Romano reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Diagnostic workups for patients with interleukin-1 mediated autoinflammatory diseases should include an audiogram and ophthalmic examination, according to data published in the Annals of the Rheumatic Diseases.
“Most patients with [cryopyrin-associated periodic syndromes (CAPS)], [tumor necrosis factor receptor-associated periodic syndrome (TRAPS)], [mevalonate kinase deficiency (MKD)] and [deficiency of IL-1 receptor antagonist (DIRA)] are managed by pediatricians and pediatric specialists, and with effective treatments, adolescents and young adults are now reaching adulthood with expectations of a normal life span,” Micol Romano, MD, of Western University, in London, Canada, and colleagues wrote.
“They now face new challenges with transitioning care to adult rheumatologists comfortable with the management of these patients,” they added. “Furthermore, pregnancy and other subspecialty needs (ie, surgery) are often not addressed adequately in the context of IL-1 mediated [systemic autoinflammatory diseases (SAIDs)]. For some patients, the diagnosis may be delayed for decades, resulting in inadequate treatment and the development of permanent disabilities that may translate into special care needs.”
To develop new points-to-consider for the management and diagnosis of IL-1 mediated systemic autoinflammatory diseases, with the ultimate goal of standardizing the level of care and improving the quality of life and disease outcomes, the American College of Rheumatology and EULAR assembled a joint multinational, multidisciplinary task force. In addition to the conveners, the task force included 19 pediatric rheumatologists, four adult rheumatologists, two health care professionals, three fellows, two methodologists and a representative from the Autoinflammatory Alliance.
The task force first met in August 2019 to define its focus, identifying CAPS, TRAPS, MVD and DIRA as the four diseases to be included in the project. The group’s methodologists then conducted a systematic literature review. Before the first consensus meeting, two surveys detailing treatment, diagnosis and long-term monitoring were administered. Statements with greater than 80% agreement were kept for further consideration.
The task force held three virtual consensus meetings from September 2020 to November 2020. Again, statements that reached 80% or greater consensus during the meetings were included in the final version of the points-to-consider.
In all, the task force approved five overarching principles and 14 points related to diagnosis, 10 points on therapy and nine points focused on long-term monitoring for patients with IL-1 mediated diseases.
The overarching principles state that:
- IL-6 mediated diseases can cause progressive damage and require a multidisciplinary team for management;
- Chronic episodic flares of unexplained systematic inflammation should get workups involving genetic testing, the extent of organ involvement and disease screening;
- A genetic diagnosis is required for the included diseases;
- The goal of treatment is to control clinical signs and symptoms and normalize laboratory biomarkers of systemic inflammation using a treat-to-target approach; and
- Long-term monitoring goals should focus on adequate treatment adjusted to the needs of the growing child, prevention of systemic and organ-specific inflammatory manifestations, encouraging self-management skills and medical decision-making, and transitioning adolescent patients to adult care.
Regarding the points-to-consider on diagnosis, the ACR/EULAR task force recommends that patients with symptoms of CAPS, TRAPS, MVD or DIRA, without the requisite genetic mutations, should be referred to specialty centers. Genetic testing should be used for diagnosis , and it may be necessary to employ deep sequencing in certain patients. Specific to CAPS, patients may present with symptoms different from CAPS, and prognosis may differ as well. Specific to TRAPS, patients with low penetrance variance in TNFRSF1A may present differently from standard TRAPS, and have a different prognosis as well.
Meanwhile, specific to DIRA, Sanger sequencing, WES or WGS, may not pick up on large deletions, complicating diagnosis.
The points also state that systemic inflammation workups should include CRP, ESR and CBC with differential.
Other diagnostic points to consider include:
- The initial workup for CAPS should include an audiogram and ophthalmic evaluation.
- TRAPS specific, certain symptoms, including long-lasting episodes of fever, migratory rashes, periorbital oedema, myalgia and family history should prompt clinical workups.
- MKD specific, clinical features including an age younger than 1 year at onset, gastrointestinal symptoms, painful lymph nodes, aphthous stomatitis, a history of triggers of periodic fever and a maculopapular rash should prompt clinical workups.
- When inflammatory diseases are unexplained, mevalonic acid in urine should trigger further workup.
- DIRA specific, clinical features including pustular psoriasis-like rashes, osteomyelitis, an absence of bacterial osteomyelitis and nail changes should trigger a clinical workup
- In patients with suspected DIRA, X-ray exams of the chest and upper and lower limbs should be included in the diagnostic workup.
Points for treatment include:
- IL-6 blocking therapy is the preferred treatment and can be initiated once a strong clinical suspicion of the diseases is established.
- IL-6 blocking therapy should not be altered during viral infections.
- CAPS-specific IL-6 blockers are currently considered standard-of-care and include anakinra (Kineret, SOBI) , canakinumab (Ilaris, Novartis) and rilonacept (Arcalyst, Kiniksa Pharmaceuticals).
- Anakinra “may be the most effective” anti-IL-6 therapy for CNS.
- TRAPS-specific IL-6 blockers are more effective than traditional disease-modifying antirheumatic drugs.
- Anti-TNF agents should be used if anti-IL-6 drugs are not impactful.
- Glucocorticoids are useful for treating acute flares, but side effects limit long-term use.
- DIRA-specific therapy that blocks IL-1 alpha and IKL-1 beta is recommended.
Points for disease monitoring include:
- Disease activity and burden should be monitored regularly and depending on severity, and development of pediatric patients should be monitored at every visit.
- Patients with systematic inflammation should be monitored for development of amyloidosis.
- Treating physicians should be aware of the increased risk for infection in patients being treated with IL-6 blockers.
- Patients should receive immunizations according to local and regional guidelines.
- When bone involvement or CNS is present, patients should be evaluated for developmental delays.
“Owing to the rarity of these disorders, statements have been developed based on low level of evidence and on expert opinion, which will probably require revisions as new knowledge is generated,” Romano and colleagues wrote. “Multicenter collaborative efforts, prospective registries and randomized trials will help to define optimal treatment strategies to relieve patient symptoms and to further improve long-term clinical outcomes. The panel also suggests areas for future research.”