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  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. High Doses of Hydroxychloroquine May Protect Against Thrombosis in SLE Emily Pond Hydroxychloroquine has been known to have a primary role in the treatment of systemic lupus erythematosus. The following article is a part of conference coverage from the 2019 American College of Rheumatology/The Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, being held in Atlanta, Georgia. The team at Rheumatology Advisor will be reporting on the latest news and research conducted by leading experts in rheumatology. Check back for more from the 2019 ACR/ARP Annual Meeting. ATLANTA — Higher prescribed doses of hydroxychloroquine (HCQ) may be associated with lower odds of thrombotic events in patients with systemic lupus erythematosus (SLE), according to study results presented at the 2019 The American College of Rheumatology/Association of Rheumatology Professionals (ACR/ARP) Annual Meeting, held November 8 to 13, 2019, in Atlanta, Georgia. Related Articles Novel Diagnostic Test Demonstrates Clinical Utility in Systemic Lupus Erythematosus Anifrolumab Effectively Reduced Disease Activity in Lupus in Phase 3 Trial 2017 Weighted Criteria Validated for Pediatric Systemic Lupus Erythematosus Investigators conducted a prospective cohort study of patients with SLE, and HCQ blood levels were ascertained at study visits by liquid chromatography-tandem mass spectrometry. Thromboses were defined as venous, including deep vein thrombosis/pulmonary embolism, or arterial, including stroke, myocardial infarction digital gangrene, or other arterial thrombosis. Patients were followed-up until index thrombotic event. Mean HCQ blood levels were calculated by averaging values obtained at all cohort visits before thrombosis. The study cohort comprised 812 patients with SLE, among whom 93% were women, 43% were black, and 46% were white. During follow-up, researchers observed thrombosis in 44 patients (5.4%): 3.0% with venous thrombosis and 2.5% with arterial thrombosis. Lupus anticoagulant was significantly associated with a prior history of any thrombosis (odds ratio [OR], 3.25; P <.0001), venous thrombosis (OR, 3.53; P <.0001), and arterial thrombosis (OR, 3.08; P <.0001). Mean HCQ blood levels were significantly reduced in patients with any thrombosis (P =.0393) and venous thrombosis (P =.0616 with superficial; P =.0249 without superficial), compared with patients with no thrombosis. In addition, higher prescribed doses of HCQ were associated with decreased odds of any thrombosis and venous thrombosis (OR, 0.88; P =.04 and OR, 0.83; P =.009, respectively, for each 1 mg/kg increase in HCQ dose). In this prospective analysis, high HCQ blood levels appeared to be protective against thrombosis in patients with SLE. The American Academy of Ophthalmologists suggests that clinicians reduce HCQ dosing; however, such adjustments “could reduce or eliminate the benefit of [HCQ] to prevent thrombosis,” the investigators wrote. Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures. Visit Rheumatology Advisor for live coverage and more news from the 2019 ACR/ARP Annual Meeting. Reference Konig M, Li J, Petri M. Hydroxychloroquine blood levels and risk of thrombotic events in systemic lupus erythematosus. Presented at: 2019 ACR/ARP Annual Meeting; November 8-13, 2019; Atlanta, GA. Abstract 2783. https://www.rheumatologyadvisor.com/home/conference-highlights/acr-2019/high-doses-of-hydroxychloroquine-may-protect-against-thrombosis-in-sle/ Please note: before taking hydroxychloroquine, it is important to see an ophthalmologist and to have annual check ups to ensure there is no eye toxicity. Do not be alarmed because this medication has been used effectively for many years. Stopping the drug will ensure there is no damage with the check ups.
  3. Biomarkers associating endothelial Dysregulation in pediatric-onset systemic lupus erythematous Wan-Fang Lee1 , Chao-Yi Wu1,2, Huang-Yu Yang2,3, Wen-I Lee1 , Li-Chen Chen1 , Liang-Shiou Ou1 and Jing-Long Huang1,2* Abstract Background/purpose: Endothelium is a key element in the regulation of vascular homeostasis and its alteration can lead to the development of vascular diseases. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with potential extensive vascular lesions, involving skin vessels, renal glomeruli, cardiovascular system, brain, lung alveoli, gastrointestinal tract vessels and more. We aimed to assess endothelial dysregulation related biomarkers in pediatric-onset SLE (pSLE) patient serum and elucidate its correlation with their clinical features, laboratory parameters, and the overall disease activity. Methods: Disease activities were evaluated by SLE disease activity index (SLEDAI). Patient characteristics were obtained by retrospective chart review. Six biomarkers associated with endothelial dysregulation, including Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Tie2, Vascular endothelial growth factor (VEGF), thrombomodulin, and a disintegrin-like and metalloprotease with thrombospondin type 1 motif (ADAMTS13) were tested through enzyme-linked immunosorbent assay (ELISA) measurement. Results: This study comprised 118 pSLE patients. Data from 40 age-matched healthy controls were also obtained. The mean diagnostic age was 13 ± 4.12 years-old and 90.7% are females. Serum levels of VEGF, Tie2, thrombomodulin were significantly higher while serum ADAMTS13 was lower in active pSLE patients when compared to those with inactive diseases (all p < 0.05). In organ specific association, serum thrombomodulin level was higher in pSLE patient with renal involvement, and serum ADAMTS13 levels was negatively associated with neurological involvement (p < 0.05). A cutoff of thrombomodulin at 3333.6 pg/ml best correlated renal involvement. (AUC = 0.752, p < 0.01). Conclusion: Endothelial dysregulation associating proteins seems to be potent biomarkers for pSLE activity as well as organ involvement in pSLE patients. These biomarkers may be beneficial in understanding of the vascular pathogenesis and disease monitoring. Keywords: Systemic lupus erythematosus, Biomarkers, Endothelial cell. https://ped-rheum.biomedcentral.com/track/pdf/10.1186/s12969-019-0369-7
