Research into a group of rare, often lethal genetic diseases spearheaded by the National Institutes of Health (NIH) has led not only to spectacular results for the afflicted children, but also is helping to explain some of the unsolved mysteries of common diseases like gout, diabetes, and coronary artery disease.
The underlying concept linking this broad array of disorders is autoinflammation, which involves dysregulation of the innate immune system. That branch of the immune system has long been considered the primitive, hard-wired component responsible for simple rapid response to "danger signals" such as microbes and fragments of dying cells.
In contrast, the adaptive branch develops and changes through life, acquiring the ability to target microbial and molecular threats more precisely, armed with activated T and B cells.
Disturbances of the adaptive branch, where the immune system turns against "self" tissues in diseases such as lupus and rheumatoid arthritis, are classified as autoimmune. In the past, certain diseases typically treated by rheumatologists were lumped in with the autoimmune diseases, even though they didn't really fit since they were not characterized by the production of autoantibodies.
Those diseases are now referred to as autoinflammatory.
This differentiation between autoimmune and autoinflammatory disease hasn't fully penetrated the awareness of the wider medical community, explained Richard Siegel, MD, clinical director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
"It's been a blind spot in our understanding of human disease," Siegel told MedPage Today.
The Prototype: FMF
In the 1980s, Dan Kastner, MD, PhD, newly arrived as a rheumatology fellow at the NIH, developed an interest in familial Mediterranean fever (FMF), which was recognized as a genetic disorder most often afflicting residents of countries along the old Silk Road, from Turkey and Armenia and then east into Asia.
Children with familial Mediterranean fever periodically developed fevers, arthralgias, and rashes without any underlying infection or other apparent triggering event. The attacks typically lasted 1 to 3 days.
"We knew the gene was inherited recessively, but we didn't know what chromosome it was located on, what its protein product was, or what the gene might do in terms of causing fevers if mutated," Kastner told MedPage Today.
Using the tools being developed for the Human Genome Project, he and his colleagues initially mapped the gene, MEFV, to a region on chromosome 16, and named its protein product pyrin.
They then determined that pyrin is an important player in the regulation of cytokine release and inflammation, particularly through interleukin (IL)-1.
"Then we started seeing patients who had similar conditions, but weren't of Mediterranean ancestry and whose attacks lasted for a month or 6 weeks," said Kastner of National Human Genome Research Institute and former head of the clinical investigation laboratory at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).
In those children, the disease appeared to be dominantly inherited, the rashes were different, and genetic analyses linked the condition with mutations in the TNF receptor. This second condition became known as TRAPS, for TNF-receptor-associated periodic syndrome.
"Having found two different genes that seemed to cause similar kinds of diseases with recurring fevers and inflammation, we began to think this was an emerging family of diseases for which we proposed the name autoinflammatory disease," Kastner recalled.
The Inflammasome, IL-1, and CAPS
In 2001, Hal M. Hoffmann, MD, of the University of California San Diego, reported in Nature Genetics on his discovery of a mutated gene causing familial cold autoinflammatory syndrome (FCAS) and Muckle Wells syndrome, autosomal dominant disorders in which children present with periodic fevers and urticarial rashes.
This gene, NLRP3, encodes the cryopyrin protein, a component of an intracellular protein complex termed the inflammasome, which is responsible for the release of activated pro-inflammatory, pyrogenic IL-1β on exposure to "danger signals."
Specifically, enzymatic activity of the inflammasome cleaves inactive caspase 1 into its active form, and activated caspase 1 in turn cleaves pro-IL-1 into a bioactive form. This release of IL-1β leads to an influx of tissue-damaging neutrophils, and in patients carrying the NLRP3 mutations, this whole process is upregulated.
These findings "provided a clear link between disease and a cellular pathway leading to overproduction of a specific inflammatory mediator," Hoffmann wrote in the Journal of Leukocyte Biology.
Soon after, mutations were found in children with another, more severe condition, known as NOMID, or neonatal onset multisystem inflammatory disease, again linked to NLRP3 and the upregulation of IL-1, but also featuring severe neurologic sequelae such as aseptic meningitis and progressive hearing loss.
These three disorders, once thought to be distinct, came to be recognized as being part of a spectrum and were subsequently referred to as cryopyrin-associated periodic syndrome (CAPS).
Treatment for CAPS previously had been largely ineffective, particularly for children on the severe end of the spectrum with NOMID, with one in five dying before reaching adulthood.
A Treatment Breakthrough: Anakinra
The understanding that IL-1 played such a prominent role in these genetic disorders, and the fact that an IL-1 blocker was available and approved for use in rheumatoid arthritis, prompted Raphaela Goldbach-Mansky, MD, also of NIAMS, to undertake a study in which 18 patients with NOMID were treated with anakinra (Kineret).
All of the patients, who had multiple disease manifestations including rash, pain, central nervous system involvement, and sensorineural hearing loss, responded rapidly, Goldbach-Mansky and colleagues reported in 2006 in the New England Journal of Medicine.
"The completeness and rapidity of response was something I had never seen," she told MedPage Today.
"Rashes that had been present since birth disappeared within 3 days. Fevers, aseptic meningitis, and joint pains disappeared," she said. "I had children on morphine every night and within a week they were off morphine."
The response has persisted for 5 years, she reported in 2012 in Arthritis & Rheumatism, in a cohort of 26 NOMID patients, with suppression of central nervous system inflammation, decreases in pain scores, and lowering in levels of inflammatory markers.
