The European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) released points-to-consider for the diagnosis and management of autoinflammatory type I interferonopathies, including chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS). The full report was published in Arthritis & Rheumatology.
An international taskforce was convened with experts from North America, South America, Europe, and Australia to develop points-to-consider for the diagnosis, treatment, and long-term management of patients with autoinflammatory type I interferonopathies.
Following an in-person meeting in August 2019, the taskforce, including rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional, formulated research questions using the patient/population, intervention, comparison, and outcomes (PICO) format for a systematic literature review (SLR). A SLR was performed to identify relevant literature published before September 2020.
Based on SLR findings, Delphi questionnaires, and 2 preconsensus meetings, draft statements with 80% or higher agreement were reviewed, discussed, and revised in 2 consensus meetings (CANDLE/PRAAS and SAVI and AGS, respectively), held online in October 2020.
A final set of 4 overarching principles and 17 disease-specific points-to-consider were developed in a postconsensus meeting using Delphi questionnaire. All taskforce members indicated their level of agreement for each recommendation.
- Chronic systemic and organ-specific inflammation is present in patients with CANDLE/PRAAS, SAVI, and AGS. When untreated, chronic inflammation results in progressive organ damage, early morbidity, and increased mortality.
- Diagnosis of CANDLE/PRAAS, SAVI, and AGS must be confirmed by genetic testing, which facilitates initiation of targeted treatments, genetic counseling, screening for complications, and informed prognosis.
- The goal of treatment of autoinflammatory type I interferonopathies is to prevent and/or decrease systemic and organ inflammation, thereby improving the quality of life.
- A multidisciplinary team is required to manage patients with CANDLE/PRAAS, SAVI, and AGS, which includes long-term monitoring of disease activity, managing and treating organ-specific injury/damage, and addressing treatment-related complications.
- For patients presenting with unexplained systemic inflammation (including elevations of C-reactive protein, erythrocyte sedimentation rate, and/or an interferon signature) and clinical features that include rashes, lipodystrophy, musculoskeletal, neurologic, pulmonary, and metabolic findings, a prompt diagnostic workup for CANDLE/PRAAS, SAVI, and AGS is required.
- Genetic evaluation
- Clinical evaluation focusing on the extent of inflammatory organ involvement
- Screening for disease-related comorbidities
- For patients with clinical symptoms of CANDLE/PRAAS, SAVI, and AGS who do not carry any of the disease-causing mutations, referral to specialty/research centers must be considered to guide further workup and treatment.
- Genetic analyses must include mutations in the following disease-causing genes:
- CANDLE/PRAAS: PSMB8, PSMA3, PSMB4, PSMB9, PSMB10, POMP, and PSMG2
- SAVI: STING1 (previously TMEM173)
- AGS: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11, and RNU7-1
- Genetic mimics of CANDLE/PRAAS, SAVI, and AGS should be recognized and included in the diagnostic workup.
- CANDLE-like conditions: splice variants in IKBKG, frameshift mutations in SAMD9L, and recessive mutations in RNASEH2 (A, B, and C)
- SAVI-like conditions: TREX1, ADA2, and COPA
- AGS-like conditions: RNASET2
- For patients with suspected CANDLE/PRAAS, SAVI, and AGS, providers must perform screening tests to assess disease- and treatment-related comorbidities.
- Skin manifestations: nodular rashes, violaceous annular rashes, panniculitis, lipodystrophy, and vasculopathic skin lesions
- Neurologic manifestations: intracerebral calcifications, leukoencephalopathy, progressive microcephaly, and cerebral atrophy
- Pulmonary manifestations: interstitial lung disease/pulmonary hypertension
- Hepatic manifestations: hepatic steatosis, hepatitis, and hepatosplenomegaly
- Metabolic manifestations: hypertension, hyperlipidemia, and glucose intolerance (metabolic syndrome)
- Musculoskeletal manifestations: arthritis, contractures, and myositis
- Growth and development: growth retardation, osteoporosis, bone development delay, and pubertal delay
- Hematologic manifestations: cytopenias (eg, lymphopenia, thrombocytopenia)
- Ophthalmologic manifestations: episcleritis, keratitis, retinopathy, and glaucoma
- Cardiac manifestations: cardiomyopathy
- Neuroimaging should be considered in patients with suspected neurologic symptoms.
- Magnetic resonance imaging (MRI) to best identify white and grey matter changes.
- Computed tomography (CT) to detect cerebral calcification; this can be considered when calcium-sensitive modalities on MRI are not available or do not detect calcification.
- Appropriate tissue sampling may help in the diagnosis of patients with presumed CANDLE/PRAAS, SAVI, and AGS.
- A basic immunodeficiency workup that includes a history of infections, lymphocyte subsets, and immunoglobulin levels is required for all patients.
- For patients with CANDLE/PRAAS, SAVI, and AGS, treatment should achieve disease control or low disease activity to prevent the progression of organ damage; for patients with SAVI and CANDLE/PRAAS, disease control should be maintained with the lowest possible dose of glucocorticoids.
- For improving CANDLE/PRAAS, SAVI, and AGS symptoms, Janus kinase (JAK) inhibitors are beneficial.
- For patients with CANDLE/PRAAS, SAVI, and AGS who are receiving treatment with Janus kinase (JAK) inhibitors, screening for treatment-related side effects is important; current recommendations include monitoring BK viral loads in urine and blood to prevent viral organ injury, such as nephropathy.
- For improving symptoms in CANDLE/PRAAS and SAVI, glucocorticoid therapy is beneficial; chronic glucocorticoid therapy does not improve the neurologic features of AGS though acute courses of glucocorticoids may be beneficial in treating noncentral nervous system inflammatory conditions.
Long-Term Monitoring and Management
- For optimal care of patients with CANDLE/ PRAAS, SAVI, and AGS, a multidisciplinary management team is required based on patient-specific disease manifestations.
- Regular monitoring of disease activity and disease burden should be performed based on disease activity and severity.
- Assessment of disease-specific symptoms using validated patient-reported outcomes and quality of life assessments by recording missing school or workdays can be used to monitor symptom control.
- For children, disease and development should be monitored during each visit.
- There taskforce did not note any evidence suggesting that COVID-19 risks to patients with CANDLE/PRAAS, SAVI, and AGS were different from those in the healthy population. Therefore, treatment for interferonopathy should not be stopped unless a specific contraindication to ongoing treatment arises.
- Overall, routine vaccines (live and attenuated) are indicated when patients with CANDLE/PRAAS and SAVI are not receiving immunosuppressive treatments or glucocorticoids. However, this guidance should be considered on a case-by-case basis.
The authors concluded, “The aim of these points to consider is to address the unmet need to provide guidance for health care professionals involved in the care of patients with the recently characterized type I interferonopathies, CANDLE/PRAAS, SAVI, and AGS.” They also noted, “[T]hese points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.”
Cetin Gedik K, Lamot L, Romano M, et al. The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type i interferonopathies: CANDLE/PRAAS, SAVI, and AGS. Arthritis Rheumatol. Published online March 21, 2022. doi:10.1002/art.42087