We have read with interest the study from Khawaja et al. entitled ''Loss of antiphospholipid antibody (aPL) positivity post-thrombosis in systemic lupus erythematosus (SLE)''(1). The authors described 31 patients with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus who presented loss of antiphospholipid antibodies (aPL) positivity after thrombotic events.
They measured four types of aPL: IgM, IgG and IgA isotypes of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). Complete disappearance after thrombosis was observed in 41% of APS patients for IgG aCL, 51% for those with IgM aCL, 50% for IgA aCL, and 20% for LAC. However, 60% of those who at the same time lost IgG aCL and 76% of those who became negative for LAC, reacquired the antibodies within five years. In contrast, only 37% and 17% of those who lost IgM or IgA aCL, reacquired the antibodies within five years, respectively. Finally, 14 (45%) patients never turned back positive during the follow-up period. They concluded that recurrence of aPL positivity is frequent in APS associated with SLE, after their disappearance in post-thrombotic states.
Until now, long term oral anticoagulation (OAC) is the cornerstone of treatment for thrombotic primary and SLE-associated APS (2). The decision to withdraw OAC in APS patients when aPL become "persistently" negative remains a matter of debate. In the light of results fro...
We have read with interest the study from Khawaja et al. entitled ''Loss of antiphospholipid antibody (aPL) positivity post-thrombosis in systemic lupus erythematosus (SLE)''(1). The authors described 31 patients with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus who presented loss of antiphospholipid antibodies (aPL) positivity after thrombotic events.
They measured four types of aPL: IgM, IgG and IgA isotypes of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). Complete disappearance after thrombosis was observed in 41% of APS patients for IgG aCL, 51% for those with IgM aCL, 50% for IgA aCL, and 20% for LAC. However, 60% of those who at the same time lost IgG aCL and 76% of those who became negative for LAC, reacquired the antibodies within five years. In contrast, only 37% and 17% of those who lost IgM or IgA aCL, reacquired the antibodies within five years, respectively. Finally, 14 (45%) patients never turned back positive during the follow-up period. They concluded that recurrence of aPL positivity is frequent in APS associated with SLE, after their disappearance in post-thrombotic states.
Until now, long term oral anticoagulation (OAC) is the cornerstone of treatment for thrombotic primary and SLE-associated APS (2). The decision to withdraw OAC in APS patients when aPL become "persistently" negative remains a matter of debate. In the light of results from Khawaja et al. (1), the discontinuation of OAC in patients with APS associated with SLE would not be advisable.
In a previous study (3), we described 11 patients with primary APS and low-risk aPL profile, who had their aPL persistently negative after thrombotic/obstetric morbidity manifestations, and in whom antithrombotic treatment was withdrawn. No new thrombotic events were observed after 20 months of follow-up.
We want to point out two different characteristics between the present study and ours: 1) our study did not include patients with SLE-associated APS; therefore, the population target of the two cohorts are not comparable; and 2) patients included in our study had low-risk aPL profile defined by the presence of only two positive aPL determinations pre-thrombosis or obstetric morbidity.
Zen et al. (4) described a small cohort of 16 patients with SLE-associated-APS in whom aPL became negative. Treatment with immunosuppressants was an independent predictor for negativization of aPL because they observed that seronegative patients received immunosuppressive therapy more frequently than patients with persistent positivity for aPL, suggesting downregulation of inflammatory pathways. Also, the immunomodulatory effect of antimalarials could contribute to aPL negativization during follow-up.
Further research is, therefore, needed to determine if discontinuation of OAC could be accepted in some patients with APS (i.e., those with primary APS and low-risk aPL profile, who had their aPL persistently negative after thrombotic/obstetric morbidity manifestations).
Declaration of conflicting interests
The authors declared no potential conflicts of interest concerning the research, authorship, and publication of this article.
Funding
The authors received no financial support for the research, authorship, and publication of this article.
