitamin D in sAPS could not be attributed purely to banning of sun exposure or the use of certain medication in these patients. In an Israeli and European cohort of patients with SLE, significant negative correlation (r=-0.12, p=0.018) was demonstrated between the serum VitD concentrations and disease activity, assessed by SLE disease activity‐2000 (SLEDAI‐2K) and European Consensus Lupus Activity Measurement (ECLAM), which were converted into standardized z‐value [94]. Severe VitD deficiency was found in 17.89% of 123 SLE patients with short disease duration, while the presence of renal disease (OR 13.3, 95% CI 2.3–76.7, p<0.01) and photosensitivity (OR 12.9, 95% CI 2.2–75.5, p<0.01) were its strongest predictors [95]. Investigation conducted in a small group of young women with newly diagnosed SLE, from one of the sunny places in Iran, gave very interesting results. VitD deficiency was highly prevalent among these patients, mild in 12.5%, moderate in 62.5% and severe in 17.5% of them [96]. It was much more pronounced in them than in general population of the similar age in that region, in whom mild VitD was present in 15.5%, moderate in 47.1% and severe in 7.1%. Very interesting was also an observation that serum VitD concentrations showed significant negative correlation with another disease activity score, the British Isles Lupus Assessment Group (BILAG) (r=-0.486, p=0.001), in spite of the short duration of disease [97]. Hypothetical explanation for the low serum concentrations of VitD in SLE patients by the existence of inhibiting anti‐VitD antibodies in circulation could not be confirmed by the literature data [97, 98]. Their existence could be proven in 4–6% of patients with SLE and 3.5% of APS patients. Its association with anti‐dsDNA (p=0.0004) could point to its potential role in this condition, but being only one of 116 different antibodies present in SLE patients characterized by the polyclonal B lymphocyte activation, it is still uncertain if it is pathogenic [97]. It seems that their presence did not affect VitD levels in these patients [97, 98], and it was speculated that they could be the consequence of high‐dose VitD consumption rather than the cause of this vitamin deficiency [99]. Once again, it is important to emphasize that VitD deficiency is more pronounced in more severe APS phenotypes, i.e. thrombotic APS [88]. It could be speculated that supplementation of this vitamin in these very patients may have certain beneficial effects [88, 99], but there is still no prospective studies proving them. Hypothesis of statins as VitD analogues has not still been tested in well‐designed, randomized prospective trials [78]. However, since its proposal, there have been many experimental and small clinical studies confirming statins therapeutic value in APS patients, particularly in those with its thrombotic form [99–103]. So, future studies are badly needed to determine all the aspects of VitD repletion in APS prevention/therapy (choice between VitD precursors, its active form or VitD analogues, their dosage and treatment goals). 8. Key messages Prevalence of metabolic syndrome in APS, primary or associated with certain rheumatic diseases, is high. Atherogenic dyslipidaemia is the most prevalent characteristic of metabolic syndrome in APS patients. Prevalence of thrombotic events was significantly higher in APS patients with coexisting metabolic syndrome, compared with APS patients without metabolic syndrome characteristics. Among APS patients, prevalence of vitamin D deficiency was significantly higher in patients with coexisting metabolic syndrome, compared with those without it. Among APS patients, vitamin D level was also significantly lower in patients with previous thrombotic events than in those without them. In the contemporary literature, there are much more data in favour of pathogenic than therapeutic role of vitamin D in thrombotic events characterizing APS and/or metabolic syndrome. So, prospective studies designed to test all the aspects of VitD repletion in prevention and/or therapy of thrombotic events in APS and/or metabolic syndrome are badly needed. 9. Conclusions Elucidating interrelationships between vitamin D deficiency, metabolic syndrome phenotype and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of modifiable risk factors and vitamin D supplementation. https://www.intechopen.com/books/a-critical-evaluation-of-vitamin-d-clinical-overview/pathogenic-and-therapeutic-role-of-vitamin-d-in-antiphospholipid-syndrome-patients?fbclid=IwAR13oFb5S8e5R6f1L-vx0pxauf2symfpH-6HRvRStXPftkvKgEoOZUc1xrk
  2. Understanding the Role of Polyautoimmunity in Rheumatic Diseases (©Zerbor,Shutterstock.com) Linda Peckel July 16, 2019 Rheumatology, Autoimmune Diseases, Modern Medicine News, News, Rheumatoid Arthritis An estimated 5 percent of the world’s population is diagnosed with one of a group of heterogeneous autoimmune rheumatic diseases (ARDs) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren’s syndrome (SS). Not only do these diseases share mechanisms and risk factors, they are often comorbid conditions recognized as polyautoimmune (PolyA) manifestations of the same underlying dysfunction. Patients with SLE are frequently positive for anti-rheumatoid factor (RF) and less often for anti-citrullinated protein antibodies associated with RA, although less than 10% are diagnosed with concomitant SLE/RA, known as rhupus. Another 10% of SLE patients are recognized to have antiphospholipid syndrome (APS) although up to 54% have been shown to carry antibodies. Other PolyA’s may include SLE/hypothyroidism, RA/autoimmune thyroid disease (AITD), and concomitant symptoms of SS with SLE, AITD, or systemic sclerosis (SSc). According to studies by Gonzalez and colleagues (the most recent of which is published in the Journal of Autoimmunity)1 , 2 patterns of PolyA have emerged: 1) Overt PolyA, which reflects more than one well-defined ARD in a single patient, and 2) Latent PolyA, in which underlying patterns of autoantibodies are identified that do not correspond to the main diagnosis, and may be predictive of 1 or more additional ARDs. The authors conducted a cross-sectional cluster analysis of patients with the most common ARDs for antibody and cytokine patterns in a cohort of 187 individuals with diagnoses of SLE, RA, SSc, and SS (n = 70, 51, 35, and 31). They found that the frequency of PolyA did not differ across all 4 ARDs, although SLE and SS were associated with a younger age of onset. Rheumatoid factor and CCP3 were identified in 84.3% and76.5% of patients with RA, who also had the highest levels of Interleukin (IL)-6, interferon (IFN)-α, and IL-12/23p40 cytokines. Antinuclear antibodies (ANAs) were most prevalent in patients with SSc (97% positive) and SLE patients (71.4%), with distinctive patterns of additional antibodies and cytokines to each disease. The study revealed six main PolyA clusters involving the 4 ARDs that may provide biomarkers useful for diagnosis of current disease as well as prediction of other ARDs over time. The authors suggested that particular attention should be paid to latent PolyA, and to the strong association of IL-12/23p40 to 3 of the 6 cluster groups. REFERENCE 1. Molano-González N, Rojas M, Monsalve DM. "Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity." J Autoimmun 2019;98:24-32. https://www.rheumatologynetwork.com/rheumatology/understanding-role-polyautoimmunity-rheumatic-diseases?rememberme=1&elq_mid=7781&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  3. APS: What Rheumatologists Should Know about Hughes Syndrome February 17, 2016 • By Graham R.V. Hughes, MD, FRCP. The problem that dogs the work of all of those treating patients with antiphospholipid syndrome (APS) is the apparent lack of knowledge of the syndrome, both by the general public, as well as by swaths of the medical fraternity. You Might Also Like Put Hughes Syndrome on Your Radar New Assays May Help in the Diagnosis & Management of Antiphospholipid Syndrome Why Antiphospholipid Antibody Syndrome Should Be On Your Radar Explore this issue February 2016 Perhaps it was ever thus—a syndrome less than 40 years old could be described as new, but a syndrome that is common, touches all branches of medicine and, above all, that is potentially treatable, surely deserves wider recognition. Some of the difficulties derive from the complex clinical nature of APS: the half diagnoses, such as the migraine patient’s diagnostic pathway, which stops at “migraine”; the “atypical angina” in a 40-year-old woman that goes no further than “atypical angina”; the second or third miscarriage that is accepted as one of nature’s misfortunes; or, especially, the memory loss in that same 40 year old who goes undiagnosed. And most troublesome, the common failure to appreciate the limitations of antiphospholipid (aPL) testing and the vital, pivotal concept of sero­negative APS. The story of APS has, for me, been an incredible journey, from the early days in the late 1970s and early 1980s, followed by the original series of publications describing the clinical features and antibody studies resulting in our description of the anti-cardiolipin syndrome and later, to the (still technically not totally correct) anti-phospholipid syndrome.1-8 In the Third International Antiphospholipid Conference in 1994 in Leuven, Belgium, my colleagues honored me by naming the syndrome, Hughes syndrome. Thirty years on, there is still great satisfaction in diagnosing and treating APS patients with such discordant-seeming features as cataplexy and stillbirth, avascular hip necrosis and vertigo, or abdominal angina and multiple fractures—to give examples from recent clinics. Why the Brain? For me, APS/Hughes syndrome is very much a neurological condition. Brain function does seem to be especially targeted—the more APS patients one sees, the wider and wider the neuropsychiatric ripples spread. There have, of course, been many promising lines of research into the pathogenesis of cerebral APS, and many mechanisms have been proposed, ranging from platelet activation, induction of tissue factor, disruption of the annexin A5 anticoagulant shield, endothelial activation and, of course, alteration of the permeability of the blood–brain barrier and direct binding to neuronal cell surfaces, some harking back to earlier forays by Bluestein, Denburg and ourselves into possible cross-reactivity between anti-lymphocyte antibodies and brain.9-13 Interactions between brain and clotting process have a long history, including the observation that the coagulation mechanism within the central nervous system has a number of differences from that found in other organs—the brain’s endothelium expressing little thrombomodulin, for example. Whatever the mechanism, it’s difficult to avoid the observation that treatment with anticoagulation (e.g., with low molecular weight [LMW] heparin) often dramatically reverses the symptoms, including the migraine, the memory difficulties and the chorea. Such observations suggest that the brain pathology in many cases might not be so much infarction, but might relate more to “sludging” of the blood supply and impaired oxygenation. Migraine & Stroke “Did you suffer from headaches as a teenager?” “Yes, doctor. They were almost weekly for a time. They went away for a few years, but they came back with a vengeance now. They run in my family.” So speaks the 30-year-old female patient with APS (the male members of the family appear less often in APS clinics). This is such an important diagnostic clue in the assessment of a patient with possible APS. Yet despite many years of experience of APS, there are surprisingly few data assessing the true