Commentary on Oral Methoxsalen Photochemotherapy for the Treatment of Psoriasis: A Cooperative Clinical Trial: From Napkin Notes to Notabilia

In December, 1976, while I was a medical student on a dermatology elective, I saw John Melski cross the Beth Israel (BI) Hospital parking lot with a black, box-like, briefcase and the most intense, absorbed expression I had ever seen on a face. In the briefcase were data forms from the oral methoxsalen photochemotherapy cooperative clinical trial. That night, as on many others, John’s wife Linda would teletype the data from their home to the hospital computer with one hand while she cradled their baby with the other. Behind Melski’s countenance were no doubt thoughts of PUVA (photochemotherapy with psoralens plus ultraviolet A), or, as I recently learned, a growing fear that he would be buried alive by the mounting stacks of boxes which contained the PUVA treatment records of more than a thousand patients. At the time, Melski was a fellow in computer medicine at the Beth Israel Hospital, Harvard Medical School, working in the laboratory of Howard Bleich. They had been enlisted to participate in the design and analysis of a project that is still ongoing, and which has become one of the largest, longest, and most careful follow-up studies of a single disease and its treatment in the history of dermatology. The chief of dermatology at the BI was Irwin Freedberg, one of the multicenter trial participating investigators and editor of the Journal of Investigative Dermatology. According to Melski, Freedberg’s ‘‘clear vision’’ of the JID’s role in communicating not only to academicians but to practitioners as well was the single most important reason that it was ultimately published there. The role model of Freedberg and his ilk was also what led Melski to become a dermatologist. But we have come to the end almost before the beginning, and the tale of the multicenter PUVA trial is one of people, vision, monumental effort, important notes on napkins, and intrigue, not to mention a stickup at gunpoint. The story of the multicenter trial cannot be separated from the story of PUVA itself, and that goes back no less than 3500 years to the treatment of vitiligo in ancient Egypt and India [1]. But in the early 1970s at Massachusetts General Hospital, a group of people with remarkably complementary interests came together and took a partly conceptual and partly technological inventive leap that took psoralens from the pharaohs to Faraday. That leap was the development of a new high-intensity ultraviolet A (UVA) light source and its combination with the use of orally administered methoxsalen in the treatment of psoriasis. Fitzpatrick and Pathak had been interested in oral psoralens for nearly two decades [2,3]. Parrish, who had just completed his dermatology residency, was interested in the comparative effects of ultraviolet radiation, especially UVA, and had finally convinced Robert Levin and the GTE Sylvania company to make a high intensity UVA light source to pursue his investigations. Tanenbaum, who had become interested in photobiology as a medical student by listening to a guest lecture by Leonard Harber, had some elective time coming up in his residency at Harvard and wanted to do a research project he could complete in the last six months of his second year. Why not try the new light source in looking at oral psoralen phototoxicity in the treatment of psoriasis and other diseases? Some basic and clinical groundwork had already been laid by the Harvard group and others [1]. For example, it was known that psoralens plus UVA caused inhibition of DNA synthesis. Mortazawi [4], Tronnier and Schule [5], and Walter and Voorhees [6] had looked at the use of topical psoralens with longwave UV in the treatment of psoriasis, and Weber published on the subject in 1974 [7]. The MGH group, however, tried the new high intensity ultraviolet A light source with oral 8-MOP on two patients on White 8, the dermatology ward. The first was a women with mycosis fungoides, the second a 35-year-old Irish policeman with psoriasis. Both responded quickly, and cleared dramatically in 10–12 treatments. As luck would have it, both were ideal candidates with (fair) skin type II and plaque lesions. Had the first patients been eythrodermic or skin type I, burning might have nipped the study in the bud. Had they been skin types III or IV, early tanning might have made the response less impressively rapid. More patients were treated in succession, some in bilateral comparison fashion, and the results were striking. Sometime near the spring of 1974, Fitzpatrick decided to ‘‘export’’ the MGH experience to Vienna. His former student, Klaus Wolff, agreed to test the early MGH protocol on a group of Austrian psoriatics. Before he left for Vienna, Fitzpatrick wrote the following on a napkin still in Tanenbaum’s possession, ‘‘PHOTOCHEMOTHERAPY OF EPIDERMAL (psoriasis) AND LYMPHOPROLIFERATIVE DISORDERS (Mycosis Fungoides) WITH PSORALEN PLUS LONGWAVE U.V. (U.V.A.),’’ (Fig 1). The significance of introducing that term, and of its acronymic sister, PUVA, in casting the die for what came next cannot be overestimated. Writing of diseases, Richard Asher said that without a name, a disease ‘‘has no official clinical existence. We cannot discuss it or investigate it or write