Understanding lupus

What is the history of lupus?

The history of lupus erythematosus (LE) has been reviewed in all the major textbooks on this disease1,2,3 and was the subject of an article in a journal in 1983.4  This article concentrates on developments in the present century which have greatly expanded our knowledge about the pathophysiology, clinical-laboratory features, and treatment of this disorder.

The history of lupus can be divided into three periods:  the classical period which saw the description of the cutaneous disorder, the neoclassical period which saw the description of the systemic or disseminated manifestations of lupus, and the modern period which was heralded by the discovery of the LE cell in 1948 and is characterized by the scientific advances noted above. 

The history of lupus during the classical period was reviewed by Smith and Cyr in 1988.5 Of note are the derivation of the term lupus and the clinical descriptions of the cutaneous lesions of lupus vulgaris, lupus profundus, discoid lupus, and the photosensitive nature of the malar or butterfly rash. 

The word ‘lupus’ (Latin for ‘wolf’) is attributed to the thirteenth century physician Rogerius who used it to describe erosive facial lesions that were reminiscent of a wolf's bite.1,4  Classical descriptions of the various dermatologic features of lupus were made by Thomas Bateman, a student of the British dermatologist Robert William, in the early nineteenth century;  Cazenave, a student of the French dermatologist Laurent Biett, in the mid-nineteenth century; and Moriz Kaposi (born Moriz Kohn), student and son-in-law of the Austrian dermatologist Ferdinand von Hebra, in the late nineteenth century. 

The lesions now referred to as discoid lupus were described in 1833 by Cazenave under the term “erythema centrifugum,” while the butterfly distribution of the facial rash was noted by von Hebra in 1846.  The first published illustrations of lupus erythematosus were included in von Hebra's text, Atlas of Skin Diseases, published in 1856.

The Neoclassical era of the history of lupus began in 1872 when Kaposi first described the systemic nature of the disorder:

“...experience has shown that lupus erythematosus ... may be attended by altogether more severe pathological changes, and even dangerous constitutional symptoms may be intimately associated with the process in question, and that death may result from conditions which must be considered to arise from the local malady.”6

Kaposi proposed that there were two types of lupus erythematosus; the discoid form and a disseminated form.  Furthermore, he enumerated various symptoms and signs which characterized the disseminated form including (1) subcutaneous nodules, (2) arthritis with synovial hypertrophy of both small and large joints, (3) lymphadenopathy, (4) fever, (5) weight loss, (6) anemia, and (7) central nervous system involvement.6

The existence of a disseminated or systemic form of lupus was firmly established by the work of Osler in Baltimore7 and Jadassohn in Vienna8 in 1904.  Over the next thirty years, pathologic studies documented the existence of nonbacterial verrucous endocarditis (Libman-Sacks disease)9 and wire-loop lesions in individuals with glomerulonephritis;10 such observations at the autopsy table led to the construct of collagen disease proposed by Kemperer and colleagues in 1941.11  This terminology, ‘collagen vascular disease,’ persists in usage more than seventy years after its introduction.

The sentinel event in the mid-1900s which heralded the modern era was the discovery of the LE cell by Hargraves and colleagues in 1948.12  The investigators observed these cells in the bone marrow of individuals with acute disseminated lupus erythematosus and postulated that the cell

“... is the  result of ... phagocytosis of free nuclear material with a resulting round vacuole containing this partially digested and lysed nuclear material ...”

This discovery ushered in the present era of the application of immunology to the study of lupus erythematosus; it also allowed the diagnosis of individuals with much milder forms of the disease. This possibility, coupled with the discovery of cortisone as a treatment13, changed the natural history of lupus as it was known prior to that time.

Two other immunologic markers were recognized in the 1950s as being associated with lupus:  the biologic false-positive test for syphilis14 and the immunofluorescent test for antinuclear antibodies.15  Moore, working in Baltimore, demonstrated that systemic lupus developed in 7 percent of 148 individuals with chronic false-positive tests for syphilis and that a further 30 percent had symptoms consistent with collagen disease.14

Friou applied the technique of indirect immunofluorescence to demonstrate the presence of antinuclear antibodies in the blood of individuals  with systemic lupus.15  Subsequently, there was the recognition of antibodies to deoxyribonucleic acid (DNA)16 and the description of antibodies to extractable nuclear antigens (nuclear ribonucleoprotein [nRNP], Sm, Ro, La), and anticardiolipin antibodies; these autoantibodies are useful in describing clinical subsets and understanding the etiopathogenesis of lupus.

