The History of Lupus Erythematosus

Ravi K. Mallavarapu, MD; Edwin W. Grimsley, MD, FACP

Disclosures

South Med J. 2007;100(9):896-898. 

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Content

The history of medicine stimulates the intellectual and humanistic qualities that make the practice of our profession unique. This article explores the history of lupus erythematosus from the origins of the name to the most modern therapeutic advances.

Systemic lupus erythematosus is a chronic, relapsing, inflammatory, and often febrile multisystemic disorder of the connective tissue, characterized principally by involvement of the skin, joints, kidneys, and serosal membranes. The word lupus means wolf in Latin, as the destructive injuries the disease caused brought to mind the bites of this animal.[1,2] The earliest usage of the term lupus in the English literature is in the 10th century biography of St. Martin, written in 963 AD. However, Hippocrates is generally considered the first to have described cutaneous ulceration; calling it herpes esthiomenos, which means, gnawing dermatosis.[3] Several authorities have suggested that lupus was included under this name. Rogerius Frugardi (1230 ad) used the term lupus to describe erosive facial lesions and Giovanni Manardi (1530 ad) used the same to denote boils and ulceration of the lower extremity.[1,3] In the superstitious Middle Ages, the grotesque appearance of some lupus sufferers brought the myth of werewolves to the minds of people. These were feared to be human beings who had strange powers to transform themselves into animals.[1] It is obvious that fearful fantasy borders meaningful linguistics in such imagery. Local language use, beliefs, and related pathologic conditions that may have coexisted during the specific time have to be considered carefully in the study of the history of any disease. Rudolph Virchow, after an extensive review of the works of the Medieval and Renaissance periods, concluded that any process involving ulceration or necrosis of the lower limbs or face was loosely labeled lupus before the mid-19th century.[4]

Robert Willan (1757-1808), a British dermatologist, described destructive lesions of the face and nose under the heading of lupus. Cutaneous tuberculosis or lupus vulgaris was included under this classification and was named lupus willani after him. Thomas Bateman,[5] who was Willan's student, completed his work after his untimely death. The first clear description of lupus erythematosus is credited to Laurent Theodore Biett of the Paris School of Dermatology, who called it erythema centrifugum.[6] His student, Pierre Louis Alphee Cazenave, published Biett's work and coined the term lupus erythematosus in 1833. Cazenave classically described lupus as a rare condition, which appears most frequently in young females who are otherwise healthy, attacking the face chiefly. Round red patches, slightly elevated, about the size of a shilling, gradually increase in size and sometimes spread over the greater part of the face. The edges of the patches are prominent, and the center, which retains its natural color, is depressed. There is heat and redness but no pain or itching. It is essentially a chronic affection though its appearance would indicate otherwise.[7] It is obvious that the disease being described by Cazenave[7] is discoid lupus. In 1866, Ferdinand von Hebra[8] used the metaphor of a butterfly to describe the classic malar rash. He had initially named the condition, seborrhea congestiva.

The next stage in our understanding of this disease was largely due to the work of Moriz Kaposi and the Vienna School of Medicine. In 1872, Kaposi[9] first described the systemic signs of the disorder. These included fever, weight loss, lymphadenopathy, anemia, and arthritis. The name discoidal lupus, as pertaining to the exclusively cutaneous form of the disease, is credited to Kaposi. Kaposi and Cazenave clearly distinguished lupus erythematosus from lupus vulgaris or cutaneous tuberculosis, although there was a lot of confusion around that time due to the coexistence of both diseases in patients. In the same five years that Kaposi diagnosed 22 cases of discoid lupus erythematosus (DLE), 279 cases of lupus vulgaris were seen in his department, and, in fact, one of Kaposi's patients with DLE died as a result of pulmonary tuberculosis. Kaposi maintained that DLE had no relation whatsoever to tuberculosis, but this was disputed until the first part of the 20th century, when extensive pathologic studies dispelled this myth.[6]

Sir William Osler[10] coined the term systemic lupus erythematosus, which included his own recognition of cardiac, pulmonary, and renal problems in some patients, and observations of the cutaneous manifestations of lupus. Osler observed 29 patients from 1894 to 1903 who presented with erythema as visceral injuries. Only two of these patients clearly had lupus erythematosus. One was a 15-year-old girl with a photosensitive malar rash, joint pain, pleuritis, fever, and nephritis. The other was a 24-year-old woman who also had a malar rash, in addition to fever, chills, lymphadenopathy, and pulmonary involvement.[10] Jonathan Hutchinson[11,12] described the photosensitive nature of the malar rash, and Sequira and Balean described acroasphyxia, or Raynaud phenomenon, and lupus nephritis in 1902.[6] Jadassohn's[13] exhaustive review of discoid and systemic lupus in 1904 contributed greatly to our understanding of this disease. The descriptions of pulmonary involvement in lupus by Alfred Kraus and Carl Bohac in 1908, and of noninfectious endocarditis by Emanuel Libman and Benjamin Sacks[14] in 1923, are significant contributions to our current understanding of the disease. Initially, the presence of cutaneous involvement was considered mandatory to the diagnosis of lupus erythematosus. However, George Belote and H.S. Ratner confirmed that the endocarditis of Libman-Sacks was a manifestation of the disease even without cutaneous involvement. Paul Klemperer, George Baehr, and A.D. Pollack[15] described wire loop nephritis in 1935.

