Jan Gösta Waldenström and rheumatology

Introduction 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 macroglobulinemia and it coincided with the 10th biennial international workshop of Waldenström's macroglobulinemia, discussing advances in the genetic basis, pathogenesis and treatments of the disease.2 Jan Waldenström 7[MO1] (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 2nd 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 connections 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 porphyria4 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 ESR. Conditions with elevated sedimentation rate (ESR) caught his special attention. An early witness is a paper from 1937, analysing 5 cases diagnosed with uveoparotitis, a rare condition most prevalent in women and considered by many to be a form of tuberculosis. He noticed the several multiorgan manifestations, the similarities with von Mikulits' disease and Boeck's sarcoid, the presence of high ESR, unspecific Wasserman reaction, absence of proof of tuberculosis, presence of xerostomia, and frequent CNS manifestations.5 Today the diagnosis could have been IgG4 related disease in several 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 longstanding ESR exceeding 120 mm, and had it analysed by the new technique of free boundary electrophoresis by K.O. Pedersen in the Department of Physical Chemistry. In 1943 he described 3 cases from this population characterised by repeated bouts of declive purpura, leaving spots of brown discoloration, mild anaemia, and on the whole, good general health. Two of the 3 women also had dry eye problems and one had dry mouth and swollen parotis glands. He named the condition 'purpura hyperglobulinemica'.6 Similar patients were soon identified by others and labelled 'Waldenström's purpura hyperglobulinemica', citing his Swedish 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 SLE. The serum albumin concentration remained normal in line with the benign nature of the condition.7 The author 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 the 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 hypogammaglobinaemia 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 lead to the distinction between polyclonal reactive and monoclonal malignant conditions, perhaps JW's most important scientific contribution.9 In 1950 JW was invited to speak at the first German congress of Gastroenterology in Germany after the war. 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 gamma-globulin and prominence of plasma cells in the liver. Some but not all developed cirrhosis.10 In 1951 a similar observation was presented as an abstract by Henry Kunkel's group.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. ANAs 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, staff, and highly respected by Malmö's ambitious administrators. Within 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 un-fragmented internal medicine, although expecting members of the staff to select an area of special expertise within it. Rheumatology was only established as a speciality in Sweden in 1969 and the first generation of rheumatologists were specialists in internal medicine. But in Malmö autoimmune disorders like SLE were specilalité De la maison and 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 the most junior house officer was two cases with frequent infections, antibody deficiency disease, labelled as adult 'acquired' hypogammaglobinaemia. The professor 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 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 etiology. When I showed the pedigree starting in the mid eighteens century to the professor, JW was of course pleased, and when I presented the brief report with his name after mine he said 'Fine, send it to The Lancet'. Unfortunately he erased his own name from the manuscript although it clearly was his idea based on his ground work. The paper was accepted without changes.14 The story was later supported by a following 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. Just coming from JWs department in Malmö usually resulted in red carpet reception. Several of JW's international contacts and visitors were prominent in rheumatology. Henry Kunkel, Morris Ziff, Eric Bywaters, Barbra Ansell, Norman Talal, Eng Tan, Bob Winchester and Ralph C Williams are some names that come to mind (figure 2). He 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.