Article Text

The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist
  1. Micol Romano1,
  2. Z Serap Arici2,
  3. David Piskin3,
  4. Sara Alehashemi4,
  5. Daniel Aletaha5,
  6. Karyl S Barron6,
  7. Susanne Benseler7,
  8. Roberta Berard8,
  9. Lori Broderick9,
  10. Fatma Dedeoglu10,
  11. Michelle Diebold11,
  12. Karen L Durrant12,
  13. Polly Ferguson13,
  14. Dirk Foell14,
  15. Jonathan Hausmann15,
  16. Olcay Y Jones16,
  17. Daniel L Kastner6,
  18. Helen J Lachmann17,
  19. Ronald M Laxer18,
  20. Dorelia Rivera12,
  21. Nicolino Ruperto19,
  22. Anna Simon20,
  23. Marinka Twilt7,
  24. Joost Frenkel21,
  25. Hal Hoffman22,
  26. Adriana A de Jesus23,
  27. Jasmin Beate Kuemmerle-Deschner24,
  28. Seza Ozen25,
  29. Marco Gattorno26,27,
  30. Raphaela Goldbach-Mansky28,
  31. Erkan Demirkaya29
  1. 1 Department of Pediatrics, Division of Pediatric Rheumatology, Behcet and Autoinflammatory Disease Center, Western University, London, Ontario, Canada
  2. 2 Department of Pediatric Rheumatology, Sanliurfa Mehmet Akif Inan Training and Research Hospital, Sanliurfa, Sanliurfa, Turkey
  3. 3 Lawson Health Research Institute and Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
  4. 4 Translational Autoinflammatory Diseases Section (TADS), Laboratory of Clinical Immunology and Microbiology (LCIM), NIAID, NIH, Bethesda, Maryland, USA
  5. 5 Division of Rheumatology, Medical University of Vienna, Wien, Austria
  6. 6 Division of Intramural Research, National Institute of Allergy and Immunology, NIH, Bethesda, Maryland, USA
  7. 7 Division of Rheumatology, Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  8. 8 Division of Pediatric Rheumatology, Department of Paediatrics, Schulich School of Medicine&Dentistry, Western University, London, Ontario, Canada
  9. 9 Division of Pediatric Allergy, Immunology, and Rheumatology, University of California and Rady Children's Hospital, San Diego, California, USA
  10. 10 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
  11. 11 Division of Pediatric Rheumatology, Department of Paediatrics, LHSC Children's Hospital, London, Ontario, Canada
  12. 12 Autoinflammatory Alliance, San Francisco, California, USA
  13. 13 Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
  14. 14 Department of Pediatric Rheumatology and Immunology, University of Muenster, Muenster, Germany
  15. 15 Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA
  16. 16 Department of Pediatrics, Walter Reed National Military Medical Center (WRNMMC), Bethesda, Maryland, USA
  17. 17 Department of Medicine, University College London, London, UK
  18. 18 Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada
  19. 19 IRCCS Istituto Giannina Gaslini, UOSID Centro Trial, Genova, Italy
  20. 20 Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
  21. 21 Department of Pediatrics, Wilhelmina Kinderziekenhuis Polikliniek Algemene Kindergeneeskunde, Utrecht, Utrecht, The Netherlands
  22. 22 Division of Pediatric Allergy, Immunology, and Rheumatology, University of California at San Diego, San Diego, California, USA
  23. 23 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  24. 24 Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tübingen, Germany
  25. 25 Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
  26. 26 UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  27. 27 Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini
  28. 28 Translational Autoinflammatory Diseases Section (TADS), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
  29. 29 Division of Paediatric Rheumatology, Department of Paediatrics, Behcet and Autoinflammatory Disease Center and Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
  1. Correspondence to Professor Erkan Demirkaya, Department of Paediatrics, University of Western Ontario, London, ON N6A 3K7, Canada; Erkan.Demirkaya{at}


Background The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes.

Objective To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management.

Methods A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care.

Results The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA.

Conclusion The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.

  • Cytokines
  • Cryopyrin-Associated Periodic Syndromes
  • Inflammation
  • Interleukin 1 Receptor Antagonist Protein

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Systemic autoinflammatory diseases (SAIDs) are a group of multisystem immunodysregulatory disorders caused primarily by the dysfunction of the innate immune system.1 Currently, SAIDs comprise a wide range of disorders with systemic and organ-specific inflammation in the absence of infections or autoimmunity.2–6 In a subset of genetically defined SAIDs, the pathogenesis is driven by increased release or signaling of the proinflammatory cytokine interleukin-1 (IL-1).2 7 8

The conditions addressed by this task force include the IL-1 mediated SAIDs (monogenic forms) that are most frequently evaluated by rheumatologists, and which have US Food and Drug Administration/European Medicines Agency (FDA/EMA) approval for IL-1 targeted therapies. Cryopyrin-associated periodic syndromes (CAPS)9 10 or NLRP3-associated autoinflammatory diseases (NLRP3-AIDs)11 are the spectrum of rare autosomal dominant autoinflammatory diseases caused by gain-of-function mutations in NLRP3, 9 12–16 ranging from familial cold autoinflammatory syndrome (FCAS; mild NLRP3-AID phenotype), Muckle-Wells syndrome (MWS; moderate NLRP3-AID phenotype) to neonatal onset multisystem inflammatory disease /chronic infantile neurological cutaneous and articular (NOMID/CINCA; severe NLRP3-AID phenotype). The other IL-1 mediated SAIDs included are, tumour necrosis factor receptor-associated periodic syndrome (TRAPS), an autosomal dominant disease caused by mutations in TNFRSF1A 17 18 encoding the tumour necrosis factor receptor type 1, and mevalonate kinase deficiency (MKD) caused by autosomal recessive loss-of-function mutations in the mevalonate kinase gene (MVK), resulting in a deficiency of mevalonate kinase enzyme.19–22 Lastly, deficiency of IL-1 receptor antagonist (DIRA) caused by biallelic deleterious loss-of-function mutations in the IL1RN gene encoding the IL-1 receptor antagonist was addressed by the task force.2 The most common IL-1 mediated autoinflammatory disease, familial Mediterranean fever, is not addressed, as EULAR-endorsed recommendations were published for this disease in 2016.23