  4. It is estimated that more than 330 million people currently suffer from Dry Eye Syndrome worldwide. Although often misunderstood, the complex disease can even lead to a chronic vision threatening disorder, conjunctivochalasis (CCh). Certain modern day conveniences are thought to be a cause in the increase of the condition, with extended viewing of digital screens, laser eye surgery, exposure to air conditioning and increased life expectancy to blame for the growing incidence. LO2A Eye Drops Artificial tear preparation, presented in sterile, uni-dose vials to minimize risk of infection and contamination. LO2A is currently registered and marketed by its inventor in Germany and Switzerland for the treatment of Dry Eye Syndrome ("Dry Eye"), in Hungary for the treatment of Dry Eye and Conjunctivochalasis ("CCh") and in the Netherlands for the treatment of Dry Eye and Sjögren’s Syndrom. LO2A was developed by Prof. Shabtay Dikstein (School of Pharmacy, Hebrew U. – 1990s), as substitute for natural tears, to lubricate and protect ocular surface tissues. Well-established safety profile over more than 10 years of sales in Europe through local distributors, with no material known side effects. Preservative-free (Preservatives have recognized potential for irritation and sensitization; can damage the ocular surface and cornea) Can be used with any contact lenses Anti-irritant properties Non-Newtonian viscosity profile Available in uni-dose and future multi-dose form Wize Pharma holds exclusive marketing & distribution rights in US, ROW(*), Ukraine & Israel Sold by the inventor as: Hylan® – Germany, the Netherlands Lacrycon® – Switzerland Conheal® – Hungary Dry Eye Syndrome ("Dry Eye") Multifactorial disease of the tear and ocular surface resulting in discomfort, visual disturbance and tear film instability with potential damage to the ocular surface.* Tear layer protects the surface of the eye, providing nutrition Injury is a dynamic process, resulting in change in tear composition & symptoms of burning, redness, blurred vision, etc. Dry Eye is the most frequent symptom treated by ophthalmologists Epidemiological studies show dry eye will occur in 14-33% of population. Market size in 2014 est. + $2.5B, increasing steadily every year. Increase in incidence with age and other factor Conjunctivochalasis (CCh) Conjunctivochalasis (CCh) is a complication of dry eye Aseptic, chronic inflammation of the conjunctiva; on a background of dry eye syndrome Common age-related eye condition over 50; increases in frequency & severity with age Also markedly increased in people wearing contact lenses, regardless of age Appears in one third of dry eye patients Inflammation condition is sustained; not spontaneously reversible Severe CCh (Stage 3) can only be treated by invasive surgical treatment, which can cause considerable discomfort Sjögren’s Syndrome Sjögren’s syndrome is a chronic long-term auto-immune disease The patient's white blood cells attack the saliva and tear glands, leading to dry mouth and eyes While Sjögren’s syndrome can develop at any age, the majority of patients are diagnosed after the age of 40 with 90% of patients female There are approximately 4,000,000 people in the USA and 500,000 in the UK with Sjögren’s Syndrome
  5. Study Confirms Urgent, Unmet Needs in Childhood-Onset Lupus Experts identify lupus nephritis and neuropsychiatric disease among highest research priority areas. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) and Lupus Foundation of America (LFA) conducted a first-of-its-kind, multidisciplinary research effort on childhood-onset lupus to assess research priorities for addressing this life-threatening disease. Results from the study, “Research Priorities in Childhood-Onset Lupus: Results of a Multidisciplinary Prioritization Exercise” published in Pediatric Rheumatology, conclude that the highest areas needing research in childhood lupus are nephritis, clinical trials, biomarkers, neuropsychiatric disease, and refractory skin disease. The study also revealed a strong need for multidisciplinary collaboration moving forward. When asked which sub-specialties in addition to rheumatology should collaborate in childhood lupus research, 92% suggested collaborating with nephrologists, 73% with dermatologists, and 68% with mental health specialists. Children with lupus have more pervasive and life-threatening organ involvement compared to adults with lupus, and an estimated 6,000 US children and adolescents are currently living with the disease which has few treatment options and no cure. Over 250 members of CARRA, Midwestern Pediatric Nephrology Consortium (MWPNC) and Pediatric Dermatology Research Alliance (PeDRA) Connective Tissue Disease Group participated in the study. Click image to view larger Inflammation of the Kidneys Nephritis (inflammation of the kidneys) was identified as the number one research priority. Up to 80% of children with lupus develop nephritis, which increases risk of kidney failure, cardiovascular disease and death. Lupus nephritis (LN) requires prolonged therapy, often with toxic medications, and complex treatment plans. Although there have been many advances over the last several decades and many people with lupus can enjoy good health and normal activities, LN is still a driving factor in increased complications, hospitalizations and mortality rates, especially in children versus adults with lupus. Cognitive Impairment Lupus commonly affects the brain in children and can cause strokes as well as severely impair the ability to think through tasks. Neuropsychiatric disease (involvement of the nervous system) was also identified as a top challenge for clinicians and researchers treating children with lupus. Neuropsychiatric complications can have substantial negative impact on cognitive development, educational and vocational outcomes in children and adolescents with lupus. Up to 65% of children with lupus develop neuropsychiatric involvement over the course of their disease, with up to 85% developing neuropsychiatric involvement in the first two years from diagnosis.1 The burden, ranging from missed school or even school failure to major challenges with treatment adherence, can have an enormous impact on a child’s psychological development and quality of life. Today, the treatment of childhood lupus is generally extrapolated from adult clinical trials data and optimal drug dosing, duration of therapy and outcomes measurement may differ for pediatric patients. Specific to nephritis and neuropsychiatric disease, important focus areas across all lupus experts were determining best treatments, biomarkers/pathophysiology, drug discovery/novel treatments, understanding long term outcomes, and refining provider reported quality measures. Of note, understanding long term outcomes was ranked highly important across every research area. “This study underscores the urgency for childhood lupus research. We are committed to investing in this area, and our partnership with CARRA as leaders in this field will bolster our progress as we work together to elevate childhood lupus research,” said Stevan Gibson, President and CEO, Lupus Foundation of America. “The findings from the study offer a roadmap to guide future research endeavors, so that the scope and devastation of lupus in children aligns with received funding.” “This is the first published research prioritization effort among experts in childhood lupus, which highlights the lack of evidence that exists specific to this disease. There are important differences between adults and children, and significant knowledge gaps limit our understanding of the best treatments and long term outcomes in children with lupus,” said Aimee Hersh, Chair of the CARRA Systemic Lupus Erythematosus Committee. “This multidisciplinary approach to identifying research priorities emphasizes the need for collaboration for childhood lupus care and research. The results from this exercise will help set a research agenda moving forward.” The study, Research Priorities in Childhood-Onset Lupus: Results of a Multidisciplinary Prioritization Exercise, appears in Pediatric Rheumatology. Systemic Lupus Erythematosus in Children and Adolescents, Pediatric Clinics of North America, Volume 59, Issue 2, April 2012 https://www.lupus.org/news/study-confirms-urgent-unmet-needs-in-childhoodonset-lupus
