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Lupus

Overview of Lupus

Irene Blanco, MD, MS 
Reviewed on July 22, 2024
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Introduction and Historical Overview

Lupus, or systemic lupus erythematosus (SLE), is a chronic, multisystem, autoimmune disorder with a heterogeneity of presentation so remarkable that is has also been termed “the disease with a thousand faces”. The most overt presentations of SLE are cutaneous lesions. Because the skin lesions of SLE were thought to resemble wolf bites, the name “lupus” – “wolf” in Latin – has been used as a descriptor since at least the early middle ages. While the name persisted through the centuries, it was applied to a variety of cutaneous lesions, including those caused by infections and skin cancer. Much progress in understanding the disease and distinguishing it from other disorders was made in the 19th century. The first known depiction of lupus (Figure 1-1) appears in Robert Willan and Thomas Bateman’s “Delineation of Cutaneous Diseases,” originally published in 1817; at the time, no…

Introduction and Historical Overview

Lupus, or systemic lupus erythematosus (SLE), is a chronic, multisystem, autoimmune disorder with a heterogeneity of presentation so remarkable that is has also been termed “the disease with a thousand faces”. The most overt presentations of SLE are cutaneous lesions. Because the skin lesions of SLE were thought to resemble wolf bites, the name “lupus” – “wolf” in Latin – has been used as a descriptor since at least the early middle ages. While the name persisted through the centuries, it was applied to a variety of cutaneous lesions, including those caused by infections and skin cancer. Much progress in understanding the disease and distinguishing it from other disorders was made in the 19th century. The first known depiction of lupus (Figure 1-1) appears in Robert Willan and Thomas Bateman’s “Delineation of Cutaneous Diseases,” originally published in 1817; at the time, no distinction was made between tuberculotic skin lesions – lupus vulgaris – and modern cutaneous lupus. The second component of the name, “erythematosus,” was joined to “lupus” in the mid-19th century by the French dermatologist Pierre Louis Alphée Cazenave to describe the reddish skin lesions of SLE (“erythros” meaning “red” in Ancient Greek). The Hungarian dermatologist Moritz (Mór) Kaposi is credited with recognizing the systemic nature of SLE in 1872, noticing that the disease causes constitutional symptoms and is potentially fatal.

Today, we know that SLE is characterized by an autoimmune response, specifically the generation of anti-nuclear antibodies (ANAs) which bind endogenous nucleic acids and a number of other intracellular autoantigens. This realization is the culmination of research efforts in the latter half of the 20th century, beginning with the discovery of lupus cells in 1948 (also known as LE cells or Hargraves cells, which are now understood to represent neutrophils or macrophages that have phagocytosed the ANA-reactive nuclear material of another cell), followed by the discovery of ANAs and the recognition that DNA is their principal target in the 1950s.Since autoantibodies to non-nuclear antigens are also present in patients with SLE, the term ANA may not be strictly correct, but it has not thus far been supplanted by an alternative.

Treatment and management strategies for lupus have evolved together with the increasing scientific and clinical understanding of the disease. Early attempts at treatment dating back to at least the middle ages involved cutting off or cauterizing (using fire or caustic chemicals) the skin lesions. The turn of the 20th century saw counterproductive attempts to use ionizing or UV radiation against the lesions, as well as the beginnings of truly effective therapy with the use of antimalarials (quinine, alone or in combination with salicylates). Major developments in treatment occurred in the second half of the 20th century (Figure 1-2), which saw the introduction of glucocorticoids (1948-1952), quinacrine (1951), cyclophosphamide (1954), hydroxychloroquine (1956), azathioprine, methotrexate and tacrolimus (1950s-1960s), cyclosporine (1981), and mycophenolate mofetil (1980s). The last decade of the 20th century and the first decade of the 21st saw the development of immunomodulatory biologic agents, including belimumab and anifrolumab. These developments resulted in a marked increase in the 10-year survival rate among patients with SLE: from ~60% in 1950 to >90% in the 1980s. However, the overall survival rate appears to have reached a plateau in the 1990s, and complete control of disease activity and full remission of all symptoms remain out of reach for many patients.

While SLE continues to be a challenging disease, advances in the understanding of its basic biology continue to accrue, opening up potential new therapeutic avenues. Novel agents targeting B cells, T cells, dendritic cells, interferon or other inflammatory cytokines, and interactions between individual immune system components, are currently under investigation. Some of the specific manifestations of SLE, including neuropsychiatric lupus and hematologic disease, remain challenging because of a limited understanding of their specific pathophysiology.