IL-1 mediated SAIDs are caused by chronic systemic and organ-specific inflammation, leading to progressive organ damage and dysfunction.24–27 Acute disease flares can be life-threatening and contribute to the high morbidity and mortality in untreated patients.17 28 29 In this rapidly evolving group of rare diseases, there is a need to harmonise care that reflects our current knowledge of genetics, diagnosis, treatment and monitoring for all patients globally.

The natural history of untreated patients with pathogenic mutations causing CAPS,10 30 31 TRAPS,18 MKD32 and DIRA2 has been characterised in the literature and forms the basis for the guidance on monitoring disease progression and organ damage. Disease severity is dependent on the level of systemic and organ-specific inflammation. Risk factors associated with adverse outcomes include specific mutations, clinically severe phenotypes, frequent and severe inflammatory episodes and organ damage at the time of initial presentation.17 33–36 The life-changing positive impact of treatments targeting IL-1 has been documented in patients with CAPS, TRAPS, MKD and DIRA. There is also mounting evidence for the benefits of maintenance treatment to prevent the progression of organ damage, thus pointing to the importance of early diagnosis and initiating treatment early in life.33 34 37 38

An early and accurate genetic diagnosis allows for referral for genetic counselling, directs appropriate screening for potential complications, informs prognosis and improves our ability to define individual treatment goals and to tailor treatment decisions.33–37 Most patients with CAPS, TRAPS, MKD and DIRA are managed by paediatricians and paediatric specialists, and with effective treatments, adolescents and young adults are now reaching adulthood with expectations of a normal life span. They now face new challenges with transitioning care to adult rheumatologists comfortable with the management of these patients. Furthermore, pregnancy and other subspecialty needs (ie, surgery) are often not addressed adequately in the context of IL-1 mediated 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.

The above considerations led to the convening of a task force that was charged with developing standardised guidance for diagnosis, treatment and long-term monitoring of patients with CAPS, TRAPS, MKD and DIRA that target paediatricians, internists and subspecialists (particularly rheumatologists). The statements were developed as a resource for physicians to facilitate management, for policy makers who have a role in authorising patients’ access to diagnostic tools and treatment options, as well as for patients and caregivers to provide knowledge and allow for setting appropriate expectations. Finally, these guidelines aim to standardise the level of care with a goal of improving quality of life and disease outcomes worldwide.


With approval granted by the EULAR and the American College of Rheumatology (ACR) executive committees, the IL-1 mediated autoinflammatory diseases task force was convened to develop guidance on diagnosis, treatment and monitoring of four different IL-1 mediated SAIDs, including CAPS, TRAPS, MKD and DIRA. The task force was led by two conveners (ED and RG-M) and consisted of 19 paediatric and four adult rheumatologists, who were selected based on their expertise in the treatment and care of these patients. In addition, the task force included two healthcare professionals, three fellows, one patient representative from the Autoinflammatory Alliance and two methodologists. The 31 task force members were from 17 centres in seven different countries from across Europe, the United States and Canada. EULAR39 and the (ACR) standardised operating procedures were followed during the project (see online supplemental methods). The first meeting was convened in August 2019 in Bethesda, Maryland, USA, to define the focus of the task force, which identified four IL-1 mediated SAIDs to be included in this points to consider project. In line with the EULAR standardised operating procedures, the target audience was defined as healthcare professionals, policy makers, health insurance companies, patients and their caregivers. The group worked to determine the PICO (Population, Intervention, Comparison, Outcome) questions related to diagnosis, monitoring and management of these diseases. Using the PICO questions defined during the first meeting, a systematic literature review was performed by three research fellows (MR, ZSA, DP) with support from a librarian (DH) and the senior methodologists (ED, DA) to identify relevant publications using PubMed, Embase and the Cochrane Library through August 2020.

Before the first consensus meeting, two surveys that included statements or items pertaining to diagnosis, treatment and long-term monitoring were distributed to all task force members via RedCap. The task force members were asked to indicate their agreement with each statement or item with yes or no. A free-text option was provided to capture every member’s comments or suggestions for modification; and a request was made to add items to be addressed, edited or altered. Consensus was achieved using the Delphi technique. Draft statements with 80% or higher agreement were retained. Comments and suggestions provided in the questionnaires were used to modify the draft statements and to add additional items. The revised and amended statements were then sent through a second round of questionnaires. After the two rounds, the draft statements were revised to incorporate all suggestions and reviewed by the steering committee members. These draft statements were then included for discussion at the consensus meetings.

Owing to the COVID-19 pandemic, three consensus meetings were held online between September and November 2020. At the consensus meetings, statements that did not reach a greater than 80% consensus were discussed in a round robin discussion, reworded, amended and refined and were then voted on again. If a statement did not achieve ≥80% agreement after discussion, refinement and revoting, the statement was excluded. All statements that achieved ≥80% agreement were considered a final statement for inclusion in the final version of the points to consider. For each statement, the Oxford levels of evidence (LoE) and the grade of the recommendation (GoR) were assigned based on the systematic literature review by the fellows under the supervision of the methodologist.40 The final statements annotated with the LoE and GoR were sent through an online survey to all task force members again; and each member was asked to provide their level of agreement (LoA) on a scale of 0 (absolutely disagree) to 10 (absolutely agree). The mean and SD of the LoA with each statement were calculated. The manuscript was reviewed and approved by all task force members and the EULAR/ACR executive committees before submission to the journal.