  6. Rheumatology, the journal of the British Society for Rheumatology, is offering free access (through December 31) to its ten most highly cited papers of 2017 and 2018. https://academic.oup.com/rheumatology/pages/highly_cited_articles Highly Cited Articles Rheumatology publishes a wide range of high quality original scientific papers with a focus on basic, clinical, and translational research in rheumatology. Ten of the highest cited papers published in 2017 and 2018 can be explored below for free until the end of December 2019. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies Frances Rees, Michael Doherty, Matthew J Grainge, Peter Lanyon, Weiya Zhang The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease Christian Dejaco, Christina Duftner, Frank Buttgereit, Eric L. Matteson, Bhaskar Dasgupta Secukinumab sustains improvement in signs and symptoms of psoriatic arthritis: 2 year results from the phase 3 FUTURE 2 study Iain B McInnes, Philip J Mease, Christopher T Ritchlin, Proton Rahman, Alice B Gottlieb, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults Caroline Gordon, Maame-Boatemaa Amissah-Arthur, Mary Gayed, Sue Brown, Ian N. Bruce, et al. The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus Myles J. Lewis, Ali S. Jawad A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies Iago Pinal-Fernandez, Maria Casal-Dominguez, Julio A. Huapaya, Jemima Albayda, Julie J. Paik, et al. Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis Jaejoon Lee, Ayala Luria, Christopher Rhodes, Harini Raghu, Nithya Lingampalli, et al. What drives osteoarthritis?—synovial versus subchondral bone pathology Thomas Hügle, Jeroen Geurts The British Society for Rheumatology Guideline for the Management of Gout Michelle Hui, Alison Carr, Stewart Cameron, Graham Davenport, Michael Doherty, et al. More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy Eleni Tiniakou, Iago Pinal-Fernandez, Thomas E. Lloyd, Jemima Albayda, Julie Paik, et al.
  7. A stay-at-home August. Our little dog, Lucy, has been ill and we daren’t risk travel. Yet there are upsides to our August at home. London is different, tourists outnumber commuters, seats in trains, peace over Brexit while the ‘remainers’ take their August break in Provence. No conferences or medical meetings, though September promises to be busy, with our own annual Hughes Syndrome patients’ meeting fully subscribed (we plan another in March next year). Also, there is the 13th international antiphospholipid conference in Manchester. This biannual conference has grown and grown. The first conference, which we organised at Hammersmith Hospital in 1984 (a year after our original papers on the syndrome in 1983) attracted, I think, 47 attendees! This year, the conference returns to England for the first time – to Manchester and organised by my friend Prof. Ian Bruce. As before, the abstracts of the papers will be published in the journal ‘LUPUS. I also hope to provide a summary for our charity website ghic.world/ Patient of the month Leg pain Mrs SR, aged 55, previously well, suffered from acute pain and swelling in her left calf. She had been on an organised walk the day before and at first attributed the pain to muscle spasm. The following day the pain and discomfort spread to the other leg and with it, a darkish discolouration in the right toes. Mrs SR’s GP arranged for an urgent appointment at the nearest vascular clinic. The initial findings suggested two separate problems, a probable DVT (deep vein thrombosis) in the left leg and more seriously, an arterial clot in the right leg. Mrs SR was admitted for further investigation. To cut a long story short, Mrs SR underwent arterial surgery to remove the artery obstruction and was treated with Warfarin anticoagulation. Further investigation showed a surprisingly normal arterial tree. A slight mitral valve leak was found, but thought not to be significant. Slowly, painfully, the ischaemic big toe healed. Further tests? Routine blood tests were essentially normal, including blood sugar, cholesterol and screens for malignancy and infection. Further history Mrs SR mentioned to the houseman that her sister suffered from Lupus. Lupus tests were negative,.but the houseman (a locum) had heard of Antiphospholipid Syndrome – a cousin of Lupus – and ran the blood tests. All three tests positive, strongly positive. The whole clinical picture (possibly including the cardiac valve leak) fitted the diagnosis. Treatment: long term Warfarin, probably at high level. Outlook good, provided the patient kept a careful watch over her anticoagulant control. What is this patient teaching us? To suffer both a venous thrombosis as well as an arterial thrombosis certainly suggests Hughes Syndrome. (Most other clotting disorders cause venous thrombosis only). Oddly, there were no other obvious precipitating factors or clues (except perhaps the leaky valve). Wrong! There was a clue. A strong one. Mrs SR had a strong family history of auto-immune diseases – Lupus and now possibly Hughes Syndrome (and maybe more). The more we seek, the more we find genetic linkages within the growing autoimmunity world family. (Prof G Hughes', The London Lupus Centre)
