International Journal of Rheumatic Diseases 2013; 16: 611–614
EDITORIAL
New perspectives and insights to Asian systemic lupus erythematosus: renal disease, genetic predisposition and disease activity
In this issue of the International Journal of Rheumatic Diseases, several papers focus on new investigations or new recommendations for Asian systemic lupus erythematosus (SLE). Previous work has consistently shown that Asian patients have higher rates of renal involvement compared to Caucasian patients1,2 and that lupus nephritis is a significant cause of chronic renal failure.3 Asian SLE patients may also have poorer outcomes and more severe renal involvement.4 As such, one of the papers in this volume focuses on Asian lupus nephritis management guidelines. Led by a panel of 15 nephrologists and rheumatologists from different Asian regions with extensive interest and experience in lupus nephritis, the Asian Lupus Nephritis Network (ALNN) steering group provides a summary of the current literature regarding lupus nephritis treatment options in Asian patients and provides expert consensus views about Asian lupus nephritis treatment.5 After summarizing the current lupus nephritis recommendations from the Kidney Disease Improving Global Outcomes (KDIGO), American College of Rheumatology (ACR), and the joint European League against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA), ALNN provides some summary suggestions for treatment of lupus nephritis in Asian patients based upon published Asian studies and expert opinion. However, these ALNN guidelines are based upon data garnered from predominantly Chinese patients. Asian lupus nephritis patients from the middle east and south Asian countries, including the subcontinent, need to be studied as they may require different treatment options and guidelines due to differences in disease presentation and progression. Strong conclusions cannot be drawn from the two papers on lupus nephritis from Iran in this issue,6,7 due in part to small sample sizes and the retrospective nature of their studies; however, high
prevalence of renal failure in both the cohorts are noteworthy. As in all racial groups, treatment is guided by histological and clinical nephritis severity, as well as by extra-renal lupus manifestations.5 Mild to moderate renal disease, including patients with Class II mesangial proliferative, may be treated with moderate disease corticosteroids with or without an additional immunosuppressive agent as a steroid-sparing agent. Class III or Class IV lupus nephritis, or Class V with heavy proteinuria, requires early identification and treatment with induction therapy (4–6 months) requiring high-dose corticosteroids and an immunosuppressive agent, usually with intravenous (IV) pulse cyclophosphamide (CYC), mycophenolate mofetil (MMF) or oral CYC based upon cost, compliance, and geographical access. MMF has been shown to be well tolerated in SLE patients often with higher efficacy, less toxicity and lower infection rates than CYC, as well as less significant drug interactions with commonly used concurrent lupus medications.8,9 Additionally, MMF is well suited for treatment of lupus nephritis as despite impaired renal function, MMF is rapidly absorbed with no significant changes in circulating levels of the active metabolite.9 Based upon its efficacy and tolerability in the majority of Asian patient studies, MMF in combination with corticosteroids is the most commonly recommended initial therapy. In lupus nephritis patients, carefully controlled MMF dosages have been associated with improved renal outcomes at a 1 year follow-up.10 Recommendations are to use 1.5–2 g daily in Asian patients and not to reduce the daily dose to below 1.5 g within the first year and not to below 1 g daily within the second year. It is important to note that taking MMF with food can alter the absorption of the drug; as such, MMF should be taken on an empty stomach to obtain the recommended daily dose.11 Data are needed to help understand which
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Editorial