Systematic literature review

The details for the literature search strategy and summary of results are described in the online supplemental material. Briefly, randomised controlled trials (RCTs), cohort studies, cross-sectional studies, case–control studies and case reports including more than three cases were included. Review articles, conference abstracts, book chapters, single case reports and articles written in a language other than English were excluded. For CAPS, of 2041 references identified, 72 studies were selected for inclusion. For TRAPS, of 1161 references identified, 47 studies were selected for inclusion. For MKD, of 1806 references identified, 51 studies were selected for inclusion. For DIRA, of 557 references identified, two studies were selected for inclusion. In total, from the 5565 references identified, 172 were included. After a group discussion that included the results of the systematic literature review, the consensus process was initiated.

Overarching principles

During the consensus meeting, seven overarching principles and 55 candidate statements were discussed and voted on. The task force decided to merge two overarching principles. Owing to lack of agreement, the task force eliminated 26 statements (12 referring to CAPS, 6 to TRAPS, 2 to MKD and 6 to DIRA). The task force agreed on a final set of five overarching principles (table 1) and 33 points to consider (tables 2–4).

Table 1

Overarching principles for the diagnosis, treatment and monitoring of CAPS, TRAPS, MKD and DIRA

Table 2

Points to consider for the diagnosis of CAPS, TRAPS, MKD and DIRA

Table 3

Points to consider for the treatment of CAPS, TRAPS, MKD and DIRA

Table 4

Points to consider for the monitoring of CAPS, TRAPS, MKD and DIRA

Table 5

Disease specific monitoring of CAPS, TRAPS, MKD and DIRA*

CAPS, TRAPS, MKD and DIRA typically present with complex clinical features and phenotypes in the neonatal or early childhood period; these include features of systemic and organ-specific inflammation2 17 28 29 36 presenting with early onset of fever, abdominal pain, rash, musculoskeletal symptoms, neurologic manifestations and elevated biomarkers of systemic inflammation.17 35 41–45 The specific biomarkers of systemic inflammation included in this document are referred to as acute phase reactants and include: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum amyloid A protein (SAA)46 and S100 proteins, which in most patients correlate with disease activity.41 47 48 The first goal (overarching principle A) is to recognise patients with potential monogenic IL-1 mediated SAIDs and to establish a multidisciplinary team for diagnosis, treatment and long-term management. Delay in treatment initiation can result in rapidly progressive organ damage,24–27 morbidity and increased mortality.34 49 50 Overarching principle B outlines the need to initiate a clinical workup that assesses the extent of the inflammatory organ involvement and screens for treatment-related comorbidities, a process that often requires a multidisciplinary team of subspecialists.24 25 47 The third goal (overarching principle C) highlights the need for an accurate genetic diagnosis, which in many countries may be required to access the IL-1 blocking biological agents that prevent life-threatening complications,47 51 52 and facilitate access to supportive care.24 25 47

The goals of treatment (overarching principle D) are to rapidly control disease activity by suppressing systemic and organ inflammation. IL-1 blockade has been FDA53–55 and EMA56 57 approved for CAPS, TRAPS, MKD and DIRA.49 58 Rapid disease control using these agents is critical in preventing the development of irreversible early inflammation-related organ damage, and minimising side effects from the use of other drugs that are ineffective and/or carry substantial toxicities.

There are currently no cures for these lifelong diseases. Overarching principle E outlines long-term monitoring goals that focus on evaluating disease activity, assessing and monitoring signs and symptoms of disease-specific organ inflammation, growth and development, and adjusting therapeutic doses according to growth, or control of symptoms and inflammation. Monitoring should be developmentally appropriate, include adjustments for adolescence,59 be tailored to accommodate cognitive (ie, learning and behavioural disorders) and physical disabilities (ie, bone deformities, hearing and vision loss)29 60 and prepare patients for transitioning to adult specialists. This transition can be challenging and lengthy and may put patients at risk of unfavourable outcomes. Therefore, the task force emphasised the need to include goals that foster self-management skills and medical decision-making (ie, including reproductive health) throughout the life of the patient.59 61

Focus on the diagnosis of IL-1 mediated SAIDs, including recognising clinical diagnostic and damage-related features of the respective diseases, genetic testing, disease-specific clinical and laboratory workup and initiation of early treatment: points to consider 1–14

Disease-specific clinical features of untreated CAPS, TRAPS, MKD and DIRA and the resulting organ damage have been characterised in clinical descriptions of patient cohorts before anti-IL-1 treatment was used.2 17 36 62 These signs and symptoms form the basis of evidence-based classification criteria for CAPS,48 TRAPS and MKD41 and are listed in table 2—recommendations 8 (CAPS), 10 (TRAPS), 11 (MKD) and 13 (DIRA), respectively. In combination with the molecular analyses, these features help physicians to recognise disease-specific characteristics and differentiate these conditions from clinically complex diseases that can present with overlapping inflammatory manifestations, including systemic juvenile idiopathic arthritis, adult-onset Still’s disease, neoplasms, infections and autoimmune disorders.63 64

Genetic workup: points to consider 2–6

Suggestive clinical features should trigger a genetic investigation, as genetic testing is a crucial component of an accurate diagnosis of CAPS, TRAPS, MKD and DIRA.41 65 Next-generation sequencing (NGS) platforms are now widely used and are replacing the Sanger sequencing “gene by gene” approach.51 52 66–68 NGS is therefore generally recommended.52 63 66 69 70 In certain conditions, Sanger sequencing of a single gene may be cost-effective, such as in patients with a known familial disease or classic disease features. In some countries, Sanger sequencing may be the only modality of genetic testing available.52 71–73