  8. 10 Challenges in Treating Lupus 10 most important challenges in treating patients with SLE. (©Blueringmedia,AdobeStock) Gregory M. Weiss, M.D. June 13, 2019 We have come a long way since the introduction of glucocorticoids for the treatment of systemic lupus erythematosus (SLE). A one-year survival rate of 50 percent has become a 10-year survival of 90 percent due to advances in treatment. Even with improved treatment and prognosis several challenges remain in the management of SLE. In this article, we highlight the 10 most important challenges in treating patients with SLE as outlined by Laurent Arnaud, M.D., Ph.D., of Strasbourg, France, in a review published in Lupus Science & Medicine earlier this year. 1) Treat to target favoring disease remission (or low disease activity) In 2016, a large international panel sought to define remission in systemic lupus erythematosus (SLE). The panel was able to agree on three principles: Remission should be a durable state. A validated index should be used. Distinction should be made between remission on and off therapy. While at the same time the Asia Pacific Lupus Collaboration developed a Low Disease Activity State index, the challenge remains to validate whether these definitions are predictive of outcomes and ultimately used as targets in treat-to-target management of SLE. 2) Limiting the use of glucocorticoids While glucocorticoids have played a major role in the improvement of systemic lupus erythematosus (SLE) prognosis, a large number of patients never discontinue glucocorticoids. Glucocorticoid dose predicts its overall exposure which can increase the risk of damage accrual even at low doses. Several challenges exist with regards to glucocorticoid treatment in SLE: Using a low dose glucocorticoid or a glucocorticoid free regimen should be discussed as a major target. Glucocorticoid management should be addressed as an important concern in future research with glucocorticoid tapering schemes, glucocorticoid-related adverse events, damage accrual and cumulative glucocorticoid doses being examined. Glucocorticoid doses should be managed using more objective tools such as the glucocorticoid cumulative dose, follow-up of disease activity and damage, and recording of glucocorticoid-related adverse events. 3) Deriving more comprehensive tools for the evaluation of disease activity Do to multiple organs being involved in systemic lupus erythematosus (SLE), it is difficult to define disease activity as a whole. While several tools have been developed to assess the overall activity of the disease, in most cases the clinician has to form a judgment with regard to whether each manifestation is due to SLE or some other cause. The authors believe that a more objective and reproducible measure of disease activity is needed and may include biomarkers and utilization of modern technology such as deep machine learning. 4) Developing more effective and better tolerated drugs While drug therapy in systemic lupus erythematosus (SLE) has improved, several gaps remain in the care of SLE patients such as the progression of lupus nephritis to end-stage kidney disease. For example, in lupus nephritis, a significant proportion of patients still progress towards end-stage kidney disease. “Our group has recently published a systematic review (in the Annals of Rheumatic Diseases) of 74 targeted therapies for SLE, showing that we may expect great changes in the therapeutic tools available for SLE treatment,” the authors wrote. “We believe that current challenges are shifting from whether some new drugs will be available to the identification of the best strategy for the selection of the most adequate drug (or drug combination) at the patient level, to warrant a positive balance between efficacy and side effects. The need to investigate biomarkers that would allow adequate prediction of response to therapy remains high, but when solved will allow a more rational selection of the optimal pharmacological agent within the broad pipeline of targeted therapies for SLE.” These current challenges are shifting from whether new drugs will be available to identifying the best strategy for the selection of the most adequate drug, or drug combination, at the patient level. Identifying strong biomarkers will allow a more rational selection of the optimal pharmacological agent. 5) Dissecting the heterogeneity of the disease at the molecular and genetic level Both environmental and genetic factors play roles in the development and exacerbation of systemic lupus erythematosus (SLE). To date, a large number of nucleotide polymorphisms have been implicated in SLE however none of them have utility on their own in the diagnosis or treatment of patients. An important challenge will be to develop an optimal genetic model for patients’ sub-stratification using multiomics to better personalize medicine for patients with SLE 6) Identifying relevant biomarkers for individualized treatment Matching the right treatment to the individual patient remains a challenge in SLE. Traditional markers such as anti-double-stranded-DNA fall short and should give way to multiomics, which utilize high-throughput tools such as next-generation sequencing and computerization of data, to open the door for an integrated and personalized treatment approach. Non-coding RNAs, owing to being tissue-specific regulators of gene expression, may emerge as important makers of flares in SLE. It remains a challenge to develop a holistic approach to SLE, a challenge that will require a specialized interface between all providers. 7) Managing fertility and pregnancy Pregnancy remains a significant challenge in women with systemic lupus erythematosus (SLE). We as clinicians have to improve the outcomes of pregnancy in patients with aPL and/or anti-SSA/B antibodies. The overall prognosis of pregnancy in SLE is better when the disease has been in remission for at least six months, or one year for nephritis with a low organ damage score. Strong predictors of complications during pregnancy with SLE include: Active SLE at the time of conception and/or positivity for lupus anticoagulant or triple positivity, use of antihypertensive treatments, and low platelet count. Finally, clinicians should be aware that pregnancy complications can mimic SLE flares and anti-phospholipid antibodies can lead to both maternal and fetal adverse events. Managing comorbidities Late cardiovascular morbidity and mortality have increased along with overall systemic lupus erythematosus (SLE) patient survival. One challenge here is that measures validated for determining cardiovascular disease risk are based on North American populations and may not be adapted from the general population to patients with SLE. Infections remain an serious comorbidity with SLE. Vaccines should be used provided immunosuppressive therapy does not contraindicate use. Osteoporosis can be significant in SLE patients especially with glucocorticoid treatment. Anti-osteoporotic treatment should be considered. 9) Improving the network of care More light should be shed on rare diseases like systemic lupus erythematosus (SLE). We need to improve early diagnosis while limiting diagnosis uncertainty. Training of new clinicians should included recognition of rare diseases and education should be provided to practicing caregivers, patients, and their families alike. Global awareness should be the goal. 10) Favoring a holistic approach All aspects of the patient with SLE should be addressed. Patient reported outcome measures can facilitate holistic treatment and lead to better quality of life. Just as organ damage is a concern, so should fatigue, depression, pain, sleep disturbance and obesity be. Better trials are needed in an effort to find non-pharmacological interventions aimed at treating the whole patient. Finally, individual factors such as race, smoking, and socioeconomic background should be taken into consideration when developing a plan for patients with SLE. REFERENCE Renaud Felten, Flora Sagez, Pierre-Edouard Gavand, et al. “10 most important contemporary challenges in the management of SLE.” Lupus Science & Medicine 2019;6:e000303. DOI:10.1136/ lupus-2018-000303 https://www.rheumatologynetwork.com/lupus/10-challenges-treating-lupus
