The changing face of lupus: evolution of diagnostics and treatments

Kate D Honnor, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Road, Cambridge, CB2 0SP.

Systemic lupus erythematosus (SLE) is a variable disease which has been a source of fascination, and perplexity, for physicians over the years. The muddled early descriptions of the disease and evolving diagnostic criteria testify to its complexity. This article summarises past and present diagnostics and treatments, and relates these to current ideas of SLE pathogenesis.

From early descriptions to the modern Classification

SLE is a multisystem autoimmune disease involving numerous immunological abnormalities and variable clinical manifestations. With such diversity it is unsurprising that there is much confusion over the first descriptions of this disease. Although the origin of the name lupus (Latin for wolf) is unclear, its medical use is seen as early as the 10th century in the writings of Hebernius of Tours:

“He was seriously afflicted and almost brought to the point of death by the disease called lupus” [1].

During the 19th century, numerous physicians used the term lupus to describe skin rashes, however some of these reports refer to cutaneous tuberculosis, to which the name lupus vulgaris is now given. Pierre de Cazenave wrote the first detailed modern description of cutaneous lupus [2] and also noted the sun-sensitive distribution of rashes, which we now identify as the malar rash (butterfly rash) and other photosensitive skin reactions. Extending disease description beyond the cutaneous features, Moriz Kaposi described systemic symptoms in some of his lupus patients, although he was unsure whether these symptoms were part of lupus or co-incidental. The connection between rashes and extra-cutaneous symptoms, including arthritis, nephritis, and pericarditis, was made by William Osler in articles between 1872 and 1895.

It is estimated that 70% of all cases of lupus are SLE (the term lupus referring to this), of which half of these are organ-threatening and half are non-organ-threatening. The remainder of cases are related variants of lupus such as cutaneous lupus (15%, discoid lupus erythematosus is the most common form), mixed connective tissue disease (MCTD, 5%), overlap syndromes (5%), and drug-induced lupus (5%) [3].

SLE is now understood to be a multi-system autoimmune disease characterised by polyclonal B cell activation leading to the production of a range of autoantibodies, which exert pathology via type II and type III hypersensitivity mechanisms. The aetiology is unclear but thought to involve a combination of genetic, hormonal and environmental factors. The first SLE classification criteria were published in 1971, with later revisions, by the American College of Rheumatology.

Diagnostic tools and clues to pathogenesis

The first laboratory test to have unusual associations with lupus is the Wasserman test for syphilis (complement fixation test). During the early 20th century, it was observed that there was an increased incidence of false-positive reactions in lupus patients [1]. This is now known to be due to the presence of anti-phospholipid antibody in some lupus patients (30-40%). Anti-phospholipid syndrome (APS, 10% of SLE patients) is associated with a prothrombotic tendency, recurrent fetal loss and neurological manifestations. Autoantibodies occurring in APS include anti-cardiolipin antibody and lupus anticoagulant. The presence of these antibodies may be detected by the inappropriately-named ‘lupus anticoagulant test’. This is a composite of tests which detects the presence of an inhibitor (antiphospholipid antibodies) to the coagulation cascade. In fact ‘anti-phospholipid antibodies’ often bind not to phospholipid, but instead to phospholipid-binding proteins: anti-cardiolipin binding to β2-Glycoprotein I (β2GPI), and antibodies with a lupus anticoagulant effect (anticoagulant effect only in vitro) binding to either prothrombin or β2-GPI [4]. In the Wasserman test, the antigen is Treponema pallidum cardiolipin, to which serum proteins such as β2-GPI can bind.

Testing for false-positive reactions was superseded by the discovery of the LE cell. In 1948, Hargraves observed that in the bone marrow aspirate of patients with confirmed or suspected SLE, there were mature neutrophils containing phagocytosed partially-digested nuclear material from apoptotic cells. LE cells are not normally present in the blood of SLE patients, but can be found in the buffy coat (layer of white blood cells and platelets following centrifugation of peripheral blood) after an incubation period, as well as in synovial fluid, cerebrospinal fluid and pericardial or pleural effusions [5].

It has emerged that apoptosis plays a key role in the pathogenesis of SLE. CD4+ T cell Fas expression has been shown to be increased in SLE, in addition to increased intracellular caspase-3 expression in CD4+ T cells which suggests the Fas-mediated apoptotic pathway is active [6]. Enhanced apoptosis may explain cytopenias (especially lymphopenia) commonly observed in SLE patients, as well as promoting exposure of anionic phospholipids with pro-coagulant activity (e.g. phosphatidylserine flipping from inner to outer leaflet of the plasma membrane during apoptosis). Clearance of apoptotic cells has been shown to be disturbed in SLE, for example there are reduced number and impaired phagocytic activity of tingible body macrophages in the germinal centres of lymph nodes in SLE patients, resulting in the presence of apoptotic material on the surface of follicular dendritic cells [7]. Increased apoptosis and reduced clearance of apoptotic material could thereby facilitate the exposure of apoptosis-derived neoepitopes to which tolerance is not established. This sets the scene for anti-nuclear antibody (ANA) production, present in 96% of SLE patients [3].

