• Users Online: 178
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
SYMPOSIUM-RHEUMATOLOGY
Year : 2014  |  Volume : 19  |  Issue : 1  |  Page : 28-36

Advances in management of systemic lupus erythematosus


Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication1-Feb-2014

Correspondence Address:
Subramanian Shankar
Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-9903.126235

Rights and Permissions
  Abstract 

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems. In the past 40 years, prognosis for patients with SLE has improved significantly because of advances in the understanding of molecular mechanisms involved in the pathogenesis of disease, which has translated into early diagnosis and novel therapeutic strategies. This article will focus on three aspects that have shaped this transformation, namely; a revisit to diagnostic criteria, development of newer biomarkers, and incorporation of newer targeted therapies.

Keywords: Advances, connective tissue disorder, systemic lupus erythromatosus


How to cite this article:
Shankar S, Behera V. Advances in management of systemic lupus erythematosus. J Mahatma Gandhi Inst Med Sci 2014;19:28-36

How to cite this URL:
Shankar S, Behera V. Advances in management of systemic lupus erythematosus. J Mahatma Gandhi Inst Med Sci [serial online] 2014 [cited 2019 May 25];19:28-36. Available from: http://www.jmgims.co.in/text.asp?2014/19/1/28/126235


  Introduction Top


Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems. In the past 40 years, prognosis for patients with SLE has improved significantly because of advances in the understanding of molecular mechanisms involved in the pathogenesis of disease, which has translated into early diagnosis and novel therapeutic strategies. This article will focus on three aspects that have shaped this transformation, namely; a revisit to diagnostic criteria, development of newer biomarkers, and incorporation of newer targeted therapies.


  Classification Criteria of SLE Top


Pitfalls in existing criteria for SLE

Criteria for SLE classification was devel­oped by the American College of Rheumatology (ACR) in 1971, and revised in 1982 and 1997. [1] These criteria were not weighted for specificity, sensitivity or disease severity, and often excluded patients with early or limited disease. In fact, data from tertiary centres suggested that only 60% of patients referred for SLE fulfilled the ACR criteria, whereas another 15% of patients had SLE features but did not fulfill the cri­teria. [2] The major pitfalls with ACR criteria, which created the need for newer criteria, [3] included the following.

  • The 1982 criteria were biased and weighted toward cutaneous lupus, with four cutaneous criteria. However, the newer therapies for SLE were largely directed against renal or other major organ involvement.
  • Hypocomplementemia (omitted in the 1982 criteria) has been shown to be strongly associated with SLE, and its exclusion from SLE criteria often missed patients with SLE.
  • Advances have been made in autoantibody assays, such as the anti-phospholipid, anti-dsDNA, and anti-Sm antibodies. The criterion for anti-phospholipid antibodies has not been subjected to validation, and its inclusion may lead to confusion between SLE and primary APS. The appropriateness of new commercial enzyme-linked immunosorbent assay (ELISA) for anti-DNA has not been evaluated.
  • Many of the existing criteria require redefinition and refinement based on current practice. This is especially relevant for the renal and neurologic criteria (only psychosis and seizure are included) to reflect the breadth of neurologic lupus, as noted by the ACR neurologic classification criteria. [4]
  • Future criteria must be generalizable to multiple ethnic groups and be internationally valid. Different frequencies of individual criteria for different ethnicities have already been shown for African-Americans and for Japanese.
  • Future criteria need to include input from non-rheumatology specialists who frequently care for and diagnose lupus, including dermatologists, neurologists, and nephrologists.


SLE is likely a disease with multiple subsets. Accurate classification criteria would allow future clinical trials to look at treatment variability by subset, including chronic cutaneous lupus and APS.

SLICC criteria

This created the way for the "Systemic Lupus International Collaborating Clinics (SLICC) Classification 2012 Criteria." SLICC group is an international group of investigators dedicated to SLE clinical research. The SLICC classification criteria for SLE represent an 8-year effort of clinical review, consensus, and statistical analyses. The new criteria are simple, include most SLE patients, and retain specificity while being more sensitive.