  9. Pregnant SLE Patients Discontinue Meds When They Shouldn't (©SydaProductionsShutterStock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology Recent evidence shows that pregnant women with systemic lupus erythematosus (SLE) often discontinue their lupus medications during pregnancy despite recommendations to continue them. The findings, reported by Mary A. De Vera, M.D., of the University of British Columbia, appear in the July 16 online issue of Lupus. “Considering the patterns of medication use seen in this study, it appears that expectant mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided,” the authors wrote. “Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions.” Since lupus primarily affects women in their childbearing years, pregnancy can be a time fraught with risk and complications such as stillbirth, preterm labor and miscarriage. A significant portion of pregnant women with systemic lupus erythematosus will experience flares late in the pregnancy or after the birth. While concerns over taking medications during pregnancy exist, it is recommended that women with lupus continue their antimalarial drugs like hydroxychloroquine throughout gestation and during breast-feeding, according to GR de Jesus, et al. writing in the July 12, 2015 online issue of Autoimmune Diseases. The authors of the Lupus study sought to characterize the frequency of use of anti-malarial drugs, immunosuppressants and other medications, before, during and after pregnancy with particular interest on discontinuation of antimalarials and immunosuppressants during pregnancy. THE STUDY This was a population-based study of 284 women with systemic lupus erythematosus and 376 pregnancies. They were assessed for the discontinuation of antimalarials and immunosuppressants. Use of other lupus medications were also recorded. Rates of antimalarial use and azathioprine during the study period were 33.2 percent and 11.4 percent respectively. The authors further found that 26.3 percent of pregnancies in lupus patients were exposed to glucocorticosteroids and 23.7 percent to non-steroidal anti-inflammatory drugs. Pre-pregnancy antimalarial use stood at 36.2 percent, which dropped to 19.1 percent during the first trimester, 16.7 percent in the second, and held relatively steady at 17 percent in the third. Use rebounded to 31.1 percent after delivery. Pre-Pregnancy azathioprine was used by 11.7 percent, which dropped to 6.6 percent in the first trimester, 6.4 percent during the second, 6.9 percent in the third and rose to 10.4 percent after delivery. 33.2 percent of patients were exposed to glucocorticosteroids before pregnancy, 14.9 percent in the first trimester, 13.3 percent in the second trimester, 19.7 percent in the third trimester and 25.3 percent after delivery. 34.8 percent were exposed to NSIADs before pregnancy and 19.1 percent after pregnancy. Antimalarials were discontinued at a rate of 28.9 percent in the 12 months preceding pregnancy and 9.7 percent during pregnancy from the first trimester to the second and 26 percent from the second trimester to the third. Having had more children was associated with discontinuing antimalarials before pregnancy and time since lupus diagnosis was associated with higher odds of discontinuing antimalarials during pregnancy. Azathioprine was discontinued at a rate of 29.2 percent before pregnancy, 8.0 percent from the first to the second trimester and 9.1 percent from the second to third. Take-home points for clinicians and final thoughts The high rates of discontinuation, in particular antimalarial treatment underscore the disconnect between the recommended treatment for lupus during pregnancy and the reality. “As these findings conflict with the afore- mentioned recommendations regarding the continued use of antimalarials during SLE pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy,” the authors write. Compliance is a serious concern. Strong evidence and concise recommendations are useless if patients are not following the treatment plan. The responsibility rests with the clinician to disseminate the knowledge pregnant women need to make the right choices about continuing their medication regimen when both systemic lupus erythematosus and pregnancy coincide. REFERENCE Zusman, E. Z., Sayre, E. C., Aviña-Zubieta, J. A., & De Vera, M. A. (2019). “Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.” Lupus. July 16, 2019 https://doi.org/10.1177/0961203319863111 https://www.rheumatologynetwork.com/lupus/pregnant-sle-patients-discontinue-meds-when-they-shouldnt
  10. Pregnant SLE Patients Discontinue Meds When They Shouldn't (©SydaProductionsShutterStock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology Recent evidence shows that pregnant women with systemic lupus erythematosus (SLE) often discontinue their lupus medications during pregnancy despite recommendations to continue them. The findings, reported by Mary A. De Vera, M.D., of the University of British Columbia, appear in the July 16 online issue of Lupus. “Considering the patterns of medication use seen in this study, it appears that expectant mothers with SLE would benefit from having a discussion with their care providers about how to manage their disease during their pregnancy, which medications are safe to take, and which should be avoided,” the authors wrote. “Knowing medication use in pregnant women with SLE is key to understanding how to support patients with family planning and pregnancy decisions.” Since lupus primarily affects women in their childbearing years, pregnancy can be a time fraught with risk and complications such as stillbirth, preterm labor and miscarriage. A significant portion of pregnant women with systemic lupus erythematosus will experience flares late in the pregnancy or after the birth. While concerns over taking medications during pregnancy exist, it is recommended that women with lupus continue their antimalarial drugs like hydroxychloroquine throughout gestation and during breast-feeding, according to GR de Jesus, et al. writing in the July 12, 2015 online issue of Autoimmune Diseases. The authors of the Lupus study sought to characterize the frequency of use of anti-malarial drugs, immunosuppressants and other medications, before, during and after pregnancy with particular interest on discontinuation of antimalarials and immunosuppressants during pregnancy. THE STUDY This was a population-based study of 284 women with systemic lupus erythematosus and 376 pregnancies. They were assessed for the discontinuation of antimalarials and immunosuppressants. Use of other lupus medications were also recorded. Rates of antimalarial use and azathioprine during the study period were 33.2 percent and 11.4 percent respectively. The authors further found that 26.3 percent of pregnancies in lupus patients were exposed to glucocorticosteroids and 23.7 percent to non-steroidal anti-inflammatory drugs. Pre-pregnancy antimalarial use stood at 36.2 percent, which dropped to 19.1 percent during the first trimester, 16.7 percent in the second, and held relatively steady at 17 percent in the third. Use rebounded to 31.1 percent after delivery. Pre-Pregnancy azathioprine was used by 11.7 percent, which dropped to 6.6 percent in the first trimester, 6.4 percent during the second, 6.9 percent in the third and rose to 10.4 percent after delivery. 