Anti-dsDNA antibodies (type of ANA found in half of SLE patients) have been shown to be necessary to produce the LE cell phenomenon [8], and this may be due to anti-dsDNA antibodies inhibiting enzymatic cleavage of DNA in nuclei from dead cells and promoting their phagocytic uptake by neutrophils [9]. As well as helping to explain the formation of the LE cell, it has been speculated that these anti-dsDNA antibodies may actually induce apoptosis [9].

The LE cell test is no longer used to diagnose SLE due to poor sensitivity and specificity. Instead an ANA test is preferred, although this has relatively poor specificity as these antibodies are found in patients with other autoimmune conditions as well as being present in low titre in elderly people. However a high titre and a homogenous ANA pattern (on immunofluorescence) indicates aberrant adaptive autoimmune activity.

Complement levels (in particular C3 and C4) and anti-dsDNA titres are useful in disease activity monitoring. Consumption of complement is often seen during disease flares, thought to be due to activation of the complement cascade by immune complexes, with the resulting products of complement activation (and Fc receptor ligation) causing tissue injury [1]. In addition to this damaging role, the complement system is thought to have a more subtle and paradoxical role in SLE- actually preventing disease development. Homozygous deficiency of any of the proteins of the classical pathway (C1, C4, C2) is strongly associated with development of SLE [11]. Partial C4 deficiency may be a risk factor for SLE, for example the C4A null allele (no protein produced) is associated with SLE across multiple HLA haplotypes and ethnic groups [12]. One of the protective mechanisms of complement could be via clearance of immune complexes thus reducing their deposition in tissues (C4b and C3b bound to immune complexes can interact with the receptor CR1 on red blood cells, delivering the immune complexes to the reticuloendothelial system for removal). However complement, especially C1q, could also have a protective role via promoting the clearance of apoptotic cells, so reducing the exposure of autoantigens [13].

Targetted therapies

Before the 1990s, SLE management was limited to non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials (e.g. hydroxychloroquine), corticosteroids, and immunosuppressive agents such as azathioprine, methotrexate and cyclophosphamide. “Biologics” are the newer treatments which have arisen from our increasing understanding of pathogenesis. Rituximab, a chimeric monoclonal antibody, has been used in the treatment of refractory SLE for 8 years [14]. Rituximab specifically binds to CD20, a B cell lineage-specific membrane protein, first present at the pre-B cell stage and lost at the plasmablast stage [15]. Rituximab treatment causes depletion of circulating B cells, possibly via complement mediated cytotoxicity, antibody dependent cell mediated cytotoxicity, and apoptosis induction [16]. Efficacy of rituximab therapy has been demonstrated in a number of clinical trials, with improvements of various SLE manifestations such as nephritis, autoimmune cytopenias and CNS disease. Unfortunately the recent phase II/III EXPLORER trial in the USA did not show rituximab to have clinical efficacy [14]. Reasons for this are unclear, but may include patient selection and the use of corticosteroids in both treatment and placebo groups. Surprising results such as these undoubtedly reaffirm the complexity of this disease.

Although B cell depletion is achieved following rituximab therapy, there have been reports of clinical improvement without decreased autoantibody titres [17]. This suggests the importance of the multiple roles of B cells in SLE pathogenesis besides acting as precursors to plasma cells, such as antigen presentation to cognate T cells, T cell costimulation activity and the secretion of cytokines and chemokines. Analysis of ANA show that the majority are affinity matured and isotype switched to IgG indicating T cell-B cell co-operation in autoantibody production [10]. Biologics inhibiting B cell-T cell costimulation are currently being investigated as possible treatments. For example, abatacept is a recombinant fusion protein composed of the extracellular domain of CTLA4 (ligand of the costimulatory molecule B7) and the Fc region of human IgG1. By acting as a soluble B7 receptor, abatacept prevents B7 on the antigen presenting cell binding to CD28 on T cells, thus preventing the co-stimulation necessary to activate naive T cells [14].

