Tool Developed to Assess Autoinflammatory Disease Burden

A damage index to measure morbidity caused by the 4 most common monogenic autoinflammatory diseases has been developed by a consortium working under the auspices of the European Union's ERA-NET PRIOMEDCHILD.

A validated instrument to measure morbidity caused by the 4 most common monogenic autoinflammatory diseases has been developed thanks to a consortium working under the auspices of the European Union’s European Research Area Network—Priority Medicines for Children (ERA-NET PRIOMEDCHILD). The initiative is part of PRIOMEDCHILD’S New Drugs for Rare Diseases: Cost-Effectiveness Modelling in Cryopyrin-Associated Periodic Syndromes (RaDiCEA) project.

The tool, an autoinflammatory disease damage index (ADDI), is the outcome of consensus building between medical specialists and patients and their caregivers. The index aids in the assessment of multi-organ damage and prognosis in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS). The tool also will be crucial to clinical outcomes studies of monogenic autoinflammatory diseases.

The study authors pointed out that, although a severity index exists for FMF and other rheumatic diseases — such as systemic lupus erythematosus and juvenile idiopathic arthritis, among others — they fall short of covering the disease spectrum known to hereditary autoinflammatory syndromes. Also, whereas targeted therapy is available for patients with certain forms of monogenic autoinflammatory disease, patients with CAPS, who can show signs of signs of neurological, visual, or auditory damage despite early diagnosis; patients with late diagnoses; and those for whom pharmacotherapy is unaffordable or unavailable are particularly vulnerable to progressive morbidity and disability. An instrument that can quantify long-term disease burden, therefore, can act as a powerful leveraging tool for expanding access to care.

The ADDI was developed by polling the top 40 enrollers of patients in the Eurofever Registry, a European research database for patients with autoinflammatory diseases, and 9 invited experts from the Americas. Participants were polled, in multiple rounds via online surveys (ie, via the Delphi method) through which damage items and definitions were selected. Twenty-two patients and their parents also rated damage items and suggested new items for the survey. Items and definitions were formally weighted in a scoring system that utilized decision-making software following a face-to-face consensus meeting.

A literature search to better define damage items was conducted prior to polling. The polling then determined which items would be included in the index. Specifically, if an item was endorsed by 80% or more of the experts, then it was included in the ADDI. Items given a 50% to 80% endorsement were revisited in the next polling round. The ADDI was then established in a consensus meeting of 30 experts and a patient representative. A scoring system was subsequently devised with software (1000minds) that uses a patented decision-making system going by the acronym PAPRIKA (Potentially All Pairwise RanKings of all possible Alternatives).

The result, which is currently considered preliminary, contains 18 items within 8 organ-system categories: reproductive, renal/amyloidosis, developmental, serosal, neurological, ears, ocular, and musculoskeletal. It can be quickly administered — reportedly taking only 5 minutes.

“The ADDI will make it possible to analyse outcomes in patient groups and compare the results of different studies, but also to systematically measure damage in a single patient,” the authors wrote. “By developing the ADDI, we aim to have a more structural follow-up of damage associated with monogenic autoimmune diseases,” said Neinke ter Haar, MD, from University Medical Centre in Utrecht, the Netherlands. 

The study’s lead investigator told Rheumatology Advisor that “This is a crucial step for patient care, as damage will have a severe and life-long impact on their daily activities.” The team intends to validate the ADDI using patient cases of CAPS, FMF, MKD, and TRAPS and longitudinal cohorts. 

Summary & Clinical Applicability

The ADDI will provide a structure to follow damage associated with monogenic autoimmune diseases, which is crucial for development of patient care strategies.


  • Strengths of this phase of the ADDI initiative include the large number of participating experts, inclusion of patient input, and methodology
  • Among the limitations were an under-representation of patients with FMF and the overall number of patient participants that was not as voluminous as the research team had hoped, possibly due to the fact that enrollment was only extended to English-speakers. 

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  1. ter Haar NM, Annink KV, Al-Mayouf SM, et al. Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis. 2016 Nov 3. doi: 10.1136/annrheumdis-2016-210092. [Epub ahead of print]

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