33.2 percent of patients were exposed to glucocorticosteroids before pregnancy, 14.9 percent in the first trimester, 13.3 percent in the second trimester, 19.7 percent in the third trimester and 25.3 percent after delivery. 34.8 percent were exposed to NSIADs before pregnancy and 19.1 percent after pregnancy. Antimalarials were discontinued at a rate of 28.9 percent in the 12 months preceding pregnancy and 9.7 percent during pregnancy from the first trimester to the second and 26 percent from the second trimester to the third. Having had more children was associated with discontinuing antimalarials before pregnancy and time since lupus diagnosis was associated with higher odds of discontinuing antimalarials during pregnancy. Azathioprine was discontinued at a rate of 29.2 percent before pregnancy, 8.0 percent from the first to the second trimester and 9.1 percent from the second to third. Take-home points for clinicians and final thoughts The high rates of discontinuation, in particular antimalarial treatment underscore the disconnect between the recommended treatment for lupus during pregnancy and the reality. “As these findings conflict with the afore- mentioned recommendations regarding the continued use of antimalarials during SLE pregnancies, they suggest the importance of educating women with SLE who are pregnant or planning to become pregnant on the benefits and risks of medications during pregnancy,” the authors write. Compliance is a serious concern. Strong evidence and concise recommendations are useless if patients are not following the treatment plan. The responsibility rests with the clinician to disseminate the knowledge pregnant women need to make the right choices about continuing their medication regimen when both systemic lupus erythematosus and pregnancy coincide. REFERENCE Zusman, E. Z., Sayre, E. C., Aviña-Zubieta, J. A., & De Vera, M. A. (2019). “Patterns of medication use before, during and after pregnancy in women with systemic lupus erythematosus: a population-based cohort study.” Lupus. July 16, 2019 https://doi.org/10.1177/0961203319863111 https://www.rheumatologynetwork.com/lupus/pregnant-sle-patients-discontinue-meds-when-they-shouldnt
  11. SLE Breakthrough Finds a Link Between Microbial Translocation and Autoantibodies (©AysezgicmeliShutterstock.com) Gregory M. Weiss, M.D. August 7, 2019 Lupus, Modern Medicine News, News, Rheumatology A previously unknown direct relationship has been found between microbial translocation from the gastrointestinal tract and autoantibody levels in patients with systemic lupus erythematosus. The findings by, Gary Gilkeson, M.D., and Wei Jiang, M.D., of the Medical University of South Carolina in Charleston, appear in the May 20 online issue of Arthritis and Rheumatology. The authors state, “An understanding of the mechanism of autoantibody induction in systemic lupus erythematosus (SLE) can lead to the development of therapeutic targets that prevent autoantibody production thereby slowing disease onset, mitigating downstream inflammation and reducing tissue damages.” Systemic lupus erythematosus is a chronic autoimmune mediated inflammatory disease that results from a loss of tolerance to the patient’s own antigens leading to autoantibody production. It is known that genetic factors influence the development of lupus leading to clustering of the disease within families. The source of autoantibody production in systemic lupus erythematosus remains elusive and is likely multifactorial with genetic, environmental, immunologic, and hormonal factors contributing to development of the disease. Recent research has implicated increased intestinal permeability in the pathogenesis of autoimmune disease. While under normal conditions the gastrointestinal tract serves as a barrier to environmental antigens, however, in certain disease states, this barrier may be compromised allowing translocation of gut microbes into the bloodstream. The authors sought to determine the role of microbial translocation in systemic lupus erythematosus. They examined lupus patients and their first-degree relatives comparing them to healthy controls. Two cohorts were included in the study. The first group consisted of 18 unrelated healthy control subjects and 18 first-degree relatives of systemic lupus erythematosus patients. The second included 19 healthy controls and 21 lupus patients. Plasma autoantibodies and lipopolysaccharide levels were measured and DNA bacterial DNA was extracted from plasma to determine if translocation had occurred. From the bacterial DNA microbiome species was determined. Auto-antigen array demonstrated higher plasma levels of a large spectrum of autoantibodies in systemic lupus erythematosus patients and first-degree relatives of lupus patients compared to healthy controls. Four representative lupus-related IgG autoantibodies including anti-double stranded DNA, anti-nucleosome, anti-single stranded DNA and anti-chromatin were increased in lupus patients and first-degree relatives compared to healthy control subjects. Compared to unrelated healthy control subjects, systemic lupus erythematosus patients and parents or children who were first-degree relatives had increased microbial translocation as evidenced by plasma lipopolysaccharide levels. First-degree relatives of lupus patients but not lupus patients themselves had decreased intestinal species diversity when compared to healthy controls. Take-home points and final thoughts First-degree relatives of systemic lupus erythematosus patients also have significantly elevated levels of lupus related autoantibodies. Increased levels of lipopolysaccharide in these patients are consistent with prior research linking infection, bacterial translocation and autoimmunity. The authors state, “The increased translocation of bacterial products into the systemic circulation from the permeable mucosa suggests that insights into autoimmune pathology can be gained from studying the circulating microbiome as opposed to other sites.” In a letter to the editor the authors discuss why they believe bacterial diversity was decreased in relatives