The final criteria were derived using recursive partitioning [5] ("tree-based" approach) (using the CART software package), in which patients were categorized into two groups based on all candidate variables, and the resulting partitions were evaluated. A simple rule was applied - the patient must satisfy at least four criteria, including at least one clinical criterion and one immunologic criterion or the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-dsDNA antibodies. The SLICC classification criteria were subjected to rigorous testing. The new patient sample used for validation consisted of 690 patients and included patients from multiple centers with multiple diagnoses that have clinical features, which overlap with the clinical features of lupus.

The key features in SLICC criteria are that lupus nephritis alone with ANA positivity can be classified as SLE. Hypocomplementemia becomes an important component and multiple neurological syndromes like myelitis and mononeuritis multiplex have been included. The new SLICC criteria has a sensitivity and specificity of 94% and 92% compared to ACR criteria having 86% and 93%, respectively.

*Classify a patient as having SLE if

  • The patient satisfies four of the criteria (listed in [Table 1]) including at least one clinical criterion and one immunologic criterion; or
  • The patient has biopsy-proven nephritis compatible with SLE and with ANA or anti-dsDNA antibodies.
Table 1: Clinical and immunological criteria used In SLICC criteria*


Click here to view



  Biomarkers In SLE Top


Biomarkers are very useful in diagnosis, evaluation, and management of SLE and can be of help in early detection of a disease flare and monitoring disease activity. An ideal biomarker should accurately detect disease activity and guide therapy at every stage of SLE.

Need for novel biomarkers

Autoantibodies like ANA and dsDNA have been the traditional agents used in the diagnosis of SLE. But ANA has a low specificity for SLE, and its sensitivity may be as low as 70%, especially early in the disease. [6] Anti-dsDNA is better with 95% specificity but has a low sensitivity. [7] This created the need for novel biomarkers for SLE. Decades of extensive work has led to discovery of a number of candidate biomarkers, the precise clinical utility of which-outside of the research setting-awaits determination. [8]

New biomarkers in SLE

The newer biomarkers developed for use in SLE are given in [Table 2]. [9] Anti-nucleosome antibodies are associated with organic damage and are useful in diagnosis of SLE, drug-induced lupus, disease flares, and early detection of lupus nephritis. [10] Anti-C-1q antibodies, NMDA receptor antibody, and anti-alpha actinin antibody have also shown promise in early diagnosis of SLE and diagnosis of flares. Numerous biomarkers have been investigated in lupus nephritis and have shown a role in early detection of renal pathology, predicting flares, and predicting chronic kidney disease as given in [Table 2] and [Table 3].
Table 2: Novel biomarkers in diagnosis of SLE[11]


Click here to view
Table 3: Novel Biomarkers in Lupus Nephritis[27,28]


Click here to view


Alternative biomarkers

New high-throughput technologies, such as transcriptomics and proteomics, have been applied in search for biomarkers. Interferon-signature gene expression corre­lates with autoantibody profiles in SLE and may be useful in cutaneous lupus, discoid lupus, and neuromyelitis optica. [29] Micro RNAs (MiRNAs) play a crucial role in maintaining immune system development and function, and are implicated in SLE. Unique miRNA expression signatures in SLE have the potential to not only act as biomarkers for the diagnosis and assessment of SLE but may be the future therapeutic potential in management of SLE. RNA microarray analyses of peripheral blood leukocytes can distinguish between SLE flare and infection and might be useful in the diagnosis and monitoring of the disease.

Future insights - SLE biomarkers [30]

Next-generation SLE biomarkers

The focus today is shifting towards discovering biomarkers that predict onset of SLE in susceptible indi­viduals, development of flares in patients with established SLE, predicting disease outcomes, and assessing the effectiveness of therapeutic interventions. These will allow proactive institution of thera­peutic and even preventive strategies so that the therapeutic efficacy can be enhanced while treat­ment-related side effects can be minimized.

Pharmacodynamic biomarkers [31]

New biomarkers are being searched to aid identification of patients who might respond favorably to a particular biologic, selection of the type and dose of biologics used, and evaluation of therapeutic efficacy. An illustra­tive example is sifalimumab and rontalizumab, anti-IFNα monoclonal antibodies under evaluation for the treatment of SLE, which were developed based on the seminal discovery of the interferon signature and related biomarkers.


