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Found 62 results

  1. Pathogenic and Therapeutic Role of Vitamin D in Antiphospholipid Syndrome Patients By Svetlana Jelic, Dejan Nikolic, Dragomir Marisavljević and Ljudmila Stojanovich Submitted: November 5th 2015Reviewed: August 2nd 2016 Published: April 26th 2017 DOI: 10.5772/65071 Abstract In this chapter, the novel findings on interrelationship between vitamin D status and two well‐known prothrombotic states, antiphospholipid syndrome, particularly its thrombotic phenotype, and metabolic syndrome will be reviewed. We shall present the results obtained from patients included in Serbian National Antiphospholipid Syndrome Registry, 68 patients with primary antiphospholipid syndrome (PAPS) and 69 patients with antiphospholipid syndrome associated with certain autoimmune rheumatic disease (sAPS), as well as 50 patients with pure metabolic syndrome (MetS). These results will be analysed and compared with the novel literature data. Prevalence of MetS in APS is high, with the atherogenic dyslipidaemia as its most prevalent characteristic. Prevalence of thrombotic events was significantly higher in APS patients with coexisting MetS, compared with those without MetS. Among APS patients, prevalence of VitD deficiency was significantly higher than in patients with pure MetS. VitD level was also significantly lower in APS patients with coexisting MetS or previous thrombotic events than in those without them. Elucidating interrelationships between VitD deficiency, MetS and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of modifiable risk factors and VitD supplementation. Keywords vitamin D antiphospholipid syndrome metabolic syndrome classification criteria thrombosis Chapter and author info Show + 1. Introduction The antiphospholipid syndrome (APS), primary or associated with certain autoimmune rheumatic diseases, especially systemic lupus erythematosus, represents prothrombotic state. Coexistence of metabolic syndrome (MetS) and autoimmune rheumatic diseases is already recognized [1, 2], while clinical significance of MetS in patients with APS has not been systematically studied [3]. Recent recognition of certain pleiotropic functions of vitamin D (VitD) has enabled us to hypothesize on its role in the pathogenesis of obesity, MetS, APS, autoimmunity and thrombosis. Therefore, the aim of this review will be: (1) to clarify the possible linking role of VitD between APS and MetS, (2) to critically assess the need for estimation of VitD status in APS patients, depending on the coexistence of MetS and (3) to explore the potential therapeutic role which VitD, as an immunomodulator and anti‐thrombotic agent, could have in these patients. 2. Basic definitions Metabolic syndrome (MetS) and antiphospholipid syndrome (APS) are among most prevalent and still highly controversial syndromes. While clinical relevance of antiphospholipid antibodies (aPL) was recognized more than 30 years ago, definite classification criteria for antiphospholipid syndrome were given at the International Workshop in Sapporo, Japan 1998 [4] and revised 2006 in Sidney, Australia [5]. Very interesting proposal of APS criteria based on biological mechanisms is presented lately aiming at simplicity and greater accuracy and, at the same time, avoiding non‐specific formulations [6] (Table 1). Recent investigations have also shown that, beside characteristic thrombotic or obstetric symptoms, there is growing number of systemic non‐criteria manifestations (for example, thrombocytopenia, livedo reticularis, skin ulcerations, pseudovasculitis, migraine and epilepsy) correlating with certain type of aPL and with important predictive role [7, 8]. It is likely that a prominent place among these manifestations belongs to components of MetS, but it is still to be proved. The prevalence of APS in the general population is estimated to be around 2–4%. Initial Reaven's postulate in 1988, which draw attention to the causal association between insulin resistance with ensuing hyperinsulinemia and cardiovascular diseases [9], was followed by numerous definitions of MetS. Three of them, i.e. definitions given by World Health Organization (WHO) [10], the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) [11] and International Diabetes Federation (IDF) [12], were most frequently used and still neither of them is obsolete. While all three definitions share central obesity, atherogenic dyslipidaemia and arterial hypertension as common criteria, WHO definition put the insulin resistance in focus of metabolic syndrome while an obligatory criterion requested by IDF definition is elevated waist circumference (WC) with population‐ and country‐specific cut‐offs (Table 2). All of these three definitions are very similar but different enough, especially when used for the assessment of prevalence of MetS in some other entities, in this case, among patients with APS. Even the latest joint attempt of several major professional organizations (the IDF Task Force on Epidemiology and Prevention, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity) to unify interconnected cardio‐metabolic risk factors into a universal definition of metabolic syndrome did not seem to be final [13]. Table 1. Antiphospholipid syndrome definitions. Similar ambiguity exists concerning the definition of adequate circulating VitD level, as well as of its deficiency and insufficiency. Earlier definition of VitD insufficiency by its blood level of <20 ng/mL (50 nmol/L), given by the World Health Organization (WHO) [14], has been recently accepted by most researchers as a definition of the deficiency of this vitamin [15, 16]. Its insufficiency is defined as a VitD concentration between 20 and 30 ng/mL (50 and 75 nmol/L), while its concentrations >30 ng/mL (75 nmol/L) are regarded as sufficient [17, 18]. The WHO definition10 NCEP ATP III definition11 IDF definition12 Insulin resistance plus ≥ 2 of: ≥ 3 of: Central obesity plus 2 of: Atherogenic dyslipidaemia Hypertension Microalbuminuria Impaired fasting glucose/Glucose intolerance/Diabetes Table 2. Metabolic syndrome definitions—similar but different enough. 3. Experience from Serbian National APS Registry 3.1. Patients and methods Study included a total of 137 APS patients, attending outpatient clinic of the University Medical Center Bezanijska kosa, all Caucasians, who were previously enrolled in Serbian National APS Registry. These patients represented only the part of those so far included in this Registry, which is still growing and is still unable to appraise the prevalence of APS among general population in Serbia. Among studied patients, 68 were PAPS patients (59 females, nine males, mean age 43.51+10.58 years) and 69 sAPS patients (61 females, eight males; mean age 47.83+15.67 years). All studied APS patients have met 2006 updated Sydney criteria [5] which requested the presence of at least one clinical criteria (i.e. vascular thrombosis or multiple and recurrent foetal losses) and at least one of antiphospholipid antibodies (aPL), i.e. lupus anticoagulant (LA), anticardiolipin (aCL) and/or anti‐β2‐glycoprotein 1 (β2GP1) antibodies. Most of our sAPS patients had APS associated with systemic lupus erythematosus (SLE) (n=60; 87%), while the rest had Sjögren's syndrome (n=8; 11.5%) and ankylosing spondylitis (n=1; 1.5%). Mean duration of these rheumatic diseases in sAPS patients was 5.69+2.87 years, ranging from 1 to 13 years. Characteristics of two subgroups of APS patients were compared with 50 MetS patients (35 females, 15 males; mean age 47.68+11.66 years). The presence of metabolic syndrome among studied patients was determined according to the International Diabetes Federation (IDF) clinical definition [12]. An obligatory criterion for MetS requested by this definition is abdominal obesity defined by elevated waist circumference (WC) with gender‐ and ethnic‐specific cut‐offs, meaning 94 cm for males, and 80 cm for females belonging to European population. Besides abdominal obesity, two or more of the four additional criteria (a) hypertriglyceridemia >150 mg/L, confirmed or already treated; (b) high density lipoprotein (HDL) cholesterol <40 mg/dL in males or <50 mg/dL in females; (c) blood pressure >130/85 mmHg, newly diagnosed or already treated; (d) impaired fasting glycaemia, >100 mg/dL or previously diagnosed diabetes) are necessary for the diagnosis. For every participant, clinical data concerning thrombotic events, their appearance, management and follow‐up were obtained from medical charts review. As thrombotic events, the following were recorded: superficial and deep venous thrombosis, pulmonary embolism, peripheral arterial occlusion, cerebral vascular accident and myocardial infarction. After an overnight fast, height (m), weight (kg) and waist circumference (cm) were measured in every participant with underwear and without shoes. Waist circumference (WC) was measured at the level of the umbilicus while the participant was standing and breathing normally. Body mass index (BMI) was calculated according to the widely accepted formula dividing body weight by the square of individual's height. Morning samples of venous blood (3–5 mL) were withdrawn from every participant for the analysis of serum glucose and lipids. Serum vitamin D levels were determined in every participant . The study was approved by the Institutional Ethics Committee. All examinations were conducted according to the most recent amendment of Declaration of Helsinki (Edinburgh, 2000), only after obtaining an informed consent for participation in the study from every subject. Statistical analysis was performed using the STATISTICA 10 software program. Descriptive statistics was used. Prevalence of MetS as well as of its individual components, within studied groups of patients was expressed as percentage. Testing significance of their differences, the Student's t‐test and Fisher's exact test were used, considering p value <0.05 statistically significant. 3.2. Results 3.2.1. Prevalence of MetS among patients with APS Metabolic syndrome was observed in high percentage of patients with APS. Its prevalence did not differ significantly between PAPS (36.76%) and sAPS (42.03%) patients (p=0.53). Anthropometric and metabolic syndrome characteristics among studied groups are given in Table 3. Borderline statistical significance of the difference in WC value was observed when two subgroups of APS patients were compared with MetS patients (F=2.77, p=0.065), while BMI has differed highly significantly between these groups (F=9.765, p=0.0001). In spite of slightly lower BMI and slightly higher WC in PAPS patients, neither BMI (p=0.434) nor WC (p=0.275) did differ significantly between two subgroups of APS patients. Atherogenic dyslipidaemia, represented by hypertriglyceridemia and low HDL cholesterol, was the most prevalent characteristic of metabolic syndrome among PAPS patients. In spite of this, prevalence of low HDL cholesterol among PAPS patients were significantly lower than in MetS patients (48.3% vs. 70%, p=0.02). Prevalence of hypertriglyceridemia (45.59% vs. 42.03%, p=0.67) and low HDL cholesterol (48.53% vs. 53.62%, p=0.55) did not differ significantly between PAPS and sAPS patients. Hypertension was significantly less prevalent among these patients compared with MetS (23.53% vs. 58%, p=0.0002) and even with sAPS (23.53% vs. 52.17%, p=0.0007) patients. The least prevalent characteristic of metabolic syndrome among patients with APS was hyperglycaemic disorder. Compared with MetS patients in whom impaired fasting glycaemia, glucose intolerance or diabetes were present in as much as 36%, these disorders were observed in only 5.88% of PAPS patients (p=0.0001) and 4.35% of sAPS patients (p<0.0001). MetS PAPS sAPS BMI (kg/m2) 32.09+6.14 27.81+5.98 28.54+4.22 WC (cm) 93.67+14.36 90.73+9.18 88.53+11.91 TG > 150 mg/dL (%) 58 45.59 42.03 HDL < 40/50 mg/dL (%) 70 48.53** 53.62 Hypertension (%) 58 23.53**** 52.17§§ IFG, IGT, DM (%) 36## 5.88**** 4.35 Table 3. Anthropometric and metabolic syndrome characteristics among studied groups. *p < 0.05, PAPS vs. MetS. **p < 0.01, PAPS vs. MetS. #p < 0.01, sAPS vs. MetS. §p < 0.01, PAPS vs. sAPS. 3.2.2. Prevalence of thrombotic events among APS patients with or without MetS Compared with patients with metabolic syndrome, prevalence of thrombotic events was significantly higher among patients with PAPS (52.94% vs. 22%, p=0.0009) and sAPS (56.52% vs. 22%, p=0.0003). Thrombotic events were reported with similar prevalence in PAPS and sAPS patients (p=0.674). When compared with APS patients without characteristics of MetS, thrombotic events were significantly more frequent among MetS positive patients with sAPS (75.86% vs. 42.5%, p=0.0075). Although higher among MetS positive, compared with MetS negative patients with PAPS, difference of prevalence of thrombotic events among these two subgroups of PAPS patients did not reach statistical significance (68% vs. 44.19%, p=0.0622). 