but not in lupus patients themselves. They found after reanalyzing the data that diversity differences did not occur within a specific racial group but did between different races. They point out that, “while race may play a role in differences in circulating microbiome diversity, additional studies are needed to confirm this hypothesis.” Systemic lupus erythematosus is a very complex disease with an etiology that has remained elusive. The authors have discovered a possible infectious cause of lupus that could lead to focus on intestinal integrity and possibly uncover medications that we are using that compromise gut barrier. While the discovery of bacterial translocation in lupus opens the door for future investigation into preventing this from happening, the sheer number of different possible causes for systemic lupus erythematosus remains daunting. With continued efforts like those of the authors, we take important steps toward understanding lupus in the hopes of improving the quality of life of those who suffer from it. REFERENCE Elizabeth Ogunrinde, Zejun Zhou, Zhenwu Luo, et al. "A link between plasma microbial translocation, microbiome, and autoantibody development in first-degree relatives of systemic lupus erythematosus patients." Arthritis and Rheumatology. 2019 May 20. doi: 10.1002/art.40935 https://www.rheumatologynetwork.com/lupus/sle-breakthrough-finds-link-between-microbial-translocation-and-autoantibodies?rememberme=1&elq_mid=8392&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  12. Take the Right Shots for Lupus! August 15, 2019 While August is when we savor the last weeks of summer, it is also the time to look ahead and prepare for fall. In recognition of National Immunization Month, our Chief Scientific Officer Dr. Teodora Staeva provides background on vaccines and relays government recommendations for which are safe for people with lupus. “Vaccines help to develop immunity, in other words protect against disease, by imitating an infection,” notes Dr. Staeva. “Most vaccines contain small amounts of the germs (or parts of them) that cause disease but are either killed or weakened. The vaccine prompts the immune system to produce T cells and antibodies against these germs, and thus allows the body to learn how to fight these microbes in the future. However, several rounds of vaccination are often required to achieve optimal protection.” Currently there are four main types of vaccines. Live-attenuated vaccines use the weakened (attenuated) form of the virus so that it does not cause serious illness in individuals with healthy immune systems. Vaccines with live viruses are generally NOT recommended for people with lupus. Inactivated vaccines are made by killing the germ while making the vaccine. These are considered safe and effective for people with lupus. Subunit or purified antigen vaccines use only specific pieces of the germ. Thus, they give a very robust immune response targeted to key portions of the microbe. Generally, these vaccines can be used widely, including on people with weakened immune systems. Toxoid vaccines use a toxin (harmful product) made by the germ that causes a disease. They create immunity to the parts of the germ that cause a disease instead of the germ itself. That means the immune response is targeted to the toxin instead of the whole germ. “People with lupus are at greater risk for infections due to immunosuppression, so vaccines are very important,” noted Dr. Staeva. “But speak to your doctor before getting any vaccine to determine which are right for you and when.” _________________________________________________________________________ Recommendations from the U.S. Department of Health & Human Services (HHS), Office of Women’s Health: People with lupus typically can get the following vaccines that do not contain live viruses: The flu shot (not nasal spray which contains a live form of the flu virus) Pneumonia vaccine Human papillomavirus (HPV) vaccine Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccine Vaccines with live viruses that may not be safe for people with lupus, include: Nasal spray vaccine for the flu Varicella (chickenpox) vaccine Herpes Zoster (Shingles) vaccine Measles, Mumps, Rubella (MMR) vaccine Live typhoid vaccine (oral) Sources: U.S. Department of Health & Human Services, Office of Women’s Health https://www.lupusresearch.org/take-the-right-shots-for-lupus/
  13. July 2019 22 July 2019 by Professor Graham R V Hughes MD FRCP This week, we held the 33rd annual “Ten Topics in Rheumatology” meeting in London. Organised by Professor Chris Edwards and his team from the London Lupus Centre – Professor David D’Cruz, Professor Munther Khamashta and Dr Arvind Kaul, it was a full house of 300 doctors from far and wide, including one from New Zealand. For me, it was a fantastic 2 days – the usual formula of top international speakers, short presentations and the most up-to-date reviews. Congratulations to Chris and the team. I took part in a session arranged by Professor Khamashta called “kerbside consults” – a series of cases (of Hughes Syndrome) with questions posed by the audience, as well as 3 experts – Cathy Nelson-Piercy (Consultant Obstetric Physician at St Thomas’ Hospital) and David D’Cruz (my colleague at the London Lupus Centre) and myself. One of the 4 cases presented by Professor Khamashta covered a number of aspects and I will use this case for my July blog. Patient of the Month Miss G.L., a 25 year old secretary, developed an acute deep vein thrombosis of the leg at the age of 23. There had been no prior clues to the diagnosis apart from a past history of frequent pre-menstrual headaches. She had never smoked or taken oestrogen-containing drugs. There was no family history of thrombosis or auto-immune disease. However, her tests for antiphospholipid antibodies (aPL) were positive – strongly positive, and “triple-positive” (all three of the currently used aPL tests – aCL, LA and anti-β2 GP1 – were positive at high level). She was treated with Warfarin. Interestingly, the headaches which had been frequent (though ‘livable’) disappeared. The Warfarin continued, perhaps longer than usual, for a year. Miss G.L. raised two topics – marriage “in a year or two” and pregnancy, and the second concerning horse riding. She asked whether it was now safe to stop the Warfarin, prior to taking up horse riding again, or at least to convert to aspirin. What would you do? Perhaps not surprisingly, the three experts gave rather differing opinions. The first agreed with a change to aspirin. After all, this was a venous thrombosis and not arterial, and the risk of re-thrombosis on aspirin was small. The second expert discussed pregnancy. The treatment of pregnancy in Hughes Syndrome was becoming almost standardised worldwide, with low molecular weight heparin, plus or minus aspirin being first choice. The warfarin, if continued, could be changed to heparin as