role of APS in the wider world of migraine. There are so many reasons to study the association—the response to anticoagulation—usually good, often striking—the study of siblings and other family members of migraine/APS patients. And above all else, the links now being reported between migraine and stroke. Like migraine, stroke is one of the recognized complications of APS/Hughes syndrome. Figures as high as 1 in 5 young strokes (under 45) having positive aPL tests have been reported.14-19 However, as with migraine, recognition of aPL in the etiology of stroke is, in general, still poor. For example, childhood stroke—well recognized clinically—is a prime target for aPL studies. Some years ago, the U.K. government launched a major stroke initiative, educating the public about the symptoms, signs and treatment of stroke. The antiphospholipid syndrome wasn’t on the list. Seizures In 1985, we observed that in lupus patients, seizures were more common in those patients with positive aPL tests.20 Since then, it has become clear that epilepsy, in all its forms, is an important accompaniment of APS. So much so, that in one study of idiopathic epilepsy in teenagers, 1 in 5 was found to be aPL positive.21 The initial midwife or obstetrician’s screening should include a simple questionnaire to rule out APS. The ramifications of these observations are many. Let me give two clinical examples: Firstly, temporal lobe epilepsy in APS may be under-recognized. One of my patients, a woman with classical APS, became an EEG technician. During her training she used four of her siblings as guinea pigs. Three had abnormal temporal lobe activity. It’s interesting to see how often a family history of epilepsy crops up in the history taking of patients with APS. The second clinical anecdote has been published elsewhere.22 A 42-year-old patient had a past history of mild lupus. However, her major problem—and one with a significant impact on her busy life—was recurrent seizures, both petit mal and grand mal, the latter requiring specialist care and the combination of a number of anti-epileptic drugs. During her stay in London, she developed a DVT (she was found to be aPL positive), and routine anticoagulation with warfarin was started. An immediate and unexpected bonus was a marked reduction in the frequency and severity of the seizures, requiring far less aggressive anti-epileptic treatment. Memory Loss Possibly the commonest manifestation of APS is memory loss. Often, the problem only sees the light of day when the patient is asked about the symptom. So many patients confess to worries about Alzheimer’s. To date, detailed clinical studies are few and far between. From time to time, and, it must be said, in a fairly desultory fashion, we have carried out psychometric testing on selected APS patients—and the results have often been surprising. Even more so, given the striking improvement seen in memory tests when anticoagulation is commenced.23 Multiple Sclerosis In view of the prominence of neurological features, including visual disturbance and fluctuating myelopathy, seen in APS, it is not surprising that a number of cases are diagnosed as MS.24,25 The subject is far from straightforward. Some in neurology declare that positive aPL tests are, in fact, sometimes seen in classical MS. I would prefer to turn the picture around. Such patients, at least some, may be APS first and MS second. Although anecdotally a number of such cases respond to anticoagulation, in others the response is, at best, borderline. Uthman has recently reviewed the fairly substantial literature on APS vs. MS.26 Other Neurological Features These include balance problems (a number of cases presenting as Meniere’s), chorea (sometimes severe),27,28 anosmia, sleep disturbance (including cataplexy and narcolepsy) and, recently, autonomic disturbance with a series of cases of POTS (postural orthostatic tachycardia syndrome).29 One of the questions on which there is debate is the prevalence of psychiatric manifestations. It has been my view that acute psychosis has been more a feature of lupus than APS, but in this I may be wrong. One of my patients, a woman with APS and OCD (obsessive compulsive disorder), improved with anticoagulation treatment. Interestingly, her teenage son, also a patient with OCD (and aPL positive), found the neuropsychiatric manifestations were far less prominent when aspirin treatment was started. Not the Brain Bone & joints—Have you suffered any fractures? A question not perhaps part of the routine history taking in APS patients. And yet, spontaneous bone fracture is becoming well recognized following the report of 27 spontaneous metatarsal fractures by Dr. Shirish Sangle in APS patients.30 Anecdotal reports suggest that (ischemic) bone fractures may be an important manifestation of the disease: My colleague, Professor Munther Khamashta, has a Hughes syndrome patient with normal DEXA and parathyroid studies who has had 57 spontaneous fractures. Clearly, this is an important area for clinical research. Likewise, avascular necrosis (AVN) hip pain is not uncommon in our APS patients. MRI has shown early AVN in some cases with no other risk factors, such as steroids. My clinical impression is that the hip pain often improves when heparin or warfarin is started. Heart—A major concern is the presence of angina and other cardiac symptoms in APS. Despite a few early reports of myocardial ischemia and coronary thrombosis, it’s only in recent years that publications revealing a high frequency of these complications have increased in frequency. Two examples are the research of Greco et al showing a relatively high prevalence of positive aPL tests in patients with cardiac ischemia, and the striking observation that women smokers on the pill who were aPL positive had a relative risk of 22 times for the development of myocardial infarction.31,32 The cardiac links are increased by the reporting of an association with cardiac syndrome X, angina with normal coronary angiographs.33 It’s a fair bet that aPL testing will become a standard in the cardiology clinic, especially in symptomatic women under 40. GI tract & liver—Since we made our observations on focal stenotic lesions in various arteries, including celiac and mesenteric arteries, we have focused more on symptoms of abdominal angina in patients with aPL/APS.34 This is a difficult condition to quantify, but we have seen a number of cases in whom clopidogrel or heparin has resulted in improvement (sometimes marked) in post-prandial pain. Although liver involvement in lupus is rare, abnormal liver function tests in APS are seen frequently. Although these can presage serious liver thrombosis, such as Budd-Chiari syndrome or the HELLP syndrome in pregnancy warning of impending catastrophic APS, more commonly, they have a more benign prognosis.35,36 One very positive case history: Back in the early 1980s, I saw a teenage girl with a DVT, positive aPL and Budd-Chiari syndrome. Prognosis poor? Thirty-plus years on, she remains well—on careful lifelong warfarin managed by her physicians in Portugal. Goldblatt’s disease, the kidney & APS—Renal artery stenosis, seen on a clear background of otherwise normal arteries, can mimic Goldblatt’s early observations on the development of hypertension in animals with experimentally occluded renal arteries. The discovery of renal artery stenosis localized lesions by Sangle led to similar findings in other vessels, leading to theories about localized thrombotic/endothelial pathology.37 Skin: livedo reticularis, an enigma—Although skin ulcers, dilated veins and subungual splinter hemorrhages are well-known sequelae of skin thrombosis in APS, livedo reticularis has an aura of mystery.38,39 Diagnostically, its presence is an important clue in patients suspected of having Hughes syndrome—including seronegative APS. Looking back over some of the conditions mentioned in this article—MS, migraine, multiple fractures, memory problems—for example, one wonders whether careful noting of the presence or absence of livedo might prove significant in the differential diagnosis of these conditions. One thing is certain: The presence of livedo adds an extra dimension to the severity of the clinical picture. Pregnancy Of course, the headline story of the syndrome is in pregnancy, where the success rate of healthy deliveries in aPL-positive pregnancies has soared from under 15% to over 90%. Without a doubt, diagnosis and treatment of these cases has been a significant advance in the world of obstetrics.40 Sadly, all of us working with APS have looked after aPL-positive patients (some of whom had suffered early miscarriages) who lost a baby late in the pregnancy. Stillbirth. Two years ago, The Times of London published a lead article titled, “The Stillbirth Scandal,” highlighting the poor stillbirth figures in the U.K.41 Yet some cases of stillbirth in the aPL-positive women could have been prevented. For example, a recent study from Utah found that aPL pregnancies had a three- to fivefold increased odds of stillbirth.42 Would more routine aPL testing in pregnancy help? Cost considerations apply. Miscarriage is common, and there are numerous causes. Thus, the current recommendation is to reserve testing for those women with three or more miscarriages. This does seem harsh. Perhaps a simple screening process might help. I have suggested that part of the initial midwife or obstetrician’s screening should include a simple three-part questionnaire: Have you had a thrombosis? Are you a migraine sufferer? Do you have a family history of autoimmune disease (i.e., lupus, RA, multiple sclerosis, thyroid disease)? I am sure that such a simple questionnaire might help identify a small at-risk group. In most centers, once the mother and baby are safely sent home, there is no long-term follow-up. Yet often, APS patients presenting at, say, the age of 40 with a thrombotic problem, give a past history of miscarriage 20 years earlier. In an ideal world, women with recurrent miscarriage deserve regular long-term follow-up. But the world is far from ideal. Lupus & APS The early clinical studies of APS were carried out in lupus clinics, and could well have included “lupus features.” Perhaps surprisingly, time has shown little difference between primary APS and the APS associated with lupus. There are, undoubtedly, some classical features of lupus (e.g., Libman Sachs endocarditis, stroke, seizures) that are more likely to be aPL related. It also appears likely that aPL positivity in lupus confers a higher chronicity index. The passage of time has also revealed one positive finding: It’s very unusual for patients with primary APS to develop lupus in later years. The Big 3 The association between Hughes syndrome, Sjögren’s and hypothyroidism is so common that I have taken to calling them the big 3. Clinically, it’s an important association because the clinical symptoms of the three conditions—fatigue, cold circulation, aches and pains, and balance and memory problems—are common to all three. Similarly, many of these patients are burdened with the label fibromyalgia. Each of the three interconnecting syndromes can respond well to treatment—for example, the clinical Sjögren’s to hydroxychloroquine and so on. Many of these patients are on my two trees treatment—willow (aspirin) and cinchona (quinine). Seronegative APS I believe that one of the benefits of a trainee clinician’s time spent in the lab is the recognition that many laboratory tests are open to variation. Many, many studies have attempted to assess the importance of titer, immunoglobulin class, triple or double positivity, relevance of “other” aPL such as anti-phosphatidyl-serine