October 18, 2018
3 min read

Lupus: A Look Back at the Discovery of the Original Diagnostic Biomarker

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The cover story this month brings together a group of leaders in the space of systemic lupus erythematosus care and research who remind us that nothing comes easily in studying this enigmatic disease. However, I would like to digress for a bit to revisit how we have actually come to view this disease in the current light.

Leonard Calabrese, DO
Leonard H.

For centuries, lupus was a nonspecific disorder ascribed to anyone who had the rash reminiscent of the sign of the wolf, and thus was highly nonspecific. It was not until the 18th and 19th centuries that dermatologists, such as Laurent-Théodore Biett, Pierre Louis Alphée Cazenave, Ferdinand von Hebra and others, described the cardinal features of the skin in both discoid and systemic disease.

Consider that, until late in the 19th century, there was little to no recognition that the now-named systemic lupus erythematosus — named by von Hebra — was actually a systemic disease! The seminal description of the systemic manifestations such as arthritis, fever, lymphadenopathy and other aspects is credited to von Hebra’s son-in-law Morris Kaposi (yes, of Kaposi’s sarcoma fame) who described such in a clinical series.

The final bit of sleuthing that led to the recognition of SLE as a systemic, rather than merely a dermatologic, disorder should be credited to — at least in my opinion — the great Sir William Osler. He described 29 cases of “visceral manifestations of Erythema Group of Skin Disorders” and noted the capacity for redundancy or overlap of all varied clinical manifestations and, importantly, the capacity for the systemic manifestations described by Kaposi to occur without rash! Pretty good sleuthing, I would say, in the total absence of biomarkers.

Source: J3D3, from Wikimedia Commons
Source: J3D3, from Wikimedia Commons

The 20th century led to the construction, piece by piece, of a more complete picture of the systemic manifestations of the disease including: nephritis by Paul Baehr, the cardiac manifestations by Emanuel Libman and Benjamin Sacks and ultimately, much of the histopathology by Paul Klemperer and others. Still, the absence of a diagnostic biomarker plagued the field and relegated lupus to a fascinating but very rarely diagnosed disease.

The final chapter of this captivating history comes from the Mayo Clinic where Malcom M. Hargraves, MD, served as a hematologist; he was the first to note the presence of a peculiar cell type in bone marrow specimens that appeared as a large phagocyte, which had engulfed a homogenized body that appeared nuclear in nature. The first such example was identified in a young child with fever, constitutional signs and symptoms and a leukemoid reaction. Hargraves subsequently collected a number of similar observations over the next several years — all in bone marrow preparations — and ultimately felt that they were emblematic, if not diagnostic, of SLE and reported these results in the Mayo Clinic Proceedings.


This served as a landmark discovery and a giant step forward in the effort to develop a laboratory diagnostic test; however, it was severely limited in its utility by the fact that it took a bone marrow specimen to find it — clearly a disincentive for early and aggressive diagnosis.

I will end with a more personal chapter of this story which brings SLE to Cleveland and the Cleveland Clinic where I have worked for more than 40 years. In 1947, John Haserick, MD, a fellow in dermatology at the University of Minnesota, was working with noted hematologist, Dorothy Sunberg, MD, a member of the graduate research examining committee of Robert Morton, MD, a fellow in the Mayo graduate school who presented the lupus erythematosus cell work in his thesis; Sunberg and Haserick quickly sought out to duplicate Morton’s work.

Shortly thereafter, Haserick departed for the Cleveland Clinic, where he was appointed as a staff dermatologist. Following up on evidence of the Mayo team and working with the chemist Lena Lewis, PhD, and others, Haserick nailed down that indeed the lupus erythematosus cell phenomenon was due to a serum factor, which had been long suspected by Hargraves. They further demonstrated that this LE factor was a 7S protein and a gamma globulin. From there, I think you know the rest of the story of ANA, anti-DNA, ENA and a long list of candidate biomarkers that now make SLE so readily diagnosable.

It is interesting that I recently showed this image to a large group of rheumatology fellows and virtually no one could identify it! Sometimes I think it’s good to remember the mysteries and the people who came before us. These images were given to me by senior members of our dermatology department and I appreciate the chance to share with you. If you have good stories on this or any other aspect of rheumatology history just shout me out, either by email to calabrl@ccf.org or to me on Twitter @LCalabreseDO.

Disclosure: Calabrese reports serving as an investigator and a consultant to Horizon Pharmaceuticals.