patients, and at what time-points, MMF can be safely discontinued without subsequent flare.12 IV pulse corticosteroids may be required for patients with crescentic involvement of ≥10% of the glomeruli or with deteriorating renal function. Triple therapy with tacrolimus, MMF and corticosteroids may also be beneficial13 but needs further study. Further recommendations are provided within the manuscript.5 Of course, therapy needs to be used in combination with blood pressure control, minimization of vascular risk factors and reno-preservation. To this end, the usage of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been shown to reduce proteinuria and improve serum albumin in lupus nephritis patients.14,15 Addition of these medications to the standard MMF or MMF combination therapies needs to be further examined in additional diverse populations. Additional studies in the optimal management of crescentic lupus nephritis or thrombombotic microangiopathy, the role of mycophenolic acid blood level monitoring, the role of biologics in treatment, the optimal surveillance and management of infectious complication and the management of patients who are intolerant to current treatments are all highlighted by the study authors.5 A portion of the SLE patient population experiences gastrointestinal (GI) intolerance of MMF leading to withdraw of MMF from their treatment regimen or poor patient compliance with the prescribed dosages. Mycophenolate sodium has fewer GI adverse events than MMF and is increasingly used in organ transplant patients.16–19 Further evaluation of the efficacy of mycophenolate sodium may be warranted in Asian SLE patients as suggested by the pilot study by Yahya and colleagues20 in this volume. Unfortunately, this small (n = 14), open-label study from Malaysia in non-renal lupus was unable to conclusively answer this question, but provides additional support for further evaluation in larger study populations. In addition, studies within other Asian populations without large treatment trials (which to date have focused primarily in China, with smaller studies from Japan, Korea and Malaysia) are warranted and may provide other important treatment nuances in this large, heterogeneous compilation of “Asian lupus”. Early predictors of Asian SLE patients at increased risk of lupus nephritis, or biomarkers of response, would also be useful, as would a better understanding of the Asian lupus nephritis patients at the highest risk of developing end stage renal failure. Another of the papers in this month’s journal focuses on assessing the frequency and associated variables with
612
end stage renal disease (ESRD) looking at longitudinal information from the Taiwan National Health Insurance Research Database.21 Through queries of new SLE diagnoses between 2000–2002 (n = 4130), 2.5% (n = 103) developed ESRD by the end of 2008. Male gender and younger age at diagnosis were associated with ESRD within SLE. Additionally, Lin and colleagues observed a poor rate of survival in young SLE patients with ESRD.21 Strengths of this study include its nationwide population-based cohort, relatively long followup (up to 8 years), the comparison group of other patients with ESRD without SLE, an understudied lupus nephritis population from Taiwan and capture of patients at close to disease diagnosis. Weaknesses include use of ICD9 codes for diagnoses surrogates without confirmation by clinical evaluation or medical record review, lack of control or correction for co-morbidity confounders such as hypertension, diabetes or lack of medical intervention for lupus nephritis, lack of biopsy information, and lack of a prospective cohort design allowing careful characterization of clinical, laboratory, socioeconomic, therapeutic and demographic features. Another interesting fact is that 84 SLE patients were excluded from the study as they developed ESRD within 6 months of SLE diagnosis, leading to other potentially interesting questions on the outcome, associated variables and causes of ESRD in these additional lupus patients which form a cohort of almost equal size to the chronic ESRD cohort studied in the paper. Of course, having genetic and other biomarker information on these patients who do and do not develop ESRD would have also been very interesting and useful. Two papers in this issue examine genetic associations with two different candidate genes and SLE in distinct Asian populations.22,23 Dai and colleagues show that the low-binding allele FcgRIIIa-158F is a risk factor for SLE in the Chinese population, using a cohort of 732 SLE patients (390 lupus nephritis and 342 non-nephritis lupus) and 886 controls (OR = 1.29, P = 0.0009).22 No association with lupus nephritis was found with this genotype; however, the risk allele was enriched in SLE patients with serositis and low levels of complement.22 They added these new data to published information from 11 additional studies (spanning China, Taiwan, Japan, Korea, Thailand and Asian populations and varying in size from the 732 patients in this study to as small as 13 in the first published work in this area) to perform a meta-analysis with 2,561 Asian SLE patients (1339 with nephritis, 1131 without nephritis) for association with FcgRIIIa-158F. Association was again found with the F-allele of FcgRIIIa and SLE (OR [95%