3.2.3. Vitamin D status among APS patients depending on MetS and/or thrombotic events Low VitD status (insufficiency or deficiency) was highly prevalent among PAPS (insufficiency in 27.94% and deficiency in 36.76%) and sAPS patients (insufficiency in 30.43% and deficiency in 40.58%), as well as among patients with pure MetS (insufficiency in 20% and deficiency in 32%). In comparison with patients with pure MetS (28.58+14.32 ng/mL), VitD concentrations were lower in PAPS (25.76+12.18 ng/mL) and sAPS patients (23.81+11.22 ng/mL), but with statistically significant difference only between these concentrations in sAPS patients and patients only with MetS (p=0.04). Significantly lower VitD level was observed in those with coexisting MetS (MetS +), compared with those without it (MetS -) both in PAPS (MetS +: 22.0+8.52 vs. MetS -: 27.0+13.49 ng/mL, p=0.05 ) and sAPS patients (MetS +: 18.83+9.16 vs. MetS -: 27.42+11.28 ng/mL, p=0.0012). Also, significantly lower VitD level was observed in APS patients with thrombotic events (TE+), compared with those without these events (TE -), both in PAPS (TE +: 20.61+12.18 vs. TE -: 31.56+12.72 ng/mL, p=0.0001 ) and sAPS patients (TE +: 20.67+10.43 vs. TE -: 27.9+11.04 ng/mL, p=0.007). In 11 (22%) of patients with MetS, but without APS, some thrombotic event was confirmed. In those patients, VitD levels were also significantly lower than in those without these events (TE +: 18.45+10.66 vs. TE -: 31.43+13.63 ng/mL, p=0.003). However, both in PAPS and sAPS patients, with coexisting MetS, previous thrombotic events did not influence serum VitD levels (PAPS: p=0.12; SAPS: p=0.93). 4. Relationship between antiphospholipid syndrome and metabolic syndrome Estimation of prevalence of MetS in general population seems to depend to a substantial degree on the used definition, at least in certain countries or in certain ethnic groups [19–22]. Its prevalence varies between <10% in China and as much as 60% among women of Samoa [23]. Different prevalences of MetS, ranging between 18 and 48%, were also recorded among populations of different European countries and regions [20–22, 24–26]. It is interesting to emphasize that even in populations in which comparable prevalence of MetS was found using each of three already mentioned definitions, level of agreement between them was not good. As could be expected, worse agreement was found between WHO‐NCEP ATP III and WHO‐IDF than between NCEP ATP III‐IDF definitions because of the central obesity as common denominator of the last two definitions [20, 21, 23]. This observation raised the possibility that in fact different individuals were identified as having MetS by different definitions of this syndrome [23]. In a search for factors that contribute to the manifestations of APS, MetS came into a focus surprisingly late. Data on coexistence of these two syndromes are still relatively scarce, particularly considering that of MetS and primary APS (PAPS). 4.1. Metabolic syndrome in primary antiphospholipid syndrome patients Recently, prevalence of MetS among PAPS patients has been assessed by Medina et al. [3] and Rodrigues et al. [27]. Both surveys were performed in Hispanics among whom MetS has the highest prevalence [28]. Defined by the IDF criteria, the prevalence of MetS among 71 Brazilian PAPS patients was 33.8% [27]. Comparable prevalences of MetS were recorded among 58 Mexican PAPS patients, using NCEP ATP III (34.5%) or IDF definitions (37.9%), while it was only 17.2% when WHO definition was applied [3]. It has been hypothesized that these cases, identified by WHO definition, were insulin resistant and with more severe forms of MetS [3, 29]. However, in investigation conducted by Medina et al., prevalence of MetS among PAPS patients was higher than in corresponding general population (17.2% vs. 13.6%) when WHO definition was used [3]. Same as in general population without APS [20, 21, 23], among PAPS patients agreement between WHO and NCEP ATP III definitions of MetS was low (κ value 0.394), moderate between WHO and IDF definitions (κ value 0.427), while only between NCEP ATP III and IDF definitions agreement was good (κ value 0.851) [3]. Regarding individual components of MetS, atherogenic dyslipidaemia was most prevalent among Mexican PAPS patients, being present in approximately half of them [3]. Significantly higher mean triglyceride levels and significantly lower mean HDL levels were previously reported among PAPS patients in comparison with controls [30–33]. Some specific autoantibodies could influence lipoprotein levels and effects in these patients. These antibodies may interfere with paraoxonase (PON) activity of HDL and, indirectly, beta‐2‐glycoprotein I (beta‐2‐GPI) [32, 33], thus promoting LDL oxidation. Relationships between lipid profile, certain anti‐lipoprotein antibodies, inflammatory markers and clinical manifestations of PAPS were meticulously investigated [31–33], but on relatively small number of patients and with inconsistent results. Delgado Aves et al. have not demonstrated any correlation between the observed decrease in PON activity and either aPL nor antibodies against HDL (anti‐HDL) in PAPS patients [33]. However, pro‐inflammatory and prothrombotic roles were proposed for anti‐HDL, being present in higher titre among asymptomatic persistently aPL positive subjects, as well as in PAPS patients with thrombotic events, when compared with patients with inherited thrombophilia and healthy controls [32]. It has been also hypothesized that hypertriglyceridemia could be the result of decreased degradation as a consequence of an inhibition of lipoprotein lipase (LPL) by aPL [3]. Currently, there are only scarce data on prevalence of antibodies against LPL (anti‐LPL) in PAPS patients, speaking against their existence and influence [31]. Different authors have observed similar prevalences of hypertension among PAPS patients (22.4 and 26.3%) [3, 31], not differing significantly from that in controls (20%). Nevertheless, among PAPS patients, hypertension was significantly more frequent in those with arterial thrombosis, with which it was independently associated [31]. It is interesting that in spite of highly prevalent insulin resistance (32.8%), hyperglycaemic disorders were present in only 5% of PAPS patients [3]. 4.2. Metabolic syndrome in patients with antiphospholipid syndrome associated with autoimmune rheumatic diseases. The literature data on coexistence of MetS and numerous rheumatic diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, osteoarthritis, gout) are fairly extensive [1, 34–42]. The prevalence of MetS among patients with these disorders ranges between 14 and 62.8% [1, 3]. Qualifier “antiphospholipid syndrome associated with certain autoimmune rheumatic disease” (sAPS), which replace currently obsolete term “secondary APS”, refers mainly to the systemic lupus erythematosus (SLE) despite the still unscrambled puzzle of their relations [5]. It has been speculated that high prevalence of MetS among these patients might be the consequence of certain pharmacologic interventions, particularly of chronic corticosteroid therapy [43]. However, the presence of MetS in as much as 16% of 1494 young (35.2+13.4 years) SLE patients with rather short disease duration (24.1+18.0 weeks) seems to be enough to reject this relationship as causal [2]. Nevertheless, it should be kept in mind that duration and magnitude of corticosteroid exposure could aggravate well‐known cardiovascular risk factors clustering as characteristics of MetS. On the other hand, other pharmacological interventions, primarily methotrexate (MTX) use in patients with rheumatoid arthritis, have been depicted as independent factors for reduced prevalence of MetS in these patients, especially those older than 60 years [44, 45]. This beneficial effect of MTX was attributed to its anti‐inflammatory, as well as to some still unclear drug‐specific effects, i.e. affecting adenosine levels and, concomitantly, glucose and lipid metabolism, or decreasing homocysteine levels as an indirect effect of simultaneous use of folic acid [44]. However, other authors reported somewhat conflicting results not being able to confirm decreasing prevalence of MetS in subjects treated with MTX, among total of 353 patients with rheumatoid arthritis [46]. 5. Vitamin D and thrombosis Prothrombotic state is one of the well‐known characteristics of both antiphospholipid and metabolic syndrome. It has rather complex pathogenesis in which VitD status has an important role affecting primarily immune‐mediated thrombosis. Indirect proofs for this relationship are as follows: (a) existence of nuclear VitD receptors in vascular smooth muscle cells, endothelial cells, cardiomyocytes, platelets, as well as in most types of the immune cells [47–51], and (b) expression of cytochrome P450 enzyme, CYP27B1 activity by the same cell types, enabling local synthesis of biologically active form of VitD, 1,25(OH)2D [52]. There is substantial experimental data indicating that VitD plays significant role in maintenance of physiological balance between thrombosis and haemostasis [47]. It has been demonstrated that VitD exerts following actions: in monocytes, expression of tissue factor (TF) is downregulated, while the expression of thrombomodulin (TM) is upregulated [53]; in vascular smooth muscle cells, the expression of TM is upregulated, but there is also downregulation of plasminogen activator inhibitor‐1 (PAI‐1) and thrombospondin‐1 (THSP‐1) [54]; in endothelial cells, platelet activation is attenuated as well as the expression of vascular cell adhesion molecule‐1 (VCAM‐1) [55]. Net result of numerous effects of this vitamin on different haemostatic factors is its antithrombotic role. Prothrombotic state that exists in VitD receptor knockout animal models proves the importance of these extra‐skeletal effects of VitD as well as the observation that all of them are VitD receptor‐mediated [47, 56]. However, there are still relatively few indirect and even less direct clinical evidences for the association between VitD status and thrombotic events in humans. First of them came from the epidemiological studies in which have been observed that cardiovascular morbidity and mortality depended on season of the year and latitude [47, 57, 58]. Seasonal variations were also demonstrated for tissue plasminogen activator (tPA) antigen, fibrinogen, D‐dimer