Two other major advances in the modern era have been the development of animal models of lupus and the recognition of the role of genetic predisposition to the development of lupus.  The first animal model of systemic lupus was the F1 hybrid New Zealand Black/New Zealand White mouse.18 This murine (mouse) model has provided many insights into the immunopathogenesis of autoantibody formation, mechanisms of immunologic tolerance, the development of glomerulonephritis, the role of sex hormones in modulating the course of disease, and evaluation of treatments including recently developed biologic agents such as anti-CD4, among others.  Other animal models that have been used to study systemic lupus include the BXSB and MRL/lpr mice, and the naturally occurring syndrome of lupus in dogs.19

The familial occurrence of systemic lupus was first noted by Leonhardt in 1954 and later studies by Arnett and Shulman at Johns Hopkins.20  Subsequently, familial aggregation of lupus, the concordance of lupus in monozygotic twin pairs, and the association of genetic markers with lupus have been described over the past twenty years.21  Molecular biology techniques have been applied to the study of human lymphocyte antigen (HLA) Class II genes to determine specific amino acid sequences in these cell surface molecules that are involved in antigen presentation to T-helper cells in individuals  with lupus.  These studies have resulted in the identification of genetic-serologic subsets of systemic lupus that complement the clinico-serologic subsets noted earlier.  It is hoped by investigators working in this field that these studies will lead to the identification of etiologic factors (e.g., viral antigens/proteins) in lupus.

Over the last decade or so, we have witnessed significant advances in the understanding of the genetic basis of lupus22, 23, and of the immunological derangements which lead to the clinical manifestations of the disease24,25. Advances have been made in the assessment of the impact of the disease in general26, and in minority population groups, in particular27-28 and efforts are being made towards defining lupus biomarkers which may help both to predict disease outcome and to guide treatments. 29,30

Finally, no discussion of the history of lupus is complete without a review of the development of therapy.  Payne, in 1894, first reported the usefulness of quinine in the treatment of lupus.31 Four years later, the use of salicylates in conjunction with quinine was also noted to be of benefit.32  As noted, cortisone/corticosteroids were introduced for the treatment of lupus in the middle part of the 20th century by Hench.33  Presently, corticosteroids are the primary therapy for almost all individuals with lupus. 

Antimalarials, used in the past principally for lupus skin and joint involvement, are now recognized to prevent the occurrence of flares, the accumulation of damage, and the occurrence of early mortality.34-36 Cytotoxic/immunosuppressive drugs are used for glomerulonephritis, systemic vasculitis, and other severe life-threatening manifestations of lupus.37 Newer biologic agents are now used, either off-label38, 39 or after approval by regulatory agencies in the U.S., Europe, and other countries.40 Other potential drug products are being investigated as new disease pathways are being discovered.

Thus, the history of lupus, although dating back at least to the Middle Ages, has experienced an explosion in this century, especially during the modern era over the past 60 years.  It is hoped that this growth of new knowledge will allow a better understanding of immunopathogenesis of the disease and the development of more effective treatments.

REFERENCES

1.  Lahita RG. Introduction. In: Lahita RG, ed. Systemic Lupus Erythematosus. New York: John Wiley and Sons. 1987; 1-3. (Fifth edition published 2010)

2.  Benedek TG. Historical background of discoid and systemic lupus erythematosus. In: Wallace DJ, Hahn BH, eds. Dubois' Lupus Erythematosus. Philadelphia: Lippincott Williams & Wilkins/Wolters Kluwer, 7th edition, 2007, pp. 2-15. (Eighth edition published 2012)

3. Iglesias, A. Los primeros pasos (The First Steps). In: Gamarra A. Historia del Lupus y del Sindrome Antifosfolipídico (History of Lupus and of the Antiphospholipid Syndrome). Barranquilla, Colombia. Universidad Simón Bolivar, 2011; 33-118 (Second edition published 2011)

4.  Boltzer JW. Systemic lupus erythematosus. I. Historical aspects. MD State  Med J 1983; 37:439.

5.  Smith CD, Cyr M. The history of lupus erythematosus from Hippocrates to Osler.  Rheum Dis Clin North Am 1988; 14:1.

6.  Kaposi MH.  Neue Beitrage zur Keantiss des lupus erythematosus.  Arch Dermatol Syphilol 1872; 4:36.

7.  Osler W. On the visceral manifestations of the erythema group of skin diseases (third paper).  Am J Med Sci 1904; 127:1.

8.  Jadassohn J. Lupus erythematodes.  In: Mracek F, ed. Handbach der Hautkrakheiten. Wien: Alfred Holder, 1904; 298-404.

9.  Libmann E. Sacks B.  A hitherto undescribed form of volvular and mural endocarditis.  Arch Intern Med 1924; 33:701.

10. Baehr G, Klemperer P, Schifrin A.  A diffuse disease of the peripheral circulation usually associated with lupus erythematosus and endocarditis.  Trans Assoc Am Physicians 1935; 50:139.