International Journal of Rheumatic Diseases 2013; 16: 611–614
Editorial
CI] = 1.25 [1.12–1.40]), but no longer with lupus nephritis as had been suggested previously with smaller Asian studies.22 Additional work is warranted to understand the functional significance of the FcgRIIIa-158F allele in Asian lupus nephritis, as well as to understand how this association may be contributing to some aspects of lupus within and across select ethnic backgrounds. Another small study in this issue23 did not show association of CTLA4 polymorphisms in 180 Iranian SLE patients compared to 304 controls; however, the study was likely underpowered and lacks assessment of the potential impact of population stratification. Two lupus papers in this journal edition approach novel areas in potential lupus pathogenesis and biomarker development in patients from China. One of them focuses on Organelle membranes that undergo conformational changes to tubuloreticular structures (TRS) after physiological stressors, such as viral infections, starvation and various disease states. Mak and colleagues24 demonstrate that supra-physiological levels of interferon-alpha can induce TRS as measured by transmission electron microscopy in cell lines in a dose-dependent fashion. In addition, the frequency of TRS mean range in PBMCs of lupus patients was significantly higher compared to that of healthy subjects and the higher TRS scores correlated with increased SLEDAI levels. Additional information is needed regarding whether the patients with higher levels of TRS also had higher interferon signatures or interferon activity. In addition, at least five of the 15 SLE patients tested had no detectable TRS and how those patients differed from the other patients is not clear. Finally, if these associations are confirmed in larger, longitudinal studies, then the mechanisms by which TRS might be driving lupus pathogenesis will need to be discovered; however, this is a novel area of investigation which warrants additional study. Another small and elegant study in the current issue, also from China25, by Lin Jin et al. reports CD24hiCD27 + CD19 + B cells as a biomarker for new onset SLE, as well as for SLE in longitudinal samples. These results sound promising and replication studies are needed. We also agree with Tung and colleagues26 and hope that high seroprevalence of HHV-8 infection in Taiwanese lupus patients without viral DNA load may indeed reflect an epiphenomenon, as lupus can serve as a museum of historical cross reactive polyclonal antibodies. As evident based upon the large cadres of lupus patients and growing numbers of lupus investigators
International Journal of Rheumatic Diseases 2013; 16: 611–614
within these Asian communities, significant advances are being made in the evaluation and care of systemic lupus erythematosus in Asian countries. Additional work in therapeutic, genetic, prognostic and biomarker work is underway and will provide more insights to the unique and common aspects of lupus pathogenesis within and across Asia, as well as the rest of the world.
CONFLICT OF INTEREST The authors declare no conflicts of interest. Judith A. JAMES1,2 and Debashish DANDA3 1
Departments of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, 2 Departments of Medicine, Microbiology & Immunology, and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, and 3Departments of Clinical Immunology & Rheumatology, Christian Medical College & Hospital, Vellore, India
REFERENCES 1 Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N (2012) Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res 64, 159–68. 2 Chakravarty EF, Bush TM, Manzi S, Clarke AE, Ward MM (2007) Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum 56, 2092–4. 3 Saxena R, Mahajan T, Mohan C (2011) Lupus nephritis: current update. Arthritis Res Ther 13, 240. 4 Mok CC (2005) Prognostic factors in lupus nephritis. Lupus 14, 39–44. 5 Mok CC, Yap DYH, Navarra SV et al. (2013) Overview of lupus nephritis management guidelines and perspective from Asia. Int J Rheum Dis 16, 625–36. 6 Shariati-Sarabi Z, Ranjbar A, Monzavi SM, Esmaily H, Farzadnia M, Zeraati AA (2013) Analysis of clinicopathologic correlations in Iranian patients with lupus nephritis. Int J Rheum Dis 16, 731–8. 7 Fatemi A, Kazemi M, Sayedbonakdar Z, Farajzadegan Z, Karimzadeh H, Moosavi M (2013) Long-term outcome of biopsy-proven lupus nephritis in Iran. Int J Rheum Dis 16, 739–46. 8 Zhu B, Chen N, Lin Y et al. (2007) Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 22, 1933–42.