etc.43,44 Broadly, all of these have relevance, but in the clinic, some don’t fit, such as those patients with all of the clinical features of APS whose aPL tests remain doggedly negative. Some years ago, we wrote a paper introducing the term seronegative APS, calling attention to patients with strong clinical features of APS but with negative tests.45 The concept goes back to the early days of seronegative RA and seronegative lupus—both of which labels, although based on clinical observation alone, had important therapeutic and prognostic consequences. Three possible explanations for seronegative APS are: 1) The diagnosis is incorrect (unlikely in all cases); 2) the previously positive tests have become negative over time (uncommon in my experience); or 3) new tests are needed.46 Perhaps the most potent reason for open-mindedness about seronegative APS comes from family studies. Some weeks ago, I saw a pair of identical twins—the first with classical seropositive APS, who later brought along her (absolutely) identical twin sister. The second twin had identical sets of symptoms, but unlike the first twin, she had negative aPL tests. Both patients responded to treatment. Once a year, we hold a patients meeting at our hospital. At the last meeting, we arranged a simple anonymous questionnaire with two questions: Are you a patient with APS or a friend/spouse? Have you any close female relative (sister, mother, aunt) with autoimmune disease (i.e., lupus, RA, thyroid, multiple sclerosis, APS)? The result: Sixty percent of patients had a positive history of autoimmune illnesses in close relatives. Less than 20% of friends/spouses answered positive. It may be that my own experience is skewed by referral bias from families of APS patients—but seropositive or not, most patients with seronegative APS respond just as well to treatment. If some of these individuals in the family study did, in fact, have seronegative APS yet were potentially responsive to treatment, then the possibilities are intriguing. Perhaps a higher percentage of our migraine, young stroke, young angina patients might benefit from a closer look for more of the clues to APS—the dry Schirmer’s, the livedo, the family history of autoimmune disease—for example. Treatment Aspects In many ways, it’s disappointing to confess that 30 years on, there are few new treatments. Introduction of the new oral anticoagulants in the treatment of APS has been predictably cautious, and it is too early to generalize.47 Statins, IVIG and hydroxychlorquine have been thrown into the mix and, of course, anti-B cell therapy has received favorable anecdotes. A recent study from Paris suggested that sirolimus, used in renal transplantation, might have a protective effect on aPL-induced vasculopathy.48 So in 2016, the current treatment of APS is still largely confined to aspirin, clopidogrel, heparin and warfarin. Low-dose aspirin, despite its detractors, is, of course, first choice in many APS patients. However, clopidogrel remains a useful alternative in patients with gastritis or in asthmatics. But there is a third role for clopidogrel—important in the real world of practical medicine—that is, in those patients who, for whatever reason, have tried aspirin, without clear benefit. Heparin—Low molecular weight heparin has, in most countries, largely replaced old heparin, and with it, fears of thrombocytopenia and osteoporosis have largely disappeared. This is an important point to make, because many practitioners are reluctant to prolong heparin usage. Two observations: First, a number of patients improve dramatically on heparin, only to feel less well on warfarin. Where to go next? When dosage issues, warfarin resistance and compliance are (hopefully) ruled out, one immediate option is a temporary return to heparin. In some cases, temporary has turned into semi-long term. In our APS clinic we have a couple dozen such patients who, by choice, have remained on subcutaneous heparin for two years or more. Yes, they have experienced bruising, but so far, we have not seen worsening DEXA scans. The second (and very clinical) observation concerns a heparin trial. It is a regular observation that aPL/APS patients on heparin during pregnancy are often headache free for the full eight or nine months. This led us to develop a clinical tool—a therapeutic trial that has stood us in good stead. The trial is a three- or four-week course of LMW heparin.49 Let me give an example of its use: In the aPL/APS patient with increasingly severe headaches despite aspirin/clopidogrel (and with a normal brain MRI), a trial of 10,000 units of dalteparin (or enoxaparin) for three or four weeks can achieve substantial results. First, it can give a surprisingly clear indication of whether anticoagulation is the correct path. Second, in the traumatized patient who has been down the familiar pathway of multiple specialist consultations, with borderline clinical success, it can be a major turning point—the first palpable sign of improvement. Warfarin—There is little new to say about warfarin. It has been vilified by the media, but it remains one of the most useful drugs in our armamentarium. Warfarin, to put it in simple terms, protects against stroke and heart attack in APS. Mention has been made of the frequent need for a higher INR in many APS patients—especially those with neurological features. I am a strong believer in the use of self-testing INR machines whenever possible in our patients. Sadly, some anticoagulant clinics oppose the use of self-testing machines. To me, this is wrong. Look at the freedom self-testing for insulin-dependent diabetics has achieved. As physicians, I believe we have a duty (until better, newer anticoagulants become established) to support warfarin as a largely safe, effective medicine that has saved many thousands of lives. Miscellany Spontaneous bone fracture is becoming well recognized following the report of 27 spontaneous metatarsal fractures by Dr. Shirish Sangle in APS patients. Image Credit: Puwadol Jaturawutthichai/shutterstock.com The Family—It comes as no surprise that a family history is an important clue in Hughes syndrome. Autoimmune disease (particularly thyroid) crops up regularly as a diagnosis in relatives of our patients. But how often are these family cases diagnosed? Examples could include the 17-year-old daughter of an APS patient suffering from headache and glandular fever, the sibling with multiple sclerosis or the mother and aunt of a newly diagnosed APS patient who suffered a stroke in their early 40s. It is not inconceivable that APS has changed the course of history, as in the case reported by my friend, Dr. Gerald Weissmann, of Queen Anne of England who had 17 failed pregnancies and died childless, thereby bringing an end to the Stuart reign and the start of the Hanoverians—with George III, American Colony taxes, the revolution and the birth of the U.S.50 The Offspring—To date, most studies have suggested that the offspring of aPL-positive mothers have no major adverse effects (other than, perhaps, the later-developing inherited APS features in some). However, some worrying case reports of fetal and neonatal problems indicate a need for further study. The ongoing studies of Drs. Anne Parke, Angela Tincani, Maria Claire Boffa and others will, in time, provide some of these missing data.51,52 Classification vs. diagnosis— Dear Doctor, I would be grateful if you could advise on this patient. She developed thrombosis on the oral contraceptive pill. She has had one positive test for aPL, but did not have a repeat test 12 weeks later. As in the case of lupus, classification criteria do sometimes become mixed up with diagnosis. Many patients don’t come armed with tests “12 weeks apart” (this criterion was introduced to cover the risk that an inter-current infection might have led to a transient positive aPL test—not a major factor in our assessment of this patient). There are also financial considerations, such as in the following study from Beirut, Lebanon. “Only 50.5% had both aCL and LA tested. … The cost of each test was around US$50 for the patient. … It remains to be seen whether the test costs might partly explain the very small percentage of patients who did undergo a follow-up confirmatory test.” The recognition of the many non-thrombotic manifestations of APS has added to the importance of separating diagnosis from classification. Perhaps, laboratory advances in the measurement of potential risk markers will, in time, come to our aid.44 Fear of Flying—This clinical anecdote appears regularly in my clinic. So much so that I believe it needs further study. A number of my APS patients, notably before treatment has been started, suffer badly from prolonged jet lag after a long-haul flight, with fatigue, headache and confusion, sometimes lasting for days. Interestingly, once heparin or warfarin treatment is successfully commenced, this phenomenon disappears. Whether these symptoms relate to mild cerebral hypoxia second to slightly reduced cabin pressure is not known. Nevertheless, some of my patients with APS will supplement their aspirin treatment prior to a long-haul flight with an injection of LMW heparin. Although the placebo effect may be considerable, I am sufficiently impressed by the clinical experience of these (observant) patients to believe that the phenomenon of prolonged jet lag in many of our patients is very real. The Future—At the 14th International Congress on Antiphospholipid Antibodies held in Rio de Janeiro in 2013, I was asked for my predictions on the future of APS.23 In summary, I believe: aPL testing will become worldwide and routine; Over-the-counter aPL testing kits will become available; A substantial subset of migraine sufferers will have new hope; APS will become recognized as the major link between migraine and stroke; Heart attacks in young women (especially those under 45) will be reduced; Strokes in those under 45 will be reduced; Some cases of accelerated arterial disease will be recognized as being associated with (untreated) aPL; Some cases of memory loss are treatable; APS will continue to have a profound effect on our clinical assessment and treatment of lupus; and Finally, to return to the opening theme, the incidence of stillbirth will be reduced, thanks, in part, to a more proactive approach to aPL testing in pregnancy. To repeat a sentence taken from the 1983 paper:1 For those of us hardened into nihilism by years of study of various autoantibodies in SLE, there is a rare sense of excitement at the implications of the associations now being reported. Thirty years on, that clinical excitement remains undimmed. Graham R.V. Hughes, MD, FRCP, is a consultant rheumatologist and head of the London Lupus Centre. He trained at The London Hospital, and spent two years in New York working on the introduction of the DNA-binding test, under the leadership of Dr. Charles Christian. In 1971, he opened a specialist clinic in London, dealing uniquely with lupus and related diseases. He is founder and editor of the international journal, Lupus. In 1983, he described the antiphospholipid syndrome and in 1991, was awarded the ILAR (world research) prize for this work. Other honors include Doctor Honoris Causa in the Universities of Marseille and Barcelona, and Master of the ACR. References Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed). 1983 Oct 15;287(6399):1088–1089. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin in antibodies: Detection by radioimmunoassay and association with thrombosis in SLE. Lancet. 1983 Nov 26;2(8361):1211–1214. Boey ML, Colaco CB, Gharavi AE, et al. Thrombosis in SLE: Striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed). 