Not long ago, after all.
Dr. Dilan Dissanayake
“Patients with autoinflammatory diseases are all around us, but many go several years without a diagnosis,” Dr. Dissanayake, a rheumatologist at the Autoinflammatory Disease Clinic at the Hospital for Sick Children, Toronto, said during the annual meeting of the Society for Pediatric Dermatology. “The median time to diagnosis has been estimated to be between 2.5 and 5 years. You can imagine that this type of delay can lead to significant issues, not only with quality of life but also morbidity due to unchecked inflammation that can cause organ damage, and in the most severe cases, can result in an early death.”
Effective treatment options such as biologic medications, however, can prevent these negative sequelae if the disease is recognized early. “Dermatologists are in a unique position because they will often be the first specialist to see these patients and therefore make the diagnosis early on and really alter the lives of these patients,” he said.
While it’s common to classify autoinflammatory diseases by presenting features, such as age of onset, associated symptoms, family history/ethnicity, and triggers/alleviating factors for episodes, Dr. Dissanayake prefers to classify them into one of three groups based on pathophysiology, the first being inflammasomopathies. “When activated, an inflammasome is responsible for processing cytokines from the [interleukin]-1 family from the pro form to the active form,” he explained. As a result, if there is dysregulation and overactivity of the inflammasome, there is excessive production of cytokines like IL-1 beta and IL-18 driving the disease.
Clinical characteristics include fevers and organ involvement, notably abdominal pain, nonvasculitic rashes, uveitis, arthritis, elevated white blood cell count/neutrophils, and highly elevated inflammatory markers. Potential treatments include IL-1 blockers.
The second category of autoinflammatory diseases are the interferonopathies, which are caused by overactivity of the antiviral side of the innate immune system. “For example, if you have overactivity of a sensor for a nucleic acid in your cytosol, the cell misinterprets this as a viral infection and will turn on type 1 interferon production,” said Dr. Dissanayake, who is also an assistant professor of pediatrics at the University of Toronto. “As a result, if you have dysregulation of these pathways, you will get excessive type 1 interferon that contributes to your disease manifestations.” Clinical characteristics include fevers and organ involvement, notably vasculitic rashes, interstitial lung disease, and intracranial calcifications. Inflammatory markers may not be as elevated, and autoantibodies may be present. Janus kinase inhibitors are a potential treatment, he said.
The third category of autoinflammatory diseases are the NF-kappaBopathies, which are caused by overactivity of the NF-kappaB signaling pathway. Clinical characteristics can include fevers with organ involvement that can be highly variable but may include mucocutaneous lesions or granulomatous disease as potential clues. Treatment options depend on the pathway that is involved but tumor necrosis factor blockers often play a role because of the importance of NF-KB in this signaling pathway.
From a skin perspective, most of the rashes Dr. Dissanayake and colleagues see in the rheumatology clinic consist of nonspecific dermohypodermatitis: macules, papules, patches, or plaques. The most common monogenic autoinflammatory disease is Familial Mediterranean Fever syndrome, which “commonly presents as an erysipelas-like rash of the lower extremities, typically below the knee, often over the malleolus,” he said.
Other monogenic autoinflammatory diseases with similar rashes include TNF receptor–associated periodic syndrome, Hyper-IgD syndrome, and systemic juvenile idiopathic arthritis.
Other patients present with urticarial rashes, most commonly cryopyrin-associated periodic syndrome (CAPS). “This is a neutrophilic urticaria, so it tends not to be pruritic and can actually sometimes be tender,” he said. “It also tends not to be as transient as your typical urticaria.” Urticarial rashes can also appear with NLRP12-associated autoinflammatory syndrome (familial cold autoinflammatory syndrome–2), PLCgamma2-associated antibody deficiency and immune dysregulation, and Schnitzler syndrome (monoclonal IgM gammopathy).
Patients can also present with pyogenic or pustular lesions, which can appear with pyoderma gangrenosum–related diseases, such as pyogenic arthritis, pyoderma gangrenosum, arthritis (PAPA) syndrome; pyrin-associated inflammation with neutrophilic dermatosis; deficiency of the IL-1 receptor antagonist; deficiency of IL-36 receptor antagonist; and Majeed syndrome, a mutation in the LPIN2 gene.
The mucocutaneous system can also be affected in autoinflammatory diseases, often presenting with symptoms such as periodic fever, aphthous stomatitis, and pharyngitis. Cervical adenitis syndrome is the most common autoinflammatory disease in childhood and can present with aphthous stomatitis, he said, while Behcet’s disease typically presents with oral and genital ulcers. “More recently, monogenic forms of Behcet’s disease have been described, with haploinsufficiency of A20 and RelA, which are both part of the NF-KB pathway,” he said.
Finally, the presence of vasculitic lesions often suggest interferonopathies such as STING-associated vasculopathy in infancy, proteasome-associated autoinflammatory syndrome and deficiency of adenosine deaminase 2.
Dr. Dissanayake noted that dermatologists should suspect an autoimmune disease if a patient has recurrent fevers, evidence of systemic inflammation on blood work, and if multiple organ systems are involved, especially the lungs, gut, joints, CNS system, and eyes. “Many of these patients have episodic and stereotypical attacks,” he said.
“One of the tools we use in the autoinflammatory clinic is to have patients and families keep a symptom diary where they track the dates of the various symptoms. We can review this during their appointment and try to come up with a diagnosis based on the pattern,” he said.
Since many of these diseases are due to a single gene defect, if there’s any evidence to suggest a monogenic cause, consider an autoinflammatory disease, he added. “If there’s a family history, if there’s consanguinity, or if there’s early age of onset – these may all lead you to think about monogenic autoinflammatory disease.”
During a question-and-answer session, a meeting attendee asked what type of workup he recommends when an autoinflammatory syndrome is suspected. “It partially depends on what organ systems you suspect to be involved,” Dr. Dissanayake said. “As a routine baseline, typically what we would check is CBC and differential, [erythrocyte sedimentation rate] and [C-reactive protein], and we screen for liver transaminases and creatinine to check for liver and kidney issues. A serum albumin will also tell you if the patient is hypoalbuminemic, that there’s been some chronic inflammation and they’re starting to leak the protein out. It’s good to check blood work during the flare and off the flare, to get a sense of the persistence of that inflammation.”
Dr. Dissanayake disclosed that he has received research finding from Gilead Sciences and speaker fees from Novartis.
*This story was updated on 9/20/2021.