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Editorial
9 Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34, 429–55. 10 Daleboudt GM, Reinders ME, den Hartigh J et al. (2013) Concentration-controlled treatment of lupus nephritis with mycophenolate mofetil. Lupus 22, 171–9. 11 Abd Rahman AN, Tett SE, Staatz CE (2013) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clin Pharmacokinet 52, 303–31. 12 Rovin BH, Parikh SV, Hebert LA et al. (2013) Lupus nephritis: induction therapy in severe lupus nephritis– should MMF be considered the drug of choice? Clin J Am Soc Nephrol 8, 147–53. 13 Ikeuchi H, Hiromura K, Takahashi S et al. (2013) Efficacy and safety of multi-target therapy using a combination of tacrolimus, mycophenolate mofetil and a steroid in patients with active lupus nephritis. Mod Rheumatol. [Epub ahead of print]. 14 Kitamura N, Matsukawa Y, Takei M, Sawada S (2009) Antiproteinuric effect of angiotensin-converting enzyme inhibitors and an angiotensin II receptor blocker in patients with lupus nephritis. J Int Med Res 37, 892–8. 15 Tse KC, Li FK, Tang S, Tang CS, Lai KN, Chan TM (2005) Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. Lupus 14, 947–52. 16 Calvo N, Sanchez-Fructuoso AI, Conesa J, Moreno A, Barrientos A (2006) Renal transplant patients with gastrointestinal intolerability to mycophenolate mofetil: conversion to enteric-coated mycophenolate sodium. Transplant Proc 38, 2396–7. 17 Salvadori M (2005) Long-term administration of entericcoated mycophenolate sodium in kidney transplant patients. Transplant Proc 37, 909–11. 18 Salvadori M, Holzer H, de Mattos A et al. (2004) Entericcoated mycophenolate sodium is therapeutically equiva-
614
19
20
21
22
23
24
25
26
lent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4, 231–6. Traitanon O, Avihingsanon Y, Kittikovit V et al. (2008) Efficacy of enteric-coated mycophenolate sodium in patients with resistant-type lupus nephritis: a prospective study. Lupus 17, 744–51. Yahya F, Jasmin R, Ng CT, Cheah TE, Sockalingam S (2013) Open label randomized controlled trial assessing the efficacy of mycophenolate sodium against other conventional immunosuppressive agents in active systemic lupus erythematosus patients without renal involvement. Int J Rheum Dis 16, 724–30. Lin W-H, Guo C-Y, Wang W-M et al. (2013) Incidence of progression from newly diagnosed systemic lupus erythematosus to end stage renal disease and all-cause mortality: a nationwide cohort study in Taiwan. Int J Rheum Dis 16, 747–53. Dai M, Zhou Z, Wang X, Qian X Huang X (2013) Association of FccRIIIa-158V/F with systemic lupus erythematosus in a Chinese population. Int J Rheum Dis 16, 685–91. Shojaa M, Javid N, Amoli M, et al. (2013) No evidence of association between CTLA-4 polymorphisms and systemic lupus erythematosus in Iranian patients. Int J Rheum Dis 16, 681–4. Mak A, Almsherqi ZAM, Lai Y-W, Cheak AAC, Deng Y (2013) Intracellular tubulo-reticular structures of peripheral blood mononuclear cells as an ultra-structural marker of disease activity in systemic lupus erythematosus: a pilot study. Int J Rheum Dis 16, 692–7. Jin L, Weiqian C, Lihuan Y (2013) Peripheral CD24hiCD27 + CD19 + B cells subset as a potential biomarker in naıve systemic lupus erythematosus. Int J Rheum Dis 16, 698–708. Tung YC, Ke LY, Tsai SM, Lu PL, Tsai WC (2013) High seroprevalence of human herpesvirus 8 infection in patients with systemic lupus erythematosus. Int J Rheum Dis 16, 709–14.