The modern period of our understanding of this disease began in 1948, when Mayo Clinic hematologist Malcolm Hargraves[16] discovered the LE cell. Serum from patients with lupus erythematosus was added to bone marrow preparations from normal subjects. When compared with control preparations, this induced the formation of clumps of polymorphonuclear leukocytes around amorphous masses of nuclear material. In 1954, Miescher and Fauconnet observed that absorption of lupus serum with nuclei prevented its ability to induce the LE cell phenomenon, suggesting that a globulin in the serum was reacting with, or destroying, the nuclei. This was followed by the demonstration by George Friou[17] in 1958, that the substance in the serum of patients with lupus erythematosus that reacted to the nuclei of cells was gamma globulin, and the target in the nucleus was DNA complexed to histones. He called it the antinuclear factor and further described the indirect immunoflourescence test to detect antinuclear antibodies. These observations in the late 1950s clearly demonstrated an autoimmune pathologic process underlying lupus erythematosus and paved the way for a new area of research. Autoantibodies like nuclear ribonucleoprotein (nRNP), Sm, Ro, La, and anticardiolipin antibodies are useful in describing clinical subsets and understanding the pathogenesis of lupus and other autoimmune diseases. While trying to develop a serologic test for syphilis, Wasserman[18] in 1906 first described a complement-fixing antibody that reacted with extracts from bovine hearts. In 1941, the relevant antigen was identified as cardiolipin,[19] which became the basis for the Venereal Disease Research Laboratory (VDRL) test for syphilis. Screening for syphilis lead to the observation that many patients with systemic lupus erythematosus had a positive VDRL test, without any other clinical or serologic evidence of syphilis.[20] Moore and Lutz[21] reported the results of an investigation into the phenomenon of biologic false positivity in 1955. Lupus erythematosus developed in 7% of 148 subjects with false positive tests for chronic syphilis and a further 30% had symptoms consistent with collagen disease.

Leonardt, Arnett, and Schulman[22] at Johns Hopkins University described the familial aggregation of lupus and concordance in monozygotic twins. The discovery of a lethal kidney disease in the New Zealand Brown White hybrid mouse in 1959 at Otago Medical School in New Zealand was another important breakthrough.[23] This murine model has provided many insights into the mechanisms of immunologic tolerance, imunopathogenesis of autoantibody formation, development of glomerulonephritis, and the evaluation of newer therapeutic agents in lupus erythematosus. Drug-induced lupus erythematosus was first described in 1954 at the Cleveland Clinic with the antihypertensive, hydralazine. The first classification criteria for systemic lupus erythematosus were established in 1971 and required 4 of 14 criteria. In 1982, the criteria were revised by the American College of Rheumatology because of advances in serologic testing (ANA and anti-dsDNA) and improved biostatistical techniques.

Edmund L. Dubois was a pioneer in the study of lupus erythematosus in the modern era. A graduate of Johns Hopkins University, Dr. Dubois[24] was the principal editor of the first lupus textbook, Dubois' Lupus Erythematosus. The Edmund L. Dubois Memorial Lectureship presented by the American College of Rheumatology Research and Education Foundation recognizes an outstanding investigator in the field of systemic lupus erythematosus every year. An important contribution of Dr. Dubois was his recognition that there is no classic pattern to the disease, and, hence, there is a need for the diagnosis to be based on an overall view of the entire clinical picture.[24]

No description of the history of lupus erythematosus would be complete without mention of the advances in the treatment of this disease. Payne[25] first reported the use of quinine in the treatment of lupus erythematosus in 1894. The Nobel Prize winning discovery of ACTH and cortisone by Philip S. Hench[26] greatly benefited patients with lupus erythematosus. Sulzberger and Wittens' discovery of hydrocortisone was useful for treating DLE. In 1951, quinacrine was the first antimalarial to be used in the treatment of DLE. Later, chloroquine and hydroxychloroquine were found to be useful in both the systemic and cutaneous forms. The era of immunosuppression began in 1952 with nitrogenous mustard. Currently, immunomodulation has become an important therapeutic approach in the management of this disease. Cyclophosphamide (an alkylating agent which prevents cell division by cross-linking DNA strands and decreasing DNA synthesis), mycophenolate mofetil (which inhibits inosine monophosphate dehydrogenase, the rate-limiting step in de novo purine synthesis, with selective effects on lymphocytes), and azathioprine (an imidazolyl derivative of mercaptopurine which antagonizes purine metabolism), are examples of this approach. Biologic agents like rituximab, a monoclonal antibody directed against the CD20 antigen on B-lymphocytes, and Lymphostat B, a fully human monoclonal antibody to B lymphocyte stimulator, constitute another modern approach. Transplantation of hematopoietic stem cells for refractory disease and costimulatory blockade involving inhibition of T-cell activation which is required for T-cell dependent B-cell responses, hold promise in the future for patients of this disease.[27]

Famous people who had lupus erythematosus include the acclaimed writer Flannery O'Connor and the great composer, Ludwig van Beethoven. O'Connor suffered from her first attack of systemic lupus erythematosus in 1950. She returned to Milledgeville, Georgia, where she lived with her mother on her ancestral farm, Andalusia. In spite of the illness, O'Connor continued to write, and at times she lectured about creative writing in colleges. O'Connor died on August 3, 1964, at the age of 39 from a flare of the disease.[28] The great music composer Ludwig van Beethoven may well have had systemic lupus erythematosus. The excellent life-mask of 1812 reveals an elongated atrophic scar particularly suggestive of lupus. The portraits clearly show flushing of the cheekbones and nose.[29]

The history of lupus erythematosus over the stream of time presents a fascinating study. With modern therapeutic advances, the mortality rate from lupus erythematosus has decreased substantially. Current research holds promise for further improvement in the prognosis of this disease in the future.

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