and von Willebrand factor (vWF) concentrations in 6538 British subjects without significant cardiovascular disorders, aged 45 years [59]. In this population, negative correlation between VitD level and tPA, fibrinogen and D‐dimer concentrations was observed indicating that at least some of the seasonal variations of these thrombotic markers could be attributed to the VitD status. More direct proof for the association between VitD status and thrombosis came from the research conducted in huge population of 18 791 subjects from general population of Copenhagen [60]. Authors have observed that every quartile of a decrease in VitD concentrations was accompanied by an increase in risk of venous thromboembolism (VTE), resulting in a 37% increased VTE risk between subjects with the VitD concentrations, in the lowest quartile and those in highest quartile. Recent publication which retested the seasonality of different cardiovascular events in regard to VitD levels, in the Scottish Heart Health Extended Cohort (SHHEC), brings a dose of confusion in previously proposed relations. Namely, it failed to prove that seasonal appearance of cardiovascular events resembled seasonal variations in serum VitD concentrations nor that these events expressed more pronounced seasonality in those with lower VitD concentrations, compared with those with its higher concentrations [61]. But, during follow‐up, significant correlations were observed between lower baseline concentrations of VitD and subsequent incident cardiovascular morbidity and incident cardiovascular and all‐cause mortality [61]. Results of recent trials assessing the effects of VitD supplementation on the risk of thromboembolism were inconclusive [62–64]. In the Multiple Environmental and Genetic Assessment (MEGA) case‐control study which included 2506 patients with venous thrombosis, thrombotic risk was 37% lower in those supplemented with various vitamins including VitD [62]. However, in a large cohort of postmenopausal women (n=36282) from the Women's Health Initiative, daily supplementation with calcium and VitD failed to reduce the overall risk of thromboembolism [63]. Even when high doses (300,000 IU) of VitD were given intramuscularly, in a small group of patients with proven deep vein thrombosis and pulmonary embolism, observed reduction in plasma concentrations of P‐selectin and high‐sensitive C‐reactive protein (hs‐CRP) did not reached statistical significance [64]. Additional information could be expected from the ongoing Vitamin D and OmegA‐3 Trial (VITAL) and that is why the results of this investigation are eagerly awaited [65]. 6. Role of vitamin D in metabolic syndrome Currently, increasing prevalence and co‐existence of obesity, MetS and hypovitaminosis D represent serious public health concern [66, 67]. New data have considerably changed hierarchy of MetS components, with the shift of the focus from obesity and insulin resistance, firstly toward fatty liver and now toward VitD deficiency [68]. It is still questionable if relationship between VitD status and obesity is unidirectional or bidirectional, with the accumulating evidence favouring the influence of VitD on body composition and not vice versa. Namely, few years ago tempting hypothesis on essential role of VitD in evolvement of obesity has been postulated [68]. It started from a situation that is completely opposite to the “thrifty genotype hypothesis” proposed long ago [69] and gave the feasible explanation not only for obesity and MetS epidemic in adults but also for their growing prevalence among children [70]. According to this hypothesis, we are living in “obesogenic” environment, loaded with energy resources and unsuitable for efficient metabolism. It has been proposed that VitD as an ultraviolet (UV)‐B radiation sensor (i.e. decline in its concentrations) could induce shift toward “winter metabolism”, characteristic for MetS [68]. If this is true, then it could be expected that VitD supplementation may be efficient in prevention and treatment of obesity and MetS. Significant decrease in body fat mass after 12 week of VitD repletion (25 μg of cholecalciferol daily), compared to placebo (−2.7+2.0 kg vs. −0.4+2.0 kg, p<0.001), could be the proof for this presumption [71]. It was also speculated that VitD deficiency during pregnancy could lead to the epigenetic changes predisposing, in that manner, new‐born children to obesity and MetS later in life [68, 70]. Experimental support for these assumptions is the expression of VitD receptors on adipocytes and its involvement in adipogenesis which is regulated by the intracellular concentrations of VitD [72], as well as inhibition of lipid accumulation in adipocytes and their atrophy achieved by the knock‐down of VitD receptors [72, 73]. Nowadays, VitD deficiency is common even in general population (49%), but significantly more prevalent (p=0.006) and quite similar in overweight/obese patients with MetS (72%) and without MetS (69%) [74]. Premise that exaggerated adiposity could lead to VitD insufficiency or deficiency by its seclusion within adipose tissue could not be confirmed. It has been shown that VitD concentrations varied considerably (range 4–2470 ng/g) in the subcutaneous abdominal fat of 17 severely obese patients (BMI=48.7+8.1 kg/m2) undergoing bariatric surgery [75]. In spite of the average weight loss of 54.8 kg after one year and continuous VitD supplementation with more than 2500 IU/day, mean serum VitD concentrations did not change significantly during this period (23.1+12.6 vs. 26.2+5.36, p=0.58) [75]. Most of the studies have confirmed that serum VitD concentrations significantly inversely correlated with obesity parameters, BMI (r=-0.159, p=0.007) [74], or waist circumference (p<0.001) [76] as well as with serum triglycerides (r=-0.149, p=0.012) [76]. In the lowest quartiles of VitD concentrations corresponding to its severe deficiency, odds ratio (OR) for hypertriglyceridemia was 2.74 (95% CI: 1.64–4.57) [77]. This association between serum concentrations of VitD and triglycerides could be explained by the activation of lipoprotein lipase by VitD in adipocytes [76]. No significant relation could be demonstrated between VitD status and total‐ (r=-0.044, p=0.461) [74], low density lipoprotein (LDL)‐ (r=-0.005, p=0.932) and high density lipoprotein (HDL)‐cholesterol (r=0.065, p=0.276) [74]. Interestingly, hypothesis was proposed ten years ago stating the possibility that statins could be the analogues of VitD, acting via same receptors, particularly when we are talking about their mutual effect of enhancement of immune competence [78]. So, it seems that this absence of association between VitD status and parameters of cholesterol metabolism made this hypothesis shaky to some extent. Another component of MetS for which association with VitD status has not been unequivocally confirmed is hypertension. Variability of blood pressure driven by the seasons or latitude speaks for the existence of this association, as well as the results of experimental studies pointing to VitD as an inhibitor of the renin‐angiotensin‐aldosterone axis [79, 80]. Negative correlation between VitD concentrations and blood pressure was demonstrated in most but not all of the surveys. This negative association was stronger in subjects younger than 50 years [81–83], while the absence of any relationship between VitD status and hypertension was also registered in some of the trials [74, 76, 84, 85], particularly those conducted in older subjects [84, 85]. However, in postmenopausal women with the VitD concentrations in the lowest quartiles corresponding to its severe deficiency, odds ratio (OR) for hypertension was 1.81 (95% CI: 1.15–2.85) [77]. 7. Role of vitamin D in antiphospholipid syndrome Although APS represents acquired, autoimmune condition, its pathophysiology and, especially pathophysiology of thrombosis in APS is highly heterogeneous, involving different genes and acquired factors [86], VitD insufficiency/deficiency being among them. Same as for relationship between MetS and APS, much more is known about the impact of VitD status on antiphospholipid syndrome, associated with autoimmune rheumatic diseases, than on primary antiphospholipid syndrome. Patients with PAPS represent the population of particular interest for the investigation of interrelations with components of MetS and/or VitD status since these patients, unlike those with sAPS, were not treated with drugs (i.e. corticosteroids, immunosuppressants) which may affect expression of most of the MetS characteristics as well as VitD level. One of the first announcements on the prevalence of VitD insufficiency or deficiency in PAPS and their impact on its manifestations dated from 2010 [87]. This letter to the editor presented the results of research conducted by Brazilian investigators in the group of forty‐six PAPS patients, younger than 60 years, in whom the VitD levels were assessed in the autumn, when it was expected to be highest. VitD deficiency was found in 11% and insufficiency in 74% of these PAPS patients, resembling the findings of Italian authors [88] which have reported the prevalence of VitD deficiency in 17% and insufficiency in 60% of PAPS patients. It is interesting that Brazilian authors have noticed that VitD insufficient PAPS patients tended to be more overweighed than those with adequate VitD level [87]. Also, it seems that thrombotic APS is characterized with significantly lower concentrations of VitD than purely obstetric clinical syndrome (20.8 vs. 33.3 ng/ml, p<0.01) [88] highlighting once again the role of this vitamin in thrombosis. High prevalence of VitD deficiency among patients with APS (49.5%) and its significant correlation with thrombotic events were confirmed by Israeli authors [68]. In vitro, they have also demonstrated VitD ability to inhibit anti‐β2‐glycoprotein I autoantibody (anti‐β2‐GPI Ab)‐mediated TF expression [89]. Seasonal variations in VitD concentrations were demonstrated in PAPS patients same as in healthy controls, with preserved differences in its level between these two groups through all seasons [88, 90]. These differences were most pronounced during summer, while they were not statistically significant only during the spring. This observation was somewhat surprising, given the lack of banning from sun exposure in these patients. That sun avoidance is not a cause of highly prevalent VitD deficiency and insufficiency in PAPS patients was indirectly demonstrated in previous Italian studies [88, 90] by observed absence of any difference in VitD levels between antinuclear antibodies (ANA)‐positive and negative PAPS patients. Until now, there is no valid explanation for the probable cause‐and‐effect relationship between insufficient VitD level, on one side, and PAPS or sAPS, on the other. There are only assumptions, and even they are much better clarified for sAPS [91–93], especially that accompanying SLE [91, 94, 95]. It is obvious that low levels of vitamin D in sAPS could not be attributed purely to banning of sun exposure or the use of certain medication in these patients. In an Israeli and European cohort of patients with SLE, significant negative correlation (r=-0.12, p=0.018) was demonstrated between the serum VitD concentrations and disease activity, assessed by SLE disease activity‐2000 (SLEDAI‐2K) and European Consensus Lupus Activity Measurement (ECLAM), which were converted into standardized z‐value [94]. Severe VitD deficiency was found in 17.89% of 123 SLE patients with short disease duration, while the presence of renal disease (OR 13.3, 95% CI 2.3–76.7, p<0.01) and photosensitivity (OR 12.9, 95% CI 2.2–75.5, p<0.01) were its strongest predictors [95]. Investigation conducted in a small group of young women with newly diagnosed SLE, from one of the sunny places in Iran, gave very interesting results. VitD deficiency was highly prevalent among these patients, mild in 12.5%, moderate in 62.5% and severe in 17.5% of them [96]. It was much more pronounced in them than in general population of the similar age in that region, in whom mild VitD was present in 15.5%, moderate in 47.1% and severe in 7.1%. Very interesting was also an observation that serum VitD concentrations showed significant negative correlation with another disease activity score, the British Isles Lupus Assessment Group (BILAG) (r=-0.486, p=0.001), in spite of the short duration of disease [97]. Hypothetical explanation for the low serum concentrations of VitD in SLE patients by the existence of inhibiting anti‐VitD antibodies in circulation could not be confirmed by the literature data [97, 98]. Their existence could be proven in 4–6% of patients with SLE and 3.5% of APS patients. Its association with anti‐dsDNA (p=0.0004) could point to its potential role in this condition, but being only one of 116 different antibodies present in SLE patients characterized by the polyclonal B lymphocyte activation, it is still uncertain if it is pathogenic [97]. It seems that their presence did not affect VitD levels in these patients [97, 98], and it was speculated that they could be the consequence of high‐dose VitD consumption rather than the cause of this vitamin deficiency [99]. Once again, it is important to emphasize that VitD deficiency is more pronounced in more severe APS phenotypes, i.e. thrombotic APS [88]. It could be speculated that supplementation of this vitamin in these very patients may have certain beneficial effects [88, 99], but there is still no prospective studies proving them. Hypothesis of statins as VitD analogues has not still been tested in well‐designed, randomized prospective trials [78]. However, since its proposal, there have been many experimental and small clinical studies confirming statins therapeutic value in APS patients, particularly in those with its thrombotic form [99–103]. So, future studies are badly needed to determine all the aspects of VitD repletion in APS prevention/therapy (choice between VitD precursors, its active form or VitD analogues, their dosage and treatment goals). 8. Key messages Prevalence of metabolic syndrome in APS, primary or associated with certain rheumatic diseases, is high. Atherogenic dyslipidaemia is the most prevalent characteristic of metabolic syndrome in APS patients. Prevalence of thrombotic events was significantly higher in APS patients with coexisting metabolic syndrome, compared with APS patients without metabolic syndrome characteristics. Among APS patients, prevalence of vitamin D deficiency was significantly higher in patients with coexisting metabolic syndrome, compared with those without it. Among APS patients, vitamin D level was also significantly lower in patients with previous thrombotic events than in those without them. In the contemporary literature, there are much more data in favour of pathogenic than therapeutic role of vitamin D in thrombotic events characterizing APS and/or metabolic syndrome. So, prospective studies designed to test all the aspects of VitD repletion in prevention and/or therapy of thrombotic events in APS and/or metabolic syndrome are badly needed. 9. Conclusions Elucidating interrelationships between vitamin D deficiency, metabolic syndrome phenotype and thrombotic events in APS patients open up the possibility of distinguishing those subjects with the particularly high cardiovascular risk and ensuing need for the strict control of modifiable risk factors and vitamin D supplementation. https://www.intechopen.com/books/a-critical-evaluation-of-vitamin-d-clinical-overview/pathogenic-and-therapeutic-role-of-vitamin-d-in-antiphospholipid-syndrome-patients?fbclid=IwAR13oFb5S8e5R6f1L-vx0pxauf2symfpH-6HRvRStXPftkvKgEoOZUc1xrk
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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/
  8. 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
  9. Understanding the Role of Polyautoimmunity in Rheumatic Diseases (©Zerbor,Shutterstock.com) Linda Peckel July 16, 2019 Rheumatology, Autoimmune Diseases, Modern Medicine News, News, Rheumatoid Arthritis An estimated 5 percent of the world’s population is diagnosed with one of a group of heterogeneous autoimmune rheumatic diseases (ARDs) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren’s syndrome (SS). Not only do these diseases share mechanisms and risk factors, they are often comorbid conditions recognized as polyautoimmune (PolyA) manifestations of the same underlying dysfunction. Patients with SLE are frequently positive for anti-rheumatoid factor (RF) and less often for anti-citrullinated protein antibodies associated with RA, although less than 10% are diagnosed with concomitant SLE/RA, known as rhupus. Another 10% of SLE patients are recognized to have antiphospholipid syndrome (APS) although up to 54% have been shown to carry antibodies. Other PolyA’s may include SLE/hypothyroidism, RA/autoimmune thyroid disease (AITD), and concomitant symptoms of SS with SLE, AITD, or systemic sclerosis (SSc). According to studies by Gonzalez and colleagues (the most recent of which is published in the Journal of Autoimmunity)1 , 2 patterns of PolyA have emerged: 1) Overt PolyA, which reflects more than one well-defined ARD in a single patient, and 2) Latent PolyA, in which underlying patterns of autoantibodies are identified that do not correspond to the main diagnosis, and may be predictive of 1 or more additional ARDs. The authors conducted a cross-sectional cluster analysis of patients with the most common ARDs for antibody and cytokine patterns in a cohort of 187 individuals with diagnoses of SLE, RA, SSc, and SS (n = 70, 51, 35, and 31). They found that the frequency of PolyA did not differ across all 4 ARDs, although SLE and SS were associated with a younger age of onset. Rheumatoid factor and CCP3 were identified in 84.3% and76.5% of patients with RA, who also had the highest levels of Interleukin (IL)-6, interferon (IFN)-α, and IL-12/23p40 cytokines. Antinuclear antibodies (ANAs) were most prevalent in patients with SSc (97% positive) and SLE patients (71.4%), with distinctive patterns of additional antibodies and cytokines to each disease. The study revealed six main PolyA clusters involving the 4 ARDs that may provide biomarkers useful for diagnosis of current disease as well as prediction of other ARDs over time. The authors suggested that particular attention should be paid to latent PolyA, and to the strong association of IL-12/23p40 to 3 of the 6 cluster groups. REFERENCE 1. Molano-González N, Rojas M, Monsalve DM. "Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity." J Autoimmun 2019;98:24-32. https://www.rheumatologynetwork.com/rheumatology/understanding-role-polyautoimmunity-rheumatic-diseases?rememberme=1&elq_mid=7781&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  10. Fatigue in Patients with Lupus is Real Fatigue in patients with systemic lupus erythematosus (SLE) has been linked to anti-NR2 antibodies, which responds to treatment with belimumab, a study shows. (©ArtemidaPsy,Shutterstock.com) Whitney J. Palmer June 24, 2019 Lupus, Rheumatology, Women's Health Patients with systemic lupus erythematosus (SLE) who have higher levels of antibodies to the receptor in the brain associated with memory and learning also experience more severe levels of fatigue, new research shows. The results, published in a recent issue of Annals of Rheumat ic Diseases, identifies a link between fatigue—one of the most challenging symptoms patients with systemic lupus erythematosus face—and the presence of anti-NR2, a brain-reacting antibody. “The presence of anti-NR2 antibodies in patients with lupus with fatigue is a helpful diagnostic tool and may offer a major approach in the therapeutic management of this important disabling symptom in patients with lupus,” said Andreas Schwarting, M.D., a rheumatologist, immunologist, and medical director at the University Medical Center of the Johannesburg-Gutenberg University Mainz in Germany. Elevated levels of anti-NR2 have been reported in 25 percent to 38 percent of patients with lupus, they said, so these findings could affect a substantial number of patients. To determine the impact of these autoantibodies, researchers analyzed blood samples from 426 patients with lupus. They also assessed fatigue severity using a self-reporting questionnaire. The findings found that patients with higher anti-NR2 levels experienced the more significant impacts of fatigue, including motoric and cognitive fatigue. Researchers found no correlation between anti-NR2 levels and renal function, erythrocyte sedimentation rate, or C-reactive protein. Study results also showed belimumab effectively relieved fatigue. Patients receiving belimumab for six months to 36 months saw a significant decline in their levels of anti-NR2 antibodies, as well as a clinically significant drop in their fatigue scores. Overall, investigators said, the findings could directly impact patient care. “The results of our study offer a sustained clinical advantage: to add an objective measurement of fatigue in lupus patients to a subjective questionnaire,” they said. “Anti-NMDAR antibodies should be identified routinely for patients with lupus suffering from fatigue.” REFERENCE Schwarting A, Mockel T, Lutgendorf F, et al. "Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies." Annals of Rheumatic Diseases(2019), doi: 10.1136/annrheumdis-2019-215098. https://www.rheumatologynetwork.com/lupus/fatigue-patients-lupus-real?rememberme=1&elq_mid=7437&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  11. Fracture Risk is High in Lupus Patients with systemic lupus erythematosus (SLE) are at an increased risk for fractures, new research shows. The risk is particularly high among patients with lupus nephritis. (©PollapatChirawongShutterstock.com) Whitney J. Palmer June 24, 2019 Lupus, Joint/Bone Health, News, Rheumatology Patients with systemic lupus erythematosus (SLE) are at an increased risk for fractures, new research shows. The risk is particularly high among patients with lupus nephritis. In a study published in a recent issue of Arthritis & Rheumatology, investigators foiund that patients with lupus nephritis were far more likely to break a bone than patients who do not have lupus. “Patients with lupus nephritis may be at particularly high risk of fracture due to secondary or tertiary hyperparathyroidism and vitamin D deficiency,” said study author Sara Tedeschi, M.D., MPH, a rheumatology fellow at Brigham and Women’s Hospital. To assess fracture risk, researchers examined medical records for 47,709 lupus patients, including 9,449 patients who also had lupus nephritis. They identified pelvic, wrist, hip, and humeral fractures and compared these records to those of 190,836 patients without lupus. According to results, all lupus patients had a two-fold higher risk for any fracture compared to patients without lupus. Lupus nephritis patients have a three-fold risk over non-lupus patients and a 1.6-fold increase over lupus patients. However, findings did indicate that African American patients with lupus experienced a lower fracture risk than other study participants. When examining risk for specific types of fractures, investigators found lupus patients were at high risk for hip and pelvic fracture compared to patients without lupus. The risk was also elevated, though not as much, for humerus and wrist fractures. Researchers also discovered younger lupus patients had a 2.3-times higher fracture risk than younger patients who didn’t have lupus. Lupus patients over age 50 had a two-fold fracture risk increase. Less than half of patients with lupus received glucocorticoid treatment, indicating use of this medication was only responsible for some increased fracture risk. Ultimately, investigators said, these results reinforce the importance of identifying high-risk patients who have lupus and lupus nephritis to monitor them and provide for fracture prevention. REFERENCE Tedeschi S, Kim S, Guan H, Grossman J, Costenbader K. "Comparative Fracture Risks Among United States Medicaid Enrollees With and Those Without Systemic Lupus Erythematosus." Arthritis & Rheumatology (2019), doi: 10.1002/art.40818 https://www.rheumatologynetwork.com/lupus/fracture-risk-high-lupus?rememberme=1&elq_mid=7437&elq_cid=1830808&GUID=9D824BFE-EF27-47A3-BAE0-900DC34C90C7
