Professor Daniel Kastner transformed the understanding of unexplained recurrent inflammatory disease, uncovering the genetic causes of multiple syndromes and creating an entirely new field of rheumatology.
The physician-scientist who gave rheumatologists a new way to understand inflammatory disease has died, leaving behind a legacy that transformed diagnosis, genetics, and patient care across the world.
Professor Daniel L. Kastner, widely regarded as the father of autoinflammatory disease, died peacefully in California on 26 July, aged 75, surrounded by his family, said International Society of Systemic Autoinflammatory Diseases president Professor Erkan Demirkaya.
“For so many of us in this field, Dan wasn’t just its founding figure; he was a friend, a mentor, and often the person who first made us feel that our work truly mattered,” said Professor Demirkaya.
“News like this makes the world of autoinflammatory disease feel suddenly smaller.”
Over more than four decades at the US National Institutes of Health, Professor Kastner solved some of medicine’s most enduring diagnostic puzzles by combining careful bedside observation with emerging genomic technologies.
His discoveries not only identified the causes of rare hereditary fever syndromes but also fundamentally changed thinking about how the immune system drives disease.
Before Professor Kastner’s work, patients with recurrent fevers and unexplained episodes of systemic inflammation were often misdiagnosed, labelled with autoimmune conditions or left without a diagnosis altogether.
His research demonstrated that dysregulation of the innate immune system could produce inflammatory disease independently of the adaptive immune response, leading to the concept of autoinflammatory disease – now recognised as a major branch of immune-mediated illness alongside autoimmunity.
That conceptual shift has shaped both research and clinical practice, providing a framework for understanding a growing number of inherited and acquired inflammatory disorders and accelerating the development of targeted therapies.
Among Professor Kastner’s landmark discoveries was the identification of mutations in the MEFV gene as the cause of familial Mediterranean fever, one of the most common inherited autoinflammatory diseases.
His laboratory also characterised tumour necrosis factor receptor-associated periodic syndrome (TRAPS), helping define the molecular basis of hereditary recurrent fever syndromes.
Even after helping establish the field, Kastner continued to redefine it. In 2020, he and colleagues described VEXAS syndrome, a severe adult-onset inflammatory disease caused by acquired UBA1 mutations that rapidly became recognised by rheumatologists worldwide as the explanation for many previously mysterious cases of treatment-resistant systemic inflammation.
More recently, his team identified CRIA syndrome, adding another genetically defined autoinflammatory disorder to the expanding catalogue of diseases his work helped uncover.
His scientific achievements were recognised internationally, including with the 2021 Crafoord Prize in Polyarthritis, one of the highest honours in rheumatology and closely associated disciplines. He also served as scientific director of the National Human Genome Research Institute while continuing to lead research into rare inflammatory disorders.
But colleagues say his influence reached well beyond his publications.
“It’s easy to list Dan’s achievements: the discovery of the MEFV gene, TRAPS, the concept of autoinflammatory disease itself, VEXAS, CRIA, and the many patients whose decades-long diagnostic conundrums he finally solved,” said Professor Demirkaya.
“But those who knew him will remember him less for the accolades and more for his kindness and genuine interest in people – patients, trainees, and junior colleagues with a half-formed idea.
“He had that rare gift of making everyone in the room feel that their question was the most interesting one he’d heard all day.
“Whether at the NIH bedside, where it all began, or on a stage accepting the Crafoord Prize, he carried the same curiosity, enthusiasm, and humility.
“Many of us have our own memories of Dan: a conversation at a conference, an email he took the time to answer, or a piece of advice that shaped a career.
“ISSAID exists today because of the community he built and the generosity with which he nurtured it.
“Our thoughts are with his family, to whom we extend our deepest sympathy and our heartfelt thanks for sharing him with us for so many years. He will be profoundly missed.”
Tributes flowed for Professor Kastner on social media platforms from a myriad of clinicians and researchers whose paths had crossed with him over the years.
Associate Professor Jonathan Akikusa, chair of the Australian Paediatric Rheumatology Group, told Rheumatology Republic Professor Kastner “was a legend in the field of medicine, particularly the field of autoinflammation”.
“He was fond of Australia and Australians – having spent time in Adelaide as a student – and was the invited paediatric speaker at the ARA ASM in 2016 in Darwin at which he dazzled with both his intellect and engaging speaking style but also his genuine warmth, sense of fun, and humility,” Professor Akikusa said.
“It was at that meeting that the APRG presented him with his first pair of RM Williams boots which he absolutely adored and wore at every meeting at which I subsequently saw him.”
Dr Morgan Cheatham, a partner and head of Healthcare & Life Sciences at Breyer Capital, said it had been “the privilege of a lifetime to learn from Dr Kastner during my brief time at National Human Genome Research Institute”.
His approach to medical genetics and undiagnosed disease work left a lasting impression, and I think of him every time I meet a patient with an unspecified autoinflammatory syndrome.
“I remember Dr. Kastner as a warm, patient, and welcoming presence. In our most recent conversation, I asked him how he approached his work in novel gene and disease discovery,” Dr Cheatham wrote on LinkedIn.
“He told me that you really have to pay attention to patients, their symptoms, and the subtleties in their stories. If it sounds like something you’ve seen before, but with even the slightest twist, don’t ignore it, pull the thread.
“That is where the answer often lies. It was a three-hour conversation, and we had joked about turning it into a podcast episode.”
Professor Seza Ozen, president of the Paediatric Rheumatology European Association, also took to LinkedIn to share a tribute.
“Some people change a field. Dr Daniel L. Kastner helped create one. Through his groundbreaking work, he transformed our understanding of autoinflammatory diseases and brought answers, hope, and effective treatments to patients and families worldwide,” Professor Ozen wrote.
“Dan was also a valued friend of the PReS community. His generosity, mentorship, and passion for discovery inspired so many of us and helped shape the careers of countless clinicians and scientists.
“Today, we honour his remarkable legacy and the lasting impact he has had on medicine, paediatric rheumatology, and human immunology. He will be deeply missed and fondly remembered.”
