How to Recognize an Autoinflammatory Disorder

ORLANDO—As adult rheumatologists, we know we’re supposed to know about autoinflammatory disorders. They’re on the boards. But because these conditions typically present in childhood, our experience diagnosing and treating them may be limited. At the 2022 ACR Education Exchange, April 28–May 1, Jay Mehta, MD, MS, associate professor of clinical pediatrics, Division of Rheumatology, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, discussed a practical, clinical approach to patients with autoinflammatory disorders.

Periodic Fever Syndromes & the Innate Immune System

Periodic fever syndromes (PFS) are disorders of the innate immune system involving three or more unexplained fevers in a six-month period that occur at least seven days apart. Patients are typically well between episodes, a situation unlike that with other causes of recurrent fevers.

The spectrum of autoinflammatory and autoimmune disorders spans innate to adaptive immunity, and includes monogenic, polygenic and mixed-pattern diseases.

Dr. Mehta

“This [explanation] is a gross oversimplification of the immune response,” Dr. Mehta says. “But the innate immune system is a primitive, evolutionarily conserved system that plays a crucial role in the early recognition of foreign pathogens. Neutrophils and mononuclear phagocytes come first, and it’s not until three to four days later that other cells kick in. Autoantibodies and autoreactive T cells aren’t involved here.”¹

Autoinflammatory disorders may involve genetic mutations of the inflammasome or an environmental trigger in a genetically susceptible host. The inflammasome is a collection of signaling pathways and receptors that come together when the body is exposed to a foreign pathogen.

“The inflammasome releases interleukin [IL] 1 and IL-18. These are endogenous pyrogens that raise body temperature in an effort to get rid of pathogens. Mutations in the inflammasome result in abnormal production of IL-1 and/or IL-18 independent of some sort of organism.”²

Questions to Ask

Dr. Mehta walked the audience through questions he asks when considering autoinflammatory disorders in the diagnostic process:

1. How long has it been between symptom episodes? Can you predict the next flare on a calendar?
2. How long do the episodes last?
3. Can you predict when an episode is about to happen? If the patient can predict the episode, this is a good sign they have a PFS.
4. How does the patient look between episodes? If they look well, consider PFS.
5. What other symptoms are present during the fever? Rash, pharyngitis, lymph node swelling, serositis (e.g., chest pain, abdominal pain), conjunctival injection, oral ulcers, myalgias or arthralgias point toward PFS.
6. What’s the patient’s racial background? A lot of these diseases are Mendelian disorders, so this factor can be relevant.
7. Is there a family history of recurrent infections, fevers or unexplained cardiac or kidney failure suggestive of amyloid?
8. Do clues suggest immunodeficiency, such as unusual infections poorly responsive to antibiotics or failure to thrive?

Clinical Scenarios

Dr. Mehta illustrated some of the more common autoinflammatory disorders via clinical scenarios for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated syndrome (TRAPS) and periodic fever with aphthous stomatitis, pharyngitis and asdenitis (PFAPA).

Scenario 1: An 8-year-old boy presents with periodic fevers, which he has been experiencing for six months. Febrile episodes occurred in the past two days and were associated with abdominal pain, left ankle pain and a rash.

FMF is the most common PFS, typically affecting people of Mediterranean descent before the age of 20. This autosomal recessive disorder is caused by a mutation of the MEFV gene, which encodes for pyrin, a part of the inflammasome.

Episodes are typically short (lasting 12–72 hours). Ninety-five percent of patients with FMF experience abdominal pain due to peritoneal serositis, which may mimic an acute abdomen and/or cause constipation and ileus. Pleural and pericardial serositis are less common than abdominal involvement. Arthralgias, myalgias, arthritis and erysipeloid erythematous rashes, commonly on the dorsum of the foot, may also occur.

Screening for amyloidosis remains an important part of the care of patients with FMF. Dr. Mehta recommended periodic urinalysis to check for proteinuria because renal failure is a major concern.

“You make amyloid every time you get inflamed. So if you’ve got a patient with monthly episodes of inflammation, that’s a lot of amyloid depositing in organs over a lifetime,” he said.

Treatment is daily colchicine, followed by IL-1 inhibition (e.g., canakinumab). Flares are treated with non-steroidal anti-inflammatory drugs and glucocorticoids on demand.