  Treatment of SLE Top


Conventional therapies

Early diagnosis and better treatment options of SLE and its complications have markedly improved the 5-year survival of patients with SLE. However, morbidity, especially renal failure, and mortality from cardiovascular events after long-term follow up are still an important issue. With the use of conventional therapies like corticosteroids, anti-malarials, aspirin, and hydroxychloroquine, half of patients with organ-threatening disease do not survive 20 years after diagnosis, and the quality of life for those individuals with all forms of SLE is usually seriously compromised. [32] Thus, there is a need for improved therapies for SLE, which has led to promising new leads in SLE therapy. Hydoxychloquine acts by reducing the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells, processing and transport of the peptide-MHC complex to the cell membrane and results in down-regulation of the immune response against autoantigenic peptides. 33 Studies have shown that hydroxychloroquine is an essential medication in lupus nephritis, neuro lupus and has got a role in alleviating cutaneous, articular and other manifestations of SLE. 34 The benefits also include a favorable effect on lipid profile, lower side effects and a protection against the occurrence of thrombotic events. 35 Its efficiency has also been demonstrated in the reduction of the risk of flares and to have a protective effect on survival in people with SLE. 36


  Targeted Therapy In SLE Top


Principle of targeted therapy

B lymphocytes play a central role in the pathogenesis of SLE. Pathogenic autoantibodies produced by B cells leads to tissue damage via immune complex formation, complement activation, and direct effects on cells. They also contribute to immune dysregulation by producing cytokines, presenting antigens, and regulating T-cell functions. [37] The regulatory and effector functions of T cells are also abnormal in patients with SLE. Elevated levels of certain cytokines / chemokines / growth factors made by monocytes / macrophages and endothelial cells also drive lupus disease activity and organ damage. These include B-cell activating factor (BAFF)/B lymphocyte stimulator, tumor necrosis factor (TNF) alpha, INF-a, IFN-γ, interleukin (IL)-12, IL-6, IL-10, and MCP-1. [38] Over the last few years, multiple studies have targeted these and other appropriate pathways in the therapy of SLE as given in [Figure 1]. Newer molecules have been developed targeting these pathways as given in [Table 4].
Figure 1: Possible targets in treatment of SLE

Click here to view
Table 4: Targeted Therapies in SLE[51]


Click here to view


Rituximab

Rituximab (RTX) is a chimeric monoclonal antibody that binds CD20, a protein expressed on B cells at all stages of development. Multiple open-label studies have reported the efficacy of RTX in patients with severe refractory SLE and catastrophic anti-phospholipid syndrome with maximal clinical benefit to be evident even after 18 months. [39] Case series clearly suggest that RTX ameliorates hemolytic anemia, thrombocytopenia, arthritis, and probably central nervous system vasculitis associated with SLE. [40]

Two initial randomized, double-blind, placebo-controlled trials namely EXPLORER and LUNAR [41],[42] to objectively assess the efficacy and safety of RTX in generalized lupus" or nephritis-specific lupus were not successful where all patients were given high doses of corticosteroids and immune-suppressives as well. But EXPLORER study showed significant improvement in anti-dsDNA and complement levels. But a recent review evaluated the use of RTX in 188 SLE patients from 35 studies, reporting efficacy rates approaching 90 percent. [43]

In a recently published RITUXILUP study by Lightstone et al., the efficacy of treating lupus nephritis without maintenance steroids was tried using two doses of 1 g rituximab with methyl prednisolone (500 mg) on days 1 and 15 and maintenance treatment of mycophenolate mofetil. The study showed that about 90% of patients achieved complete remission in this regimen creating a ray of hope that oral steroids can be safely avoided in lupus nephritis with the use of rituximab. [44]

The dosage of RTX may vary from low doses (100 mg weekly) used in thrombocytopenia of lupus to high doses (375 mg/m2 IV weekly) used in severe or refractory cases. To summarize, although RTX cannot be considered first-line therapy for mild-to-moderate SLE, it is of benefit in severe refractory disease.

Belimumab

The B-lymphocyte stimulator (BLyS) is important for the survival of B cells, and studies have shown overexpression of BLyS in SLE [45] with higher BLyS levels correlating with SLE disease activity. Belimumab is a fully human monoclonal antibody that selectively targets and inhibits BLyS resulting in autoreactive B cell apoptosis. [46]

In serologically active SLE patients, Belimumab led to a significantly better response over placebo and led to a significant reduction in B-cell counts, rise in complement levels, and reduction in immunoglobulin levels and anti-dsDNA levels. [47] Belimumab was further evaluated in two large randomized, double-blind, placebo-controlled, multicenter phase 3 trials, BLISS-52 and BLISS-76 including 865 and 826 seropositive SLE patients, respectively. [48],[49] Belimumab was well tolerated, achieved significantly better results, delayed time to first SLE disease flare, and led to significant reduction in steroid doses than placebo.