International Journal of Rheumatic Diseases 2013; 16: 611–614
EDITORIAL
New perspectives and insights to Asian systemic lupus erythematosus: renal disease, genetic predisposition and disease activity
In this issue of the International Journal of Rheumatic Diseases, several papers focus on new investigations or new recommendations for Asian systemic lupus erythematosus (SLE). Previous work has consistently shown that Asian patients have higher rates of renal involvement compared to Caucasian patients1,2 and that lupus nephritis is a significant cause of chronic renal failure.3 Asian SLE patients may also have poorer outcomes and more severe renal involvement.4 As such, one of the papers in this volume focuses on Asian lupus nephritis management guidelines. Led by a panel of 15 nephrologists and rheumatologists from different Asian regions with extensive interest and experience in lupus nephritis, the Asian Lupus Nephritis Network (ALNN) steering group provides a summary of the current literature regarding lupus nephritis treatment options in Asian patients and provides expert consensus views about Asian lupus nephritis treatment.5 After summarizing the current lupus nephritis recommendations from the Kidney Disease Improving Global Outcomes (KDIGO), American College of Rheumatology (ACR), and the joint European League against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA), ALNN provides some summary suggestions for treatment of lupus nephritis in Asian patients based upon published Asian studies and expert opinion. However, these ALNN guidelines are based upon data garnered from predominantly Chinese patients. Asian lupus nephritis patients from the middle east and south Asian countries, including the subcontinent, need to be studied as they may require different treatment options and guidelines due to differences in disease presentation and progression. Strong conclusions cannot be drawn from the two papers on lupus nephritis from Iran in this issue,6,7 due in part to small sample sizes and the retrospective nature of their studies; however, high
prevalence of renal failure in both the cohorts are noteworthy. As in all racial groups, treatment is guided by histological and clinical nephritis severity, as well as by extra-renal lupus manifestations.5 Mild to moderate renal disease, including patients with Class II mesangial proliferative, may be treated with moderate disease corticosteroids with or without an additional immunosuppressive agent as a steroid-sparing agent. Class III or Class IV lupus nephritis, or Class V with heavy proteinuria, requires early identification and treatment with induction therapy (4–6 months) requiring high-dose corticosteroids and an immunosuppressive agent, usually with intravenous (IV) pulse cyclophosphamide (CYC), mycophenolate mofetil (MMF) or oral CYC based upon cost, compliance, and geographical access. MMF has been shown to be well tolerated in SLE patients often with higher efficacy, less toxicity and lower infection rates than CYC, as well as less significant drug interactions with commonly used concurrent lupus medications.8,9 Additionally, MMF is well suited for treatment of lupus nephritis as despite impaired renal function, MMF is rapidly absorbed with no significant changes in circulating levels of the active metabolite.9 Based upon its efficacy and tolerability in the majority of Asian patient studies, MMF in combination with corticosteroids is the most commonly recommended initial therapy. In lupus nephritis patients, carefully controlled MMF dosages have been associated with improved renal outcomes at a 1 year follow-up.10 Recommendations are to use 1.5–2 g daily in Asian patients and not to reduce the daily dose to below 1.5 g within the first year and not to below 1 g daily within the second year. It is important to note that taking MMF with food can alter the absorption of the drug; as such, MMF should be taken on an empty stomach to obtain the recommended daily dose.11 Data are needed to help understand which
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Editorial
