Comparison Chart

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Acronym Name SAID group Gene Inheritance Ethnicity Frequency Timing of symptoms Age of onset Skin cutaneous Neurologic Auditory Ophthalamic Cardiopulmonary Abdominal Lymphatic Joints bones muscles cartilage Vasculitis Amyloidosis Abnormal labs
NLRP12-associated Autoinflammatory Disease (NLRP12-AID), NLRP12-Associated Periodic Fever Syndrome – aka Familial Cold Autoinflammatory Syndrome 2 (FCAS2), or Guadeloupe Periodic Fever NLRP12-associated Autoinflammatory Disease, (Monarch-1) NLRP12 Autosomal dominant. Spontaneous mutations, some familial groups. [29] [30] Unknown. Cases in Guadeloupe, US, Martinique, France, Italy, and Armenia. [38] [39] [75] Unknown, but rare 1-3, to up to 7-15 days of fevers 39–40°C, rash and pain. Onset after exposure to cold or cooling temperatures. [38] [39] Neonatal/early infancy. Rash, fevers, symptoms may be present at birth. [38] [39] Present during flares: Cold-induced urticaria-like or malar rash noted in some patients. [39] Some with apthous ulcers. [38] [39] Ice cube test is negative. Fevers 39–40°C myalgia, headaches with flares. Sensorineural hearing loss. Other neurological symptoms are not noted. [31] Many have increased sensorineural hearing loss. [38] [39] Not noted. [38] [39] Not noted. [38] [39] Some patients have abdominal pain with flares. [39] Some patients with lymphadenopathy. [39] Myalgia, arthralgia, fatigue and malaise with flares. Permanent bone or joint damage not noted. [39] Not noted. [38] [39] Not noted. [39] Elevated CRP may be noted during flares. But some patients do not have elevated CRP with flares. [39]
PLCG2-associated Antibody Deficiency & Immune Dysregulation (PLAID) – aka Familial Atypical Cold Urticaria (FACU) or FCAS3 PLCG2-associated Heterozygous genomic deletions within the PLCG2 gene. [64] Autosomal dominant. Unknown. Most reported cases with European ancestry. Unknown but rare. Onset <5 minutes after exposure to cold air (evaporative cooling). [64] Frequent sinusitis or pneumonia, and respiratory infections. Concurrent autoimmune diseases. [64] [65] Onset in infancy-under 6 months of age. Lifelong symptoms, but some find the symptoms less severe in adulthood. [64] [65] Cold-triggered. Cold urticaria, erythema and itching post cold exposure (air, wet skin, cold food). Some w/angioedema; chronic granulomata. Some with ulcerative and cutaneous lesions from cold exposure.[132] Negative Ice cube test. [64] Not noted. [64] [65] No fevers noted with cold-induced urticaria. [64] [65] Not noted. [64] [65] Uncommon. [66] 44% with recurrent sinus and/or respiratory infections, >50% with allergies, asthma and/or autoimmune diseases. [65] Not noted. Some have concurrent autoimmune diseases that may involve other organs. [65] Not noted. Some need IVIG for low immunoglobulins & frequent infections. A few with combined variable immune deficiency (CVID). [65] Not noted. [64] [65] Some have concurrent autoimmune diseases that may involve the joints, such as inflammatory arthritis or undifferenciated connective tissue diseases. [65] Not noted. [64] [65] Not noted. [64] [65] High IgE. Low serum IgA, IgG, IgM. Decreased circulating CD19+ B cells, IgG+ & IgA+ memory B cells, NK cells. >60% +ANA. WBC normal. [64] [65]
Neonatal Onset Multisystem Autoinflammatory Disease - aka Chronic Infantile Neurological Cutaneous Articular Syndrome (NLRP3-AID-severe) Cryopyrin Associated Periodic Syndromes (CAPS) NLRP3-associated Autoinflammatory Diseases (NLRP3-AID) NLRP3 Autosomal dominant. Most cases are due to spontaneous mutations. Very few familial cases. [1] Any­, present in all races. [1] Estimated frequency 1:1 million, mostly due to spontaneous genetic mutations. [5] Continuous, with increased symptoms and fever during flares. [1] Chronic inflammation noted between flares. Neonatal/early infancy. Rash, symptoms, and abnormal labs are often present at birth. [1], [6] Ever-present, urticaria-like rash with increased neutrophils at the eccrine coils. Rash increases with flares. Some patients have cold-induced flares in addition to constant symptoms. [1] [4] A few with apthous ulcers. Negative ice cube test. Headaches, fever, fatigue, chronic aseptic meningitis, and elevated or high intracranial pressure (ICP). Papilledema is common. Many have mental delay and/or cognitive delay, impairments, or intellectual disability. A few have seizures. Strokes are rare. [6] Many