References
1. Khawaja M, Magder L, Goldman D, Petri MA. Loss of antiphospholipid antibody positivity post-thrombosis in SLE. Lupus Sci Med. 2020;7(1):1–7.
2. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat-Chalumeau N, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296–304.
3. Coloma Bazán E, Donate López C, Moreno Lozano P, Cervera R, Espinosa G. Discontinuation of anticoagulation or antiaggregation treatment may be safe in patients with primary antiphospholipid syndrome when antiphospholipid antibodies became persistently negative. Immunol Res. 2013;56(2–3):358–61.
4. Zen M, Loredo Martinez M, Benvenuti F, Gatto M, Saccon F, Larosa M, et al. Prevalence, outcome and management of patients with SLE and secondary antiphospholipid antibody syndrome after aPL seroconversion. Rheumatology. 2020;1–8.
Dr Olsen and Karp have summarised data from several important papers on the use of novel diagnostic tests for earlier diagnosis of SLE. I agree in the importance of this problem, for the early exclusion of SLE in people with benign ANA positivity, and early intervention in people destined to develop SLE or related disease.
I also agree with the key challenges in such research. Previous studies have been limited by a retrospective design. Inclusion of patients with variable symptom duration or patient populations that were selected for certain clinical characteristics may bias findings by conditioning on the outcome. Also, putative biomarker results need to be appraised alongside routine diagnostic tests, not in isolation.
These challenges were met in our previous study into these questions[1]. We invited all ANA-positive referrals to our centre with an onset of the symptoms that triggered referral within the past 12 months to participate, ensuring an unbiased sample appropriate to the clinical question. We collected detailed data on clinical presentation, routine immunology assessments, patient and physician reported severity, and family history, and integrated these data into our biomarker evaluation. Our patients were recruited and followed up prospectively in a standardised schedule of visits with strict assessment of criteria and a "flare hotline" in case new symptoms developed.
By doing so, we were able to reliably demonstrate the value...
Dr Olsen and Karp have summarised data from several important papers on the use of novel diagnostic tests for earlier diagnosis of SLE. I agree in the importance of this problem, for the early exclusion of SLE in people with benign ANA positivity, and early intervention in people destined to develop SLE or related disease.
I also agree with the key challenges in such research. Previous studies have been limited by a retrospective design. Inclusion of patients with variable symptom duration or patient populations that were selected for certain clinical characteristics may bias findings by conditioning on the outcome. Also, putative biomarker results need to be appraised alongside routine diagnostic tests, not in isolation.
These challenges were met in our previous study into these questions[1]. We invited all ANA-positive referrals to our centre with an onset of the symptoms that triggered referral within the past 12 months to participate, ensuring an unbiased sample appropriate to the clinical question. We collected detailed data on clinical presentation, routine immunology assessments, patient and physician reported severity, and family history, and integrated these data into our biomarker evaluation. Our patients were recruited and followed up prospectively in a standardised schedule of visits with strict assessment of criteria and a "flare hotline" in case new symptoms developed.
By doing so, we were able to reliably demonstrate the value of interferon gene expression scores as independent predictors of progression suitable for exclusion of future SLE or early intervention at first clinic assessment. These biomarkers had previously been validated against disease activity in established SLE and shown to differentiate SLE and RA.
These results should therefore be considered alongside those cited in the review.
[1] Md Yusof et al. Ann Rheum Dis. 2018 Oct;77(10):1432-1439.
Dear editor;
We have read with great interest the article published by Haque et al. which was about association between atherosclerotic process, cardiovascular outocomes and systemic lupus erythematosus (SLE). It is reported that only SDI score, triglyceride level and cyclophosphamide exposure was predictive for future cardiovascular events and factors related with plaque progression were defined(1).