  12. Treatment with Tofacitinib Helps Relieve Arthritis and Rash Symptoms in Lupus Patients, Study Shows lupusnewstoday.com/2019/05/31/tofacitinib-relieve-arthritis-skin-rash-symptoms-sle/ Ana PenaMay 31, 2019 Tofacitinib tablets, a medicine approved to treat rheumatoid and psoriatic arthritis, may work for lessening signs and symptoms of arthritis and skin rash in people with systemic lupus erythematosus (SLE), a small study has found. These findings were reported in the letter “Successful treatment of arthritis and rash with tofacitinib in systemic lupus erythematosus: the experience from a single centre” that was published in the journal Annals of Rheumatic Diseases. Tofacitinib is marketed by Pfizer with the brand name Xeljanz for treating rheumatoid and psoriatic arthritis in adults who have failed treatment with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs). The medicine also has been approved to help manage inflammation in adults with ulcerative colitis, another chronic inflammatory condition. It blocks the activity of certain janus kinases (JAK) enzymes, which are critical for the activity of the immune system. By targeting JAKs, tofacitinib inhibits the activity of several signaling molecules, including interferons and interleukins known to have a role in SLE development and progression. Clinical data collected from rheumatoid arthritis patients indicates that tofacitinib can act quickly to reduce inflammation, as corticosteroids do, but without the side effects of steroids. Tofacitinib has been used off-label to treat SLE in some patients, but there is still very little data about the effectiveness and safety of this treatment for lupus. That’s why a group of researchers at the Peking Union Medical College Hospital in China evaluated tofacitinib’s effectiveness in a group of 10 lupus patients seen at the center. Nine women and one man received 5 mg of tofacitinib two times a day, and were followed by the team for at least four weeks and up to one year. At each follow-up visit, patients were monitored for disease activity with laboratory tests, such as measurement of anti-dsDNA antibodies and complement C3 levels, and by using scoring systems commonly used in clinics — SLE Disease Activity Index-2000 (SLEDAI-2K) and physician’s global assessment (PGA). Within one year, tofacitinib yielded a quick resolution of arthritis in all four patients who had such symptoms, and promoted significant relief in skin rash in six of nine participants. All those patients who experienced improvements achieved clinical remission of arthritis or skin rash. Tofacitinib’s effectiveness for rash, however, was more uncertain. In two patients, the medicine improved symptoms only partially or not at all. And another patient even experienced a flare during the follow-up period. Despite the rapid benefit seen for disease activity, SLE blood markers remained unchanged during the study. This agrees with prior tests reported for a different JAK inhibitor, baricitinib (sold in the U.S as Olumiant), in lupus patients and animal models. Two patients experienced treatment-related adverse events. One had herpes varicella zoster (shingles) and the other had alopecia (spot baldness). Both continued on tofacitinib, but their dosage was tapered and they ended up achieving disease remission. Based on these findings the team believes that “tofacitinib can rapidly improve the symptoms and signs of arthritis and partially improve skin rash in patients with SLE, sparing steroid to reach [clinical remission].” In view of the small number of patients studied and the variable periods of follow-up for each of them, researchers stress that more studies are needed to confirm tofacitinib’s effectiveness and define its specific indication in patients with SLE.
  13. Gene Changes Key to Successful Pregnancy in Lupus April 29, 2019 Pregnant women with lupus are more likely to suffer complications than those who don’t. Lupus Research Alliance Scientific Advisory Board members Dr. Virginia Pascual, Professor at Weill Cornell Medicine; and Dr. Jane Salmon, Collette Kean Research Professor at Hospital for Special Surgery, and their colleagues asked if testing the blood, of pregnant women with lupus, using advanced technologies could identify, early in pregnancy, lupus patients at high risk for complications. Their new paper in the Journal of Experimental Medicine shows that during uncomplicated pregnancy in both healthy and lupus women some genes that incite the immune system become less active. These changes may make the immune system less aggressive and reduce the odds that it will attack the fetus. However, women with lupus who had pregnancy complications, including preeclampsia, did not show the desirable decrease in these immune signatures. Doctors came up with the term “lupus” because they thought the disease’s skin inflammation looked liked a wolf’s bite. The study “supports the idea that in some cases, pregnancy can ‘tame the wolf.’” Drs. Timothy Niewold and Shilpi Mehta-Lee wrote in a commentary on the paper. They note that the findings may enable doctors to identify patients with lupus who are susceptible to pregnancy complications and need careful monitoring To the immune system, a fetus developing in the womb resembles a foreign invader. Normally during pregnancy, the mother’s immune system develops what researchers call tolerance and avoids attacking the fetus. But when patients with lupus become pregnant, their immune system may be less likely to develop tolerance to the fetus, leading to complications such as preeclampsia, premature birth, and even death of the fetus. In the new study, Dr. Pascual and colleagues compared 92 pregnant women with lupus to 43 pregnant women who didn’t have the disease. The researchers obtained blood samples from the women during and shortly after their pregnancies. To detect the earliest changes associated with pregnancy onset, the scientists also analyzed blood from patients undergoing assisted reproductive technology. The researchers evaluated the patients’ immune system by measuring the activity of different genes that help determine how strongly it responds to potential threats. For a subset of these study participants, the investigators also examined the types of cells that are producing the specific immune responses. Early in pregnancy, the activity of key genes decreased in women who didn’t have lupus, probably increasing their tolerance to the developing baby. The researchers saw similar changes in women with lupus who had successful pregnancies. However, the immune system of women with lupus who went on to develop complications was not turned down. Their immune system might be more likely to attack the fetus or prevent its proper development. This inability to turn down the immune activity appears to be a risk factor for adverse pregnancy outcomes in lupus. Testing for these changes in gene activity might pinpoint patients with lupus who are more likely to develop pregnancy complications and who needs careful monitoring and specific therapeutic intervention to improve the outcome. https://www.lupusresearch.org/gene-changes-key-to-successful-pregnancy-in-lupus/
  14. APRIL 2019 11 April 2019 by Professor Graham R V Hughes MD FRCP Easter comes late this year. Frenetic Brexit politics – the Westminster establishment fighting to overturn the ‘popular vote’. So sad. Last week I gave a lecture at an ‘immuno-therapy’ meeting in Madrid. Three hundred attendees, including representatives of the Spanish patients’ APS Society. The atmosphere was fantastic. So many doctors (and patients’) wanting to learn more about our syndrome. Talking about ‘learning more’, we now have a date for our own Patients’ Meeting – Friday, 13th September 2019. (For details of the programme and admission, please visit our website: www.ghic.world). This year we are opening up the meeting to include topics on Sjogren’s and lupus, as well as antiphospholipid syndrome. I will also send this blog, as well as details or our annual Patients’ Meeting, to our colleagues in Spain. Patient of the Month “I still feel tired all the time”. Mrs J.S. aged 55, was referred by her G.P. complaining of a variety of symptoms, including aches and pains, headaches, constipation, pins and needles and mental sluggishness. Above all else, she felt constantly fatigued. Despite this very full set of symptoms, the diagnosis remained uncertain. The pins and needles in both hands were put down to carpal tunnel syndrome. But there was little else to find. In view of the frequent headaches, Mrs J.S. was referred to a neurologist who arranged for further tests, including a brain MRI (which showed two small ‘dot’ lesions – reported as probably not significant. To her credit, the neurologist considered lupus and arranged lupus blood tests among the more routine ones. The tests came back showing a normal blood count. However, the ESR (the guide to inflammation) came back ‘borderline positive’ at 35 (normal under 20). The tests for lupus were essentially negative (anti-DNA negative, ANA ‘weak’ (1 in 80). What is the diagnosis (1)? The penny dropped. Could this be thyroid? Bilateral carpal tunnel syndrome is certainly seen in ‘low thyroid’, and significantly Mrs J.S. had a sister with ‘Hashimotos thyroiditis’ – and underactive thyroid with auto-immune features. As with all her other tests the thyroid blood tests were ‘borderline’. Nevertheless, the fatigue, the constipation, the aches and pains, could all be down to ‘low thyroid’. Following a *‘kerbside consult’, with her endocrinology colleague, she instituted thyroxine treatment. Within 2 months the pins and needles were gone and the mental sluggishness, as well as the constipation, were improving. BUT – the aches and pains and the fatigue remained – as bad as ever. What is the diagnosis (2)? It turned out that Mrs J.S. had suffered a series of miscarriages in her early 20’s and she and her husband remained childless. Could the problems – especially the frequent headaches – be due to Hughes Syndrome? Sure enough the antiphospholipid antibody (aPL) tests were strongly positive – not even ‘borderline’. She was started on clopidogrel (‘Plavix’) – an anti-clotting drug similar to aspirin (Mrs J.S. had previously tried aspirin but found it caused indigestion. Result? An almost immediate lessening of the headaches. And, if anything, a further improvement in her memory problems. BUT: no improvement in the fatigue or the aches and pains. What is the diagnosis (3)? Mrs J.S. was referred to a lupus clinic. Again, the results were similar (‘borderline’ ANA and negative anti-DNA). The lupus clinic doctor had seen this before – possible ‘Sjogren’s syndrome’. And, sure enough, the Shirmer’s test – a simple ‘blotting paper’ eye test was completely dry – a useful and very inexpensive screening test for the dry eyes of Sjogren’s Syndrome. Low dose hydroxychloroquine (Plaquenil) (one a day) was started. Three months later at follow-up clinic, ‘fatigue gone. Aches gone. Back to normal life”. What is this patient teaching us? I often talk of ‘The Big Three’ diseases – Lupus, Sjogren’s and Hughes Syndrome, which can overlap clinically However, the world of auto-immune diseases in which I practice includes another ‘big three’, which frequently go together : Hughes Syndrome, Sjogren’s Syndrome and low thyroid (often, specifically, Hashimoto’s thyroiditis) – three ‘named’ syndromes. Clearly, to miss one or even two of the triad would be an ‘under-treatment’. The three conditions can have similar features. And fortunately, potentially very successful treatment – thyroid, aspirin (or Plavix) and hydroxychloroquine. I call the combination of aspirin and hydroxychloroquine (derived from quinine) my ‘two trees’ – treatment –willow and cinchona. Perhaps the biggest lesson from this patient is that there may be more than one diagnosis causing the problems. PROFESSOR GRAHAM R V HUGHES MD FRCP Head of The London Lupus Centre London Bridge Hospital http://www.ghic.world/blog/april-2019
