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- systemic lupus erythematosus
- rheumatoid arthritis
- fever syndromes
- autoimmune diseases
- purpura hyperglobulinemica
On 2 September 1943, Jan Waldenström (1906–1996) successfully submitted a paper to Acta Medica Scandinavica describing two patients with a new disease. The discovery was to make him world famous.1 This year marks the 75th anniversary of macroglobulinaemia and it coincided with the 10th biennial international workshop of Waldensm’s macroglobulinaemia, discussing advances in the genetic basis, pathogenesis and treatments of the disease.2 Jan Waldenström (JW) would have enjoyed this workshop immensely, sharing the information that over 95% of the patients had somatic mutations affecting the MYD88 gene on the second chromosome as well as the impressive advances in treatment. Attending this excellent meeting brought back memories of my time as Waldenström’s PhD student and triggers me to compose this vignette, focusing on connexions between the interests of my mentor and rheumatology. For a more comprehensive account of Jan Waldenström’s legacy, I recommend Robert Kyle’s superb obituary, published in Blood, a journal JW was attached to from its start.3
After the successful defence of his landmark PhD thesis on acute intermittent porphyria,4 Waldenström’s interest focused on haematology. He worked in Uppsala, a university where the study of proteins had prominence. There, The Svedberg had developed the ultracentrifuge and Arne Tiselius the free electrophoresis and Robin Fåhreus the elevated sedimentation rate (ESR). Conditions with ESR caught JW’s special attention. An early witness is a paper from 1937, analysing five cases diagnosed with uveoparotitis, a rare condition most prevalent in women and then considered by many to be a form of tuberculosis. He noticed several multiorgan manifestations, the similarities with von Mikulicz disease and Boeck’s sarcoid, the presence of high ESR, unspecific Wassermann reaction, absence of proof of tuberculosis, presence of xerostomia and frequent central nervous system manifestations.5 Today, the diagnosis could have been IgG4-related disease in several if not all of these patients. This early paper also shows a keen interest in inflammatory systemic conditions.
In the early 1940s, JW collected serum from some 100 patients with long-standing ESR exceeding 120 mm and had the samples analysed by the new technique of free boundary electrophoresis by KO Pedersen in the department of physical chemistry. In 1943, he described three cases from this population characterised by repeated bouts of declive purpura, leaving spots of brown discolouration, mild anaemia and, on the whole, good general health. Two of the three women also had dry eye problems and one had dry mouth and swollen parotid glands. He named the condition ‘purpura hyperglobulinemica’.6 Similar patients were soon identified by others and labelled ‘Waldenström’s purpura hyperglobulinemica’, citing his Swedish-language communication that contained only a brief summary in English. A more comprehensive later report presented new cases, detailed case histories and a colour illustration of the typical skin changes (figure 1), and discussed the systemic nature of the condition in depth. Other organ manifestations included lymphadenopathy, uveoparotitis, Sjögren’s syndrome and systemic lupus erythematosus (SLE). The serum albumin concentration remained normal in line with the benign nature of the condition.7 JW was surprised that this English paper was hardly ever cited.8
In 1949, Jan Waldenström was appointed as the first professor and chairman of internal medicine at Malmö General Hospital, the new second teaching hospital of Lund University. In Malmö, he continued investigating what he now called gammapathies. The new technique of paper electrophoresis refined by Carl-Bertil Laurell dramatically simplified identification of patients with hypergammaglobulinaemia and serum electrophoresis became a routine test. In collaboration with Sten Winblad, sera were also routinely examined for presence of antibodies to bacterial antigens by a package called ‘total serology’. Combined, this led to the distinction between polyclonal reactive and monoclonal malignant conditions, perhaps the most important of all scientific contributions made by JW.9
In 1950, JW was invited to speak at the first post–World war II German congress of Gastroenterology. There, he presented a few cases of a new form of active chronic hepatitis, predominantly in young women with high ESR, very high concentration of gammaglobulin and prominence of plasma cells in the liver. Some but not all of the patients developed cirrhosis.10 ,11 A similar observation was presented at a meeting in the USA by Kunkel et al.11 This condition was also soon observed by other investigators and known under several names. One that has survived is chronic active hepatitis. Sheila Sherlock has summarised the clinical spectrum of the disease based on 115 of her own cases and emphasised the systemic nature which is characteristic of an autoimmune disorder.12 Ulcerative colitis, skin rashes, glomerulonephritis, pulmonary infiltrates and Hashimoto’s thyroiditis were common. Antinuclear antibodies were found in 40% and rheumatoid factor in 70% of her cases.
In Malmö, JW soon emerged as a charismatic leader, equally popular among patients, medical students and staff, and highly respected by Malmö’s ambitious hospital administrators. Within a few years, the department, although frugally staffed, became the leading academic internal medicine unit in the country. JW was a firm believer in the blessing of unfragmented internal medicine, although expecting members of the staff to select an area of special expertise within it. Rheumatology was only established as a specialty in Sweden in 1969, and the first generation of rheumatologists were specialists in internal medicine. But in Malmö, autoimmune disorders like SLE were speciallité de la maison. Talbott and Ferrandis’ ‘Collagen Diseases’ was obligatory reading.13 The book from 1956 still rests on my shelf.
International visitors were frequent guests and fellows came to work with the famous professor. Patients with rare or unclear disease were referred to him from all over Sweden. One example which directly affected me as junior house officer was two cases with extremely low gammaglobulins and antibody deficiency disease, labelled as adult acquired hypogammaglobulinaemia. JW had interviewed the women who came from different hospitals in the country and not simultaneously. In spending good time talking to them, he happened to find out that both had roots in Visseltofta, a village 100 miles to the north of Malmö. I was given the task to find out if they had common ancestors. After some months of searching in old church registers, this in fact turned out to be the case, hinting at a possible genetic aetiology. JW was of course pleased to see the pedigree, and when I presented a brief report with his and my name, he said “Fine, send it to The Lancet”. Unfortunately, he erased his own name from the manuscript probably to do me a special favour. The paper was accepted without changes.14 The observation was later supported by a larger report.15 The disease now is named common variable immunodeficiency and genomic technology including next-generation sequencing reveals its complex genetic basis and explains links to autoimmunity.16 The Lancet paper was my first publication as internist and it opened the way to USA where I was to become a rheumatologist.
Several of JW’s international contacts and visitors were prominent in rheumatology. Henry Kunkel, Morris Ziff, Eric Bywaters, Barbara Ansell, Norman Talal, Eng Tan, Bob Winchester and Ralph C Williams are some names that come to mind (figure 2). JW never passed New York without visiting Henry Kunkel at the Rockefeller Institute where he enjoyed making ward rounds. A paper titled “Forty years with the gammaglobulins”17 gives further personal proof of JW’s close ties with rheumatology, which certainly facilitated my path into the specialty. My own visits with Henry Kunkel’s small group usually included a seminar where the presenter was allowed to use the blackboard but not to show slides. The group then had lunch and after lunch went to the library and browsed through the new journals of the day. Electronic journals had not been born.
Although best known for the discovery of macroglobulinaemia, he must also be credited for the distinction between polyclonal reactive and monoclonal malignant hypergammaglobulinaemia. In Malmö, JW initiated a large study of families with SLE.18 The topic of his last PhD student was polymyalgia rheumatica (19). We can justify the epithet “honorary rheumatologist”.
The author is grateful for valuable help from professors Anders Waldenström and Tore Saxne.
Handling editor Josef S Smolen
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; internally peer reviewed.