SLE is a multisystemic disorder and lupus nephritis is one of the main manifestions of the disease. It usually presents with proteinuria and deteriorated renal glomerular functions. Renin angiotensinogen antgiotensin system (RAAS) inhibitors are used in patients with lupus nephritis to reduce proteinuria and kidney function protection(3). Angiotensin II (AT II) has unfavorable effects on endothelial functions. AT II binds AT 1 receptors and promotes vasoconstriction and production of proinlammatory cytokines and proliferation factors. It is shown by several studies that RAAS inhibitors improves endothelial functions and induces the regression of atherosclerotic process(3).
Microalbuminuria (MAU) and proteinuria are related with worse cardiovascular outcomes. Microalbuminuria causes endothelial dysfunction and associated with accelerated atherosclerosis(4). MESA study demonstrated that coronary calcification is significantly higher in patients with microalbuminuria than counterparts without MAU. Not only presence but also amount of MAU is associated with insu...
Dear editor;
We have read with great interest the article published by Haque et al. which was about association between atherosclerotic process, cardiovascular outocomes and systemic lupus erythematosus (SLE). It is reported that only SDI score, triglyceride level and cyclophosphamide exposure was predictive for future cardiovascular events and factors related with plaque progression were defined(1).
SLE is a multisystemic disorder and lupus nephritis is one of the main manifestions of the disease. It usually presents with proteinuria and deteriorated renal glomerular functions. Renin angiotensinogen antgiotensin system (RAAS) inhibitors are used in patients with lupus nephritis to reduce proteinuria and kidney function protection(3). Angiotensin II (AT II) has unfavorable effects on endothelial functions. AT II binds AT 1 receptors and promotes vasoconstriction and production of proinlammatory cytokines and proliferation factors. It is shown by several studies that RAAS inhibitors improves endothelial functions and induces the regression of atherosclerotic process(3).
Microalbuminuria (MAU) and proteinuria are related with worse cardiovascular outcomes. Microalbuminuria causes endothelial dysfunction and associated with accelerated atherosclerosis(4). MESA study demonstrated that coronary calcification is significantly higher in patients with microalbuminuria than counterparts without MAU. Not only presence but also amount of MAU is associated with insulin resistence, hyperlipidemia and endothelial dysfunction(5). Cyclophosphamide is usually given when the patient has severe renal involvement so proteinuria may explain the relationship between cyclophosphamide exposure and future cardiovascular events.
To conclude; as most of medications were evaluated in the study, we think that it would be better either use of RAAS inhibitor was also assessed. Moreover, presence and the amount of proteinuria should give additional valuble information in the study population.
References;
1. Haque S, Skeoch S, Rakieh C et al. Progression of subclinical and clinical cardiovascular disease in a UK SLE cohort: the role of classic and SLE related factors. Lupus Sci Med. 2018 Nov 17;5(1):e000267.
2. Aziz F, Chaudhary K. Lupus Nephritis: A Treatment Update. Curr Clin Pharmacol. 2018;13(1):4-13.
3. Radenkovic M, Stojanovic M, Nesic IM et al. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications. Indian J Med Res. 2016 Aug; 144(2): 154–168.
4. Nada DW, El Morsy S, Abu-Zaid MH et al. The role of microalbuminuria as a predictor of subclinical cardiovascular events in rheumatoid arthritis patients and its relation to disease activity. Clin Rheumatol. 2018 Mar;37(3):623-630.
5. Hyo Eun Park, Nam Ju Heo, Minkyung Kim, Su-Yeon Choi. Significance of Microalbuminuria in Relation to Subclinical Coronary Atherosclerosis in Asymptomatic Nonhypertensive, Nondiabetic Subjects. J Korean Med Sci. 2013 Mar; 28(3): 409–414.
Dear editor,
We read with interest the article of Idborg et al.1 who recently analyzed the role of several inflammatory mediators, and their usefulness as biomarkers in the measurement of activity of disease and the identification of clinical subphenotypes in systemic lupus erythematosus (SLE). Although interesting, these results may benefit of further discussion in light of systems medicine.