CAPS and TRAPS are autosomal dominant diseases caused by gain-of-function mutations in NLRP3 and TNFRSF1A 18 genes, respectively, and can be familial63 74 or caused by de novo mutations. In CAPS, de novo mutations are most frequently found in patients with severe phenotypes.7 Somatic mutations in these patients may be undetected by standard coverage of NGS and may require deep sequencing, though this analysis may not be available to all providers.51 74–77 In contrast, MKD and DIRA are caused by recessive loss-of-function mutations in MVK 78 79 and IL1RN 2 genes, respectively. In patients with clinical symptoms suggestive of MKD or DIRA, Sanger sequencing, whole exome sequencing and whole genome sequencing may not detect large deletions.2 If appropriate, chromosomal microarray analysis by comparative genomic hybridization array or by single nucleotide polymorphism array should be performed.2 For the genetic diagnosis of DIRA, PCR and sequencing using specific deletion breakpoint primers to screen reported IL1RN large deletions may aid the genetic evaluation in selected ethnic backgrounds (ie, Puerto Rico, Brazil, India).2 80 81 If a genetic diagnosis cannot be made following routine genetic workup, patients should be referred to a research centre of excellence with expertise in the molecular diagnosis of SAIDs.

One significant challenge is the interpretation of genetic results that have not been classified or validated as pathogenic mutations, including variants of uncertain significance, that is, variants that have not been described previously or studied functionally, or likely benign variants that may be present in the general population at a relatively high frequency and could be low-penetrance mutations with inconsistent clinical significance. Patients with these genetic findings may display distinct clinical and biologic phenotypes, and can include IL-1β and non-IL-1β-mediated inflammatory pathway activation, which may have implications for their management, further emphasising the need for specialty care.

Clinical workup: points to consider 7–14

In IL-1-mediated SAIDs patients, systemic inflammation typically accompanies clinical signs and symptoms, which can be episodic/periodic or chronic/persisting.36 82 MKD, TRAPS and the mildest form of CAPS, known as FCAS, may in rare cases, present with intermittent episodes (flares of symptoms) separated by periods of perceived improvement.17 41 65 83–85 However, most patients except for patients with milder disease (ie, some patients with FCAS and TRAPS) have evidence of chronic subclinical inflammation between episodes. Patients with more severe forms of CAPS such as MWS or NOMID/CINCA, or those with severe MKD with almost complete absence of the enzymatic activity of mevalonate kinase, or with DIRA, all present with chronic systemic inflammation that rarely spontaneously remits. In general, markers of systemic inflammation correlate with disease symptoms and risk of organ damage.75 86–88 Historically, CRP, ESR and, if available, SAA46 have been used to assess systemic inflammation. Additionally, S100 proteins89 have been used by some investigators as sensitive markers in research settings. How to best use S100 protein markers for patient care, given increased clinical availability, remains under investigation. The diagnostic workup across all four diseases is broadly similar and can be synchronised. Typical signs and symptoms of active disease (ie, hepatosplenomegaly), organ inflammation and damage should prompt a diagnostic workup (tables 2 and 5).

The clinical presentation of the CAPS disease spectrum includes systemic inflammation and an urticaria-like rash with histologic features of a neutrophilic dermatosis involving eccrine glands, which is present in almost all patients.24 43 75 86 88 90–92 Cold-induced flares often last less than 24 hours and are most often observed in patients at the mild end of the disease spectrum (FCAS).14 42 A negative localised cold challenge (ice cube test) differentiates FCAS from patients with cold urticaria.42 Progressive sensorineural hearing loss is often seen in moderately (MWS) and severely (NOMID/CINCA) affected patients,24 29 60 75 while neurologic findings (chronic aseptic meningitis, increased intracranial pressure, cognitive impairment)87 93 and skeletal abnormalities (distal femur overgrowth, frontal bossing) are typically seen in NOMID/CINCA.75 86 Ophthalmologic involvement can vary and most typically includes conjunctivitis, but keratitis, episcleritis and anterior and/or posterior uveitis have also been described. Increased intracranial pressure may cause papilloedema and subsequent optic disc atrophy. Therefore, a slit lamp examination and retinal evaluation should be performed in all patients with CAPS at baseline.25 43 88 In patients with suspected neurologic involvement, brain imaging28 94 95 and lumbar puncture may be needed to evaluate for elevated intracranial pressure or aseptic meningitis, while a specialised brain MRI scan can detect cochlear enhancement, cerebral atrophy and ventriculomegaly.87 96 Epiphysial bony overgrowth, commonly found around the knees, may be assessed by bone MRI or radiograph.25 26 92

TRAPS is characterised by episodes of fever lasting more than 7 days, abdominal pain that can mimic an acute abdomen, variable chest pain and, rarely, testicular pain.17 41 70 Especially in adults, a subchronic disease course might be observed, with fatigue, diffuse limb pain and persistent elevation of acute phase reactants.17 Periorbital oedema and myalgias might herald the onset of an attack. Typical findings of a flare include painful, migratory skin plaques with hazy edges that are erythematous, swollen and warm3 and predominantly affect the limbs. Suspected fasciitis may be imaged by MRI.97 There is now consensus that population frequent variants of uncertain significance, such as R121Q (previously referred to as R92Q) should not be considered as pathogenic.17 45 98–103 Therefore, the interpretation of these variants should occur in the context of the inflammatory phenotype by an expert in the field if available.