Compared to conventional treatment, it was hoped biologics would more selectively target components of the immune system, thereby increasing efficacy and reducing side-effects. While these newer treatments have been valuable in the treatment of refractory disease, they do not differentiate between autoreactive and “helpful” leukocytes, and there is therefore an increased risk of infection. With the key issue in autoimmune disease being loss of tolerance to self, a potential direction for SLE therapy is therefore restoration of tolerance by the targeting of autoreactive B and T cells. Abetimus is a synthetic toleragen consisting of four dsDNA strands attached to a non-immunogenic carrier platform. This drug was intended to cause inactivation of B cells directed against dsDNA, via cross-linking of the surface immunoglobulin molecules on these autoreactive B cells. Abetimus also interacts with soluble anti-dsDNA antibody, forming small complexes which are removed from the circulation [14]. Anti-dsDNA IgG antibodies have been implicated in the pathogenesis of lupus nephritis, for example these antibodies have been shown to bind to the glomerular basement membrane, and high titres are often associated with active lupus nephritis [1]. In a large randomised placebo-controlled study, abetimus reduced circulating anti-dsDNA antibody levels in lupus nephritis patients, however abetimus did not significantly prolong the time to renal flare [18].

Restoration of tolerance by targeting the T cell population is currently under active research. Tolerance therapy using a very low dose of the histone epitope H4 (71-94) was found to reduce autoantibody levels, delay nephritis and prolong lifespan in lupus-prone mice. This histone epitope induced CD8+ and CD4+CD25+ regulatory T cells, which suppressed autoantigen-specific responses of lupus T cells. In addition, low dose therapy with this histone epitope appears to have inhibited the expansion and migration of inflammatory Th17 cells to target organs [19].

Final comments

With increasing understanding of the pathogenesis of SLE, it is hoped that new drugs can be developed to aid the management of this chronic disease. Finding drugs which selectively act on the aberrant cells of the immune system, rather than a “blanket immunosuppression”, remains a challenge. An important direction of future research is the role of T cells in SLE pathogenesis and manipulation of the T cell population to restore tolerance against self.


1. Wallace DJ., et al. Dubois’ Lupus Erythematosus. Seventh Edition. USA: Lippincott Williams & Wilkins; 2007; 2,7-8, 216.

2. Wallace DJ., et al. Pierre Cazenave and the first detailed modern description of lupus erythematosus. Semin Arthritis Rheum. 1999, 28(5):1. doi:10.1016/S0049-0172(99)80014-6

3. Wallace DJ. Lupus The Essential Clinician’s Guide. First Edition. USA: Oxford University Press; 2008; 8,11,51.

4. Austen et al. Samter’s Immunologic Diseases. Sixth Edition. USA: Lippincott Williams & Wilkins; 2001; 572.

5. Hepburn AL. The LE cell. Rheumatology (Oxford).2001, 40:826-827.

6. Xue et al. Abnormal Fas/FasL and caspase-3-mediated apoptotic signalling pathways of T lymphocyte subset in patients with systemic lupus erythematosus. Cell Immunol. 2006, 239(2):121-128. doi:10.1016/j.cellimm.2006.05.003

7.Baumann et al. Impaired uptake of apoptotic cells into tingible body macrophages in germinal centres of patients with systemic lupus erythematosus. Arthritis Rheum 2002;46:191–201.

8. Engel HJ. Studies on the genesis of LE cells in supravital preparations. Blut 1968;17:93–110. doi:10.1007/BF01640601

9. Böhm I. LE cell phenomenon: nuclear IgG deposits inhibit enzymatic cleavage of the nucleus of damaged cells and support its phagocytic clearance by PMN. Biomedicine & Pharmacotherapy 2004, (58) 196–201. doi:10.1016/j.biopha.2003.12.010

10. Bruns et al. Nucleosomes are major T and B cell autoantigens in SLE. Arthritis Rheum. 2000, 43(10);2307-15.

11. Pickering et al. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 2001, 76:227-324. doi:10.1016/S0065-2776(01)76021-X

12. Yang et al. The intricate role of complement C4 in human systemic lupus erythematosus. Curr Dir Autoimmun. 2004, 7:98-132. doi:10.1159/000075689

13.Walport MJ. Complement and systemic lupus erythematosus. Arthritis Res. 2002, 4(Suppl 3):S279-S293. doi:10.1186/ar586

14. Sousa et al. Treating lupus: from serendipity to sense, the rise of the new biologicals and other emerging therapies. Best Practice & Research Clinical Rheumatology. 2009, 23: 563–574. doi:10.1016/j.berh.2008.12.006

15. Edwards and Cambridge. B-cell targeting in RA and other autoimmune diseases. Nat Rev Immunol. 2006. 6,394. doi:10.1038/nri1838

16. Looney, R.J. Treating autoimmune disease by depleting B cells. Ann Rheum Dis.2002. 61,863. doi:10.1136/ard.61.10.863

17. Vigna-Perez. Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res.Ther. 2006 . 8,R83. doi:10.1186/ar1954

18. Horowitz et al. Abetimus sodium: a medication for the prevention of lupus nephritis flares. Expert Opin Pharmacother. 2009, 10(9):1501-7. doi:10.1517/14656560902946419

19. Kang et al. Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells. The Journal of Immunology. 2007, 178: 7849–7858.