Authors concluded that the two main inflammatory mediators related with activity of SLE were TNF-α and p-albumin. However, previous studies have found that TNF-α and the TNF/IL-10 ratio were higher in patients with low activity of disease,2 and that TNF-α antagonists may induce SLE-like disease.3 These controversial data argues against a generalized model based on TNF-α as clinical activity biomarker, and advocate for the influence of other mediators in such a condition.
As shown by Idborg et al., IL-6, IL-10, IL-15, MCP-1, IP-10, MIP-1α, ESR, anti-dsDNA and U-albumin/creatinine were also positively correlated with activity of disease,1 suggesting that the exclusive role of TNF-α and p-albumin on activity of disease is unlikely. In fact, the pathological functions of these biomarkers are not isolate since they emerge from the interactions among them and between cells and tissues (i.e., systems medicine).4
In this sense, cytokine and autoantibody clusters (i.e., neutral, chemotactic/anti-phospholipid antibodies, and IFN-α/dsDNA) have been reported to be associat...
Dear editor,
We read with interest the article of Idborg et al.1 who recently analyzed the role of several inflammatory mediators, and their usefulness as biomarkers in the measurement of activity of disease and the identification of clinical subphenotypes in systemic lupus erythematosus (SLE). Although interesting, these results may benefit of further discussion in light of systems medicine.
Authors concluded that the two main inflammatory mediators related with activity of SLE were TNF-α and p-albumin. However, previous studies have found that TNF-α and the TNF/IL-10 ratio were higher in patients with low activity of disease,2 and that TNF-α antagonists may induce SLE-like disease.3 These controversial data argues against a generalized model based on TNF-α as clinical activity biomarker, and advocate for the influence of other mediators in such a condition.
As shown by Idborg et al., IL-6, IL-10, IL-15, MCP-1, IP-10, MIP-1α, ESR, anti-dsDNA and U-albumin/creatinine were also positively correlated with activity of disease,1 suggesting that the exclusive role of TNF-α and p-albumin on activity of disease is unlikely. In fact, the pathological functions of these biomarkers are not isolate since they emerge from the interactions among them and between cells and tissues (i.e., systems medicine).4
In this sense, cytokine and autoantibody clusters (i.e., neutral, chemotactic/anti-phospholipid antibodies, and IFN-α/dsDNA) have been reported to be associated with activity of SLE.5 Thus, data from Idborg et al. study could have been treated differently (i.e., cluster analysis) in order to obtain an interaction between the mediators evaluated and disease activity.
References
1 Idborg H, Eketjäll S, Pettersson S, et al. TNF-α and plasma albumin as biomarkers of disease activity in systemic lupus erythematosus. Lupus Sci Med 2018;5. doi:10.1136/lupus-2018-000260
2 Gomez D, Correa PA, Gomez LM, et al. Th1/Th2 cytokines in patients with systemic lupus erythematosus: is tumor necrosis factor alpha protective? Semin Arthritis Rheum 2004;33:404–13.
3 Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011;50:619–25. doi:10.1111/j.1365-4632.2011.04871.x
4 Kirschner M. Systems Medicine: Sketching the Landscape. Methods Mol Biol 2016;1386:3–15. doi:10.1007/978-1-4939-3283-2_1
5 Pacheco Y, Barahona-Correa J, Monsalve DM, et al. Cytokine and autoantibody clusters interaction in systemic lupus erythematosus. J Transl Med 2017;15:239. doi:10.1186/s12967-017-1345-y
The Editor,
Lupus Science and Medicine
BMJ Journals
Dear Madam/Sir,
Our esteemed peer Dr. Boers has editorialised1 on our recently published study of associations of glucocorticoid use with damage accrual in SLE2, suggesting that studies of the type reported are ‘harmful’. As this is such a serious accusation, we feel compelled to respond, even though we suspect that in the end the views of the authors and of Dr Boers as serious physician-researchers are in fact highly aligned. Essentially, we do not resile from our view that long-term reliance on glucocorticoids for the control of inflammation in SLE carries harm, and that steroid-reducing regimens for SLE management are urgently needed. At no time in our report, and certainly not in our clinical practice, do we advise against the use of these drugs, though such an imprecation was implied (incorrectly) in Dr Boers’ editorial. Rather, it is our view that strategies to achieve control of disease activity with reduced reliance on glucocorticoids, such as improving the use of non-glucocorticoid agents or the introduction of novel therapies, are as urgently needed as ever – and that complacency about the chronic use of glucocorticoids in SLE is not an acceptable status quo.