Patients with MKD usually present in the first year of life5 104 with recurrent episodes of fever lasting 4 to 6 days104, gastrointestinal symptoms (severe abdominal pain with vomiting and diarrhoea), cervical lymphadenopathy, aphthous stomatitis and/or skin rash (urticarial or maculopapular).32 64 84 105–110 The most severe form of MKD namely mevalonic aciduria, presents with severe cognitive impairment, and patients can present with hyperinflammation leading to macrophage activation syndrome36 along with the clinical features described above.84 110 111 Febrile attacks triggered by vaccinations suggest a diagnosis of MKD.36 85 112–115

High levels of circulating immunoglobulin D that were described formerly and led to the name hyper IgD syndrome have low diagnostic sensitivity and specificity.82 105 116 117 However, elevated urine mevalonate levels during disease flares, due to reduced MVK enzyme activity and accumulation of mevalonic acid, are more specific for MKD118 119 and can be used to aid in diagnosis.

Patients with DIRA present with early-onset pustular rashes that can be triggered by mechanical stress (pathergy), with sterile osteomyelitis, and nail changes (onychomadesis).2 120 Although the inflammatory markers are typically highly elevated, fever may be absent. Vertebral involvement can include odontoid osteomyelitis, resulting in destruction and neck instability, vertebral block formation and gibbus-like spinal changes that need to be screened for by MRI or CT.2 120 In contrast to patients with CAPS, TRAPS and MKD, patients with DIRA rarely present with flare-associated fever. In patients with presumed DIRA, a diagnostic workup includes assessing peripheral neutrophilia and elevated inflammatory markers, determining bone involvement (ie, X-ray or bone MRI) and genetic testing.2 120 The differential diagnosis for DIRA includes chronic recurrent multifocal osteomyelitis (CRMO),121 122 synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO)123 syndrome and pustular psoriasis.124 Genetic testing for monogenic defects with overlapping clinical features should include LPIN2, FGR, FBLIM1 for CRMO,125 126 CARD14 for CARD14-mediated psoriasis (CAMPS),127 128 IL36RN for deficiency of IL-36 receptor antagonist,127 128 AP1S3 128 for other pustular psoriasis and MEFV for pyrin-associated autoinflammation with neutrophilic dermatosis.129

Focus on the treatment of IL-1 mediated diseases: points to consider 15–24

Disease management involves a shared decision-making approach and a combination of pharmacologic and non-pharmacologic interventions. The current standard of care for patients with CAPS, TRAPS, MKD and DIRA is subcutaneous IL-1 targeted biologic therapy when available.28 49 130–132 While the specific pharmacologic mechanisms, pharmacokinetics, disease indications and costs differ for each of the three available drugs, anakinra (Kineret), rilonacept (Arcalyst) and canakinumab (Ilaris), each blocks the effect of IL-1β on the IL-1 receptor and downstream signaling, resulting in improved symptom control, as well as reduced systemic and tissue/organ inflammation. Anakinra is a recombinant IL-1 receptor antagonist with a short half-life that binds to the IL-1 receptor and blocks both IL-1α and IL-1β signaling.95 133–135 Rilonacept is a recombinant fusion protein with a relatively longer half-life that binds to both IL-1α and IL-1β.130 136 137 Canakinumab is a human monoclonal antibody to IL-1β with a long half-life.49 131 138 139 As expected for treatment of rare disorders, case reports and small patient series have demonstrated the success of IL-1 blockade across the spectrum of disease. The highest level of evidence, however, stems from pivotal studies including randomised studies in CAPS137 140 141 (MWS and FCAS), in TRAPS and MKD,142 which have confirmed that rilonacept was effective in CAPS,137 and that canakinumab was efficacious in controlling and preventing flares in patients with CAPS140 and with MKD and TRAPS,142 respectively (table 3). The availability of these drugs varies significantly in different countries.

Aims of treatment are early control of disease activity, prevention of disease and treatment-related damage and optimal health-related quality of life.58 142 The ultimate goal of a treat-to-target approach is complete remission.37 In the absence of a consensus definition of remission or minimal disease activity for these diseases, remission has been defined for clinical studies and clinical monitoring as an absence of clinical symptoms and normal inflammatory markers. The instruments used to measure disease activity include daily symptom diary scores28 95 or Autoinflammatory Diseases Activity Index (AIDAI),143 and a physician global assessment (PGA) and patient–parent global assessment (PPGA). The most commonly used inflammatory marker is CRP (also known as high sensitivity or cardio CRP in some countries), with levels of less than 5 mg/L or 10 mg/L indicating adequate control of inflammation.95 120 142 Minimal disease activity has been suggested as an alternative target if remission cannot be achieved. Definitions of remission and minimal disease activity and their validations are on the research agenda for autoinflammatory diseases.142 143

Treat-to-target strategies aiming for low disease activity assessed by clinical symptoms and normalisation of serum markers of systemic inflammation are effective and used in the treatment of patients with IL-1 mediated SAIDs to find individualised and optimal dosing regimens for each patient and disease.37 IL-1 blocking therapies control inflammation in the absence of glucocorticoids.134 142 144 Treatment can delay or prevent development or progression of organ damage in patients with moderate or even severe disease activity.60 95 145 Management by a multidisciplinary team that includes subspecialists results in better disease control in patients with CAPS.37 To achieve and maintain optimal disease control, IL-1 targeted therapies need to be administered continuously in most patients, and the dose and/or frequency of administration should be adjusted for control of disease activity, normalisation of markers of systemic inflammation and for weight gain and appropriate development in the growing patient.