1983 Oct 8;287:1021–1023. Hughes GR. The Prosser White oration 1983: Connective tissue disease and the skin. Clin Exp Dermatol. 1984 Nov;9(6):535–544. Asherson RA, Mackworth-Young CG, Boey ML, Hughes GRV. Pulmonary hypertension in systemic lupus erythematosus. Br Med J (Clin Res Ed). 1983 Oct 8;287(6398):1024–1025. Derue GJ, Englert HJ, Harris EN, et al. Fetal loss in systemic lupus: Association with anticardiolipin antibodies. J Obstet Gynaecol. 1985;5(4):207–209. Hughes GR, Harris NN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol. 1986 Jun;13(3):486–489. Hughes GR. Hughes’ syndrome: The anticardiolipin syndrome. A historical view.Lupus. 1998;7 Suppl 2:S1–S4. Carecchio M, Cantello R, Comi C. Revisiting the molecular mechanism in antiphospholipid syndrome: Beyond vascular damage. J Immunol Res. 2014;2014:239398. Bluestein HG, Zvaifler NJ. Brain-reactive lymphocytotoxic antibodies in the serum of patients with SLE. J Clin Invest. 1976 Feb;57(2):509–516. Bresnihan B, Oliver N, Grigor R, Hughes GR. Brain-reactivity of lymphocytotoxic anitibodies in systemic lupus erythematosus with and without cerebral involvement. Clin Exp Immunol. 1977 Dec;30(3):333–337. Bresnihan B, Hohmeister R, Cutting J, et al. The neuropsychiatric disorder in SLE: Evidence for both vascular and immune mechanisms. Ann Rheum Dis. 1979 Aug;38(4):301–306. Denburg SD, Behmann SA, Carbotte RM, et al. Lymphocyte antigens in neuropsychiatric systemic lupus erythematosus. Relationship of lymphocyte antibody specificities to clinical disease. Arthritis Rheum. 1994 Mar;37(3):369–375. Harris EN, Gharavi AE, Asherson RA, et al. Cerebral infarction in SLE. Association with anticardiolipin antibodies. Clin Exp Rheumatol. 1984 Jan-Mar;2(1):47–51. Navarrete MG, Brey RL, Levine SR. “Cerebral disease in the antiphospholipid syndrome” in Hughes Syndrome—Antiphospholipid Syndrome. Khamashta MA, ed. Springer, London: 2000. Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Central nervous system involvement in the antiphospholipid (Hughes) syndrome. Rheumatology (Oxford). 2003 Feb;42(2):200–213. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: Systemic review and meta-analysis of observational studies. BMJ. 2005 Jan 8;330(7482):63. Nencini P, Baruffi MC, Abbate R, et al. Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischaemia. Stroke. 1992 Feb;23(2):189–193. Hughes GR. Antiphospholipid syndrome, migraine and stroke. Lupus. 2010 Apr;19(5):555–556. Mackworth-Young CG, Hughes GR. Epilepsy: An early symptom of systemic lupus erythematosus. J Neurol Neurosurg Psychiatry. 1985 Feb;48(2):185. Cimaz R, Meroni PL, Shoenfeld Y. Epilepsy as part of systemic lupus erythematosus and systemic antiphospholipid syndrome (Hughes syndrome). Lupus. 2006;15(4):191–194. Hughes GR. “Diplomatic epilepsy” in Understanding Hughes Syndrome. Springer-Verlag, London: 2009. Hughes GR. Hughes syndrome/APS. 30 years on, what have we learnt? Opening talk at the 14th International Congress on antiphospholipid antibodies. Rio de Janeiro, October 2013. Lupus. 2014;23:400–406. Cuadrado MJ, Khamashta MA, Ballesteros A, et al. Can neurologic manifestations of Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis of 27 patients and review of the literature. Medicine (Baltimore). 2000 Jan;79(1):57–68. Hughes GR. Migraine, memory loss, and “multiple sclerosis.” Neurological features of the antiphospholipid (Hughes’) syndrome. Postgrad Med J. 2003 Feb;79(928):81–83. Uthman I, Noureldine MH, Berjawi A, et al. Hughes syndrome and multiple sclerosis. Lupus. 2015 Feb;24(2):115–121. Cervera R, Asherson RA, Font J, et al. Chorea in the antiphospholipid syndrome. Clinical, radiologic, and immunologic characteristics of 50 patients from our clinics and the recent literature. Medicine (Baltimore). 1997 May;76(3):203–212. Baizabal-Carvallo JF, Bonnet C, Jankovic J. Movement disorders in systemic lupus erythematosus and the antiphospholipid syndrome. J Neural Transm (Vienna). 2013 Nov;120(11):1579–1589. Schofield JR, Blitshteyn S, Shoenfeld Y, et al. Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS). Lupus. 2014 Jun;23(7):697–702. Sangle S, D’Cruz DP, Khamashta MA, et al. Antiphospholipid antibodies, systemic lupus erythematosus, and non-traumatic metatarsal fractures. Ann Rheum Dis. 2004 Oct;63(10):1241–1243. Greco TP1, Conti-Kelly AM, Greco T Jr., et al. Newer antiphospholipid antibodies predict adverse outcomes in patients with acute coronary syndrome. Am J Clin Pathol. 2009 Oct;132(4):613–620. Urbanus RT, Siegerink B, Roest M, et al. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: A case-control study. Lancet Neurol. 2009 Nov;8(11):998–1005. Nair S, Khamashta MA, Hughes GR. Syndrome X and Hughes syndrome. Lupus. 2002;11(5):332. Sangle SR, Jan W, Lau IS, et al. Coeliac artery stenosis and antiphospholipid (Hughes) syndrome/antiphospholipid antibodies. Clin Exp Rheumatol. 2006 May–Jun;24(3):349. Mackworth-Young CG, Melia WM, Harris EN, et al. The Budd-Chiari syndrome. Possible pathogenetic role of anti-phospholipid antibodies. J Hepatol. 1986;3(1):83-86. Hanouna G, Morel N, Le Thi Huong D, et al. Catastrophic antiphospholipid syndrome and pregnancy: An experience of 13 cases. Rheumatology (Oxford). 2013 Sep;52(9):1635–1641. Sangle SR, D’Cruz DP, Jan W, et al. Renal artery stenosis in antiphospholipid syndrome (Hughes) and hypertension. Ann Rheum Dis. 2003 Oct;62(10):999–1002. Englert HJ, Loizou S, Derue GG, et al. Clinical and Immunological features of livedo reticularis in lupus. Am J Med. 1989 Oct;87(4):408–410. Sangle SR, D’Cruz DP. Livedo reticularis: An enigma. Isr Med Assoc J. 2015 Feb;17(2):104–107. Ateka-Barrutia O, Khamashta MA. The challenge of pregnancy for patients with SLE. Lupus. 2013 Oct;22(12):1295–1308. Hughes GR. The stillbirth scandal. Lupus. 2013 Jul;22(8):759–760. Silver RM, Parker CB, Reddy UM, et al. Antiphospholipid antibodies in stillbirth. Obstet Gynecol. 2013 Sep;122(3):641–657. Rodriguez-Garcia JL, Bertolaccini ML, Cuadrado MJ, et al. Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’). Ann Rheum Dis. 2012 Feb;71(2):242–244. Meroni PL, Chighizab CB, Rovelli F, et al. Antiphospholipid syndrome in 2014: More clinical manifestations, novel pathogenic players and emerging biomarkers. Arthritis Res Ther. 2014;16(2):209. Hughes GR, Khamashta MA. Seronegative antiphospholipid syndrome. Ann Rheum Dis. 2003 Dec;62(12):1127. Rodguez-Garcia JL, Bertolaccini ML, Cuadrado MJ, et al. Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies. Ann Rheum Dis. 2012 Feb;71(2):242–244. Giles I, Khamashta M, D’Cruz D, et al. A new dawn of anticoagulation for patients with antiphospholipid syndrome. Lupus. 2012 Oct;21(12):1263–1265. Canuad G, Bienaimé C, Taborin F, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. New Eng J Med. 2014 Jul 24;371(4):303–312. Hughes GR. Heparin, antiphospholipid antibodies and the brain. Lupus. 2012 Sep;21(10):1039–1040. Weissmann G. Queen Anne’s lupus: Phospholipids and the course of the empire. FASEB J. 2014 Apr;28(4):1527–1530. Mekinian A, Lachassinne E, Nicaise-Roland P, et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2013 Feb;72(2):217–222. Nalli C, Iodice A, Andreoti L, et al. Children born to SLE and APS mothers. Lupus. 2014 Oct;23(12):1246–1248. Major S, Pashayan N, Atweh S, et al. Practice patterns of antiphospholipid syndrome at a tertiary teaching hospital in Lebanon. Lupus. 2002;11(11):759–764. https://www.the-rheumatologist.org/article/aps-what-rheumatologists-know-about-hughes-syndrome/?singlepage=1
  4. APRIL 2019 11 April 2019 by Professor Graham R V Hughes MD FRCP Easter comes late this year. Frenetic Brexit politics – the Westminster establishment fighting to overturn the ‘popular vote’. So sad. Last week I gave a lecture at an ‘immuno-therapy’ meeting in Madrid. Three hundred attendees, including representatives of the Spanish patients’ APS Society. The atmosphere was fantastic. So many doctors (and patients’) wanting to learn more about our syndrome. Talking about ‘learning more’, we now have a date for our own Patients’ Meeting – Friday, 13th September 2019. (For details of the programme and admission, please visit our website: www.ghic.world). This year we are opening up the meeting to include topics on Sjogren’s and lupus, as well as antiphospholipid syndrome. I will also send this blog, as well as details or our annual Patients’ Meeting, to our colleagues in Spain. Patient of the Month “I still feel tired all the time”. Mrs J.S. aged 55, was referred by her G.P. complaining of a variety of symptoms, including aches and pains, headaches, constipation, pins and needles and mental sluggishness. Above all else, she felt constantly fatigued. Despite this very full set of symptoms, the diagnosis remained uncertain. The pins and needles in both hands were put down to carpal tunnel syndrome. But there was little else to find. In view of the frequent headaches, Mrs J.S. was referred to a neurologist who arranged for further tests, including a brain MRI (which showed two small ‘dot’ lesions – reported as probably not significant. To her credit, the neurologist considered lupus and arranged lupus blood tests among the more routine ones. The tests came back showing a normal blood count. However, the ESR (the guide to inflammation) came back ‘borderline positive’ at 35 (normal under 20). The tests for lupus were essentially negative (anti-DNA negative, ANA ‘weak’ (1 in 80). What is the diagnosis (1)? The penny dropped. Could this be thyroid? Bilateral carpal tunnel syndrome is certainly seen in ‘low thyroid’, and significantly Mrs J.S. had a sister with ‘Hashimotos thyroiditis’ – and underactive thyroid with auto-immune features. As with all her other tests the thyroid blood tests were ‘borderline’. Nevertheless, the fatigue, the constipation, the aches and pains, could all be down to ‘low thyroid’. Following a *‘kerbside consult’, with her endocrinology colleague, she instituted thyroxine treatment. Within 2 months the pins and needles were gone and the mental sluggishness, as well as the constipation, were improving. BUT – the aches and pains and the fatigue remained – as bad as ever. What is the diagnosis (2)? It turned out that Mrs J.S. had suffered a series of miscarriages in her early 20’s and she and her husband remained childless. Could the problems – especially the frequent headaches – be due to Hughes Syndrome? Sure enough the antiphospholipid antibody (aPL) tests were strongly positive – not even ‘borderline’. She was started on clopidogrel (‘Plavix’) – an anti-clotting drug similar to aspirin (Mrs J.S. had previously tried aspirin but found it caused indigestion. Result? An almost immediate lessening of the headaches. And, if anything, a further improvement in her memory problems. BUT: no improvement in the fatigue or the aches and pains. What is the diagnosis (3)? Mrs J.S. was referred to a lupus clinic. Again, the results were similar (‘borderline’ ANA and negative anti-DNA). The lupus clinic doctor had seen this before – possible ‘Sjogren’s syndrome’. And, sure enough, the Shirmer’s test – a simple ‘blotting paper’ eye test was completely dry – a useful and very inexpensive screening test for the dry eyes of Sjogren’s Syndrome. Low dose hydroxychloroquine (Plaquenil) (one a day) was started. Three months later at follow-up clinic, ‘fatigue gone. Aches gone. Back to normal life”. What is this patient teaching us? I often talk of ‘The Big Three’ diseases – Lupus, Sjogren’s and Hughes Syndrome, which can overlap clinically However, the world of auto-immune diseases in which I practice includes another ‘big three’, which frequently go together : Hughes Syndrome, Sjogren’s Syndrome and low thyroid (often, specifically, Hashimoto’s thyroiditis) – three ‘named’ syndromes. Clearly, to miss one or even two of the triad would be an ‘under-treatment’. The three conditions can have similar features. And fortunately, potentially very successful treatment – thyroid, aspirin (or Plavix) and hydroxychloroquine. I call the combination of aspirin and hydroxychloroquine (derived from quinine) my ‘two trees’ – treatment –willow and cinchona. Perhaps the biggest lesson from this patient is that there may be more than one diagnosis causing the problems. PROFESSOR GRAHAM R V HUGHES MD FRCP Head of The London Lupus Centre London Bridge Hospital http://www.ghic.world/blog/april-2019