As we stated in the opening remarks, ‘The objective of the present study was to quantify damage accrual in a prospectively followed cohort of patients with SLE and determine the association of glucocorticoid use with damage...
The Editor,
Lupus Science and Medicine
BMJ Journals
Dear Madam/Sir,
Our esteemed peer Dr. Boers has editorialised1 on our recently published study of associations of glucocorticoid use with damage accrual in SLE2, suggesting that studies of the type reported are ‘harmful’. As this is such a serious accusation, we feel compelled to respond, even though we suspect that in the end the views of the authors and of Dr Boers as serious physician-researchers are in fact highly aligned. Essentially, we do not resile from our view that long-term reliance on glucocorticoids for the control of inflammation in SLE carries harm, and that steroid-reducing regimens for SLE management are urgently needed. At no time in our report, and certainly not in our clinical practice, do we advise against the use of these drugs, though such an imprecation was implied (incorrectly) in Dr Boers’ editorial. Rather, it is our view that strategies to achieve control of disease activity with reduced reliance on glucocorticoids, such as improving the use of non-glucocorticoid agents or the introduction of novel therapies, are as urgently needed as ever – and that complacency about the chronic use of glucocorticoids in SLE is not an acceptable status quo.
As we stated in the opening remarks, ‘The objective of the present study was to quantify damage accrual in a prospectively followed cohort of patients with SLE and determine the association of glucocorticoid use with damage’; similarly, we concluded ‘our findings suggest the urgent need for a randomised study comparing the effect on damage accrual of usual care with that of a strategy that stringently limits glucocorticoid dosing’. That our report, like virtually all science that benefits from peer review, was improved in response to reviewers’ input is scarcely newsworthy. As peer reviewers we all collectively strive to help authors and readers achieve the best outcome from submitted work, be it through rejection or suggestions for improvement. Moreover, one of the longest paragraphs in our report was an assessment of the limitations of the data and its analysis, and we also clearly state the possibility that glucocorticoid dose is largely, though not completely, a surrogate measure of disease activity. We thank Dr. Boers for restating these in his editorial, although we would have preferred it to have been acknowledged that we had done likewise in our report.
While confounding by indication is a methodological concern in assessment of treatment effects using observational cohort data, there is no single standard dose of steroid applied universally for the treatment of each lupus manifestation. Furthermore, factors other than lupus activity such as musculoskeletal pain due to degenerative joint disease and fibromyalgia, often influence steroid tapering. Accordingly, in real-life cohort data sets, these variations in steroid dosing relative to disease activity score provide an opportunity to tease apart, albeit with limitation, some of the harmful effect of steroids from disease activity itself.
We accept neither the proposition that this study was fatally flawed or that its conclusions are harmful. Rather, we propose the possibility that chronic glucocorticoid exposure has hitherto-unexplored associations with harmful effects that contribute to negative outcomes in SLE above and beyond their largely metabolically-based ‘side-effects’. In unpublished studies on MRL/lpr lupus-prone mice, we have observed that glucocorticoid treatment was associated with accelerated mortality - the mechanism of this effect is as yet unknown, but glucocorticoids induce the release of macrophage migration inhibitory factor (MIF), a protein demonstrated clearly to be harmful in models of SLE by us and other groups3, 4. The most harmful thing we could do is fail to remain open to the possibility that independent of their confounding by indication, glucocorticoids are indeed causing undiscovered dose-related harmful effects with long-term use in SLE. We maintain our view that this is an area of medical science in need of deeper exploration.