It is the first and the only biologic agent approved for the treatment of refractory SLE. [50] It is used in doses of 10 mg/kg IV q 2 Weeks x 3 doses, then q 4 Weeks thereafter.

Other agents used

Epratuzumab

Epratuzumab has been used to treat patients with SLE with neuropsychiatric and cardio-respiratory symptoms of SLE, which are resistant to conventional therapies. [52] The dosage is 360 mg/m2, IV, every 2 weeks, for 4 doses.

Atacicept

Atacicept is a recombinant fusion protein, which inhibits B cell stimulation. It was tried in SLE patients, in which reductions up to 60% of mature and total B-cell populations was seen. [53]

Abatacept

Abatacept has shown benefit in SLE patients with non-life-threatening manifestations and is found to be superior to placebo in reducing symptoms and improving quality of life and reducing flares. [54] Animal data suggest a beneficial role of T-cell co-stimulation blockade (Abatacept) SLE models.

TNF a inhibitors

Two large randomized trials evaluated the efficacy and safety of TNF inhibitors (infliximab, etanercept) in SLE, but both were terminated prematurely and, therefore, they are not used for SLE. [55] The use of these is commonly associated with the induction of lupus autoantibodies and anti-TNF-induced lupus (ATIL) which can have different levels of cutaneous, renal and neurological involvement. It can be prevented by concomitant immunosuppression and is treated by withdrawal of TNF inhibitors and steroids and/or immunosuppressive therapy( in severe cases). 56

Tocilizumab (IL-6)

Interleukin-6 (IL-6) is a key proinflammatory cytokine. Tocilizumab used in doses of 2-8 mg/kg twice weekly for 12 weeks led to reduction in inflammatory markers and auto-antibody levels in SLE. [57]

Abetimus

It is an intravenously administered tetrameric oligonucleotide conjugate that safely reduces anti-dsDNA antibodies. Its use was associated with reductions in circulating anti-dsDNA antibodies. However, two pivotal trials in lupus nephritis failed to demonstrate statistically significant improvement. [58]

Eculizumab

Furie et al. reported the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single administration of eculizumab (0.1, 0.75, 2, 4, and 8 mg/kg) in 24 patients with SLE. [59]

Other therapies in SLE

Various non-biological agents and drugs that are under study for SLE. None of the above agents are significantly ameliorative of SLE, and none have been shown to significantly influence its morbidity or mortality. The salient ones are summarized below:

  1. Fish oil is ameliorative in patients with mild activity. [60]
  2. A large trial evaluating the efficacy of vitamin D is in progress.
  3. Mycophenolate mofetil is equivalent to cyclophosphamide as induction therapy for SLE nephritis and is superior to azathioprine for maintenance. [61]
  4. Topical pinecrolimus and tacrolimus are effective for chronic cutaneous SLE. [62]
  5. Leflunomide improves SLE arthritis. [63]
  6. N-acetyl cysteine improves outcome in murine lupus, and a phase 1/2 trial is underway to assess the safety and efficacy of NAC treatment in SLE. [64]


Haemopetic stem cell transplant (HSCT)

In patients with severe SLE refractory to conventional immunosuppressive treatments, allogenic HSCT can achieve sustained clinical remissions (ranging from 50% to 70% disease-free survival at 5 years) associated with qualitative immunological changes. [65]


  Conclusion Top


In recent years, advances in our understanding of the mechanisms of SLE have offered newer diagnostic modalities and better drug targets for treatment. Over the next years, we will test the efficacy of many new therapeutic agents. The coming years promise to be an exciting time for the development and trial of new pharmacological treatments and immunotherapies for patients with SLE as we benefit from improved understanding of disease pathogenesis and molecular mechanisms.