have increased sensorineural hearing loss, starting in infancy/early childhood. [1], [6] Papilledema, uveitis, iritis, conjunctivitis. Some with retinal scarring, corneal haze or vision loss. [6], [26] Some may have a pericardial effusion, or pericarditis. [1] Some patients have hepatomegaly, splenomegaly, or hepatosplenomegaly. Nausea, vomiting and abdominal pain with flares, or with elevated intracranial pressure (ICP). [6] Splenomegaly. Many have generalized lymphadenopathy. [1] Joint pain, knee valgus or varus, limb length differences are common. Some have frontal bossing of the forehead, saddleback nose, contractures, and/or have clubbing of the fingers. [1] Short stature, growth delays, failure to thrive, arthritis, and osteopenia are often noted.[1],[26] <50% of patients knees or joints have bony overgrowth (usually on the patella) with chondrocytes that are not well differentiated, plus abnormal enchondral bone formation (no inflammatory cells), along with the premature fusion of physis. [79]. Vasculitis rarely develops. [1] Elevated SAA. Secondary amyloidosis in <2% pts. [1], [6] Chronically high: ESR, CRP, SAA, anemia, granulocytic leukocytosis. Many patients have elevated IgG, IgA and IgM [1], [6]
Familial Cold Autoinflammatory Syndrome (NLRP3-AID-mild) Cryopyrin Associated Periodic Syndromes (CAPS) NLRP3-associated Autoinflammatory Diseases (NLRP3-AID) NLRP3 Autosomal dominant. Many large family groups spanning generations. Some patients with spontaneous mutations. [1] Affects all races, but many are of European descent. [1] 1:1 million, or more. In USA 300+ diagnosed – most cases are from large family groups. [2], [5] Frequency of CAPS in France is 1:360,000. [55] 12-24 hours, or longer. Onset of fever and flares is often 1-3 hours after exposure to cold or cooling temperatures. [1] Infancy, but a few present with symptoms later in childhood or adolescence. [1] Cold-induced, urticaria-like rash with increased neutrophils at the eccrine coils. [4] Almost daily rash that increases with flares. [1] Ice cube test negative. A few with apthous ulcers. Some have headaches and fatigue with fever after cold exposure. It is unknown if there are any other effects on the central nervous system (CNS) at this time. [1] Some patients have mild hearing loss – not currently known if it‘s from CAPS inflammation. [1] Conjunctivitis (non-infectious) during flares. [1] Not noted. [1] Uncommon. [1] Not noted. [1] Arthralgia, stiffness and swelling with flares. [1] Not noted. [1] Elevated serum amyloid (SAA). Secondary amyloidosis in some patients. [1], [9] High: ESR, CRP, SAA. Leukocytosis with flares. [1]
NLRC4-associated Autoinflammatory Disease, NLRC4-associated Macrophage Activation-like Syndrome (NLRC4-MAS) NLRC4-associated autoinflammatory diseases, Macrophage Activation Diseases NLRC4 (aka SCAN4, CARD12) Autosomal dominant. Not noted. Unknown-rare Injury, surgery or other stressors (physical or emotional) can trigger systemic flares of fever and macrophage activation syndrome (MAS)-like symptoms that can persist for weeks. [95] Infancy, early childhood - some at birth. [94] [95] Evanescent rash with occasional dermatographism, with a notable urticarial rash during disease flares. [94] Adult with seronegative psoriatic arthritis, and erythematous plaques. [95] Recurrent fevers, starting in early infancy. [94] [95] Uncommon for other CNS symptoms. [98]. Not noted [94] [95] [98] Not noted [94] [95] [98] Risk for multiple-organ failure, disseminated intravascular coagulation (DIC), macrophage activation syndrome (MAS)-like attacks, with Acute Respiratory Distress Syndrome (ARDS). [95] Failure to thrive, or challenges with weight gain is common. Vomiting and diarrhea during flares. Splenomegaly, transaminitis. Inflammatory infiltrates are noted in the intestine. Duodenitis, neonatal-onset enterocolitis noted (may resolve after 1 yr of age). [94] [95] [98] High risk for multiple organ failure with MAS-like attacks. [95] Splenomegaly.[94] [95] Lymphadenopathy may occur. [98] Short stature, low weight in one case. [95] Arthralgia, myalgia, and psoriatic arthriitis noted in an adult patient. [95] Not noted [94], [95] Not noted [94], [95] High (during flares): CRP, ESR, IL-18, triglycerides, ferritin (extreme ferritinemia), ALT, AST. Over-production of IL-1β and IL-18. Low during MAS-like flares): hemoglobin, platelets (thromobocytopenia), anemia, leukopenia. Normal NK cell function. [94].