  15. An Increased Risk of Dementia Possible in Lupus Stephanie Pappas Jul 13, 2016 Neuropsychiatric symptoms have long been known to affect some patients with systemic lupus erythematosus. But now, emerging evidence suggests that lupus patients may be at increased risk of dementia, as well. A retrospective study published in April in the journal Arthritis Care and Research used the Taiwan Longitudinal Health Insurance Database 2005, a random sampling of the 99.9 percent of Taiwanese citizens covered by the country's national health insurance, to compare dementia rates in people with systemic lupus erythematosus to age- and sex-matched patients without the autoimmune disease. The analysis revealed a doubled rate of dementia in SLE patients. There were 357 cases per 100,00 person-years in the lupus cohort, compared with 180 cases per 100,000 person-years in the non-SLE cohort. {Crude hazard ratio 1.92, 95 percent CI, 1.14−3.23, P< 0.001.) Dementia is a condition of gradual decline, while neuropsychiatric SLE usually manifests early in the diagnosis, wrote study author Dr. Yu-Ru Lin of Taipei Medical Hospital and colleagues. Antiphospholipid antibodies might put patients at risk of micro-stroke, they hypothesized. Alternatively, anatomical changes in the brain attributable to the disease or corticosteroid treatments may contribute to cognitive decline. Rheumatology Network spoke with Dr. Yehuda Shoenfeld, an autoimmunity researcher at Tel Aviv University in Israel, for a deeper look at the dementia-lupus connection. Though not involved with the Taiwanese study, Dr. Shoenfeld has conducted research on lupus autoantibodies and has written about neuropsychiatric lupus in the clinic. He provided his perspective on the need to better understand how lupus might affect the brain. RN: Obviously, neurologic symptoms are well-known in systemic lupus erythematosus. What is the difference between central nervous system lupus and dementia? Shoenfeld: There are neurological, physical findings and also X-ray findings in which you see defects in neurological functions, mainly nerves which can be motor or sensory or so forth. It can be represented by conversions. It can be represented by paralysis. It can be presented as paresthesia, which means it feels like ants are going on your body. So it's more in the domain of physical examination. Dementia is more that you lose your capacity for cognition, memory or so forth. You cannot detect it by X-rays, but you can detect it by talking to the patient and listening to him and you can see that he's not finding himself, I would say, in space. So this is a big difference. What is new about this study by Lin and colleagues? So far we knew that CNS lupus is quite common, 20 percent of the patients can suffer from that. There are many manifestations of CNS lupus from paralysis to conversion, from deafness to blindness, from paresthesia to pains and so forth. Dementia up until now was not part of the story of lupus - neither in regular lupus nor in CNS lupus. We did have psychotic attack in CNS lupus, which could be completely resolved upon proper therapy, for instance with corticosteroids or immunosuppressive drugs. Suddenly, there is dementia. Now, I want to remind you that lupus is a disease of young females, so it's not elderly females with dementia at this age. So the people who published the paper came with the idea that in those patients with CNS lupus, you can find, eventually, more dementia, which is a new revelation, not known so far. With my colleague, Professor Howard Amital [of Sheba Medical Center], an expert on Big Data — we asked the computer to cross the word dementia with SLE in a health database, but we did something else in this respect. We compared it to two other autoimmune diseases. I have to say that, to my great surprise, we have found also that patients with SLE have a threefold increase in dementia. We were not able so far to segregate it to the different factor that we would like to, but we found also with rheumatoid, there was an increase. There was no increase, for instance, in Behcet's syndrome. So most probably, these results are correct, and they should raise a red light. We will analyze our results and we will publish it very soon. But I think it's interesting, even though I had not believed this when I had received the paper from you. What kind of mechanisms might explain why there could be this link? When you have an organic damage to the brain, being autoimmune in nature, being the position of autoantibodies, being the position of other factors it causes chronic damage to the brain and eventually, there is some kind expression that above this threshold it can cause the psychological defects which are expressed as dementia. It's like accumulating damage. Given what is known right now, what is the message for practicing rheumatologists? Before we do anything with patients, we should confirm the results and indeed analyze what could be the mechanism and then eventually work on this to see how we could prevent this. Maybe, for instance, a very quick recovery should be installed whenever there are any signs of CNS lupus. We have to see if, indeed, it's limited only to patients with CNS lupus. There is a lot to analyze now, to learn, to study and to draw conclusions for the future. References: Lin Y-R, Chou L-C, Chen H-C, Liou T-H, Huang S-W, Lin H-W. "Increased risk of dementia in patients with systemic lupus erythematosus: A nationwide population-based cohort study." Arthritis Care & Research. 2016. doi:10.1002/acr.22914. Kivity S, Agmon-Levin N, Zandman-Goddard G, Chapman J, Shoenfeld Y. "Neuropsychiatric lupus: a mosaic of clinical presentations." BMC Medicine BMC Med. 2015;13(1):43. doi:10.1186/s12916-015-0269-8. https://www.rheumatologynetwork.com/lupus/increased-risk-dementia-possible-lupus
  16. SLE Patients at Higher Risk for Some Blood Cancers, Study Says FEBRUARY 18, 2019 BY JOANA CARVALHO IN NEWS. Click Here to receive Lupus News via e-mail Systemic lupus erythematosus (SLE) patients have a higher risk for certain cancers — including cervical, thyroid, ovarian, and oral cancer, as well as lymphoma, multiple myeloma, and leukemia — than the general population, emphasizing the importance of cancer screening programs as part of SLE management. The findings of the study, “Systemic lupus erythematosus is a risk factor for cancer: a nationwide population-based study in Korea,” were published in Lupus. SLE, the most prevalent form of lupus, is a chronic autoimmune disease characterized by behavioral and psychological symptoms including pain, fatigue, depression, and impaired cognition. Previous studies have suggested that SLE patients are more likely to be affected by certain types of cancers, including non-Hodgkin’s lymphoma, lung, liver, and vaginal cancer. “However, some studies have found a decreased risk of some hormone-sensitive cancers, such as breast, ovarian, and endometrial cancer, in SLE patients. However, whether patients with SLE have increased or decreased risk of breast cancer remains unclear,” the researchers said. In this study, investigators set out to characterize the relationship between SLE and cancer in the entire Korean population. The nationwide, retrospective, cohort study involved 21,016 SLE patients and 105,080 age- and sex-matched controls without SLE. The cohort was selected from the Korean National Health Insurance Service (NHIS) database between 2008 and 2014. Over a follow-up period of seven years, 763 (3.36%) SLE patients and 2,667 (2.54%) controls developed cancer. The incidence risk of cancer was higher in SLE patients compared to controls (6.427 vs 4.466). Incidence risk refers to the chance of a disease happening over a defined period of time. After accounting for age and sex, SLE patients showed a 44% higher risk of developing cancer. No differences in cancer risk were found between female and male SLE patients. SLE patients at higher risk for cancer were younger (under 40) and male, being 12 and 29 times more likely of developing lymphoma than control subjects. Looking at different cancer types, researchers found that SLE patients were more likely to develop cervical, thryoid, ovarian, and oral cancer, as well as lymphoma, leukemia, and multiple myeloma than controls. On the other hand, no significant differences in the risk of stomach, colorectal, liver, pancreatic, lung, breast, prostate, biliary, laryngeal, renal, bladder, nerve, and skin cancer were found between SLE patients and controls. While the mechanisms leading to increased risk of cancer in SLE patients are yet to be fully understood, the findings highlight the need for cancer screening programs among this patient population. “In conclusion, SLE is an independent risk factor for malignancy, especially cervical, thyroid, ovarian, oral … as well as lymphoma, multiple myeloma, and leukemia. The importance of cancer screening programs should be emphasized in SLE patients,” the scientists concluded. https://lupusnewstoday.com/2019/02/18/sle-patients-may-be-at-higher-risk-of-developing-certain-types-of-cancer/?utm_source=LUP+NEws+E-mail+List&amp;utm_campaign=1e70fc3e85-RSS_WEEKLY_EMAIL_CAMPAIGN_US&amp;utm_medium=email&amp;utm_term=0_50dac6e56f-1e70fc3e85-71887989
  17. Congratulations and Many Thanks to Lady Gaga! To the entire world, Lady Gaga is a winner. But to the lupus community she’s a hero. Last night at the 2019 Grammy’s, she won an award for Best Pop Solo in honor of her aunt Joanne who lost her battle with lupus at 19. Afterwards she tweeted: Lady Gaga has shared the song’s significance on social media. “I have carried a deep grief in my heart over my family’s tragedy. The loss of Joanne affected my father so deeply that it affected me. When he cried, I cried. When he was angry, I was angry. When he was hurt, I hurt. Today I transform this grief to hope and healing. After 10 years with you I still get nervous before the Grammys, but I know I have an angel with me.” Hear about lupus research from Lady Gaga's dad And watch this video to hear directly from Lady Gaga’s dad, Joe Germanotta, about why he has honoured his sister by actively supporting the Lupus Research Alliance. As a member of our Board of Directors, Joe believes that the research funded by the Lupus Research Alliance is where hope begins. Where our funded research discoveries are breaking through to deliver better treatments and a cure!