Medication dose adjustments for weight gain and growth and higher mg/kg doses to optimise treatment responses should be individualised for each patient.37 95 Some patients with CAPS may require more frequent or higher doses of these medicines than that approved by FDA or EMA (table 6), such as dosing of canakinumab more often than the approved frequency of every 8 weeks, if patients have not achieved remission.34 37 141 On-demand regimens may be used in selected patients with MKD, TRAPS and FCAS who have very mild disease and/or episodic disease manifestations and who maintain normal inflammatory markers in between episodes.146 147 Patients with severe disease manifestations, such as those with NOMID/CINCA, may require frequent adjustments and higher doses than patients with less severe diseases (table 6).37 95 141 There is a potential clinical advantage of using anakinra for patients with severe CAPS, especially for those with neurologic disease.148 149 Patients with NLRP3 variants that have not been validated as pathogenic (ie, V198M, R488K, Q703K) may respond to IL-1 blockade, and specific recommendations have previously been published.150 151 To improve symptom control, non-steroidal anti-inflammatory drugs may be efficacious when used together with IL-1 targeted therapy. Ongoing efficacy and a beneficial long-term safety profile have been demonstrated for the long-term use of all three IL-1 blockers (anakinra, rilonacept and canakinumab) in CAPS, although direct comparative studies are lacking.44 49 130 134 136–139 152–157

Table 6

Treatments based on FDA, EMA* or expert panel consensus

A large body of evidence suggests that IL-1 inhibitors should be considered as the preferred treatment for TRAPS.100 Although anakinra was the first IL-1 blocker successfully used in patients with TRAPS in small series and observational registries,100 131 145 158 the long-acting anti-IL-1β monoclonal antibody, canakinumab is currently the only IL-1 blocker that the FDA and EMA have approved for the treatment of patients with TRAPS54 57(table 6). Individual patients with TRAPS may respond to treatment with short-term glucocorticoids or etanercept; however, responses often wane and patients should be monitored for increased disease activity.45 100 159 Patients with TNFRSF1A variants that are not classified as pathogenic (ie, D41E, I57S, P75L, R121Q, N145S (previously referred to as: D12E, I28E, P46L, R92Q, N116S, respectively)) do not have TRAPS; however, they may still have signs of clinical autoinflammation requiring treatment with colchicine or biologic therapies.100

Anakinra and canakinumab have been used in children with MKD with success, but only canakinumab has been evaluated in a randomised study and approved by the FDA and EMA.54 57 142 146 Some patients with MKD with milder disease phenotypes, characterised by occasional attacks separated by symptom-free periods, can be managed with on-demand treatment.146 Glucocorticoids may also be beneficial during flares, but their extended use is limited by adverse effects.146 The panel suggested the use of IL-1 blockade, but noted that treatment could be switched to anti-tumour necrosis factor (anti-TNF) agents, if IL-1 blockade is not available or is ineffective.146

Anakinra and rilonacept both block IL-1α and IL-1β and should be used for patients with DIRA.2 80 81 120 The FDA recently approved both anakinra and rilonacept for treatment of DIRA.53 55 Blocking IL-1α may be necessary to completely block bone inflammation, as observed in a patient who developed osteitis during treatment with canakinumab, which only blocks IL-1β.121 While anakinra has been used initially in all patients with DIRA to achieve disease control, rilonacept can be used to maintain remission.120 Doses of IL-1 blocking therapies required for disease control in patients with DIRA have typically been lower than those required in patients with severe CAPS-NOMID/CINCA. Long-term sustained and complete remission is an achievable goal of treatment for patients with DIRA.

For all IL-1 mediated SAIDs, individualised dose adjustments of IL-1 blocking agents may be necessary in young patients or in those with severe disease. In infants and preschool-aged children, twice daily dosing of anakinra may be required for control of disease activity. This is probably due to the higher liver blood flow, which increases the hepatic clearance of drugs owing to the larger ratio of liver to total body mass in children than in adults.160 Some older patients with severe and difficult to control disease, including central nervous system disease, may also achieve improved disease control with twice daily dosing. While canakinumab is approved by the EMA for CAPS-NOMID/CINCA at a frequency of every 8 weeks, supporting evidence suggests that this may be inadequate, so the consensus of experts recommends more frequent dosing up to every 4 weeks for these severely affected patients based on clinical experience and numerous reports.34 37 141 This is consistent with dose frequency for other SAIDs, and with EMA-provided consumer medical information for patients with inadequate responses.57

Focus on monitoring of IL-1 mediated SAIDs: CAPS, TRAPS, MKD and DIRA: points to consider 25–33

Ongoing management includes adjustment of pharmacologic therapy, monitoring of disease activity, development of disease-related complications and recognition of drug toxicity. Additionally, individual focus on the needs of the growing child, adolescent, adult or even elderly should include age-appropriate and developmentally appropriate measures that foster self-management skills, encourage shared medical decision-making, address reproductive health issues, and facilitate timely and effective transition to adult medical care47 161 162 (table 4).

Appropriate management of patients with IL-1 mediated SAIDs necessitates a multidisciplinary team of local primary care givers working together with experienced physicians, rheumatologists and other specialists on a case-by-case basis that can include, but is not limited to, immunologists, ophthalmologists, otolaryngologists, nephrologists, neurologists and genetic counsellors, as well as physiotherapists, occupational therapists and psychosocial specialists.47 161 163 The management of patients, particularly those with cognitive (ie, learning and behavioural disorders) and those with physical disabilities (ie, bone deformities, hearing and vision loss),29 60 is complex. The physical, mental, psychosocial health and social functioning of entire families should be considered. Individualised support services, including, but not limited to, psychosocial support, genetic counselling, cognitive and learning support, school accommodations and occupational therapy and physiotherapy, may be needed to manage these challenges.110 161 163 164 Some adult patients may have increased difficulties due to their disease and chronic organ involvement that may require accommodations for work, or other aspects of their daily life.