  5. The Prevalence of Iron Deficiency Anemia in Primary Antiphospholipid Syndrome Karin KLACK, 1 Vanessa MONMA, 1 Karina PELIÇARI, 2 Simone APPENZELLER, 2 Jozélio Freire de CARVALHO3 1Nutritional Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo-SP, Brazil 2Rheumatology Division, Department of Medicine, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, Brazil 3Rheumatology Division, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo-SP, Brazil Abstract Objectives: The aim of this study was to evaluate the prevalence of subclinical and clinical iron deficiency with iron deficiency anemia in primary antiphospholipid syndrome (PAPS). Patients and methods: The study was comprised of 29 PAPS patients and 29 healthy controls matched for age, gender, and socioeconomic status. Participants received iron, folic acid, vitamin B12, and vitamin C. A battery of tests was performed to determine the iron storage. The mean disease duration was 70±51.3 months in the patient group. Results: Iron storage depletion was observed in 10.3% of the individuals in both groups (p=0.5). Iron deficient erythropoiesis (IDE) was observed in only three PAPS patients (10.3%) (p<0.001). Iron deficiency anemia (IDA) was more common in the PAPS patients compared to controls (48.2% vs. 10.3%, respectively; p=0.009). The mean iron levels were significantly lower in the PAPS group than the controls (75.5 vs. 95.8, respectively; p=0.03). Red cell distribution width-coefficient of variation (RDW-CV) (14.9 vs. 13.2; p=0.02) and red cell distribution widthstandard deviation (RDW-SD) (46.7 vs. 40.5; p=0.009) were significantly increased in the patient group. The folic acid and vitamin C levels were lower in the PAPS group than the control group (p<0.05). Conclusion: This study showed for the first time that PAPS patients have a higher incidence of IDA and IDE compared to healthy controls. This can be attributed to inadequate ingestion of folic acid and vitamin C. Introduction Antiphospholipid syndrome (APS) is characterized by a state of hypercoagulability that can potentially result in thrombosis of all segments of the vessel system,[1-3] and various hematological pathologies, such as thrombocytopenia, autoimmune hemolytic anemia (AIHA), bone marrow necrosis (BMN), and thrombotic microangiopathy, have been connected with this syndrome.[1-3] However, the prevalence of iron deficiency anemia has never been investigated as it relates to primary antiphospholipid syndrome (PAPS). Iron deficiency is defined as a reduction in total body iron to an extent that iron stores are fully exhausted and some degree of tissue iron deficiency is present. In epidemiological studies, it has been common practice to determine the prevalence of both mild iron deficiency without anemia and more advanced irondeficiency anemia.[4] Although no increased risk of gastrointestinal (GI) malignancy has been observed in APS patients so far,[5] treatment with acetylsalicylic acid (ASA) and oral anticoagulants may increase bleeding and iron loss in patients with subclinical GI disease. The aim of this study was to determine the prevalence of subclinical and clinical iron deficiency along with iron deficiency anemia in PAPS patients. Patients and Methods The study included 29 PAPS patients (25 females, 4 males; mean age 41±12 years) who had been routinely followed up at our facility and 29 healthy controls (23 females, 6 males; mean age 37±13 years) who were matched for age, gender, and socioeconomic status. We excluded patients with APS that was associated with other rheumatic conditions, such as systemic lupus erythematosus (SLE), pregnant or breastfeeding patients, and those who had taken iron supplements during the previous year. All participants fulfilled the 1999 Sapporo and 2006 Sydney APS classification criteria.[6,7] In addition, the study was approved by the local ethics committee, and all participants gave their written consent for inclusion. Both groups were interviewed regarding their demographic characteristics (age, gender, socioeconomic status, and number of pregnancies, if female) and history of GI disease, and the subjects' nutritional aspects (ingestions of iron, folic acid, vitamin B12 and vitamin C) were assessed. The daily recommended amounts of these vitamins and minerals were based on the recommendations of the Dietary Reference Intake (DRI).[8-10] To correctly assess the nutritional intake of the study participants, the open source software program Nutwin 1.5 (Federal University of Sao Paulo, São Paulo, Brazil) was used.[11] All of the subjects were submitted to the following battery of tests to determine their iron status: serum iron (Bayer AG, Leverkusen, Germany), total iron binding capacity (TIBC) (Labtest Diagnóstica SA, Lagoa Santa-Minas Gerais, Brazil), ferritin [enzyme-linked immunosorbent assay (ELISA), Abbott Laboratories, Abbott Park, IL, USA], transferrin, indirect bilirubin, iron saturation, lactate dehydrogenase (LDH), reticulocyte count, red blood cell count, hemoglobin levels, and hematocrit levels. Additionally, the patients also underwent tests concerning the following redcell indices: (i) mean corpuscular volume, (ii) mean corpuscular hemoglobin volume, (iii) mean corpuscular hemoglobin concentration, (iv) red distribution width (Abbott Cell Dyn 3000, Abbott Laboratories, Abbott Park, IL, USA), (v) red distribution width-coefficient of variation (RDW-CV), and (vi) red distribution widthstandard deviation (RDW-SD). Iron deficiency was classified into three stages of increasing severity: (i) iron storage depletion as defined by low serum ferritin, (ii) mild iron deficiency without anemia based on laboratory evidence of iron deficient erythropoiesis (IDE), and (iii) overt iron deficiency anemia (IDA).[12] Low transferrin saturation and decreased mean corpuscular volume were used to measure the IDE.[12] In addition, all individuals were screened for occult blood loss after an adequate diet and had a fecal parasitological evaluation performed on three consecutive days. Statistical analysis The data was reported as mean ± standard deviation (SD) or percent. Variables were compared between the patients and controls using Student's t-test or a chisquare test. P values of <0.05 were considered to be significant. Results The patients and controls were statistically similar with regard to age (p=0.21) and gender (p=0.33). Primary antiphospholipid syndrome manifestations and treatment. The patients with PAPS had a mean disease duration of 70±51.3 months. Thrombotic venous events were observed in 72.4% of the patients, followed by arterial events in 55.2% and obstetric events in 44.8%. In addition, positive immunoglobulin G (IgG) anticardiolipin antibodies were observed in 48.3% of the patients, and positive lupus anticoagulant was seen in 41.4%. None of the controls had a history of thrombosis. An oral anticoagulant (warfarin) was used by 96.6% of the PAPS patients, and one patient was using low-molecular-weight heparin (LMWH) and acetylsalicylic acid (ASA). Additionally, 10 patients (34.5%) were taking prophylactic omeprazole. Iron metabolism and iron-deficiency anemia Iron storage depletion was observed in three individuals (10.3%) in both groups (p=0.5). Iron deficient erythropoiesis was seen only in three PAPS patients (10.3%) (p<0.001), and IDA was found in 14 PAPS patients (48.2%) while only three (10.3%; p=0.009) had this condition in the controls (Figure 1). Although, the hemoglobin levels were similar between the PAPS patients and controls (13.4±1.7 g/dL vs. 13.9±1.4 g/dL, respectively), microcytic changes were observed in 15 PAPS patients (51.7%) but only in one control subject (3.4%) (p=0.06). Figure 1. The prevalence of iron deficiency and anemia in the primary antiphospholipid syndrome patients and the controls. PAPS: Primary antiphospholipid syndrome; IDE: Iron deficient erythropoiesis; IDA: Iron deficiency anemia. The mean iron levels were significantly lower in the PAPS patients when compared with the healthy controls (75.5 vs. 95.8, respectively; p=0.03). Furthermore, the PAPS and healthy control groups were examined regarding the red distribution width-coefficient of variation (RDW-CV) (14.9 vs. 13.2, respectively; p=0.02) and red distribution width-standard deviation (RDW-SD) (46.7 vs. 40.5, respectively; p=0.009) were statistically higher in the PAPS patients. However, no differences were observed in the two groups related to the remaining iron metabolism variables and medications (Table 1). Table 1. A comparison of biochemical tests between the primary antiphospholipid syndrome patients and the controls Causes of iron loss Hypermenorrhea was identified in two PAPS patients (8.7%) but was not seen in the controls (p=0.07). Five PAPS patients (17.2%) and one of the control subjects (3.4%) had a prior history of GI disease, but none of the participants had a previous history of GI bleeding. All of the five PAPS patients were on prophylactic omeprazole treatment, and an occult blood test was positive for two of the five (6.9%), but all of the controls tested negative (p=0.07). Furthermore, feces parasitological tests were negative for Ancylostoma duodenale, Necator americanus, Ascaris lumbricoides, Giardia lamblia, Trichuris trichiura and Schistossoma mansoni for all of the individuals in the study. Regarding iron intake, we observed that 24 PAPS patients (82.7%) and 28 of the controls (96.5%) were getting adequate amounts of iron (p=0.08), and there was no difference seen between the patients with and without anemia. Folic acid intake was significantly lower in the PAPS group compared with the controls, and only four PAPS patients (13.8%) had adequate amounts of this mineral compared with 20 in the control group (68.9%) (p<0.001). Concerning vitamin B12, 24 PAPS patients (82.7%) and 27 controls (93.1%) had adequate amounts (p=0.2), and vitamin C intake was adequate in 10 PAPS patients (34.4%) and 24 of the controls (82.7%) (p<0.001). Moreover, the anemic PAPS patients had higher amounts of folic acid and vitamin C than those that were non-anemic (p<0.05). Discussion To our knowledge, this was the first study to demonstrate that PAPS patients have IDA and IDE compared with healthy controls. Most iron in the body circulates as hemoglobin and is recycled in red cell senescence. One gram is stored in the liver, and 0.4 g in the myoglobin and cytochromes. Additionally, small amounts (3 mg) circulate that are bound to plasma transferrin.[13] Men and nonmenstruating women lose about 1 mg of body iron per day, and menstruating women may lose an additional 1 mg daily on average.[13] Dietary iron comes from a better absorbed animal source (heme-iron) and cereal and vegetable sources (non-heme iron)[13] and is absorbed by the intestinal luminal cells through a specific transporter and released into the circulation, binding to transferrin.[13] Transferrin receptors on erythroblasts bind the iron-transferrin complexes, which then undergo endocytosis. Afterwards, the iron is incorporated into the hemoglobin.