2
The role of biomarkers in the assessment of lupus

https://doi.org/10.1016/j.berh.2005.05.004Get rights and content

Although considered a prototypic autoimmune disease, the hallmark of systemic lupus erythematosus (SLE) is its heterogeneity. Accordingly, manifestations can vary widely from person to person, with the potential involvement of virtually any bodily organ. Furthermore, the genetic abnormalities underlying this condition are complicated, with diverse genetic polymorphisms described in different ethnic groups, strongly suggesting that the actual pathology underlying the immunologic disarray might not be the same for each patient. Evolving concepts of genetics and immunity have clarified that patients can carry unique arrays of exacerbating and protective factors. These factors, in conjunction with variable environmental triggers for SLE, probably determine the sequelae that an individual experiences. Therefore, it is not surprising that the clinical manifestations are diverse, the temporal sequence of organ involvement often unpredictable, and that the flares of inflammatory activity that characterize SLE can either remit without consequence or leave permanent damage in their wake. It is widely accepted that the current standard of care for SLE patients is inadequate. Programs to develop and test new drug and/or device therapies have been ongoing since the mid-1990s but have encountered formidable obstacles. With the current burst of drug discovery and the advent of several large international trials of promising new agents, the challenge to overcome these obstacles has never been greater. A burgeoning literature in the past decades nevertheless suggests that despite the complexities of the many immunologic pathways that impact on SLE, characteristic biologic markers are emerging as potential signposts that can characterize patient subgroups, predict prognosis, mark the exacerbations and remissions of SLE flares, and serve as endpoints in the determination of the dosing and timing of immune-modulating treatments. Several of the promising biomarkers are addressed in this chapter.

Section snippets

Introduction: challenges in assessing efficacy of SLE treatment

The greatest challenge to drug development in SLE has been its unpredictability, which makes treatment selection and outcome measurement intrinsically problematic. Several formally validated measures of lupus disease activity are now available for use, which combine complex assessments of varying manifestations in attempts to compare outcomes among diverse patients. These instruments are described in detail in Chapter 1 and include the SLAM (Systemic Lupus Activity Measure), SLEDAI (Systemic

An emerging field, candidate biomarkers for the guidance of therapy for SLE

The availability of validated biologic markers in SLE will be an important advance in the assessment of new treatments for SLE and optimization of their use. A credible set of biomarkers might predict whether a given patient is appropriate for a treatment and quantify their disease activity before, during and after treatment, and hence guide therapy. Some promising candidates might additionally work as surrogate endpoints (defined as markers that are detected early in the course of therapy but

The need for a cooperative international effort to validate SLE biomarkers

The major impediments to successful drug development for lupus will be solved when the development community can successfully integrate emerging knowledge about the nature of the immune dysfunction with adequate definitions of disease flare and remission. A critical component of this process will be the validation and strategic employment of a comprehensive set of biologic markers to optimize administration of investigational, immune-modulating agents and to assess their effectiveness. Methods

References (96)

  • X. Li et al.

    A novel polymorphism in the Fcgamma receptor IIB (CD32B) transmembrane region alters receptor signaling

    Arthritis and Rheumatism

    (2003)
  • M. Oh et al.

    Frequency of the Fc gamma RIIIA-158F allele in African American patients with systemic lupus erythematosus

    The Journal of Rheumatology

    (1999)
  • Y. Hitomi et al.

    CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B

    Human Molecular Genetics

    (2004)
  • D.D. Gladman

    Indicators of disease activity, prognosis, and treatment of systemic lupus erythematosus

    Current Opinion in Rheumatology

    (1994)
  • D.D. Gladman et al.

    Sensitivity to change of 3 systemic lupus erythematosus disease activity indices: international validation

    The Journal of Rheumatology

    (1994)
  • E.M. Hay et al.

    index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus

    Quartely Journal of Medicine

    (1993)
  • D.D. Gladman et al.

    Crosscultural validation and reliability of 3 disease activity indices in systemic lupus erythematosus

    The Journal of Rheumatology

    (1992)
  • W. Bencivelli et al.

    Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research III

    Clinical and Experimental Rheumatology

    (1992)
  • M.M. Ward et al.

    Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus

    The Journal of Rheumatology

    (2000)
  • M. Corzillius et al.

    Responsiveness and sensitivity to change of SLE disease activity measures

    Lupus

    (1999)
  • H.I. Brunner et al.