Long-term monitoring requires age-appropriate dose adjustment of IL-1 blocking treatment to maintain control of systemic and organ-specific inflammatory manifestations, and of laboratory markers.49 130 134 135 139 157 Systemic inflammation should be monitored by following up inflammatory markers, which include peripheral neutrophilia,165 CRP and ESR. SAA and S100 protein may be used as inflammatory markers where available.45 131

Chronic systemic inflammation can have significant effects on growth and development, and ongoing inflammation may predispose to AA amyloidosis.27 Patients with IL-1 mediated SAIDs need continuous and developmentally appropriate care during and beyond adolescence. However, up to half of adolescent patients are not appropriately transferred to adult specialist care owing to general lack of transition readiness, inadequately robust quality indicators and insufficient understanding of the needs of adolescents. This population is therefore at particular risk of unfavourable outcomes.59 61 Relevant for this group are complications related to amyloidosis, hearing loss and vision loss. Although AA amyloidosis has become less common with the early initiation of anti-IL-1 targeted treatment, adults who have had longstanding uncontrolled disease should be closely monitored.49 100 140 The task force recommended that proteinuria should be evaluated every 6 months in all patients with IL-1 mediated SAIDs, particularly in patients with a positive family history of amyloidosis as they may have other factors, including genetic variants contributing to the development of amyloidosis (ie, SAA1 variants).

Disease-specific monitoring plans that take into account the different disease manifestations in CAPS, TRAPS, MKD and DIRA are outlined in table 4. Hearing loss, central nervous system disease, bone deformities, renal failure due to amyloidosis and visual loss are the most severe organ manifestations in patients with CAPS.62 In patients with TRAPS the disease may progress from longer-lasting episodes of fever, migratory and painful rash, to a more chronic disease course with persistent inflammation in the absence of the typical fever episodes, which may still represent an important risk factor for the development of AA amyloidosis,27 and are an indication for long-term treatment with biological disease-modifying antirheumatic drugs.131 145 Rare MKD-associated manifestations include retinitis pigmentosa and hearing loss. Therefore, ophthalmologic evaluations and audiograms should be included as clinically indicated.32 35 36 118 Secondary hemophagocytosis in the context of infections has been reported and should be considered in the situation of severe disease flares in MKD.35 36 82 For all IL-1-mediated SAIDs, appropriate monitoring aims to limit or prevent complications of inflammation and disease-associated damage through ongoing individualised treatment, while encouraging the best possible quality of life for patients and families.161

Beyond objective laboratory measurements, patient-reported outcomes and disease assessment tools can be helpful in the monitoring of disease symptoms. Patient- or physician-reported outcomes110 166 167 can include measures of health-related quality of life,47 168 169 disease activity143 (ie, Auto-inflammatory Diseases Activity Index (AIDAI) for CAPS, TRAPS and MKD),100 143 154 166 169 170 global assessment scales for physicians and patients/parents142 (PGA, PPGA) and assessment of disease-related organ damage167 (ie, Auto-inflammatory Diseases Damage Index (ADDI)) that are listed in table 5. Questions about performance at school and work place and recording missing school/work days help assess the burden of disease and guide revisions to the treatment plan.163

The safety profile for IL-1 blocking treatment has generally been favourable. However, monitoring for infection, particularly respiratory tract infections with Streptococcus pneumoniae and skin infections due to Staphylococcus, is recommended.142 Even though in some conditions, such as MKD, vaccination may lead to a disease flare, patients should be vaccinated in accordance with regional recommendations.171 This includes pneumococcal vaccines, including the polysaccharide vaccine (Pneumovax) in patients with CAPS, as benefits generally outweigh the potential risks of local and systemic reactions.49 172 Patients who are receiving, or planning to initiate, anti-IL-1 targeted therapy should receive pneumococcal vaccinations. While it is preferable to administer vaccines before starting treatment, it is also acceptable to do so during treatment.49 Preliminary data suggest that an adequate antibody response to vaccines occurs in patients receiving canakinumab.49 Whether vaccines against COVID-19 have the potential to provoke disease flares is unknown; theoretical concerns about disease flare in IL-1 mediated SAIDs caused by RNA vaccines exist. However, there are currently insufficient data to make recommendations regarding COVID-19 vaccines.

Data on IL-1 treatment in pregnancy is limited.100 162 173 In women with IL-1 mediated SAIDs who require biological treatment and are considering pregnancy, a benefit-risk discussion should be held before conception, including the risk of untreated disease to mother and fetus compared with the risk of continuing biologic agents. At present, regulatory advice and clinical case series reports support the use of anakinra rather than any other anti-IL-1 agent in pregnancy.100


In recent years, we have learnt more about the phenotypic breadth and pathogenesis of IL-1 mediated SAIDs, which has led to a more efficient diagnosis and better treatment and monitoring of these diseases. An improved understanding of the pathogenesis and presentation of patients with IL-1 mediated SAIDs, along with the development of effective treatments, has dramatically improved our ability to diagnose and treat patients. As formalised training in the diagnosis and management of IL-1 mediated SAIDs is variable, many physicians, including rheumatologists, lack the knowledge to optimally manage these patients. The task force aims to raise awareness and assist both specialists and primary healthcare providers in managing patients with IL-1 mediated SAIDs. The panel has also highlighted the distinguishing clinical features of CAPS, TRAPS, MKD and DIRA in the suggested recommendations. These points for consideration attempt to address the unmet needs for guidance based on a EULAR and ACR consensus process for diagnosing, managing and treating CAPS, TRAPS, MKD and DIRA.

The task force included specialists with broad expertise in managing patients with IL-1 mediated autoinflammatory diseases, representing different countries, disease interests and practice environments. 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. Multicentre collaborative efforts, prospective registries and randomised 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 (box 1).