[13] Iron deficiency occurs when there are iron losses or when requirements exceed absorption, and it is often multifactorial.[13-15] Blood loss is the most important cause of iron deficiency in adults as each milliliter that is lost translates into a corresponding loss of approximately 0.5 mg of iron.[15] More specifically, GI blood loss is the most important culprit in men and postmenopausal women. While menstrual blood loss is known to lead to IDA in premenopausal women, coexistent GI lesions also frequently occur. We identified hypermenorrhea in two of the PAPS patients in our study and occult blood loss in five others in the PAPS group; however, these findings were not statistically different from the controls. In addition, both women who had hypermenorrhea also had IDE, and the two patients with occult blood loss had IDA and were sent for an endoscopy and a colonoscopy. Malabsorption of iron may be caused by intestinal mucosal disorders (most frequently coeliac disease), impaired gastric acid secretion (including the use of proton pump inhibitors), and gastric/intestinal bypass procedures.[13-15] Omeprazole was being used by 10 patients in this study, five of whom had a prior history of GI diseases, and three had IDA. We identified a significant reduction in folic acid and vitamin C intake in the PAPS patients versus the controls. In addition, anemic patients had lower amounts of folic acid and vitamin C than those who were non-anemic. Our PAPS patients and controls were matched for socioeconomic status. Although low socioeconomic status was not a risk factor for IDA in the women who had never been pregnant, it was for pregnant women due to their increased iron demands.[13] In conclusion, we believe that this is the first study to evaluate the prevalence of IDA and IDE in patients with PAPS. Although no endoscopic or colonoscopic investigations were performed to identify the source of occult blood loss, impaired iron absorption caused by omeprazole usage and lower folic acid and vitamin C intake amounts could contribute to these findings. We suggest that PAPS patients undergo a routine analysis of their hemoglobin levels, and when iron deficiency is suspected, adequate investigation should be performed. Moreover, patients should be advised about sufficient vitamin intake, especially folic acid and vitamin C. Acknowledgments The authors would like to acknowledge the help of Dr Appenzeller: Fundação Apoio À Pesquisa Estado São Paulo-Brasil (FAPESP 2008/02917-0 and 2009/06049-6), Conselho Nacional Pesquisa Desenvolvimento-Brasil CNPq (300447/2009-4) and Dr. Carvalho: Federico Foundation and CNPq (300665/2009-1). Declaration of conflicting interests The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. Funding The authors received no financial support for the research and/or authorship of this article. References Uthman I, Godeau B, Taher A, Khamashta M. The hematologic manifestations of the antiphospholipid syndrome. Blood Rev 2008;22:187-94. doi: 10.1016/j. blre.2008.03.005. Khamashta MA, Bertolaccini ML, Hughes GR. Antiphospholipid (Hughes) syndrome. Autoimmunity 2004;37:309-12. Vermylen J, Carreras LO, Arnout J. Attempts to make sense of the antiphospholipid syndrome. J Thromb Haemost 2007;5:1-4. Epub 2006. Cook JD. Diagnosis and management of irondeficiency anaemia. Best Pract Res Clin Haematol 2005;18:319-32. Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev 2010;9:200-2. doi: 10.1016/j.autrev.2009.04.001. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Agricultural Library. United States Departament of Agriculture. Food and Nutrition Information Center; 1998 Available from: http://www.nal. usda.gov/fnic/DRI//DRI_Thiamin/thiamin_full_report.pdf Dietary Reference Intakes for vitamin C, vitamin E, selenium, and carotenoids. National Agricultural Library. United States Departament of Agriculture. Food and Nutrition Information Center; 2000 Available from: http://www.nal.usda.gov/fnic/DRI/DRI_Vitamin_C/ vitamin_c_full_report.pdf Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Agricultural Library. United States Departament of Agriculture. Food and Nutrition Information Center; 2001 Available from: http://www.nal.usda.gov/fnic/DRI//DRI_ Vitamin_A/vitamin_a_full_report.pdf Nutwin – Programa de Apoio à Nutrição. Departamento de Informática em Saúde. DIS-UNIFESP/EPM. Universidade Federal de São Paulo - Versão 1.5, 2002. Cook J. The nutritional assessment of iron status. Arch Latinoam Nutr 1999;49:11S-14S. Pasricha SR, Flecknoe-Brown SC, Allen KJ, Gibson PR, McMahon LP, Olynyk JK, et al. Diagnosis and management of iron deficiency anaemia: a clinical update. Med J Aust 2010;193:525-32. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician 2007;75:671-8. Cook JD. Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol 2005;18:319-32. https://www.archivesofrheumatology.org/full-text/509.
  6. An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus Y K Onno Teng Edwin O W Bredewold Ton J Rabelink Tom W J HuizingaH C Jeroen Eikenboom Maarten Limper Ruth D E Fritsch-StorkKitty W M Bloemenkamp Marieke Sueters Rheumatology, kex374, https://doi.org/10.1093/rheumatology/kex374 Published: 20 November 2017 Abstract Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients. https://academic.oup.com/rheumatology/advance-article-abstract/doi/10.1093/rheumatology/kex374/4641853?redirectedFrom=fulltext
  7. Lupus anticoagulant, disease activity and low complement in the first trimester are predictive of pregnancy loss 1Division of Rheumatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA 2Division of Rheumatology and Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 3Department of Epidemiology and Public Health, University of Maryland, Baltimore, Maryland, USA Correspondence to Dr Michelle Petri; mpetri{at}jhmi.edu Abstract Introduction Multiple factors, including proteinuria, antiphospholipid syndrome, thrombocytopenia and hypertension, are predictive of pregnancy loss in systemic lupus erythematosus (SLE). In the PROMISSE study of predictors of pregnancy loss, only a battery of lupus anticoagulant tests was predictive of a composite of adverse pregnancy outcomes. We examined the predictive value of one baseline lupus anticoagulant test (dilute Russell viper venom time) with pregnancy loss in women with SLE. Methods From the Hopkins Lupus Cohort, there were 202 pregnancies from 175 different women after excluding twin pregnancies and pregnancies for which we did not have a first trimester assessment of lupus anticoagulant. We determined the percentage of women who had a pregnancy loss in groups defined by potential risk factors. The lupus anticoagulant was determined by dilute Russell viper venom time with appropriate mixing and confirmatory testing. Generalised estimating equations were used to calculate p values, accounting for repeated pregnancies in the same woman. Results The age at pregnancy was <20 years (2%), 20–29 (53%), 30–39 (41%) and >40 (3%). 55% were Caucasian and 34% African-American. Among those with lupus anticoagulant during the first trimester, 6/16 (38%) experienced a pregnancy loss compared with only 16/186 (9%) of other pregnancies (p=0.003). In addition, those with low complement or higher disease activity had a higher rate of pregnancy loss than those without (p=0.049 and 0.005, respectively). In contrast, there was no association between elevated anticardiolipin in the first trimester and pregnancy loss. Conclusions The strongest predictor of pregnancy loss in SLE in the first trimester is the lupus anticoagulant. In addition, moderate disease activity by the physician global assessment and low complement measured in the first trimester were predictive of pregnancy loss. These data suggest that treatment of the lupus anticoagulant could be considered, even in the absence of history of pregnancy loss. Key messages A positive Lupus anticoagulant in the first trimester, rather than a previous positive result, is predictive of pregnancy loss. High disease activity as well as low complement levels during the first trimester is also predictive of pregnancy loss. Introduction Rates of pregnancy loss in systemic lupus erythematosus (SLE) have improved over the decades. Clark et al1 found a decrease in fetal loss rates from 40% to 17% based on a literature review from 1960 to 2000. More recent cohort studies have reported pregnancy loss rates in the range of 10–25%.2–10 Genetic anomalies, chromosomal abnormalities, anatomical defects and hormonal dysfunction all contribute to first trimester fetal loss in patients with SLE just as they do in the general population.11–14 In SLE, however, other risk factors for poor fetal outcomes from the first trimester to the neonatal period play a major role. We previously reported four factors at the first pregnancy visit to predict pregnancy loss: proteinuria (>500 mg in a 24 h urine collection or urine protein-to-creatinine ratio >0.5), thrombocytopenia (platelet count <150 000) and antiphospholipid syndrome and hypertension (blood pressure >140/90 mm Hg).9 We have also found high lupus activity as defined by the physician global assessment score >2, on a 0–3 visual analogue scale, a risk factor for fetal loss.10 Additional risk factors reported in the literature have included positive anti-dsDNA at any time during pregnancy and low complement levels in the second trimester.2 Clowse et al,9 in a previous study of the Hopkins Lupus Cohort in 2006, found that patients with SLE with antiphospholipid antibodies, but without secondary antiphospholipid syndrome, had the same miscarriage rate as those patients without antiphospholipid antibodies (12% vs 15%). Mecacci et al,5 in a study of 58 lupus pregnancies divided into three groups (antiphospholipid syndrome, antiphospholipid antibody positive and antiphospholipid antibody negative), found no differences in the live birth rate. In a prospective study by Lima et al15in 1995 of 108 pregnancies in patients with SLE, lupus anticoagulant did not predict fetal loss (p=0.056). In 1994, Derksen et al16 described 35 pregnancies in 25 patients with SLE and found that there was no difference in the live birth rate between those patients with antiphospholipid antibodies and those without. In contrast to the previous findings, two studies have found increased rates of fetal loss in patients with antiphospholipid antibodies. In 2002, Moroni et al17studied 70 pregnancies in 48 patients with lupus nephritis. In both univariate and multivariate analyses, the presence of antiphospholipid antibodies was significantly associated with increased fetal loss. There was, however, no differentiation between the presence of lupus anticoagulant and anticardiolipin antibodies. In the PROMISSE study, Lockshin et al3 studied pregnancies in SLE or in antiphospholipid-positive women versus control pregnancies. Adverse pregnancy outcome was defined as fetal demise after 12 weeks, neonatal death prior to discharge, preterm delivery prior to 34 weeks and small for gestational age. In the PROMISSE study, lupus anticoagulant was considered positive if it was identified by any of three tests: dilute Russell viper venom time (dRVVT), a lupus anticoagulant-sensitive partial thromboplastin time or the dilute prothrombin time.21 It was found that the lupus anticoagulant predicted adverse pregnancy outcome (p<0.0001). In multivariate analysis, but not in bivariate analysis, the presence of SLE conferred a relative risk of 2.16 (p=0.005). In this paper, we report on an updated set of pregnancies from the Hopkins Lupus Cohort. Our goal was to assess the association of lupus anticoagulant detected by the dRVVT in the first trimester