D Apostolopoulos, M Nikpour, A Hoi, EF Morand.
1. Boers, M. 2017. Observational studies on glucocorticoids are harmful! Lupus Sci Med 4(1) e000219.
2. Apostolopoulos, D. et al. 2016. Independent association of glucocorticoids with damage accrual in SLE. Lupus Sci Med 3(1) e000157.
3. Hoi, A.Y. et al. 2006. Protection from crescentic glomerulonephritis in MIF-deficient MRL/lpr mice associated with reductions in macrophage recruitment and MCP-1. Arthritis Rheum 54(9) S283-S283.
4. Leng, L. et al. 2010. A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr mice. J Immunol 186(1) 527-538.
Geraldino-Pardillaet al.1 recently published an interesting article analysing one of the most important aspects of systemic lupus erythematosus (SLE): the risk of cardiovascular disease, a leading cause of death in SLE patients. Although there were no healthy control group to compare, and the SLE patient sample size was limited, their conclusions are clinically valuable and should be taken into consideration.
The usefulness of the corrected QT interval (QTc) as a marker of atherosclerosis risk is well-established in the general population and in some sub-groups with high cardiovascular risk. QTc prolongation is also linked to cardiovascular events and mortality during follow-up2-3. QTc interval prolongation in SLE patients has been described in previous studies4.However, no data on the clinical repercussions of this finding are available. Our research group recently published a paper on the positive correlation between QTc interval prolongation in SLE patients and higher arterial stiffness measured by pulse-wave velocity5. The association was independent of hypertension and age. Our data complement those published by Geraldino-Pardilla et al.1, suggesting an independent association between QTc interval prolongation and subclinical atherosclerosis. However, there is no evidence of the long-term clinical effects of this association. Prospective studies with large sample sizes and long follow-up periods are required to study the potential long-term effects. In any case...
Geraldino-Pardillaet al.1 recently published an interesting article analysing one of the most important aspects of systemic lupus erythematosus (SLE): the risk of cardiovascular disease, a leading cause of death in SLE patients. Although there were no healthy control group to compare, and the SLE patient sample size was limited, their conclusions are clinically valuable and should be taken into consideration.
The usefulness of the corrected QT interval (QTc) as a marker of atherosclerosis risk is well-established in the general population and in some sub-groups with high cardiovascular risk. QTc prolongation is also linked to cardiovascular events and mortality during follow-up2-3. QTc interval prolongation in SLE patients has been described in previous studies4.However, no data on the clinical repercussions of this finding are available. Our research group recently published a paper on the positive correlation between QTc interval prolongation in SLE patients and higher arterial stiffness measured by pulse-wave velocity5. The association was independent of hypertension and age. Our data complement those published by Geraldino-Pardilla et al.1, suggesting an independent association between QTc interval prolongation and subclinical atherosclerosis. However, there is no evidence of the long-term clinical effects of this association. Prospective studies with large sample sizes and long follow-up periods are required to study the potential long-term effects. In any case, this paper highlights the role that QT interval analysis could play in cardiovascular risk stratification in SLE patients.
References
1 Geraldino-Pardilla L, Gartshteyn Y, Piña P, et al. ECG non-specific ST-T and QTc abnormalities in patients with systemic lupus erythematosus compared with rheumatoid arthritis. Lupus Science & Medicine 2016;3.e000168.
2 Dekker JM, Crow RS, Hannan PJ, et al, ARIC Study. Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women: the ARIC study. J Am Coll Cardiol 2004;43:565-71.
3 Panoulas VF, Toms TE, Douglas KM, et al. Prolonged QTc interval predicts all-cause mortality in patients with rheumatoid arthritis: an association driven by high inflammatory burden. Rheumatology (Oxford), 2014;53:131-7.