Enlarge  Figure 1-1: Facial Presentation of “Lupus” from Willan and Bateman’s “Delineations of Cutaneous Diseases”. Source: Adapted from: Bateman T, Willan R. <em>Delineations of Cutaneous Diseases: Exhibiting the Characteristic Appearances of the Principal Genera and Species Comprised in the Classification of the Late Dr. Willan; and Completing the Series of Engravings Begun by That Author</em>. New ed. London: Bohn; 1840.
Figure 1-1: Facial Presentation of “Lupus” from Willan and Bateman’s “Delineations of Cutaneous Diseases”. Source: Adapted from: Bateman T, Willan R. Delineations of Cutaneous Diseases: Exhibiting the Characteristic Appearances of the Principal Genera and Species Comprised in the Classification of the Late Dr. Willan; and Completing the Series of Engravings Begun by That Author. New ed. London: Bohn; 1840.
Enlarge  Figure 1-2: Drug Development in SLE. Key: Studies with immunosuppressive drugs and other disease-modifying agents evolved between 1948 and the 1990s. Clinical trial methodology in rheumatology in general was further addressed by OMERACT in the 1990s and in SLE specifically by the FDA guidance documents and by the development of composite response indices. Targeted therapies were first studied in the 1990s, leading to the approval of belimumab in 2011. Key: ANA, anti-nuclear antibody; BILAG, British Isles Lupus Assessment Group; CD40L, CD40 ligand; CLASI, clinical lupus assessment for skin involvement; DHEA, dehydroepiandrosterone; LE, lupus erythematosus; OMERACT, Outcome Measures in Rheumatology; SF-36, short-form 36; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SRI, systemic lupus response index. Source: Adapted from: Wallace DJ. The evolution of drug discovery in systemic lupus erythematosus. <em>Nat Rev Rheumatol</em>. 2015;11(10):616-620.
Figure 1-2: Drug Development in SLE. Key: Studies with immunosuppressive drugs and other disease-modifying agents evolved between 1948 and the 1990s. Clinical trial methodology in rheumatology in general was further addressed by OMERACT in the 1990s and in SLE specifically by the FDA guidance documents and by the development of composite response indices. Targeted therapies were first studied in the 1990s, leading to the approval of belimumab in 2011. Key: ANA, anti-nuclear antibody; BILAG, British Isles Lupus Assessment Group; CD40L, CD40 ligand; CLASI, clinical lupus assessment for skin involvement; DHEA, dehydroepiandrosterone; LE, lupus erythematosus; OMERACT, Outcome Measures in Rheumatology; SF-36, short-form 36; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; SRI, systemic lupus response index. Source: Adapted from: Wallace DJ. The evolution of drug discovery in systemic lupus erythematosus. Nat Rev Rheumatol. 2015;11(10):616-620.

References

  • Arnaud L Vollenhoven Rvan. Advanced Handbook of Systemic Lupus Erythematosus. Cham Switzerland: Adis; 2018.
  • Arnaud L. The history of lupus throughout the ages. Lupus Sci Med. 2020;7.
  • Barnett R. Systemic lupus erythematosus. Lancet. 2016;387(10029):1711.
  • Fanouriakis A, Bertsias G. Changing paradigms in the treatment of systemic lupus erythematosus. Lupus Sci Med. 2019;6(1):e000310.
  • Fanouriakis A, Tziolos N, Bertsias G, Boumpas DT. Update οn the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021;80(1):14-25.
  • Felten R, Lipsker D, Sibilia J, Chasset F, Arnaud L. The history of lupus throughout the ages. J Am Acad Dermatol. 2022;87(6):1361-1369.
  • Fu SM, Gaskin F. History of systemic lupus erythematosus with an emphasis on certain recent major issues. In: Tsokos GC, ed. Systemic Lupus Erythematosus: Basic Applied and Clinical Aspects. Second ed. London: Academic Press an imprint of Elsevier; 2020:3-8.
  • Kaul A, Gordon C, Crow MK, et al. Systemic lupus erythematosus. Nat Rev Dis Primers. 2016;2:16039.
  • Markewitz RDH, Wandinger KP. Terminology and definition of 'antinuclear antibodies': history and current debate [published online ahead of print, 2020 Mar 30]. Ann Rheum Dis. 2020;annrheumdis-2020-217166.
  • Pisetsky DS. The LE cell: crime scene or crime stopper?. Arthritis Res Ther. 2012;14(3):120.
  • Smith CD, Cyr M. The history of lupus erythematosus. From Hippocrates to Osler. Rheum Dis Clin North Am. 1988;14(1):1-14.
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