    Sensitivity of the systemic lupus erythematosus disease activity index, British isles lupus assessment group index, and systemic lupus activity measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus

    Arthritis and Rheumatism

    (1999)
  • J.P. Buyon et al.

    Estrogen/Cyclic progesterone replacement is associated with an increased rate of mild/moderate but not severe flares in SLE patients in the SELENA trial

    Arthritis and Rheumatism

    (2003)
  • G.G. Illei et al.

    Biomarkers in systemic lupus erythematosus. I. General overview of biomarkers and their applicability

    Arthritis and Rheumatism

    (2004)
  • G.G. Illei et al.

    Biomarkers in systemic lupus erythematosus. II. Markers of disease activity

    Arthritis and Rheumatism

    (2004)
  • A.A. Bengtsson et al.

    Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies

    Lupus

    (2000)
  • P. Blanco et al.

    Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus

    Science

    (2001)
  • T. Kim et al.

    Serum levels of interferons in patients with systemic lupus erythematosus

    Clinical and Experimental Immunology

    (1987)
  • O. Strannegard et al.

    Interferon and natural killer cells in systemic lupus erythematosus

    Clinical and Experimental Immunology

    (1982)
  • H. Vallin et al.

    Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells

    Clinical and Experimental Immunology

    (1999)
  • S.R. Ytterberg et al.

    Serum interferon levels in patients with systemic lupus erythematosus

    Arthritis and Rheumatism

    (1982)
  • E.C. Baechler et al.

    Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus

    Proceedings of the National Academy of Sciences of the United States of America

    (2003)
  • L. Bennett et al.

    Interferon and granulopoiesis signatures in systemic lupus erythematosus blood

    The Journal of Experimental Medicine

    (2003)
  • M.J. Walport

    Complement and systemic lupus erythematosus

    Arthritis Res

    (2002)
  • H. Molina

    Update on complement in the pathogenesis of systemic lupus erythematosus

    Current Opinion in Rheumatology

    (2002)
  • T.Y. Fauci et al.

    The spectrum of vasculitis

    Annual Internationa Medicine

    (1978)
  • K. Lange et al.

    Significance of serum complement levels for diagnosis and prognosis of acute and subacute glomerulonephritis and lupus erythematosus disseminatus

    Annual International Medicine

    (1960)
  • S. Ruddy et al.

    Human complement metabolism: an analysis of 144 studies

    Medicine (Baltimore)

    (1975)
  • C.A. Alper et al.

    Studies of the in vitro behavior of human C′3 in normal subjects and patients

    The Journal of Clinical Investigation

    (1967)
  • A.J. Sliwinski et al.

    Decreased synthesis of the third component (C3) in hypocomplementemic systemic lupus erythematosus

    Clinical and Experimental Immunology

    (1972)
  • J.A. Charlesworth et al.

    Metabolic studies of the third component of complement and the glycine rich glycoprotein in patients with hypocomplementemia

    The Journal of Clinical Investigation

    (1974)
  • J.L. Moulds et al.

    Quantitative and antigenic differences in complement component C4 between American blacks and whites

    Complement Inflammation

    (1991)
  • P. Hopkins et al.

    Increased levels of plasma anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in lupus cerebritis

    Arthritis and Rheumatism

    (1988)
  • J.P. Buyon et al.

    Assessment of disease activity and impending flare in patients with systemic lupus erythematosus. Comparison of the use of complement split products and conventional measurements of complement

    Arthritis and Rheumatism

    (1992)
  • G. Nagy et al.

    Usefulness of detection of complement activation products in evaluating SLE activity

    Lupus

    (2000)
  • S. Manzi et al.

    Measurement of erythrocyte C4d and complement receptor 1 in systemic lupus erythematosus

    Arthritis and Rheumatism

    (2004)
  • S. Manzi et al.

    Age-specific incidence rates of myocardial infarction and angina in women with Systemic Lupus Erythematosus: comparison with the Framingham study

    The American Journal of Epidemiology

    (1997)
  • M.M. Ward

    Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus

    Arthritis and Rheumatism

    (1999)
  • K. Yasojima et al.

    Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques

    Arteriosclerosis, Thrombosis, and Vascular Bioliogy

    (2001)
  • Cited by (27)

    View all citing articles on Scopus
    View full text