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The disease called systemic lupus erythematosus (SLE) went through many different stages of classification before reaching the modern criteria reflecting our current understanding of its pathogenesis. In 1872, the Viennese dermatologist Moriz Kaposi, MD, published a paper, “New Contributions to Knowledge of Lupus Erythematosus,” which provided a significant leap forward in the characterization of this condition.1,2
Born Moriz Kohn, Dr. Kaposi changed his name in 1871 following his conversion to Catholicism, in reference to his birth town Kaposvár, in the Austro-Hungarian Empire. According to JAMA Dermatology, “It is still debated why he changed his surname; it is unlikely to have been due to the pressures of anti-Semitism because Kaposi was not an opportunist, and at that time he was well established in his career. According to his own words, he changed his surname to avoid confusion with five other physicians named similarly in the Vienna School of Medicine.”3,4
At the beginning of the 19th century, the term lupus was used to describe ulcerative skin diseases that affected the face only.8 Ultimately, lupus vulgaris (the cutaneous form of tuberculosis) was thought to be a separate disease entity.7 The French dermatologist Pierre Louis Alphée Cazenave helped provide the first modern description of what would become SLE, with Cazenave applying the term lupus érythèmateux in 1850.9 This was later Latinized to lupus erythematosus by the Viennese physician Ferdinand von Hebra, who was the first to describe the signature butterfly rash, as well as two different rash patterns associated with lupus erythematosus: those of a disc-like pattern and those of a more confluent nature.2,5
Dr. Kaposi was both Dr. Hebra’s student and his son-in-law. Called by some the “father of German dermatology,” Dr. Kaposi is known for a number of achievements, including his work on Kaposi sarcoma and xeroderma pigmentosum.10 But among Dr. Kaposi’s most important contributions is his characterization of lupus.
In 1869, Dr. Kaposi published his first paper on the topic, in Archiv für Dermatologie und Syphilis. He briefly recounted the history of the term, speculated on etiology and discussed symptomatic treatment.2 In his much more extensive 42-page paper published in 1872, Dr. Kaposi included 11 detailed case studies, with extensive characterizations of symptoms, disease course and microscopy information consolidated from additional patients.1
Dr. Kaposi could present no explanation of the disease etiology, but considered the disease inflammatory in nature, based on its histopathology. He also noted that “most of the diseased are found in persons of middle age,” and “the female sex will be affected by the disease much more often than the male.” This was the first description of the systemic nature of the disease and its severe constitutional and visceral manifestations.2
For Dr. Kaposi to group together patients with such varied manifestations as arthritis, pleurisy & coma, all of whom also had cutaneous lupus, was bold & prescient.
Commentary
Dr. Salmon
Jane Salmon, MD, is a professor of medicine at the Hospital for Special Surgery and the director of the Lupus and APS Center of Excellence in New York City. “Earlier physicians had done wonderful work and wrote eloquent descriptions distinguishing lupus erythematosus from tuberculosis and other entities,” Dr. Salmon notes. “But it was Dr. Kaposi who identified lupus as a disease of young women that was systemic and life threatening. For this reason, I think this paper is really interesting.”
In his 1872 paper, which summarized and built on previous descriptions, Dr. Kaposi acknowledged others’ contributions to characterizing the disease. He wrote, “As a new experience, it is to be added that: The lupus erythematosus may also appear and progress under the appearance of a widespread or subacute, feverish eruption and then, often affected with severe local and general symptoms of illness of the entire organism which can, indeed, endanger and destroy its life.”
Dr. Salmon notes that at the time, medical scholarship heavily relied on descriptive case series. In his extensive descriptions, Dr. Kaposi said, “Edematosis and thickening, glandular, painful swelling of the skin and tissues around the joints of the middle hand fingers, toes and also of the larger joints of the knee, of the elbow,” and also mentioned “ripping, tearing, deep bone pains, especially in the main bones, especially the tibia, forearm and carpal bones.”
Dr. Salmon notes, “He mentions coma and stupor, he notes atrophy of the cortical substance and edema of the meninges. In his descriptions, we have rash, arthritis, pleurisy and central nervous system involvement, as well as constitutional signs such as fever—that’s a pretty good number of features listed in the ACR criteria for classification of lupus.”
Dr. Kaposi provided a bleak description of the disease’s most acute manifestations. “At the same time, the patients concerned had the symptoms of an intense, generalized, feverish disease. They laid on the back, had a hot, dry, cracked tongue, general prostration, disturbed consciousness. Over the course of two to three weeks, coma … and death occurred under increasing brain disorder. Among 15 female cases of lupus erythematosus, we saw this picture five times, and three times death occurred with the symptoms described.”
The difference in disease course of the two forms of rash earlier described by Dr. Hebra is detailed by Dr. Kaposi: a form of lupus that is cutaneous only (lupus erythematosus discoides) and a form of lupus that occurs with systemic and sometimes life-threatening symptoms (designated as lupus erythematosus discretus et aggregatus).