4 Cardoso CR, Sales MA, Papi JA, et al. QT-interval parameters are increased in systemic lupus erythematosus patients. Lupus 2005;14:846-52.
5 Rivera-López R, Jiménez-Jáimez J, Sabio JM, et al. Relationship between QT Interval Length and Arterial Stiffness in Systemic Lupus Erythematosus (SLE): A Cross-Sectional Case-Control Study. PLoS One 2016;11.e0152291.
To the editor,
We have read with interest the study from Khawaja et al. entitled ''Loss of antiphospholipid antibody (aPL) positivity post-thrombosis in systemic lupus erythematosus (SLE)''(1). The authors described 31 patients with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus who presented loss of antiphospholipid antibodies (aPL) positivity after thrombotic events.
They measured four types of aPL: IgM, IgG and IgA isotypes of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). Complete disappearance after thrombosis was observed in 41% of APS patients for IgG aCL, 51% for those with IgM aCL, 50% for IgA aCL, and 20% for LAC. However, 60% of those who at the same time lost IgG aCL and 76% of those who became negative for LAC, reacquired the antibodies within five years. In contrast, only 37% and 17% of those who lost IgM or IgA aCL, reacquired the antibodies within five years, respectively. Finally, 14 (45%) patients never turned back positive during the follow-up period. They concluded that recurrence of aPL positivity is frequent in APS associated with SLE, after their disappearance in post-thrombotic states.
Until now, long term oral anticoagulation (OAC) is the cornerstone of treatment for thrombotic primary and SLE-associated APS (2). The decision to withdraw OAC in APS patients when aPL become "persistently" negative remains a matter of debate. In the light of results fro...
Show MoreDr Olsen and Karp have summarised data from several important papers on the use of novel diagnostic tests for earlier diagnosis of SLE. I agree in the importance of this problem, for the early exclusion of SLE in people with benign ANA positivity, and early intervention in people destined to develop SLE or related disease.
I also agree with the key challenges in such research. Previous studies have been limited by a retrospective design. Inclusion of patients with variable symptom duration or patient populations that were selected for certain clinical characteristics may bias findings by conditioning on the outcome. Also, putative biomarker results need to be appraised alongside routine diagnostic tests, not in isolation.
These challenges were met in our previous study into these questions[1]. We invited all ANA-positive referrals to our centre with an onset of the symptoms that triggered referral within the past 12 months to participate, ensuring an unbiased sample appropriate to the clinical question. We collected detailed data on clinical presentation, routine immunology assessments, patient and physician reported severity, and family history, and integrated these data into our biomarker evaluation. Our patients were recruited and followed up prospectively in a standardised schedule of visits with strict assessment of criteria and a "flare hotline" in case new symptoms developed.
By doing so, we were able to reliably demonstrate the value...
Show MoreDear editor;
Show MoreWe have read with great interest the article published by Haque et al. which was about association between atherosclerotic process, cardiovascular outocomes and systemic lupus erythematosus (SLE). It is reported that only SDI score, triglyceride level and cyclophosphamide exposure was predictive for future cardiovascular events and factors related with plaque progression were defined(1).
SLE is a multisystemic disorder and lupus nephritis is one of the main manifestions of the disease. It usually presents with proteinuria and deteriorated renal glomerular functions. Renin angiotensinogen antgiotensin system (RAAS) inhibitors are used in patients with lupus nephritis to reduce proteinuria and kidney function protection(3). Angiotensin II (AT II) has unfavorable effects on endothelial functions. AT II binds AT 1 receptors and promotes vasoconstriction and production of proinlammatory cytokines and proliferation factors. It is shown by several studies that RAAS inhibitors improves endothelial functions and induces the regression of atherosclerotic process(3).
Microalbuminuria (MAU) and proteinuria are related with worse cardiovascular outcomes. Microalbuminuria causes endothelial dysfunction and associated with accelerated atherosclerosis(4). MESA study demonstrated that coronary calcification is significantly higher in patients with microalbuminuria than counterparts without MAU. Not only presence but also amount of MAU is associated with insu...