soon as the pregnancy test became positive. The third expert focused more on the primary thrombosis. This young woman in the prime of her life was at high risk unless treated. Although not universally accepted, a number of studies have suggested that “triple positive” aPL patients (aCL, LA and anti-β2 GP1 positive) have much stronger tendency to re-thrombose. Although Warfarin has a bad press, and interacts with many foods and drinks, it has three big pluses. Firstly, unlike many other anti-clotting treatments, its therapeutic dose can be closely controlled (many Hughes Syndrome patients living normal lives with the help of self-testing INR machines). Secondly, current experience suggests that Warfarin may be superior to newer anticoagulants (‘NOACS’) in severe APS (though admittedly, Miss G.L’s thrombosis was venous). The third specialist admitted that many of his Warfarin patients took part in horse riding (and other ‘contact’ sports) but he did recognise that, for some, the risk was too great. His rather brutal opinion was “keep the Warfarin, sell the horse”. PROFESSOR GRAHAM R V HUGHES MD FRCP Head of The London Lupus Centre London Bridge Hospital https://ghic.world/blog/july-2019
  14. Entry Requirements for Lupus Nephritis Clinical Trials Exclude Majority of Patients in UK Registry, Study Says JULY 10, 2019 BY IQRA MUMAL IN NEWS. Click Here to receive Lupus News via e-mail How clinical trials into lupus nephritis define their requirements for patient eligibility are too strict, leaving many people with active and severe disease ineligible for participation, according to a study that looked at six lupus trials and how well their “inclusion and exclusion criteria” matched patients in a large U.K. registry. Its researchers reported that a majority of registry patients, 50.6%, would not have been enrolled under published entry requirements. These findings were presented at the recent 2019 European Congress of Rheumatology(EULAR 2019), in a poster titled “How Well Do Clinical Trials Represent Real World Lupus Nephritis Patients?” Lupus nephritis (inflammation of the kidneys) can be a serious complication of systemic lupus erythematosus (SLE). The standard of care for lupus nephritis is treatment using glucocorticoids or conventional immunosuppressants. Rituxan (rituximab), an antibody that dampens some immune cells, has been used off-label to treat some with lupus nephritis, but has not shown efficacy across several clinical trials. Finding better treatments for these people requires clinical studies that determine safety and effectiveness. But stringent requirements for trial participation, often done to ensure patient homogeneity in the group studied, can result in criteria that does not accurately reflect real-world patients, the study notes. Researchers set out to evaluate clinical trial criteria for lupus nephritis by determining how closely they reflected a general population. They reviewed six recently published clinical trials involving these patients. Then they compared inclusion and exclusion criteria common across the trials to patients with active lupus nephritis in a U.K.-wide database of SLE patients called the BILAG-Biologics Register (BILAG-BR). Inclusion criteria define the characteristics that potential participants must have to be in a study, while exclusion criteria define those that disqualify from participation. The registry showed 259 people with active lupus nephritis, corresponding to 28.9% of its population. Among them, 230 had been treated with Rituxan, while the 29 others were given standard of care. Analysis showed that 70 people (30.4%) in the Rituxan group and 10 (34.5%) in the standard-of-care group that would not meet all inclusion criteria common to the six trials. The requirement that patients most often missed was not having a urine protein/creatinine ratio below 100 mg/mmol. This would exclude people with more severe kidney impairment. A majority, 118 patients or 51.3%, in the Rituxan group and six patients (20.7%) in standard-of-care also met one or more common exclusion criteria for the trials. Most often, the excluding criteria was active disease in the central nervous system and low levels of antibodies implying an immune system disorder (hypogammaglobulinaemia). Overall, more than half of registry patients (50.6%) with active lupus nephritis would not satisfy all inclusion and exclusion criteria, and likely be ineligible for clinical trial entry, the study found. Among patients deemed ineligible, those in the Rituxan group were younger (mean age, 36) compared to those given standard of care (mean age, 49). Most were also minorities (non-Caucasian) and female. “In a large national cohort of active LN [lupus nephritis] we found that 50.6% of patients would not be eligible for clinical trial entry using published entry criteria,” the researchers wrote. “This poses significant implications on the study of LN treatment in patients with more severe disease. When designing clinical trials, the stringency of eligibility criteria should be reviewed in order to provide greater representation of the target disease population,” they concluded. https://lupusnewstoday.com/2019/07/10/entry-criteria-for-lupus-nephritis-trials-exclude-majority-patients-in-uk-registry-study-finds/?utm_source=LUP+NEws+E-mail+List&utm_campaign=4dbb72aad6-RSS_WEEKLY_EMAIL_CAMPAIGN_US&utm_medium=email&utm_term=0_50dac6e56f-4dbb72aad6-71887989
  15. Medtronic Partners With Tel Aviv-Based Stroke Detection Startup Viz.ai by Meir Orbach / CTech An MRI of the human brain. Photo: Wikimedia Commons. CTech – Dublin-headquartered medical device maker Medtronic has signed a partnership agreement with stroke detection startup Viz.ai, the latter announced Monday. As part of the agreement, Medtronic will distribute Viz.ai’s technology in the US. The financial details of the agreement were not disclosed. Viz.ai develops deep learning and artificial intelligence-powered technology that can analyze brain scans and automatically transfer the information to a doctor to ensure the most immediate treatment for strokes. Viz.ai’s system connects to a hospital CT scanner and alerts the stroke specialist if a suspected large vessel occlusion (LVO) stroke has been identified, sending the radiological images directly to their smartphone. Based in San Francisco and Tel Aviv, Viz.ai was founded in 2016 after one of its founders, David Golan, suffered a brain event. The company has raised approximately $29 million to date. This is not Medtronic’s first dip in the Israeli tech pool. In September 2018, Medtronic acquired Israel-based surgical robotics company Mazor Robotics for $1.34 billion in cash. Earlier that year, it acquired medical visualization company Visionsense for $65 million. https://www.algemeiner.com/2019/07/22/medtronic-partners-with-tel-aviv-based-stroke-detection-startup-viz-ai/
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