Box 1

Research agenda

  • To create transition clinics for patients with these rare disorders and optimise treatment during this vulnerable period

  • To evaluate best treatment options during pregnancy and their effect on the fetus and newborn

  • To establish biobanks for biomarker studies to validate the markers that best correlate with disease activity and severity

  • To evaluate the effect of vaccination in triggering or exacerbating disease activity in patients with interleukin 1 (IL-1) mediated systemic autoinflammatory diseases while receiving or not receiving treatment with biologic disease-modifying antirheumatic drugs and/or glucocorticoids

  • To identify novel therapeutic targets and treatments

  • To establish multicentre collaborative efforts to address:

    • Development of prospectively enrolling registries

    • Better characterisation of phenotype-genotype correlations

    • Pathophysiology of organ damage in IL-1 mediated disorders

    • Validation of remission criteria for each disease, including patient-reported outcome measures

    • Development of minimal disease activity criteria, response criteria

    • Understanding of additional factors (epigenetics, environment) defining the disease course

  • Continuation of defining long-term outcomes, assessing long-term safety of biological agents in IL-1 mediated disorders, updating and refining disease-specific outcome instruments for measuring disease activity and severity

Ethics statements

Patient consent for publication

Ethics approval

Not applicable.


The task force gratefully thanks the librarian Darren Hamilton (London Health Sciences Centre, London, Ontario, Canada) for his contribution to the systematic literature search, Brian Feldman, Hayyah Clairman and Natasha Naraidoo for their support in conducting the Delphi process using questionnaires on the Redcap platform and EULAR, and EULAR and the American College of Rheumatology for financial and logistical support. This project is part of a series of "points to consider” consensus efforts to standardise the diagnosis and care of patients with the three major groups of known autoinflammatory diseases including 1. The IL-1 mediated diseases CAPS, TRAPS, MKD and DIRA; 2. The autoinflammatory interferonopathies chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), STING-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutieres syndrome (AGS) and 3. The early diagnosis and management of inflammatory conditions with the potential progression to hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). This research was supported in part by the intramural research programme of the NIH institutes, NIAID, NHGRI and NIAMS. We would like to acknowledge, and are grateful for, the generous and invaluable financial and organisational support from the Autoinflammatory Alliance and the systemic JIA foundation. The Autoinflammatory Alliance substantially contributed to an international meeting and workgroup organisation in August 2019 that developed the outline of the points to consider project. The funds for this project came largely from patient fundraisers, online fundraising and the work of countless volunteers who made this project possible.


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  • This article is published simultaneously in Arthritis & Rheumatology.

  • Handling editor Désirée van der Heijde

  • Twitter @hausmannmd, @drsezaozen

  • MR, ZSA and DP contributed equally.

  • Correction notice This article has been corrected since it published Online First. A new paragraph was added to disclose Dr Kuemmerle-Deschner’s work as a member of ERN-RITA.

  • Contributors All authors contributed to the formulation of the points to consider. In detail: the steering committee of the task force (ED, RG-M, MG, JBK-D, HH, SO, JF, AAd-J) defined the research questions for the systematic literature review (SLR). The SLR was conducted by MR, ZSA, DP with support from a librarian (DH) under supervision of a senior methodologist (ED). MR, ZSA, DP extracted the data. ED, RG-M, MG, JBK-D, HH, SO, JF and AAd-J synthesised the results from SLR and the Delphi questionnaires and generated draft statements. The manuscript was drafted by MR, ZSA and DP and revised in detail by the steering group members and received a final review by the convenors. DA oversaw the proceedings and provided advice of this points to consider project as EULAR methodologist. All other authors participated in the task force meetings, in two pre-meeting Delphi questionnaires, and suggested and agreed upon the research questions. All members read the final statements prior to the drafting of the manuscript, discussed results and made contributions to the text. All authors approved the final version of the manuscript.

  • Funding This work was funded by EULAR/American College of Rheumatology.

  • Competing interests DA: received grants from AbbVie, Amgen, Lilly, Novartis, Roche, Sooi and Sanofi; received consulting fees from Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz; received lecture fees from Lilly, Merck, Pfizer, Roche and Sandoz. RB: received consultation fees from Sandoz and Roche. LB: received grants from Novartis and Regeneron FD: received consulting fees from Novartis. KLD: is the president of the Autoinflammatory Alliance. PF: received grants from NIH, CARRA, Inc; consulting fees from Novartis. DF: received grants from Novartis and Sobi; received consultation fees from Boehringer Ingelheim, Chugai-Roche, Merck, Novartis and Sobi; received lecture fees from Novartis, Peer Voice and Sobi. JH: received grants from CARRA and Sobi; consultation fees from Novartis, Biogen and Pfizer. RML: received consultation fees from Novartis and he is participating on a Data Safety Monitoring/advisory Board of Sobi, Novartis, Sanofi. NR: received consulting fees from Ablynx, Amgen, AstraZeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squib, Cambridge Healthcare Research, Celgene, Domain Therapeutic, Eli Lilly, EMD Serono, GSK, Idorsia, Janssen, Novartis, Sobi, Pfizer and UCB; received lecture fees from Eli Lilly, GSK, Pfizer, Sobi and UCB; he is member of advisory boards of Pfizer and Eli Lilly. HH: received grants from Bristol Meyer Squib, Jecure, Takeda and Zomagen; received consulting fees from Novartis, Regeneron, Sobi and Aclaris, received advisory board fees from Novartis and IFM. JBK-D: received grants from Novartis and Sobi; received consulting fees from Novartis; received payment for lectures from Novartis and Sobi; received advisory board fees from Novartis. SO: lectures fees from Novartis and Sobi; meeting support from Sobi, AbbVie and Pfizer; advisory board payment from Novartis. MG: received grants from Novartis; received consultation and lecture fees from Novartis and Sobi. RG-M: received study support under government CRADAs from Eli Lilly, IFM and Sobi. ED: received grants from Sobi.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Author note Dr Kuemmerle-Deschner’s work was done in cooperation with ERN-RITA.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.