From Monogenic to Polygenic & Multifactorial
Dr. Broderick
The identification of named AIDs represents true bench-to-bedside medicine. “Autoinflammatory disease identification is driven by patients—the ones constantly coming back to the clinic that you’re just looking for a diagnosis for,” Dr. Broderick explained.
As a pediatric allergy/immunologist, Dr. Broderick thinks about immune dysregulation from a different perspective than most of us do as rheumatologists. Immune dysregulation can fall into multiple categories, ranging from immunodeficiency and atopic disease, to autoimmunity, hyperinflammation, auto-inflammation and dysimmunopoiesis (i.e., primary failure or expansion of “immune” cells, like lymphoma and myelofibrosis).
Over the past 30 years, more than 40 different monogenic disorders have been defined in the autoinflammatory space. Dr. Broderick pointed to a 2020 review of monogenic autoinflammatory disorders by rheumatologist Peter A. Nigrovic, MD, and colleagues that summarizes them particularly well.1 “This is one of the best reviews on the topic. No matter how the patient presents to you in clinic, you may be able to find the correct diagnosis in the chart in this paper,” she said.
However, we are now moving away from the monogenic, autosomal dominant and autosomal recessive AIDs into things that are a bit more common—the polygenic and multifactorial diseases. However, Dr. Broderick explained, “The challenging aspect about these diseases is that the phenotypes might not be as extreme as the monogenic disorders.” These patients’ symptoms may not be as striking, but they’re prominent enough to disrupt the daily life. “My child is sick all the time” is a common refrain heard in her clinic.
“My Child is Sick all the Time”
In the past few years, the Recurrent Fever Disorders Clinic at UCSD—Rady Children’s Hospital has grown exponentially, and Dr. Broderick and colleagues are seeing more and more patients that don’t fit into any known AID categories. Many patients are being referred given concern for periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.
PFAPA syndrome is an AID typically seen in children, and it is characterized by recurrent episodes of fever as well as painful aphthous ulcers, pharyngitis and/or cervical lymphadenopathy. Episodes last three to six days, and occur like clockwork every three to six weeks. Patients and their parents are often able to predict the next febrile flare on the calendar. They are asymptomatic between episodes. The diagnosis is primarily clinical. Steroids are effective in aborting acute episodes, but for patients with frequent or severe episodes, tonsillectomy has been shown to be curative in many cases.2
Dr. Broderick and colleagues wondered how many referrals were true PFAPA patients, and how many were just being labeled as such. “Most of the patients weren’t meeting Marshall’s criteria for PFAPA at all,” she explained. “So we used this as an opportunity to change our approach to recurrent fevers in our clinic. In the pediatric population, fevers are common, so we also wanted to find a way to reassure parents, especially during the pandemic, that not every fever is bad, but is an important aspect of the immune response.”
Dr. Broderick and her team took a close look at patients referred to their clinic for recurrent fevers. Ultimately, they found that the majority of patients either had recurrent infections or a variant of a known monogenic disorder. Some had allergies, PFAPA or diagnoses that weren’t monogenic AIDs at all (e.g., recurrent aphthous stomatitis, inflammatory bowel disease or leukemia).3 But what about the patients that just didn’t fit anywhere?
“That’s where the idea of SURF comes in,” said Dr. Broderick. “About 70–80% of patients with systemic autoinflammatory diseases fail to obtain a molecular diagnosis and most get tossed into the PFAPA category. We are trying to be clear about who is PFAPA and who isn’t, so we can optimize therapy. SURF patients are a large population that is distinct from PFAPA syndrome.” Of note, this name, coined by rheumatologist Karyl Barron, MD, seemed most appropriate because she and her colleagues are all San Diego surfers.
Evaluation & Management of SURF
Now that SURF has been described, we can start to talk about treatment. Marco Gattorno, MD, head, Unit of Rheumatology and Autoinflammatory Diseases, Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCCS) Istituto G. Gaslini, Genoa, Italy, shared updates in this regard.
Dr. Gattorno and colleagues have been following a longitudinal cohort of these patients at his institution to better understand and treat children living with SURF.4,5 “SURF is a subset of patients with recurrent fever after careful exclusion of hereditary risk factors and PFAPA,” he said. “These patients seem to have homogenous clinical features and response to treatment.” Data show that the most common features among SURF patients include fever, arthralgias, abdominal pain and myalgia.
First-line therapy for treating SURF is colchicine. In their cohort, treatment with colchicine led to complete response in about 70% of patients at the one-to-two-year mark, and 50% at the five-year mark.5 Dr. Gattorno noted, “Sixty-five percent of patients stopped colchicine because of remission, so this is really an effective drug in most of these patients. And in almost 20% of patients, we are able to withdraw colchicine due to a complete and sustained remission, but in some we have rebound disease and need to restart it. We still don’t know how many will be without therapy in the long run. In our experience, tonsillectomy was usually ineffective for these patients. This is why it’s so important to distinguish SURF from PFAPA.”
In SURF patients who don’t respond to colchicine, second-line therapy is interleukin 1 blocking therapy (e.g., anakinra, canakinumab). Patients who failed colchicine had a good response to these drugs in their cohort. However, Dr. Gattorno made an important point, stating that “if they don’t respond to colchicine, we also need to consider if this could be another undefined genetic disorder with novel genes involved.”
Dr. Gattorno and colleagues are working on an evidence-based classification decision tree for SURF patients. The manuscript is in preparation.
In Sum
The field of AIDs continues to grow and change, and it’s an exciting time to be treating these patients. “There are a lot of undifferentiated diseases in which we can find new [responsible] genes, but there are also new multifactorial diseases that we’ll need to face in the near future,” Dr. Gattorno concluded.
Samantha C. Shapiro, MD
Samantha C. Shapiro, MD, is a clinician educator who is passionate about the care and education of rheumatology patients. She writes for both medical and lay audiences and practices telerheumatology.
References
- Nigrovic PA, Lee PY, Hoffman HM. Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach. J Allergy Clinl Immunol. 2020 Nov;146(5):925–937.
- Licameli G, Jeffrey J, Luz J, et al. Effect of adenotonsillectomy in PFAPA syndrome. Arch Otolaryngol Head Neck Surg. 2008 Feb;134(2):136–40.
- Broderick L, Hoffman HM. Pediatric recurrent fever and autoinflammation from the perspective of an allergist/immunologist. J Allergy Clin Immunol. 2020 Nov;146(5):960–966.e2.
- Papa R, Penco F, Volpi S, et al. Syndrome of undifferentiated recurrent fever (SURF): An emerging group of autoinflammatory recurrent fevers. J Clin Med. 2021 May 3;10(9):1963.
- Sutera D, Bustaffa M, Papa R, et al. Clinical characterization, long-term follow-up, and response to treatment of patients with syndrome of undifferentiated recurrent fever (SURF). Semin Arthritis Rheum. 2022 Aug;55:152024.