 
  References Top

1.Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.  Back to cited text no. 1
[PUBMED]    
2.Petri M, Magder L. Classification criteria for systemic lupus erythematosus: A review. Lupus 2004;13:829-37.  Back to cited text no. 2
[PUBMED]    
3.Shankar S, Pathak A. Redefining Lupus in 2012. Chapter 99. Medicine Update 2012:449-51.  Back to cited text no. 3
    
4.The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599-608.  Back to cited text no. 4
    
5.Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-86.  Back to cited text no. 5
    
6.Meroni PL, Schur PH. ANA screening: An old test with new recommendations. Ann Rheum Dis 2010;69:1420-2.  Back to cited text no. 6
[PUBMED]    
7.Craig WY, Ledue TB. The antinuclear antibody assay: Developing criteria for reflexive anti-dsDNA antibody testing in a laboratory setting. Clin Chem Lab Med 2011;49:1205-11.  Back to cited text no. 7
[PUBMED]    
8.Ahearn JM, Liu CC, Kao AH, Manzi S. Biomarkers for systemic lupus erythematosus. Transl Res 2012;159:326-42.  Back to cited text no. 8
[PUBMED]    
9.Herbst R, Liu Z, Jallal B, Yao Y. Biomarkers for systemic lupus erythematosus. Int J Rheum Dis 2012;15:433-44.  Back to cited text no. 9
[PUBMED]    
10.Shankar S, Sharma P. Anti-nucleosome antibodies: In quest of biomarkers of disease activity in lupus. Indian J Rheumatol 2010;5:163-4.  Back to cited text no. 10
    
11.Rahman A, Isenberg DA. Systemic Lupus Erythematosus. N Engl J Med 2008;358:929-39.  Back to cited text no. 11
[PUBMED]    
12.Min DJ, Kim SJ, Park SH, Seo YI, Kang HJ, Kim WU, et al. Anti-nucleosome antibody: Significance in lupus patients lacking anti-double-stranded DNA antibody. Clin Exp Rheumatol 2002;20:13-8.  Back to cited text no. 12
[PUBMED]    
13.Zhang CQ, Ren L, Gao F, Mu FY, You YQ, Liu YH. Anti-C1q antibodies are associated with systemic lupus erythematosus disease activity and lupus nephritis in northeast of China. Clin Rheumatol 2011;30:967-73.  Back to cited text no. 13
[PUBMED]    
14.Kowal C, Degiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT, et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci USA 2006;103:19854-9.  Back to cited text no. 14
[PUBMED]    
15.Youinou P, Putterman C. The role of anti-alpha-actinin antibodies in the pathogenesis and monitoring of lupus nephritis. Arthritis Res Ther 2009;11:137.   Back to cited text no. 15
[PUBMED]    
16.Yang DH, Chang DM, Lai JH, Lin FH, Chen CH. Significantly higher percentage of circulating CD27(high) plasma cells in systemic lupus erythematosus patients with infection than with disease flare-up. Yonsei Med J 2010;51:924-31.  Back to cited text no. 16
[PUBMED]    
17.Crispín JC, Keenan BT, Finnell MD, Bermas BL, Schur P, Massarotti E, et al. Expression of CD44 variant isoforms CD44v3 and CD44v6 is increased on T cells from patients with systemic lupus erythematosus and is correlated with disease activity. Arthritis Rheum 2010;62:1431-7.  Back to cited text no. 17
    
18.Lai ZW, Borsuk R, Shadakshari A, Yu J, Dawood M, Garcia R, et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J Immunol 2013;191:2236-46.  Back to cited text no. 18
[PUBMED]    
19.Panda AK, Parida JR, Tripathy R, Pattanaik SS, Ravindran B, Das BK. Mannose binding lectin: A biomarker of systemic lupus erythematosus disease activity. Arthritis Res Ther 2012;14:R218.  Back to cited text no. 19
    
20.Kalunian KC, Chatham WW, Massarotti EM, Reyes-Thomas J, Harris C, Furie RA, et al. Measurement of cell-bound complement activation products enhances diagnostic performance in systemic lupus erythematosus. Arthritis Rheum 2012;64:4040-7.  Back to cited text no. 20
[PUBMED]    
21.Lourenço EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med 2009;9:242-54.  Back to cited text no. 21
    
22.Barbado J, Martin D, Vega L, Almansa R, Gonçalves L, Nocito M, et al. MCP-1 in urine as biomarker of disease activity in Systemic Lupus Erythematosus. Cytokine 2012;60:583-6.  Back to cited text no. 22
    