  18. Lupus: 3 Things to Know Mark L. Fuerst Dec 3, 2018 Lupus Three new studies in systemic lupus erythematosus (SLE) reveal that a gut bacterium may be linked to autoimmune diseases, including SLE; pregnancy complications in women with lupus have decreased over the past 2 decades; and physical or emotional abuse in childhood raises the risk of lupus.1-3Scroll through the slides for the latest findings and their clinical implications. http://www.rheumatologynetwork.com/lupus/lupus-3-things-know
  19. Environmental Factors Tied to Lupus Gregory M. Weiss, M.D. Tuesday, December 5, 2017 Lupus Key points • Ultraviolet light may cause flare-ups in systemic lupus erythematosus (SLE). • The chemicals found in cigarette smoke can worsen the symptoms of SLE. • Estrogen analogues such as oral contraceptives and bisphenol A (BPA), a substance used to make plastic bottles, may increase the risk of SLE. Background SLE affects women and African Americans disproportionately. Dr. Gaurav Gulati at the University of Cincinnati in Ohio points out that even though we have treatments for lupus, a complete understanding of its etiology and progression is lacking. Although genetics clearly plays a role in SLE, it appears that environmental factors may act as triggers in those who are susceptible. Dr. Gulati conducted a review of the literature related to SLE and environmental versus genetic factors; he presented his findings recently in Seminars in Arthritis and Rheumatism. The study A systematic review was conducted that looked at over 100 studies focused on SLE. The results • A triad of factors was found in one study that linked a patient’s genetics, how the patient’s DNA changes over time, and exposure to environmental factors to the development and course of SLE. • Twin studies reveal only a 24% concordance of SLE in identical siblings; this points to a conclusion that a combination of genetic predisposition and environmental factors is involved in the development of lupus. • Heavy metals and other trace elements may be triggers for SLE; uranium, lead, and cadmium are linked to autoimmunity. • Elements such as mercury, nickel, and gold have been implicated in delayed hypersensitivity and inflammation, and a higher rate of lupus has been noted among dental workers. • An increase in SLE has been found in women who take oral contraceptives and in those exposed to xenoestrogens such as BPA, a chemical found in plastics. Implications for physicians • Physicians and particularly rheumatologists who treat patients with SLE should vigorously encourage positive lifestyle modifications such as smoking cessation and avoidance of direct sunlight. • Patients with SLE should be advised to always wear sunscreen. • Rheumatologists should provide regular surveillance to their patients with SLE as changes in disease activity and treatment are warranted. References: Gulati G, Brunner HI. Environmental triggers in systemic lupus erythematosus. Semin Arthritis Rheum. 2017 Oct 5. pii: S0049-0172(17)30469-9. doi: 10.1016/j.semarthrit.2017.10.001. [Epub ahead of print]
  20. Sex Differences in Lupus Mortality Mariah Zebrowski Leach, JD, MS Monday, December 4, 2017 A comprehensive US population-based study identified an average 22-year and 12-year deficit in life expectancy among females and males with systemic lupus erythematosus (SLE), respectively, compared with the general population. Background In the United States, SLE is a source of significantly decreased life expectancy. While marked differences have been observed between the sexes in terms of the incidence, prevalence, and clinical manifestations of SLE, this area is still poorly understood. Falasinnu and colleagues1 at Stanford School of Medicine identified sex-based differences in the causes of death among SLE decedents in the United States and recognized clinically relevant comorbidities that may warrant careful consideration in patients’ clinical management. The study This study examined SLE-related deaths using the 2014 National Center for Health Statistics multiple cause of death (MCOD) database, a population-based electronic medical recording of all death certificates issued in the United States. The analysis considered not only the number of death certificates listing SLE as the underlying cause of death, but also those listing SLE in general. Demographic information considered included age, race/ethnicity, sex, educational attainment, foreign-born status, marital status, and pregnancy status. SLE decedents were compared with non-SLE decedents in the general population belonging to the same age group. The findings In 2014, there were 2,660,497 deaths in the United States, of which 2036 (0.1%) listed SLE among the causes of death. Approximately 86.2% of SLE deaths occurred among females, with a median age at death of 59 years and the highest proportion of deaths occurring between 45 and 64 years of age. In comparison, the overall median age at death for females in the general population was 81 years, and the majority of deaths occurred among females over 65 years of age. Black females experienced the greatest burden of SLE mortality. Approximately 32% of all female SLE decedents were black, compared with only 11% of non–SLE-related deaths in the general population. Female decedents with SLE had a slightly higher proportion of foreign-born individuals than the general population, but there were no other significant demographic differences. The most frequently listed comorbidities among female decedents with SLE were septicemia (4.32%) and hypertension (3.04%). Among male decedents with SLE, the median age at death was 61 years, compared with 73 years in the general population. Of male decedents with SLE, 23.5% were black, compared with only 12% in the general population. The age-standardized mortality was highest among American Indian males. There were no other demographic differences related to SLE among male decedents. The most frequently listed comorbidities among male decedents with SLE were heart disease (3.70%) and diabetes mellitus with complications (3.61%). Implications for physicians and future research This study offers an opportunity to better describe the association between SLE and related comorbidities in the context of mortality, although the MCOD data have a number of limitations. Inaccuracy on death certificates can lead to the underestimation of the SLE mortality burden, and researchers were unable to differentiate between causes of death that were related to the natural age process, disease activity, and drug therapy. Still, the MCOD data provide a comprehensive understanding of the population-based burden of SLE mortality. While female SLE patients tend to have more frequent disease exacerbations, male patients appear to have significantly greater multisystemic damage accrual and disease severity. Greater disease severity among male SLE patients may be related to under diagnosis due to selective attention given to females by physicians during clinical decision-making. This potential for gender bias needs to be carefully considered. Racial minorities generally have a disproportionately higher burden of mortality. The scope and degree of these differences in SLE are particularly pronounced, with mortality rates among black females nearly four times as high as those in white females. “Our findings reinforce the urgent need for interventions that reduce morbidity and mortality in patients with SLE to improve health outcomes and ultimately reduce health disparities,” the researchers write. They note that novel translational research programs are currently underway to attempt to address these disparities. Clinically relevant comorbidities also need to be considered more carefully in the course of patients’ clinical management and the natural history of SLE. This study revealed future targets for the investigation of sex-based differences and directions for epidemiological research. “A comprehensive understanding of causes of death and the related comorbidities can improve clinical diagnostic and therapeutic strategies, impact survival outcomes in patients living with SLE, and enhance population-based disease surveillance estimates,” the researchers conclude. References: 1. Falasinnu T, Chaichian Y, Simard JF. Impact of sex on systemic lupus erythematosus-related causes of premature mortality in the United States. J Womens Health (Larchmt). 2017;26:1214-1221. doi: 10.1089/jwh.2017.6334.