patients, and at what time-points, MMF can be safely discontinued without subsequent flare.12 IV pulse corticosteroids may be required for patients with crescentic involvement of ≥10% of the glomeruli or with deteriorating renal function. Triple therapy with tacrolimus, MMF and corticosteroids may also be beneficial13 but needs further study. Further recommendations are provided within the manuscript.5 Of course, therapy needs to be used in combination with blood pressure control, minimization of vascular risk factors and reno-preservation. To this end, the usage of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been shown to reduce proteinuria and improve serum albumin in lupus nephritis patients.14,15 Addition of these medications to the standard MMF or MMF combination therapies needs to be further examined in additional diverse populations. Additional studies in the optimal management of crescentic lupus nephritis or thrombombotic microangiopathy, the role of mycophenolic acid blood level monitoring, the role of biologics in treatment, the optimal surveillance and management of infectious complication and the management of patients who are intolerant to current treatments are all highlighted by the study authors.5 A portion of the SLE patient population experiences gastrointestinal (GI) intolerance of MMF leading to withdraw of MMF from their treatment regimen or poor patient compliance with the prescribed dosages. Mycophenolate sodium has fewer GI adverse events than MMF and is increasingly used in organ transplant patients.16–19 Further evaluation of the efficacy of mycophenolate sodium may be warranted in Asian SLE patients as suggested by the pilot study by Yahya and colleagues20 in this volume. Unfortunately, this small (n = 14), open-label study from Malaysia in non-renal lupus was unable to conclusively answer this question, but provides additional support for further evaluation in larger study populations. In addition, studies within other Asian populations without large treatment trials (which to date have focused primarily in China, with smaller studies from Japan, Korea and Malaysia) are warranted and may provide other important treatment nuances in this large, heterogeneous compilation of “Asian lupus”. Early predictors of Asian SLE patients at increased risk of lupus nephritis, or biomarkers of response, would also be useful, as would a better understanding of the Asian lupus nephritis patients at the highest risk of developing end stage renal failure. Another of the papers in this month’s journal focuses on assessing the frequency and associated variables with
612
end stage renal disease (ESRD) looking at longitudinal information from the Taiwan National Health Insurance Research Database.21 Through queries of new SLE diagnoses between 2000–2002 (n = 4130), 2.5% (n = 103) developed ESRD by the end of 2008. Male gender and younger age at diagnosis were associated with ESRD within SLE. Additionally, Lin and colleagues observed a poor rate of survival in young SLE patients with ESRD.21 Strengths of this study include its nationwide population-based cohort, relatively long followup (up to 8 years), the comparison group of other patients with ESRD without SLE, an understudied lupus nephritis population from Taiwan and capture of patients at close to disease diagnosis. Weaknesses include use of ICD9 codes for diagnoses surrogates without confirmation by clinical evaluation or medical record review, lack of control or correction for co-morbidity confounders such as hypertension, diabetes or lack of medical intervention for lupus nephritis, lack of biopsy information, and lack of a prospective cohort design allowing careful characterization of clinical, laboratory, socioeconomic, therapeutic and demographic features. Another interesting fact is that 84 SLE patients were excluded from the study as they developed ESRD within 6 months of SLE diagnosis, leading to other potentially interesting questions on the outcome, associated variables and causes of ESRD in these additional lupus patients which form a cohort of almost equal size to the chronic ESRD cohort studied in the paper. Of course, having genetic and other biomarker information on these patients who do and do not develop ESRD would have also been very interesting and useful. Two papers in this issue examine genetic associations with two different candidate genes and SLE in distinct Asian populations.22,23 Dai and colleagues show that the low-binding allele FcgRIIIa-158F is a risk factor for SLE in the Chinese population, using a cohort of 732 SLE patients (390 lupus nephritis and 342 non-nephritis lupus) and 886 controls (OR = 1.29, P = 0.0009).22 No association with lupus nephritis was found with this genotype; however, the risk allele was enriched in SLE patients with serositis and low levels of complement.22 They added these new data to published information from 11 additional studies (spanning China, Taiwan, Japan, Korea, Thailand and Asian populations and varying in size from the 732 patients in this study to as small as 13 in the first published work in this area) to perform a meta-analysis with 2,561 Asian SLE patients (1339 with nephritis, 1131 without nephritis) for association with FcgRIIIa-158F. Association was again found with the F-allele of FcgRIIIa and SLE (OR [95%