Lupus often presents with a butterfly rash.
Dr. Kaposi noted: “The lupus erythematosus discoides runs regularly and continuously in a chronic fashion, and usually without any serious complication. … Lupus erythematosus aggregates, on the other hand, also show a chronic affect, and alone more often than either from the beginning, or at least during the later course, acute eruptions occurred. Accordingly, all those intense local and deleterious general manifestations of the disease, which I have described as accompanying the acute eruption of the lupus erythematosus previously, predominantly, or almost exclusively belong to that second form of the lupus erythematosus, and this is accordingly the prognostically more serious one to watch.”
The description and characterization of rash types maps fairly well onto modern distinctions between patients who have cutaneous discoid disease only and those who have SLE. As Dr. Salmon notes, “Most patients who only have discoid disease never develop systemic lupus, whereas patients with more serious skin manifestations—subacute cutaneous lupus or vasculitis—tend to be the ones who have more systemic disease.”
Advances in Understanding
The renowned internist and educator Sir William Osler described SLE and further advanced the idea that skin disease (including lupus erythematosus) can be a sign of significant systemic illness, and that systemic manifestations may occur in some cases even without skin disease.6 By the turn of the century, SLE had become well recognized as a systemic disease, though little was known about its etiology.4 The discovery of the LE cell by Malcolm Hargrave, MD, in 1948 emphasized the systemic nature of the disease and ushered in our modern understanding of SLE.5
Dr. Salmon notes the meticulous descriptive work done by Dr. Kaposi and others of the era laid the foundations for later understanding. “He was very precise—he was phenotyping in the best way he could—describing in great detail the appearance of the rashes and evolution of the patient’s illness over months. These are starting points to understand disease mechanism. If you don’t understand the pathologic signs and symptoms of the patient, it’s hard to explore what drives them or why they occur.”
She continues, “In the 1800s, they could only describe using physical examination and microscopy. But with excellent descriptions, you can create clusters of patients with common features—which is what they did.” She also emphasizes the importance of Kaposi’s contribution in recognizing SLE as a systemic disease, because that enabled the search for underlying mechanisms.
“We could not elucidate pathophysiology of systemic diseases like lupus without first looking for commonalities and distinctions among patients,” says Dr. Salmon.
The case study approach still has relevance for continuing to advance medical knowledge. Dr. Salmon notes, “Case series of complex patients have expanded our understanding of innate immune mechanisms, specifically those with extreme phenotypes driven by unique genetic alterations in highly informative genes. They have taught us about relationships between cytokines and their signaling pathways with clinical signs and symptoms.”
For an example, she points to the work of Daniel Kastner, MD, PhD, and others who have chronicled rare syndromes involving mutations of genes involved in the inflammasome. Dr. Salmon says, “They are called autoinflammatory diseases. But if we didn’t uncover these pathways and these mutations, we would know much less about the inflammasome and the IL-1 pathway.”
Similarly, she notes work that carefully described clinical features of rare individuals who have mutations in genes related to the interferon-alpha pathway. Insights from these patients have expanded the understanding of lupus pathogenesis.
‘Dr. Kaposi was very precise—he was phenotyping in the best way he could—describing in great detail the appearance of the rashes & evolution of the patient’s illness over months. These are starting points to understand disease mechanism.’ —Dr. Salmon
Classification: Then & Now
Dr. Kaposi’s work is also interesting in the context of the current challenge of classifying patients with complex and overlapping multisystem autoimmune diseases. Earlier practitioners distinguished lupus erythematosus from other types of skin problems (like from tuberculosis); Dr. Kaposi went on to note the systemic nature of SLE and to further distinguish a discoid-type lupus from a systemic type. For Dr. Kaposi to group together patients with such varied manifestations as arthritis, pleurisy and coma, all of whom also had cutaneous lupus, was bold and prescient.
This work to find informative categories continues. “Could what we call lupus be multiple diseases that were grouped together for historic reasons or because of the presence of specific autoantibodies, like anti-DNA? Conflating heterogeneous phenotypes can facilitate discoveries of common disease mechanisms, but it can also make more difficult the teasing apart of subsets driven by different pathology,” speculates Dr. Salmon. “The commonality is autoimmunity and specific patterns of autoantibodies, and the remarkable aspect is variability of manifestations and the observations that one patient can go from one group of symptoms and signs to another. It’s very fluid.”
In terms of classification, Dr. Salmon comments on the heterogeneity of manifestations of lupus patients: Some patients have discoid cutaneous lesions, some have arthritis and photosensitivity, and others have central nervous system disease, renal disease and cytopenias.
Then there is the range of lupus-like diseases. “There appears to be a spectrum of autoimmune rheumatic diseases, including lupus, rheumatoid arthritis, scleroderma, mixed connective tissue disease, undifferentiated connective tissue disease, Sjögren’s syndrome and myositis.” She explains that some patients fit into one of those diagnoses according to defined classification criteria. Yet some may have manifestations related to another category and may evolve to fulfill criteria for two diseases. Although not very common, there are lupus patients with Sjögren’s features, myositis and inflammatory rheumatoid-like arthritis.”