11. Klemperer P. Pollack AD, Baehr G. Pathology of disseminated lupus erythematosus. Arch Path (Chicago) 1941; 32:569.

12. Hargraves MM, Richmond H, Morton R. Presentation of two bone marrow elements: The tart cell and the LE cell. Proc Staff Meet Mayo Clin 1948; 23:25.

13. Hench PS. Introduction: cortisone and ACTH in clinical medicine. Proc Staff Meet Mayo Clin 1950; 25: 474-6.

14. Moore JE, Lutz WB.  The natural history of systemic lupus erythematosus: An approach to its study through chronic biological false positive reactions. J Chron Dis 1955; 2:297.

15. Friou GJ.  Clinical application of lupus serum nucleoprotein reaction using fluorescent antibody technique. J Clin Invest 1957; 36:890.

16. Deicher HR, Holman HR, Kunkel HG.  The precipitin reaction between DNA and a serum factor in SLE. J Exp Med 1959; 109:97.

17. Tan EM, Kunkel HG.  Characteristics of a soluble nuclear antigen precipitating with sera of patients with systemic lupus erythematosus.  J Immunol 1966; 96:404.

18. Bielschowsky M, Helyer BJ, Howie JB. Spontaneous haemolytic anemia in mice of the NZB/BL strain. Proc Univ Otago Med School 1959; 37:9.

19. Hahn BH. Animal models of systemic lupus erythematosus. In: Wallace DJ, Dubois EL, eds. Lupus Erythematosus.  Philadelphia: Lea & Febiger.  1987; 130-57.

20. Arnett FC, Shulman LE.  Studies in familial systemic lupus erythematosus.  Medicine 1976; 55:313. 

21. Hochberg MC.  The application of genetic epidemiology to systemic lupus erythematosus. J Rheumatol 1987; 14:867-9.

22. Rhodes B, Vyse TJ. The genetics of SLE: an update in the light of genome-wide association studies. Rheumatology 2008; 47: 1603-11.

23.  Guerra SG, Vyse TJ, Cunninghame Graham DS. The genetics of lupus: a functional perspective. Arthritis Res Ther 2012; 14: 211.

24. Ardoin SP, Pisetsky DS, Developments in the scientific understanding of lupus. Arthritis Res Ther 2008; 10: 218.

25. Crow MK. Type I interferon in organ-target autoimmune and inflammatory diseases. Arthritis Res Ther 2010; 12 Suppl 1:S5.

26. Gladman DD, Urowitz MB. The SLICC/ACR Damage Index: progress report and experience in the field. Lupus 1999; 8:632-7.

27. Alarcon GS. Lessons from LUMINA: A multiethnic U.S. cohort. Lupus. 2008; 17: 971-6

28. Petri M. The effect of race on incidence and clinical course in systemic lupus erythematosus: The Hopkins Lupus Cohort. J Am Med Women’s Assoc 1998; 53: 9-12.

29. Merrill JT. Is individualized medicine on the horizon for lupus? Curr Rheumatol Rep 2008; 1: 257-8.

30. Merrill JT, Buyon JP. The role of biomarkers in the assessment of lupus. Best Pract Res Clin Rheumatol. 2005; 19: 709-26.

31. Payne JF.  A post-graduate lecture on lupus erythematosus.  Clin J 1894; 4:223.

32. Radcliffe-Crocker.  Discussion on lupus erythematosus.  Br J Dermatol 1898; 10:375.

33. Hench PS. The reversibility of certain  rheumatic and non-rheumatic conditions by the use of cortisone or of the  pituitary adrenocorticotrophic hormone. Ann Intern Med 1952; 36:1.

34. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamasta M. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010; 69: 20-8.

35. Alarcon GS, McGwin G, Bertoli AM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic lupus cohort (LUMINA L). Ann Rheum Dis. 2007; 66: 1168-72.

36. Fessler BJ, Alarcon GS, McGwin G, et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum 2005; 52:1473-80.

37. Bertsias GK, Ioannidis JPA, Boletis J, et al. EULAR recommendations for the management of  systemic lupus erythematosus. Report of a Task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2008; 67: 195-205.

38. Ramos-Casals M, Sanz I, Bosch X, Stone JH, Khamashta MA. B-cell depleting therapy in systemic lupus erythematosus. Am J Med 2012; 125: 327-36.

39. Diaz-Lagares C, Croca S, Sangle S, et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 2012; 11: 357-64.

40. Merrill JT, Ginzler EM, Wallace DJ, et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus s. Arthritis Rheum 2012; Jun 5 [E-pub ahead of print].

The LFA thanks Marc C. Hochberg, M.D., M.P.H., professor of medicine, epidemiology and preventive medicine at University of Maryland School of Medicine, Baltimore, MD, and Graciela S. Alarcón, M.D., M.P.H., Jane Knight Lowe, Chair of Medicine in Rheumatology, Emeritus, at The University of Alabama at Birmingham, for this information.

Medically reviewed on July 15, 2013

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