Scenario 2: A 4-year-old girl presents with periodic fevers, which she has been experiencing for 10 months. Febrile episodes last from 10 to 14 days and are associated with eye redness and swelling, thigh pain and a rash.

TRAPS is the second most common PFS and typically affects those of Irish and Scottish descent before the age of 20. Inheritance is autosomal dominant and involves a mutation of the TNFRSF1A gene, a part of the TNF-alpha receptor. TRAPS episodes are notably longer than those in FMF, with some lasting up to six weeks. Conjunctivitis, periorbital edema, migratory cellulitis-like rashes help distinguish it from other types of PFS. Rashes start on the trunk and migrate distally.  

Treatment involves prednisone and IL-1 inhibition for steroid-sparing. Colchicine is not effective for TRAPS.

“We used to treat these patients with TNF inhibition, but IL-1 inhibition works better and is now the standard of care. Interestingly, infliximab can cause disease exacerbations, but we don’t know why,” Dr. Mehta said.

Triggers of both FMF and TRAPS include stress, good stress (e.g., a birthday party), exercise and menses. Classification criteria exist to aid in the diagnosis of each for patients with and without access to genetic testing.

“Of note, negative genetic testing doesn’t necessarily rule these out if the clinical picture fits, [because] we haven’t yet identified all mutations,” Dr. Mehta added.^3,4

Scenario 3: A 4-year-old boy presents with recurrent fevers, mouth ulcers and frequent episodes of strep-negative pharyngitis.

 PFAPA is the most common acquired PFS, with no genetic etiology. Onset typically occurs before the age of 5, although reports of adult-onset disease are increasing.⁵ Episodes of high fevers, aphthous ulcers, pharyngitis, cervical adenitis and/or arthralgias last three to five days and recur every three to four weeks like clockwork. These symptoms may occur alone or in combination. Patients are asymptomatic between episodes. Rash and chest pain are notably absent from PFAPA. 

Classification criteria also exist for PFAPA. “You don’t necessarily need to send genetic testing to rule out other autoinflammatory disorders if symptoms are consistent with PFAPA, but you do need to evaluate for infection, malignancy, autoimmunity and immunodeficiency,” Dr. Mehta said.

Flares typically respond to a single dose of prednisone taken at flare onset, but interestingly steroids may shorten the intervals in between episodes for some patients. Colchicine or tonsillectomy and adenoidectomy are options if steroids don’t help. Prognosis is excellent, with symptoms resolving over time.^4,6

‘Recognizing when to suspect an autoinflammatory disorder is way more important than memorizing the specific features of them.’—Dr. Mehta

Genetic Testing

Genetic testing may be obtained via commercial laboratories if warranted by clinical suspicion.

Dr. Mehta said, “I like the Invitae Autoinflammatory and Autoimmunity Syndromes Panel. It comes back in two weeks, and if the initial panel is negative, they do expanded testing that looks for 400 genes. If insurance won’t cover it, the out-of-pocket cost is about $250—far cheaper than whole exome testing.”⁷

In Sum

If you’ve got a patient with periodic fevers, remember to screen for autoinflammatory disorders.

“Recognizing when to suspect an autoinflammatory disorder is way more important than memorizing the specific features of them. You can always look the details up,” Dr. Mehta said.

Samantha C. Shapiro, MD, is an academic rheumatologist and an affiliate faculty member of the Dell Medical School at the University of Texas at Austin. She received her training in internal medicine and rheumatology at Johns Hopkins University, Baltimore. She is also a member of the ACR Insurance Subcommittee.

References

1. Wraith DC. The future of immunotherapy: A 20-year perspective. Front Immunol. 2017 Nov 28;8:1668. eCollection 2017.
2. Manthiram K, Zhou Q, Aksentijevich I, et al. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017 Jul 19;18(8):832–842.
3. Haar N ter, Lachmann H, Özen S, et al. Treatment of autoinflammatory diseases: Results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013 May;72(5):678–685.
4. Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025–1032.
5. Cantarini L, Vitale A, Bartolomei B, et al. Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers. Clin Exp Rheumatol. Mar-Apr 2012;30(2):269–271.
6. Amarilyo G, Rothman D, Manthiram K, et al. Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group. Pediatr Rheumatol Online J. 2020 Apr 15;18(1):31.
7. Invitae autoinflammatory and autoimmunity syndromes panel. Invitae. 2022.