Dr. Salmon points out the question of categorization remains an important one to this day. “Do we lump or split? Our therapies will increasingly address specific disease mechanisms, yet until now we have been grouping based on clinical and laboratory features, very much like Kaposi. New information is emerging to guide how we lump and split patients with lupus.”
She notes that because of the limited tools available to him, Dr. Kaposi could lump or split disease groups primarily based on organ system symptoms and pathology findings. “But now we can also subset patients based on autoantibodies, gene expression profile, alleles of certain genes or other biomarkers. We are still lumping and splitting, but we have access to more precise tools than Dr. Kaposi did.”
Dr. Salmon suggests that through his careful descriptions and case studies, Dr. Kaposi was establishing a kind of early version of classification criteria for SLE. “Now, we use validated classification criteria to help us have consistent definitions of patients for clinical trials,” she says. “We are beginning to look at subsets of responders to specific therapies, using tools beyond the physical examination, clinical laboratory tests and the microscope, to approach treatment from the perspective of disease mechanism.”
Dr. Salmon provides an example of a lupus patient who has erosive arthritis and does not have nephritis. Such a patient will get treated like a patient with rheumatoid arthritis, because her joints are the main problem. Dr. Salmon says, “TNF inhibitors are actually effective in lupus patients with erosive arthritis.”
She argues that rheumatologists have been quite limited in their ability to target disease mechanisms in lupus (other than through broad immunosuppression), although some important drugs that affect key lupus-related pathways are in phase 3 trials, such as interferon-alpha receptor antibodies and JAK-STAT inhibitors. She notes, “At this point we treat the patient’s disease manifestations as best as we can.”
Indeed, physicians sometimes use drugs off label to take advantage of the mechanistic overlap of diseases on the rheumatic spectrum. “Hydroxychloroquine is a drug used for lupus patients, but we are now using it for other autoimmune conditions, such as for antiphospholipid syndrome and in pregnant anti-Ro-positive patients to prevent neonatal lupus and congenital heart block,” Dr. Salmon says. “Because these diseases blend into each other clinically, and perhaps pathogenetically, these therapies are used more generally based on plausible mechanism.”
Criteria Under Review
New criteria for lupus that have been supported by the ACR and EULAR are currently under review. These new criteria aim to provide greater sensitivity and specificity for the disease. Under the new criteria, a positive ANA is a necessary condition for a SLE diagnosis. For Dr. Kaposi, a rash was a necessary criterion.
Dr. Salmon says, “The ACR criteria for lupus are good for trials, but we don’t treat patients based on the criteria. There are patients with three, not four, criteria for lupus who rheumatologists believe have the disease and treat them accordingly.” She notes the effort to revise is important for the goal of appropriately identifying groups for lupus trials. “We have to keep revisiting how we lump and split, how we classify patients, because we want to find good therapies. And if we enroll patients that are too variable in their mechanism of disease in a trial, then the overall trial will fail, even if the drug would be amazing for an important subset of patients.”
In one sense the effort can be viewed as a continuation of the work done over 140 years ago by Dr. Kaposi. His work set the stage for further classification, understanding and, ultimately, treatment of the disease, a process that is still ongoing.
Ruth Jessen Hickman, MD, is a graduate of the Indiana University School of Medicine. She is a freelance medical and science writer living in Bloomington, Ind.
References
- Kaposi KM. Neue Beiträge zur Kenntnis des Lupus erythematosus. Arch Dermatol Syphilis. 1872;4:36–78.
- Holubar K, Fatović-Ferencić S. Cazenave, Kaposi and lupus erythematosus. A centennial and a sesquicentennial. Dermatology. 2001;203(2):118–120.
- Pesapane F, Nazzaro G, Coggi A, et al. Mór Cohen, better known as Moriz Kaposi. JAMA Dermatol. 2014;150(3):265.
- Ingber A. Why Kaposi and not Kohn? Am J Dermatopathol. 1983;5:103.
- Norman RA. The history of lupus erythematosus and discoid lupus: from Hippocrates to the present. Lupus Open Access. 2016;1:102.
- Rowell NR. Some historical aspects of skin disease in lupus erythematosus. Lupus. 1997;6(2):76–83.
- Barnett R. Case histories: systemic lupus erythematosus. The Lancet. 2016;387:1711.
- Scofield RH, Oates JC. The place of William Osler in the description of systemic lupus erythematosus. Am J Med Sci. 2009;338(5): 409–412.
- Holubar K. History of lupus erythematosus. Acta Dermatoven APA. 2006;15(4):191–194.
- Holubar K, Fatovic-Ferencic S. Moriz Kaposi. 1837–1902: A historical reappraisal.
Acknowledgment
The author thanks Jane Salmon, MD, for her extensive review of Dr. Kaposi’s seminal work in identifying systemic lupus erythematosus.