23.Michaelson JS, Wisniacki N, Burkly LC, Putterman C. Role of TWEAK in lupus nephritis: A bench-to-bedside review. J Autoimmun 2012;39:130-42.  Back to cited text no. 23
[PUBMED]    
24.Pradhan V, Patwardhan M, Ghosh K. Fc gamma receptor polymorphisms in systemic lupus erythematosus and their correlation with the clinical severity of the disease. Indian J Hum Genet 2008;14:77-81.  Back to cited text no. 24
[PUBMED]  Medknow Journal  
25.Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 2010;20:170-9.  Back to cited text no. 25
[PUBMED]    
26.Shen N, Liang D, Tang Y, de Vries N, Tak PP. MicroRNAs-novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol 2012;8:701-9.  Back to cited text no. 26
[PUBMED]    
27.Rovin BH, Zhang X. Biomarkers for Lupus Nephritis: The Quest Continues. Clin J Am Soc Nephrol 2009;4:1858-65.  Back to cited text no. 27
[PUBMED]    
28.Manoharan A, Madaio MP. Biomarkers in lupus nephritis. Rheum Dis Clin North Am 2010;36:131-43.  Back to cited text no. 28
[PUBMED]    
29.Silverman GJ, Srikrishnan R, Germar K, Goodyear CS, Andrews KA, Ginzler EM, et al. Genetic imprinting of autoantibody repertoires in systemic lupus erythematosus patients. Clin Exp Immunol 2008;153:102-16.  Back to cited text no. 29
[PUBMED]    
30.Liu CC, Kao AH, Manzi S, Ahearn JM. Biomarkers in systemic lupus erythematosus: Challenges and prospects for the future. Ther Adv Musculoskelet Dis 2013;5:210-33.  Back to cited text no. 30
[PUBMED]    
31.Yao Y, Higgs BW, Morehouse C, de Los Reyes M, Trigona W, Brohawn P, et al. Development of potential pharmacodynamic and diagnostic markers for anti-IFN-α monoclonal antibody trials in systemic lupus erythematosus. Hum Genomics Proteomics 2009;2009:374312.  Back to cited text no. 31
[PUBMED]    
32.Wallace DJ, Hahn BH, editors. Dubois′ Lupus Erythematosus. 7 ed. Philadelphia: Lippincott Williams & Wilkins; 2007.  Back to cited text no. 32
    
33.Fox R. Anti-malarial drugs: Possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus. 1996;5 Suppl 1:S4-10.  Back to cited text no. 33
    
34.Pons-Estel GJ, Alarcón GS, McGwin G Jr, Danila MI, Zhang J, Bastian HM, Reveille JD, Vilá LM; Lumina Study Group. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 2009 Jun 15;61:830-9.  Back to cited text no. 34
    
35.Costedoat-Chalumeau N, Amoura Z, Hulot JS, Lechat P, Piette JC. Hydroxychloroquine in systemic lupus erythematosus. Lancet. 2007;369:1257-8.  Back to cited text no. 35
    
36.Costedoat-Chalumeau N, Leroux G, Amoura Z, Piette JC. [Hydroxychloroquine and systemic lupus: a reappraisal]. Rev Med Interne. 2008;29:735-7.  Back to cited text no. 36
    
37.Anolik JH. B cell biology and dysfunction in SLE. Bull NYU Hosp Jt Dis 2007;65:182-6.  Back to cited text no. 37
    
38.Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H, et al. Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. J Immunol 2008;180:1938-47.  Back to cited text no. 38
    
39.Hughes G. Rituximab in lupus and beyond: The state of the art. Lupus 2009;18:639-44.  Back to cited text no. 39
    
40.Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, et al. Safety and efficacy of rituximab in systemic lupus erythematosus: Results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010;62:2458-66.  Back to cited text no. 40
    
41.Furie R, Looney RJ, Rovin B, Looney RJ, Fervenza FC, Sanchez-Guerrero J et al. Efficacy and safety of rituximab in subjects with active proliferative lupus nephritis (LN): Results from the randomized, double-blind phase III Lunar study. Arthritis Rheum 2009;60(Suppl 1):S429.  Back to cited text no. 41
    
42.Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222-33.  Back to cited text no. 42
    
43.Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009;18:767-76.  Back to cited text no. 43
    