In fact, some of the patients have been followed for up to 10 years now, with no loss of response, she said.
A result of this work was the approval, just last month, of anakinra as the first treatment of young patients with NOMID, according to a statement from the manufacturer, Swedish Orphan Biovitrum.
Two other anti-IL-1 agents, the monoclonal antibody canakinumab (Ilaris) and the fusion protein rilonacept (Arcalyst), have been approved for the treatment of the other two members of the CAPS family.
Numerous other rare, monogenic conditions have since been identified in populations worldwide, some of which respond to IL-1 blockade, such as HIDS (hyper-IgD syndrome) and DIRA (deficient in the IL-1R antagonist).
However, different pathways appear to be dominant in some other conditions, such as in CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature), which appears to have a strong interferon signature.
But beyond the successful treatment of these rare genetic disorders, the burgeoning insight into the role of the inflammasome in disease brought about the realization that these inflammatory processes had much broader reach.
Gout, Diabetes, and More
An important advance, according to Siegel, was the realization that the inflammasome could react to numerous types of stimuli, including metabolic stress molecules.
"We realized that literally hundreds of different stress stimuli, both external from the environment and even internal stress stimuli, can trigger the inflammasome," he said.
Among these triggers are uric acid, amyloid peptide, and cholesterol, it turned out.
Uric acid is released when cells are dying, explained Goldbach-Mansky. And while gout has long been understood as resulting from the deposition of uric acid crystals in the joints, only now has the resulting inflammatory cascade been revealed, showing that the process results from crystals triggering the NLRP3 inflammasome.
Moreover, small studies have shown that treatment with anakinra or other IL-1 blockers can rapidly ease the pain of gout, and while the majority of patients with gout can successfully manage the disease with lifestyle measures and conventional treatments, a subset with refractory disease may benefit from this approach, Hoffmann said in an interview with MedPage Today.
Similar findings have been seen with type 2 diabetes and heart disease, conditions that also have autoinflammatory components, with major potential implications for treatment.
"In animal models, it appeared that blocking IL-1 improved diabetes by preventing the release of human amyloid peptide and the death of pancreatic islet cells," Goldbach-Mansky said.
In addition, a double-blind trial that included 70 patients with type 2 diabetes, published in the New England Journal of Medicine, found that 13 weeks of treatment with anakinra led to improvements in beta-cell function, reductions in systemic inflammatory markers, and enhanced glycemic control.
Other proof-of-concept studies are ongoing, looking at blockade of IL-1 as a novel treatment for these more complex -- and common -- diseases.
In one study, known as CANTOS, three different doses of canakinumab are being evaluated versus placebo in 17,200 patients who have already experienced a myocardial infarction, to see if a second event can be prevented.
"This, of course, is a very common disease in Western society," Kastner said in an interview.
"Certainly this does raise a real possibility that some of these pathways we're studying in patients with relatively rare, inherited single-gene diseases may ultimately be applicable to a much broader scope of diseases," he said.
Atherosclerosis, too, is being considered for inclusion in the autoinflammatory realm. While arterial inflammation has clearly been established as underlying this disease, the mechanisms and events in the arterial wall have been less certain.
But a group of researchers led by Eicke Latz, MD, PhD, of the University of Massachusetts in Worcester, developed a microscopic technique in which they identified tiny cholesterol crystals early in the process of atherosclerotic plaque development in a murine model.
And the mediator of inflammation, they found, was activation of NRLP3 through the inflammasome.
"Based on our findings, therapeutic strategies that would reduce cholesterol crystals or block the inflammasome pathway would be predicted to have clinical benefit by reducing the initiation or progression of atherosclerosis," Latz and colleagues wrote in Nature.
"There has been an explosion in the recognition of the stimuli that go through this one very conserved pathway," said Siegel.
"It may be tempting to try treating everything with IL-1 blockade, but we don't know how that's going to play out, particularly because all the cytokine blockers do have consequences in terms of immunosuppression," he cautioned.
In addition, these medications are expensive, "and you always have to weigh the costs and risks versus what's already available," Hoffmann said.
The Next Revolution?
The enhanced understanding of the immune system represented by this research also has shown that the innate and adaptive components of immunity are intertwined, and many diseases have both autoinflammatory and autoimmune aspects.
"There is accumulating evidence that some more common polygenic immune disorders lie at the interface between autoinflammatory and autoimmune disease, combining elements of innate and adaptive immunopathology," Goldbach-Mansky and Kastner wrote in the Journal of Allergy and Clinical Immunology.
"Future research will continue to explore the genetic influences in these diseases, as well as what goes wrong in the related proteins and pathways, and to try to understand the differences between people that cause their immune systems to be overactive, making them susceptible to complex autoinflammatory diseases," Hoffmann told MedPage Today.
"As diseases of human beings, the autoinflammatory disorders are not merely guideposts to the innate immunome, but also opportunities to better the human condition," Kastner and colleagues observed in Annual Reviews of Immunology.
The extraordinary success of IL-1 blockers in the rare periodic fever syndromes "represent triumphs of molecular medicine, but the application of similar therapies to conditions like [type 2 diabetes mellitus] and atherosclerosis may represent the next breakthrough, and the development of small molecule inhibitors, if effective, would be revolutionary," they stated.