International Journal of Rheumatic Diseases 2013; 16: 611–614
Editorial
CI] = 1.25 [1.12–1.40]), but no longer with lupus nephritis as had been suggested previously with smaller Asian studies.22 Additional work is warranted to understand the functional significance of the FcgRIIIa-158F allele in Asian lupus nephritis, as well as to understand how this association may be contributing to some aspects of lupus within and across select ethnic backgrounds. Another small study in this issue23 did not show association of CTLA4 polymorphisms in 180 Iranian SLE patients compared to 304 controls; however, the study was likely underpowered and lacks assessment of the potential impact of population stratification. Two lupus papers in this journal edition approach novel areas in potential lupus pathogenesis and biomarker development in patients from China. One of them focuses on Organelle membranes that undergo conformational changes to tubuloreticular structures (TRS) after physiological stressors, such as viral infections, starvation and various disease states. Mak and colleagues24 demonstrate that supra-physiological levels of interferon-alpha can induce TRS as measured by transmission electron microscopy in cell lines in a dose-dependent fashion. In addition, the frequency of TRS mean range in PBMCs of lupus patients was significantly higher compared to that of healthy subjects and the higher TRS scores correlated with increased SLEDAI levels. Additional information is needed regarding whether the patients with higher levels of TRS also had higher interferon signatures or interferon activity. In addition, at least five of the 15 SLE patients tested had no detectable TRS and how those patients differed from the other patients is not clear. Finally, if these associations are confirmed in larger, longitudinal studies, then the mechanisms by which TRS might be driving lupus pathogenesis will need to be discovered; however, this is a novel area of investigation which warrants additional study. Another small and elegant study in the current issue, also from China25, by Lin Jin et al. reports CD24hiCD27 + CD19 + B cells as a biomarker for new onset SLE, as well as for SLE in longitudinal samples. These results sound promising and replication studies are needed. We also agree with Tung and colleagues26 and hope that high seroprevalence of HHV-8 infection in Taiwanese lupus patients without viral DNA load may indeed reflect an epiphenomenon, as lupus can serve as a museum of historical cross reactive polyclonal antibodies. As evident based upon the large cadres of lupus patients and growing numbers of lupus investigators
International Journal of Rheumatic Diseases 2013; 16: 611–614
within these Asian communities, significant advances are being made in the evaluation and care of systemic lupus erythematosus in Asian countries. Additional work in therapeutic, genetic, prognostic and biomarker work is underway and will provide more insights to the unique and common aspects of lupus pathogenesis within and across Asia, as well as the rest of the world.
CONFLICT OF INTEREST The authors declare no conflicts of interest. Judith A. JAMES1,2 and Debashish DANDA3 1
Departments of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, 2 Departments of Medicine, Microbiology & Immunology, and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA, and 3Departments of Clinical Immunology & Rheumatology, Christian Medical College & Hospital, Vellore, India
REFERENCES 1 Jakes RW, Bae SC, Louthrenoo W, Mok CC, Navarra SV, Kwon N (2012) Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res 64, 159–68. 2 Chakravarty EF, Bush TM, Manzi S, Clarke AE, Ward MM (2007) Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum 56, 2092–4. 3 Saxena R, Mahajan T, Mohan C (2011) Lupus nephritis: current update. Arthritis Res Ther 13, 240. 4 Mok CC (2005) Prognostic factors in lupus nephritis. Lupus 14, 39–44. 5 Mok CC, Yap DYH, Navarra SV et al. (2013) Overview of lupus nephritis management guidelines and perspective from Asia. Int J Rheum Dis 16, 625–36. 6 Shariati-Sarabi Z, Ranjbar A, Monzavi SM, Esmaily H, Farzadnia M, Zeraati AA (2013) Analysis of clinicopathologic correlations in Iranian patients with lupus nephritis. Int J Rheum Dis 16, 731–8. 7 Fatemi A, Kazemi M, Sayedbonakdar Z, Farajzadegan Z, Karimzadeh H, Moosavi M (2013) Long-term outcome of biopsy-proven lupus nephritis in Iran. Int J Rheum Dis 16, 739–46. 8 Zhu B, Chen N, Lin Y et al. (2007) Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant 22, 1933–42.