44.Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, Griffith M, Cairns TD, Lightstone L. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72:1280-6.  Back to cited text no. 44
    
45.Cancro MP, D′Cruz DP, Khamasht MA. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest 2009;119:1066-73.  Back to cited text no. 45
    
46.Hahn BH. Belimumab for systemic lupus erythematosus. N Engl J Med 2013;368:1528-35.  Back to cited text no. 46
    
47.Petri MA, Furie R, Merrill JT, Wallace DJ, Ginzler EM, Stohl W et al. Four year experience of belimumab, a BLyS-specific inhibitor, in systemic lupus erythematosus (SLE). American College of Rheumatology National Meeting 2009;Abstract 2069.  Back to cited text no. 47
    
48.Wallace DJ, Stohl W, Furie RA, Lisse JR, McKay JD, Merrill JT, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61:1168-78.  Back to cited text no. 48
    
49.Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum 2009;61:1143-51.  Back to cited text no. 49
    
50.Chiche L, Jourde N, Mancini J. Belimumab for systemic lupus erythematosus. Lancet2011377:2080.  Back to cited text no. 50
    
51.Rajadhyaksha AG, Mehra S, Nadkar MY. Biologics in SLE: The current status. J Assoc Physicians India 2013;61:262-7.  Back to cited text no. 51
    
52.Traczewski P, Rudnicka L. Treatment of systemic lupus erythematosus with epratuzumab. Br J Clin Pharmacol 2011;71:175-82.  Back to cited text no. 52
    
53.Dall′Era M, Chakravarty E, Wallace D, Genovese M, Weisman M, Kavanaugh A, et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus. Arthritis Rheum 2007;56:4142-50.  Back to cited text no. 53
    
54.Merrill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D′Cruz D, Wallace DJ. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: Results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:3077-87.  Back to cited text no. 54
    
55.Aringer M, Smolen JS. The role of tumor necrosis factor-alpha in systemic lupus erythematosus. Arthritis Res Ther 2008;10:202.  Back to cited text no. 55
    
56.Williams EL, Gadola S, Edwards CJ. Anti-TNF-induced lupus. Rheumatology (Oxford). 2009;48:716-20.  Back to cited text no. 56
    
57.Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, et al. Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage escalation study. Arthritis Rheum 2010;62:542-552.  Back to cited text no. 57
    
58.Horowitz DM, Furie RA. Abetimus sodium: A medication for the prevention of lupus nephritis flares. Expert Opin Pharmacother 2009;10:1501-7.  Back to cited text no. 58
    
59.Furie R, Matis L, Rollins SA, Mojcik CF. A single dose, placebo controlled, double blind, phase I study of the humanized anti-C5 antibody h5G1.1 in patients with systemic lupus erythematosus. Presented at: 2001 Innovative Therapies in Autoimmune Diseases, 2001, San Francisco, CA.  Back to cited text no. 59
    
60.Wright SA, O′Prey FM, McHenry MT, Leahey WJ, Devine AB, Duffy EM, et al. A randomised interventional trial of omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus. Ann Rheum Dis 2008;67:841-8.  Back to cited text no. 60
    
61.Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Aspreva Lupus Management Study Group: Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol 2009;20:1103-12.  Back to cited text no. 61
    
62.Lampropoulos CE, D′Cruz DP. Topical calcineurin inhibitors in systemic lupus erythematosus. Ther Clin Risk Manag 2010;6:95-101.  Back to cited text no. 62
    
63.Remer CF, Weisman MH, Wallace DJ. Benefits of leflunomide in systemic lupus erythematosus: A pilot observational study. Lupus 2001;10:480-3.  Back to cited text no. 63
    
64.ClinicalTrials.gov. Treatment of systemic lupus erythematosus with N-acetylcysteine (NCT00775476). Available from: http://clinicaltrialsgov/ct2/show/NCT00775476?term = NAC+AND+SLE&rank=1. [Last accessed on 2010 Apr 01].  Back to cited text no. 64
    
65.Illei GG, Cervera R, Burt RK, Doria A, Hiepe F, Jayne D, et al. Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann Rheum Dis 2011;70:2071-4.  Back to cited text no. 65
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Classification C...
Biomarkers In SLE
Treatment of SLE
Targeted Therapy...
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed4237    
    Printed33    
    Emailed1    
    PDF Downloaded559    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]