with the risk of pregnancy loss in patients with SLE. Patients and methods Cohort We performed an analysis of pregnancies among patients in the Hopkins Lupus Cohort for which there was a measure of lupus anticoagulant during the first trimester. The Hopkins Lupus Cohort consists of consecutively enrolled patients with SLE who have been followed by one rheumatologist (MP) from 1987 to 2012 at the Hopkins Lupus Center. Patients were seen at 4-week to 6-week intervals during their pregnancy until delivery. Pregnancy was confirmed by urine and serum beta human chorionic gonadotrophin tests and fetal ultrasound. Pregnancy losses were defined as any fetal death in utero. Pregnancy outcomes were obtained from obstetric records. Cohort pregnancies were excluded from the analysis if they were not singleton, if there was uncertainty about the outcome or if the patient was not assessed for lupus anticoagulant in the first trimester. The physician global assessment score was obtained at each visit. This validated visual analogue scale assesses lupus activity (0, no activity; 1, mild lupus activity; 2, moderate lupus activity; 3, severe lupus activity).18 Lupus anticoagulant was screened by the dRVVT and then confirmed by mixing studies and confirmatory tests.19 Anticardiolipin was determined by ELISA (Inova). Statistical analysis We identified subgroups of pregnancies based on their characteristics during the first trimester and compared them with respect to pregnancy loss rates. Subgroups were defined by age, ethnicity, year of conception, disease activity and serological activity. The statistical significance of each observed difference was determined using a generalised estimating equation approach to adjust for the fact that some women contributed more than one pregnancy. We performed a sensitivity analysis using only the first pregnancy for each woman and compared rates using Fisher's exact test. Analyses were performed using SAS V.9.2. Results This analysis is based on the 202 pregnancies for which there was a first trimester assessment of lupus anticoagulant. These 202 pregnancies were from 175 women. In total, 154 women had one pregnancy, 17 had two pregnancies, 3 had three pregnancies and 1 had five pregnancies. Fifty-three per cent of pregnancies occurred in women between the ages of 20 and 29; 41% occurred in women between the ages of 30 and 39; 3% in women over >40 and 2% in women younger than 20 years of age (table 1). The ethnic composition of our sample consisted of 55% Caucasian, 34% African-American and 11% other ethnicity. Table 1 Characteristics of singleton pregnancies in the Hopkins Lupus Cohort There were 22 pregnancy losses out of the 202 pregnancies (11%). Of these, 12 (55%) occurred within the first trimester, 9 (40%) occurred during the second trimester and 1 (5%) occurred during the third trimester. There were no statistically significant differences in frequency of pregnancy losses by age group, ethnicity or year of conception (table 2), although 3/6 pregnancies (50%) among those 40 years of age or older resulted in a pregnancy loss. Table 2 Pregnancy loss rates by characteristics of the patients First trimester lupus anticoagulant was significantly associated with an increased pregnancy loss rate (p=0.0035, table 2). In 186 pregnancies with a negative first trimester lupus anticoagulant, the pregnancy loss rate was 9%. In the 16 pregnancies with a positive lupus anticoagulant in the first trimester, there were 6 pregnancy losses (36%). Also, 4 of the 16 pregnancies with first trimester-positive lupus anticoagulant had a history of previous thrombosis; 2 of the 6 pregnancies with pregnancy loss and 2 of the 10 without. A history of lupus anticoagulant prior to pregnancy was not predictive of pregnancy loss (table 2). In fact, of the 25 patients with a history of lupus anticoagulant who did not have lupus anticoagulant during the first trimester, none had a pregnancy loss. A score of ≥2 on the physician global assessment (on a 0–3 visual analogue scale) during the first trimester was statistically associated with increased risk of pregnancy loss (29% vs 8%, p=0.005). Although the numbers in some of the subgroups were not large enough to perform a complex multivariable analysis, an analysis of the association between lupus anticoagulant in the first trimester, scores of disease activity and pregnancy loss was performed. Of the 11 patients with lupus anticoagulant but without high disease activity during the first trimester, 3 (27%) experienced a pregnancy loss. Of the three with both lupus anticoagulant and high disease activity during the first trimester, two experienced a pregnancy loss. Statistically, the association between lupus anticoagulant and pregnancy loss persisted after adjustment for high physician global assessment (p=0.013). Anticardiolipin IgG levels were measured at the first pregnancy visit in 115 pregnancies. Among the seven patients with high IgG titres, none had a miscarriage. Sixty-three per cent of pregnancies had a history of positive anticardiolipin antibodies. There was no significant difference in the pregnancy loss rate between those pregnancies with or without a history of anticardiolipin IgG antibodies (12% vs 9%, p=0.66). Low complement levels occurred in the first trimester in 83 pregnancies (41%). The pregnancy loss rate in this group was 16%. When compared with the 118 pregnancies with normal complement levels in the first trimester, the loss rate was 7% (p=0.049). A positive anti-dsDNA was not significantly associated with increased risk of pregnancy loss (15% vs 9%, p=0.19). A prednisone dose >10 mg/day at the first pregnancy visit was more frequent in those with pregnancy loss (16% vs 8%, p=0.09). Rates of pregnancy loss were somewhat elevated among those with a history of thrombosis or prior miscarriage; however, these differences were not statistically significant in this small sample. As a sensitivity analysis, we performed the same analyses using only the first pregnancy for each woman. This analysis was based on 175 women. In this analysis, we found that there was still a significant association between pregnancy loss and lupus anticoagulant in the first trimester: pregnancy losses were 5/13 (38%) vs 20/162 (6%) for those with and without lupus anticoagulant (p=0.0020). A positive association between pregnancy loss and both high disease activity and low complement was also seen in this smaller sample (p=0.016 and 0.068, respectively). Discussion Our results demonstrate an increased risk of pregnancy loss associated with the presence of lupus anticoagulant by the dRVVT at the first trimester visit; however, a history of positive lupus anticoagulant was not associated. We also found that lupus activity defined by the physician global assessment in the first trimester was significantly associated with increased risk of pregnancy loss. Other variables including age, ethnicity, high titres of anticardiolipin antibody, use of prednisone dose as a surrogate for lupus activity and the presence of anti-dsDNA were not significantly associated with increased risk of pregnancy loss. Lupus anticoagulant remained statistically significant in multiple variable models that included disease activity and low complement. The impact of antiphospholipid antibodies on pregnancy loss has previously been reported in this cohort.9 Clowse et al found an increased risk of total pregnancy loss in patients with SLE with antiphospholipid syndrome. The presence of either lupus anticoagulant or anticardiolipin antibody, but without the clinical criteria for classification of antiphospholipid syndrome, did not increase the risk of miscarriage. In this study, we looked separately at the contribution of lupus anticoagulant and anticardiolipin antibody to the risk of pregnancy loss. While lupus anticoagulant was strongly associated with increased pregnancy loss risk, anticardiolipin antibody was not associated with increased risk. Our current results differ from our past report in that we have now looked at each antiphospholipid antibody separately. Our study looked at the utility of one single lupus anticoagulant test, the dRVVT, at the first pregnancy visit with one outcome (pregnancy loss). Thus, we confirm the PROMISSE finding that only the lupus anticoagulant ‘matters’ but extend the PROMISSE finding to the most important of the adverse pregnancy outcomes, namely pregnancy loss. Our study differed from PROMISSE in that dRVVT was done as the lupus anticoagulant assay; only first trimester results were used; we excluded PROMISSE patients and a different outcome measure (pregnancy loss) was used. The PROMISSE study could not evaluate the contribution of high disease activity, as such patients were excluded. High disease activity assessed by physician global assessment score of ≥2 in our study was significantly associated with an increased risk of pregnancy loss. Prednisone dose as a surrogate for disease activity was higher as well, but did not meet statistical significance. Clowse et al,10 in a previous analysis of our cohort in 2004, demonstrated a significant decrease in the live birth rate (84% vs 57%, p=0.04) in pregnancies with high versus low lupus activity in the first trimester defined by the physician global assessment. Chakravarty et al22 defined active disease at conception as the use of 10 mg of prednisone daily. With only six pregnancy losses in the first trimester and none in the second or third trimester, they were unable to demonstrate an increased risk of pregnancy loss. We have extended our previous work to show the independent effect of disease activity in multiple variable models. Our study found that low complement during the first trimester was associated with an increased risk of pregnancy loss. Between 1992 and 2003, Ramos-Casalset al23 routinely measured complement levels in 530 female patients with SLE. They found similar rates of pregnancy loss in those patients with low complement (14%) compared with those patients with normal complement. This is in contrast to the data published by Cortes-Hernandez et al24 in 2002, in which low complement levels detected at the first visit or at 3-month intervals were significantly associated with a combination of miscarriage and stillbirth. Clowse et al2 previously compared low or normal complement levels and the presence or absence of anti-dsDNA in the Hopkins Lupus Cohort. Neither first trimester hypocomplementemia (18% vs 15%, p=0.55) nor the presence of anti-dsDNA (20% vs 13%, p=0.29) significantly increased the rate of pregnancy loss. However, low complement levels in the second trimester were associated with a significantly increased risk of fetal loss. The larger number of pregnancies in our updated analysis has allowed us to show the effect of low complement in the first trimester. Multicentre studies such as PROMISSE are ideal, but our study fills in three important gaps. First, one lupus anticoagulant assay, the dRVVT, with confirmatory testing, is predictive of pregnancy loss. Only the presence of the lupus anticoagulant during the pregnancy matters, as a history of lupus anticoagulant is not predictive. Thus, in clinical practice, a large battery of tests is unnecessary. Prophylactic treatment could be considered in these pregnancies. Second, high disease activity (omitted from PROMISSE) is a risk factor and control of disease activity before conception is essential to successful pregnancy outcome. Third, low complement in the first trimester is also a risk factor. In the non-pregnant patient with SLE, low complement in the absence of disease activity (serologically active, clinically quiescent) is not treated.25Although we cannot address treatment, our study indicates the value of low complement for the prediction of pregnancy outcome. Footnotes Contributors AM contributed to writing and editing the manuscript. MP contributed to writing and editing the manuscript. LSM provided statistical analysis and editing of the manuscript. Funding The Hopkins Lupus Cohort is supported by National Institute of Health grant AR-43727. Competing interests None declared. Patient consent Obtained. Ethics approval This cohort has been approved on a yearly basis by the Johns Hopkins Institutional Review Board. Provenance and peer review Not commissioned; externally peer reviewed. Data sharing statement No additional data are available. Received April 10, 2015. Accepted August 5, 2015. Published 9 December 2015 http://lupus.bmj.com/content/2/1/e000095.full This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/ References ↵ Clark , Spitzer , Laskin . Decrease in pregnancy loss rate in patients with systemic lupus erythematosus over a 40 year period. J Rheumatol ;:–. [AbstractFull text] ↵ Clowse , Magder , Petri . The clinical utility of measuring complement and anti-dsDNA antibodies during pregnancy in patients with systemic lupus erythematosus. J Rheumatol ;:–. doi:10.3899/jrheum.100746 [AbstractFull text] ↵ Lockshin , Laskin , . Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum ;:–. doi:10.1002/art.34402 ↵ Krizova , Ouimet , . Pregnancy outcome in systemic lupus erythematosus is improving: Results from a case control study and literature review. Open Rheumatol J ;:–.doi:10.2174/1874312900802010089 [Medline] ↵ Mecacci , Bianchi , Pieralli , . Pregnancy outcome in systemic lupus erythematosus complicated by antiphospholipid antibodies. Rheumatology (Oxford) ;:–.doi:10.1093/rheumatology/ken458 [AbstractFull text] ↵ Brucato , Doria , Frassi , . Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus ;:–.doi:10.1191/0961203302lu252oa [AbstractFull text] ↵ . Outcome of pregnancy in patients with systemic lupus erythematosus.Taiwan J Obstet Gynecol ;:–. doi:10.1016/S1028-4559(09)60208-4 [Medline] ↵ Andrade , Sanchez , Alarcon , . Adverse pregnancy outcomes in women with systemic lupus erythematosus from a multiethnic US cohort: LUMINA (LVI). Clin Exp Rheumatol ;:–. ↵ Clowse , Magder , Witter , . Early risk factors for pregnancy loss in lupus. Obstet Gynecol ;:–.doi:10.1097/01.AOG.0000194205.95870.86 ↵ Clowse , Magder , Witter , . The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum ;:–. doi:10.1002/art.20864 ↵ Lathi , Gray Hazard , Heerema-McKenney , . First trimester miscarriage evaluation. Semin Reprod Med ;:–.doi:10.1055/s-0031-1293200 ↵ Suzumori , Sugiura-Ogasawara . Genetic factors as a cause of miscarriage. Curr Med Chem ;:–.doi:10.2174/092986710793176302 ↵ Lebedev . Mosaic aneuploidy in early fetal losses. Cytogenet Genome Res ;:–.doi:10.1159/000324120 ↵ Porter , Scott . Evidence-based care of recurrent miscarriage. Best Pract Res Clin Obstet Gynaecol ;:–. doi:10.1016/j.bpobgyn.2004.11.005 ↵ Buchanan , Khamashta , . Obstetric outcomes in systemic lupus erythematosus. Semin Arthritis Rheum ;:–. doi:10.1016/S0049-0172(95)80030-1 ↵ Derksen , Bruinse , de Groot , . Pregnancy in systemic lupus erythematosus: a prospective study. Lupus ;:–.doi:10.1177/096120339400300304 [AbstractFull text] ↵ Moroni , Quaglini , Banfi , . Pregnancy in lupus nephritis. Am J Kidney Dis ;:–.doi:10.1053/ajkd.2002.35678 ↵ Petri , Genovese , Engle , . Definition, incidence and clinical description of flare in systemic lupus erythematosus. Arthritis Rheum ;:–. doi:10.1002/art.1780340802 ↵ Petri , Nelson , Weimer , . The automated modified Russell viper venom time test for the lupus anticoagulant. J Rheumatol ;:–. Pengo , Tripodi , Reber , . Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost ;:–. doi:10.1111/j.1538-7836.2009.03555.x ↵ Chakravarty , Colón , Langen , . Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obs Gynecol ;:–.doi:10.1016/j.ajog.2005.02.063 ↵ Ramos-Casals , Campoamor , Chamorro , . Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients. Lupus ;:–. doi:10.1191/0961203304lu1080oa [AbstractFull text] ↵ Cortés-Hernández , Ordi-Ros , Paredes , . Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) ;:–. doi:10.1093/rheumatology/41.6.643 [AbstractFull text] ↵ Steiman , Gladman , Ibañez , . Outcomes in patients with systemic lupus erythematosus with and without a prolonged serologically active clinically quiescent period. Arthritis Care Res (Hoboken) ;:–. doi:10.1002/acr.21568 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
  8. Pregnancy, SLE, and APS: New Guidelines Pregnancy can pose unique complications for women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), including preeclampsia and preterm birth. New guidelines issued at the 2015 annual meeting of the European League Against Rheumatism (EULAR) outline ways to reduce those risks in the context of disease activity and the impact of medications. At the same time, a large population study from Sweden presented at the EULAR meeting offers some reassurance that, for women who’ve previously had children, pregnancy does not cause an accelerated risk of cardiovascular complications. However, they urged that women with SLE must be watched carefully for disease-related effects, such as maternal-placental insufficiency-- especially those who’ve never been pregnant. The EULAR recommendations for women’s health and pregnancy include ways to deal with reduced fertility in SLE, use of birth control, assisted reproductive technology, and hormone therapy during menopause. Since SLE and APS often strike during a woman’s reproductive years, often before a woman has started or completed a family, “physicians must ensure that optimal management includes best-practice measures to reduce these risks from the onset of disease and throughout pregnancy,” stresses the lead author of the guidelines, Laura Andreoli, MD, of the Rheumatology and Clinical Immunology Unit at the University of Brescia, Italy. Recommendations include preservation of fertility with gonadotropin-releasing hormone (GnRH) analogues before women are treated with certain medications, including alkylating agents like cyclophosphamide (Cytoxan). Also included in the guidelines: Human papilloma virus (HPV) immunization should be considered for women with stable disease.Clotting risk in APS and disease activity in SLE should be taken into account when oral contraceptives and other birth control measures are being used or considered.Assisted reproduction can be considered in women with stable or inactive disease, with provisions to limit the risk of flare.Disease activity, serological markers, and renal function should be closely monitored to guard against adverse pregnancy outcomes (such as preeclampsia and preterm birth) as well as disease flares.Fetal monitoring, including ultrasound, should be done during high risk pregnancy--especially after 24-28 weeks of pregnancy to screen for placental insufficiency and other problems.Fetal echocardiography is indicated for suspected fetal dysrhythmia, especially in patients with positive anti-Ro and/or anti-La.Hydrochloroquine, glucocorticoids, azathioprine, cyclosporine-A, tacrolimus, and intravenous immunoglobulin can be used to prevent or manage SLE flares during pregnancy.For menopausal women with stable disease and no antiphospholipid antibodies, hormonal therapy can be used for severe vasomotor symptoms.Cancer screening, especially for pre-malignant cervical lesions, is needed in women taking certain immunosuppressive drugs.As for cardiovascular risks, the retrospective Swedish study of 3,232 women with SLE (72% of whom had undergone childbirth), found that incidence of cardiovascular events was highest among women who had never had children. The researchers conclude that pregnancy and its complications do not accelerate cardiovascular events to the same extent as SLE-related conditions. In fact, they suggest, for some women with lupus an uncomplicated pregnancy may be a positive sign of later cardiovascular health.
  9. Pregnancy, SLE, and APS: New Guidelines Pregnancy can pose unique complications for women with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), including preeclampsia and preterm birth. New guidelines issued at the 2015 annual meeting of the European League Against Rheumatism (EULAR) outline ways to reduce those risks in the context of disease activity and the impact of medications. At the same time, a large population study from Sweden presented at the EULAR meeting offers some reassurance that, for women who’ve previously had children, pregnancy does not cause an accelerated risk of cardiovascular complications. However, they urged that women with SLE must be watched carefully for disease-related effects, such as maternal-placental insufficiency-- especially those who’ve never been pregnant. The EULAR recommendations for women’s health and pregnancy include ways to deal with reduced fertility in SLE, use of birth control, assisted reproductive technology, and hormone therapy during menopause. Since SLE and APS often strike during a woman’s reproductive years, often before a woman has started or completed a family, “physicians must ensure that optimal management includes best-practice measures to reduce these risks from the onset of disease and throughout pregnancy,” stresses the lead author of the guidelines, Laura Andreoli, MD, of the Rheumatology and Clinical Immunology Unit at the University of Brescia, Italy. Recommendations include preservation of fertility with gonadotropin-releasing hormone (GnRH) analogues before women are treated with certain medications, including alkylating agents like cyclophosphamide (Cytoxan). Also included in the guidelines: Human papilloma virus (HPV) immunization should be considered for women with stable disease. Clotting risk in APS and disease activity in SLE should be taken into account when oral contraceptives and other birth control measures are being used or considered. Assisted reproduction can be considered in women with stable or inactive disease, with provisions to limit the risk of flare. Disease activity, serological markers, and renal function should be closely monitored to guard against adverse pregnancy outcomes (such as preeclampsia and preterm birth) as well as disease flares. Fetal monitoring, including ultrasound, should be done during high risk pregnancy--especially after 24-28 weeks of pregnancy to screen for placental insufficiency and other problems. Fetal echocardiography is indicated for suspected fetal dysrhythmia, especially in patients with positive anti-Ro and/or anti-La. Hydrochloroquine, glucocorticoids, azathioprine, cyclosporine-A, tacrolimus, and intravenous immunoglobulin can be used to prevent or manage SLE flares during pregnancy. For menopausal women with stable disease and no antiphospholipid antibodies, hormonal therapy can be used for severe vasomotor symptoms. Cancer screening, especially for pre-malignant cervical lesions, is needed in women taking certain immunosuppressive drugs. As for cardiovascular risks, the retrospective Swedish study of 3,232 women with SLE (72% of whom had undergone childbirth), found that incidence of cardiovascular events was highest among women who had never had children. The researchers conclude that pregnancy and its complications do not accelerate cardiovascular events to the same extent as SLE-related conditions. In fact, they suggest, for some women with lupus an uncomplicated pregnancy may be a positive sign of later cardiovascular health. http://www.rheumatologynetwork.com/lupus/pregnancy-sle-and-aps-new-guidelines
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