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Editorial
9 Bullingham RE, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34, 429–55. 10 Daleboudt GM, Reinders ME, den Hartigh J et al. (2013) Concentration-controlled treatment of lupus nephritis with mycophenolate mofetil. Lupus 22, 171–9. 11 Abd Rahman AN, Tett SE, Staatz CE (2013) Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clin Pharmacokinet 52, 303–31. 12 Rovin BH, Parikh SV, Hebert LA et al. (2013) Lupus nephritis: induction therapy in severe lupus nephritis– should MMF be considered the drug of choice? Clin J Am Soc Nephrol 8, 147–53. 13 Ikeuchi H, Hiromura K, Takahashi S et al. (2013) Efficacy and safety of multi-target therapy using a combination of tacrolimus, mycophenolate mofetil and a steroid in patients with active lupus nephritis. Mod Rheumatol. [Epub ahead of print]. 14 Kitamura N, Matsukawa Y, Takei M, Sawada S (2009) Antiproteinuric effect of angiotensin-converting enzyme inhibitors and an angiotensin II receptor blocker in patients with lupus nephritis. J Int Med Res 37, 892–8. 15 Tse KC, Li FK, Tang S, Tang CS, Lai KN, Chan TM (2005) Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. Lupus 14, 947–52. 16 Calvo N, Sanchez-Fructuoso AI, Conesa J, Moreno A, Barrientos A (2006) Renal transplant patients with gastrointestinal intolerability to mycophenolate mofetil: conversion to enteric-coated mycophenolate sodium. Transplant Proc 38, 2396–7. 17 Salvadori M (2005) Long-term administration of entericcoated mycophenolate sodium in kidney transplant patients. Transplant Proc 37, 909–11. 18 Salvadori M, Holzer H, de Mattos A et al. (2004) Entericcoated mycophenolate sodium is therapeutically equiva-
614
19
20
21
22
23
24
25
26
lent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 4, 231–6. Traitanon O, Avihingsanon Y, Kittikovit V et al. (2008) Efficacy of enteric-coated mycophenolate sodium in patients with resistant-type lupus nephritis: a prospective study. Lupus 17, 744–51. Yahya F, Jasmin R, Ng CT, Cheah TE, Sockalingam S (2013) Open label randomized controlled trial assessing the efficacy of mycophenolate sodium against other conventional immunosuppressive agents in active systemic lupus erythematosus patients without renal involvement. Int J Rheum Dis 16, 724–30. Lin W-H, Guo C-Y, Wang W-M et al. (2013) Incidence of progression from newly diagnosed systemic lupus erythematosus to end stage renal disease and all-cause mortality: a nationwide cohort study in Taiwan. Int J Rheum Dis 16, 747–53. Dai M, Zhou Z, Wang X, Qian X Huang X (2013) Association of FccRIIIa-158V/F with systemic lupus erythematosus in a Chinese population. Int J Rheum Dis 16, 685–91. Shojaa M, Javid N, Amoli M, et al. (2013) No evidence of association between CTLA-4 polymorphisms and systemic lupus erythematosus in Iranian patients. Int J Rheum Dis 16, 681–4. Mak A, Almsherqi ZAM, Lai Y-W, Cheak AAC, Deng Y (2013) Intracellular tubulo-reticular structures of peripheral blood mononuclear cells as an ultra-structural marker of disease activity in systemic lupus erythematosus: a pilot study. Int J Rheum Dis 16, 692–7. Jin L, Weiqian C, Lihuan Y (2013) Peripheral CD24hiCD27 + CD19 + B cells subset as a potential biomarker in naıve systemic lupus erythematosus. Int J Rheum Dis 16, 698–708. Tung YC, Ke LY, Tsai SM, Lu PL, Tsai WC (2013) High seroprevalence of human herpesvirus 8 infection in patients with systemic lupus erythematosus. Int J Rheum Dis 16, 709–14.
International Journal of Rheumatic Diseases 2013; 16: 611–614