  21. Treatment Target Shows Promise in Systemic Lupus Erythematosus Mariah Zebrowski Leach, JD, MS Monday, December 4, 2017 The lupus low disease activity state (LLDAS) is a promising treatment target in systemic lupus erythematosus (SLE), according to new research. Background Successfully applied in rheumatoid arthritis as well as in non-rheumatic conditions, a treat-to-target approach aims to improve disease outcomes through the achievement of a pre-specified goal. An international task force suggested such a strategy for the treatment of SLE.1 They recommended that the treatment target should be remission or—when that is unachievable—the lowest possible disease activity. LLDAS is a composite definition of minimal acceptable disease activity proposed by the Asia-Pacific Lupus Collaboration (APLC). LLDAS is based on the following criteria: 1. SLE Disease Activity Index 2000 (SLEDAI-2K) ≤ 4, with no activity in major organ systems 2. No new lupus disease activity compared with the previous assessment 3. Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (PGA) ≤ 1 4. Current prednisolone (or equivalent) dose ≤ 7.5 mg daily 5. Well-tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents To be considered a valid treatment target, LLDAS should be protective against damage accrual in the early SLE stages. Piga and colleagues2 at the University Clinic and AOU of Cagliari in Italy sought to determine the frequency of LLDAS achievement and its association with early damage accrual in a homogenous cohort of Caucasian patients with SLE prospectively assessed during the first 18 months of treatment after diagnosis. The study This study primarily aimed to assess the frequency of LLDAS achievement and its association with early damage, with a secondary aim to identify the main reasons for failure to achieve LLDAS. The study cohort consisted of 107 patients from the Cagliari (Italy) SLE cohort between January 2006 and December 2016. To assess LLDAS as a goal for initial treatment, the primary study endpoint was set at 6 months, with 18 months considered an appropriate time to evaluate the effect of maintenance treatment and early damage accrual. At each visit, disease activity was assessed using the SLEDAI-2K score and the PGA. At 18 months, damage accrual was assessed by the SDI and the possible attribution to corticosteroids was done according to a previous definition. Average daily dose of prednisolone (or equivalent) and ongoing use and new prescription of medications were assessed at every visit. The findings At the 6-month point, LLDAS had been achieved by 47 patients (43.9%). At 18 months, 48 patients (44.9%) were in LLDAS; 33 of them had achieved LLDAS at 6 months and were still in this condition and 15 had reached LLDAS for the first time. Of the 59 patients who were not in LLDAS at 18 months, 45 had never been in LLDAS and 14 had been in LLDAS at 6 months but no longer were at 18 months. Thus, despite a seemingly overall stable LLDAS rate, these results demonstrate the dynamic nature of this condition. On univariate analysis, the following factors were significantly associated with failure to achieve LLDAS at 6 months: renal involvement, higher SLEDAI-2K score, positive (> 10 UL/mL) anti-dsDNA antibodies, lower serum C3 and C4 values, and higher prednisolone dose and immunosuppressant drug use. On multivariate analysis, renal involvement and C4 levels were confirmed to be associated with failure to achieve LLDAS. Implications for physicians The limitations of this study are the relatively small sample size, which may have hampered study results, and the retrospective design, which prevented researchers from testing LLDAS criterion validity by comparing it with other treatment targets such as the SLE Responder Index. Nevertheless, by enrolling consecutively diagnosed patients at the time of treatment initiation and following them prospectively, the researchers were able to provide novel data on LLDAS as a potential treatment target. In this study, the most frequent reason for failure to achieve LLDAS 6 months after therapy initiation was daily prednisolone dosage > 7.5 mg. Damage was definitely attributable to steroid use in 40% of cases in this cohort. However, supported by this data and literature evidence on damage development, the researchers consider 7.5 mg/d an acceptable cutoff to define low disease activity during initial treatment. Still, they recommend a lower cutoff should be targeted to minimize risk of steroid-related damage during maintenance therapy in patients with SLE. In this cohort, patients with renal involvement and serological disorders had the lowest remission rate, and renal involvement at baseline was the most important factor associated with failure to achieve LLDAS. “LLDAS is a promising treatment target in SLE, being attainable and negatively associated with damage accrual in the early stages of the disease,” the researchers write. “However, it seems to poorly fit with the heterogeneity of clinical presentation in patients with SLE, mostly in those with renal involvement,” they conclude. References: 1. van Vollenhoven R, Voskuyl A, Bertsias G, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. 2014;73:958-967. 2. Piga M, Floris A, Cappellazzo G, et al. Failure to achieve lupus low disease activity state (LLDAS) six months after diagnosis is associated with early damage accrual in Caucasian patients with systemic lupus erythematosus. Arthritis Res Ther. 2017;19:247. doi: 10.1186/s13075-017-1451-5.
  22. Poverty Stacks the Deck Against Patients With Lupus Gregory M. Weiss, M.D. Tuesday, November 28, 2017 Lupus Poor patients with systemic lupus erythematosus (SLE) who receive Medicaid are less likely to adhere to their treatment regimen than are patients who live in more affluent areas. Adherence to SLE therapy may also be lower in areas with large African American populations and limited access to health care professionals. In addition, Medicaid patients are less likely to take hydroxychloroquine for lupus if they live in areas with fewer hospitals, high African American populations, and low provider numbers. SLE strikes women with greater frequency than men and is more than twice as common in the African American population. Dr. Candace Feldman and colleagues at Harvard Medical School note that compliance with hydroxychloroquine therapy in lupus patients is poor at baseline. “Studies in other chronic diseases demonstrate that where individuals live has a significant effect on their health-related behaviors and on disease control and outcomes,” said Dr. Feldman. It was this premise that led the authors to look into how location and resources contribute to adherence to treatment in SLE. They presented their findings at the recent American College of Rheumatologyannual meeting in San Diego, California. The study Utilizing the Medicaid database, new users of hydroxychloroquine were identified and adherence was measured over a 12-month period. The study included 10,268 subjects with SLE who were new users of hydroxychloroquine. The results • Only 15% of subjects remained adherent to hydroxychloroquine therapy based on taking the drug on 80% or more of days covered. • Zip codes with higher percentages of African American residents had lower odds of adherence. • Adherence was highest in counties with more hospitals and lowest in areas with low numbers of health care professionals. • Living in areas with higher numbers of African Americans and fewer hospitals and health care professionals independently predicted low adherence to hydroxychloroquine therapy. Implications for physicians • Low adherence to hydroxychloroquine therapy in SLE is widespread among Medicaid recipients. • Patients with SLE in predominantly low-income, African American communities are at higher risk for non-compliance to hydroxychloroquine therapy. • Lack of access to health care providers and hospitals reduces the likelihood that patients with lupus will adhere to therapy. • Physicians should make every effort to identify barriers to care and treatment adherence, especially in low-income patients with lupus who live in isolated communities with large minority populations. References: American College of Rheumatology Press Release. “Diversity Rate and Poor Access to Health Professionals May Influence Lupus Therapy Adherence.” November 4, 2017. ACR/ARHP Annual Meeting. San Diego, California.
  23. An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus Y K Onno Teng Edwin O W Bredewold Ton J Rabelink Tom W J HuizingaH C Jeroen Eikenboom Maarten Limper Ruth D E Fritsch-StorkKitty W M Bloemenkamp Marieke Sueters Rheumatology, kex374, https://doi.org/10.1093/rheumatology/kex374 Published: 20 November 2017 Abstract Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients. https://academic.oup.com/rheumatology/advance-article-abstract/doi/10.1093/rheumatology/kex374/4641853?redirectedFrom=fulltext
  24. 21 November, 2017 SAN DIEGO — At the American College of Rheumatology Annual Meeting, Joan Merrill, MD, spoke about a study that she said is further demonstration that atacicept should continue being developed as a potential treatment for lupus. According to Merrill, the results also suggest that measurements of low-disease activity may represent not just clinically meaningful endpoints, but may also “work as endpoints in clinical trials to discriminate drug from placebo.” https://www.healio.com/rheumatology/lupus/news/online/{1b289264-6a9b-47a3-86c6-9b0eb8a3980f}/video-atacicept-is-a-potential-exciting-treatment-for-lupus?utm_source=selligent&utm_medium=email&utm_campaign=rheumatology news&m_bt=1879111151405
  25. Obesity linked to worse outcomes of pain, fatigue, depression in women with lupus November 13, 2017 SAN DIEGO — Among women with systemic lupus erythematosus, obesity appears to be independently linked to worse patient-reported outcomes, suggesting that weight loss may improve outcomes for this population, according to findings presented at the American College of Rheumatology Annual Meeting. “The research that I am presenting at this conference was inspired by previous work that showed that patients with lupus experienced big deferments in patient-reported outcomes, or PROs,” Sarah L. Patterson, MD, a fellow in rheumatology at the University of California, San Francisco, and an author of the study, said in her presentation. “It's also been noted that these deferments in PROs are not fully explained by the severity of their lupus disease or by sociodemographic factors such as poverty. So, we therefore wanted to know whether body composition and, specifically, excess adipose tissue contributes to the worse health-related quality of life and greater symptom burden that we see in this particular patient population.” In the study, Patterson and colleagues identified a sample of 148 patients with SLE (65% white, 14% Asian and 13% African-American; mean age, 48 ± 12.3 years) from the Arthritis Body Composition and Disability (ABCD) study. Eligible participants were women aged at least 18 years who had a diagnosis of SLE that could be corroborated by medical record review. The researchers calculated BMI and fat mass index (FMI). FMI measures total fat mass adjusted for height and was evaluated in the study using whole dual-energy X-ray absorptiometry. Obesity was defined using two designations: FMI of at least 13 kg/m2 and BMI of at least 30 kg/m2. The following four validated patient-reported outcomes were included as dependent variables: disease activity via Systemic Lupus Activity Questionnaire, depressive symptoms via Center for Epidemiologic Studies Depression Scale, pain assessed by SF-36 pain subscale and fatigue measured by SF-36 vitality subscale. Multivariable linear regression was used to analyze correlations of obesity with patient-reported outcomes , adjusted for possible confounding factor (age, race, education, income, smoking status, disease duration, disease damage and prednisone use). Adjusted means for each outcome were then calculated based on the multivariable regression. Of the patients in the sample, 17% had poverty-level income; 86% had education beyond high school; the mean duration of disease was 16 ± 9 years; and 45% were being treated with glucocorticoids. Based on the FMI definition of obesity, 32% of patients met the criteria for obesity, whereas 30% were deemed obese by the BMI definition. The multivariate regression model found that FMI-defined obesity was correlated with worse scores on each patient-reported outcome (greater disease activity, higher levels of depression, more pain and more fatigue). In the analyses that used the traditional BMI of at least 30 kg/m2 criteria, the same correlations were seen between obesity and each of the patient-reported outcomes. “These findings have important clinical implications. The PROs that we measured, particularly pain and fatigue, are known to have profound effects on quality of life, and remain a major area of unmet need in people with lupus,” Patterson said. “In other words, there are many patients with lupus who are treated with aggressive immunomodulatory therapy and these symptoms of pain and fatigue persist. The relationship that we observed between excess fat and worse outcomes really underscores the need for lifestyle interventions for lupus patients who are overweight.” – by Jennifer Byrne Reference: Patterson SL, et al. Abstract #2263. Presented at: American College of Rheumatology Annual Meeting; Nov. 4-8, 2017; San Diego. Disclosures: The authors report no relevant financial disclosures. https://www.healio.com/rheumatology/lupus/news/online/{88b88835-9c84-4880-a058-1e4d1d926aa6}/obesity-linked-to-worse-outcomes-of-pain-fatigue-depression-in-women-with-lupus?utm_source=selligent&utm_medium=email&utm_campaign=rheumatology news&m_bt=1879111151405
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