Dear editor,
Show MoreWe read with interest the article of Idborg et al.1 who recently analyzed the role of several inflammatory mediators, and their usefulness as biomarkers in the measurement of activity of disease and the identification of clinical subphenotypes in systemic lupus erythematosus (SLE). Although interesting, these results may benefit of further discussion in light of systems medicine.
Authors concluded that the two main inflammatory mediators related with activity of SLE were TNF-α and p-albumin. However, previous studies have found that TNF-α and the TNF/IL-10 ratio were higher in patients with low activity of disease,2 and that TNF-α antagonists may induce SLE-like disease.3 These controversial data argues against a generalized model based on TNF-α as clinical activity biomarker, and advocate for the influence of other mediators in such a condition.
As shown by Idborg et al., IL-6, IL-10, IL-15, MCP-1, IP-10, MIP-1α, ESR, anti-dsDNA and U-albumin/creatinine were also positively correlated with activity of disease,1 suggesting that the exclusive role of TNF-α and p-albumin on activity of disease is unlikely. In fact, the pathological functions of these biomarkers are not isolate since they emerge from the interactions among them and between cells and tissues (i.e., systems medicine).4
In this sense, cytokine and autoantibody clusters (i.e., neutral, chemotactic/anti-phospholipid antibodies, and IFN-α/dsDNA) have been reported to be associat...
The Editor,
Lupus Science and Medicine
BMJ Journals
Dear Madam/Sir,
Our esteemed peer Dr. Boers has editorialised1 on our recently published study of associations of glucocorticoid use with damage accrual in SLE2, suggesting that studies of the type reported are ‘harmful’. As this is such a serious accusation, we feel compelled to respond, even though we suspect that in the end the views of the authors and of Dr Boers as serious physician-researchers are in fact highly aligned. Essentially, we do not resile from our view that long-term reliance on glucocorticoids for the control of inflammation in SLE carries harm, and that steroid-reducing regimens for SLE management are urgently needed. At no time in our report, and certainly not in our clinical practice, do we advise against the use of these drugs, though such an imprecation was implied (incorrectly) in Dr Boers’ editorial. Rather, it is our view that strategies to achieve control of disease activity with reduced reliance on glucocorticoids, such as improving the use of non-glucocorticoid agents or the introduction of novel therapies, are as urgently needed as ever – and that complacency about the chronic use of glucocorticoids in SLE is not an acceptable status quo.
As we stated in the opening remarks, ‘The objective of the present study was to quantify damage accrual in a prospectively followed cohort of patients with SLE and determine the association of glucocorticoid use with damage...
Show MoreGeraldino-Pardillaet al.1 recently published an interesting article analysing one of the most important aspects of systemic lupus erythematosus (SLE): the risk of cardiovascular disease, a leading cause of death in SLE patients. Although there were no healthy control group to compare, and the SLE patient sample size was limited, their conclusions are clinically valuable and should be taken into consideration.
The usefulness of the corrected QT interval (QTc) as a marker of atherosclerosis risk is well-established in the general population and in some sub-groups with high cardiovascular risk. QTc prolongation is also linked to cardiovascular events and mortality during follow-up2-3. QTc interval prolongation in SLE patients has been described in previous studies4.However, no data on the clinical repercussions of this finding are available. Our research group recently published a paper on the positive correlation between QTc interval prolongation in SLE patients and higher arterial stiffness measured by pulse-wave velocity5. The association was independent of hypertension and age. Our data complement those published by Geraldino-Pardilla et al.1, suggesting an independent association between QTc interval prolongation and subclinical atherosclerosis. However, there is no evidence of the long-term clinical effects of this association. Prospective studies with large sample sizes and long follow-up periods are required to study the potential long-term effects. In any case...
Show More