Aicardi-Goutieres syndrome(s) (subclassifications 1-7); aka Familial infantile encephalopathy, with calcification of basal ganglia and chronic cerebrospinal fluid lymphocytosis Interferon Mediated Autoinflammatory Diseases Neonatal onset, high mortality: TREX1 (AGS1), RNASEH2A (AGS4), RNASEH2C (AGS3). Later onset, lower mortality: IFIH1 (AGS7), DSRAD (AGS6), SAMHD1 (AGS5), RNASEH2B (AGS2) Autosomal recessive in most cases. TREX1 and DSRAD can also present as autosomal dominant. Not noted. Unknown-rare Episodes can last for months with the onset of symptoms and encephalopathy, in the first year of life. 40% have chilblains exacerbated by the cold, starting after 1 year of age. [106]. Some with continuous symptoms from birth. [104] Encephalopathy is often the first symptom noted in the first year of life, with fevers, irritability and progressive neurologic changes with flares of symptoms. 40% of patients develop chilblains lesions, starting in early childhood. 20% of cases have AGS symptoms at birth, but most are asymptomatic at birth. [104] 25% Die within the first year of age. [104], [105] Chiblains are the classic skin symptom seen in 40% of patients with AGS, and may be start to develop after the first year of life. [106] They can be cold-induced and/or exacerbated by cold exposure. Chilblains can be painful, pruitic, swollen, and present on the distal areas of the ears, fingers and toes. There is a range of severity, from cold fingers and toes, and/or erythematous plaques to severe tissue damage and auto-amputation. [106] Microvascular vasculitis noted. [104], [106]. May present with purpura, petechiae, acrocyanosis. Neonatal jaundice in some patients. [105] Some have aphthous ulcers [104] Fever lasting days or weeks during attacks of symptoms, with Irritabiliity. Some have seizures. Progressive encephalopathy and cerebral atrophy, mental delay and damage, starting in infancy. [104], [105], [106] Worsening microcephaly. [105]. Worsening cognitive and mental regression with deficits, that can progress to a persistent vegetative state, or death. Dystonia, Low IQ [105]. Calcifications in the white matter, or basal ganglia noted. [105]. Leukoencephalopathy. Lymphocytosis in the CSF. [105] Not noted. [104], [105], [106] Progressive eye involvement due to neurologic damage. [105]. Glaucoma, and/or cataracts in some cases. [106] Visual inattention. [104], [105], [106] and ocular jerking in some cases. [107] Not noted. [104], [105], [106] Vomiting, feeding difficulties are common. [107] Uncommon: hepatomegaly, splenomegaly (hepatosplenomegaly) [104], [105], [106]. Some cases with splenomegaly. [105], [106] Some with stiff joints. Spasticity, dystonia of the limbs or hypotonia of the trunk noted. [104] Vasculitis in the small vessels noted on skin biopsy of distal lesions from chilblains. [106] Not noted. [104], [105], [106] High: Liver enzymes, abnormal liver function tests (LFTs). CSF lymphocytosis, with increased serum and CSF alpha interferon levels. [104]. Low: Thrombocytopenia, Normal: ESR, CRP, ANA, lupus anticoagulant, Anticardiolipin, antiphospolipid, IgG, IgM, cryoglobulins, alpha-1 antitripsin. [106]
Muckle-Wells Syndrome (NLRP3-AID-moderate) Cryopyrin Associated Periodic Syndromes (CAPS) NLRP3-associated Autoinflammatory Disease (NLRP3-AID) NLRP3 Autosomal dominant. Spontaneous mutations, and some family groups with MWS spanning generations. [1] Affects all races, but many are of European descent. [1] 1:1 million, but it may be more frequent. Some large family groups. [5] Frequency of CAPS in France is 1:360,000. [55] Often lasts 2-3 days. Random onset–flares of fever and symptoms are often triggered by cold or cooling temperature. [1] Infancy, but a few present with symptoms later in childhood or adolescence. [1] Urticaria-like rash with increased neutrophils at the eccrine coils. Rash and flares can be cold-induced, or from unknown triggers. [4] Most have a daily rash that increases with flares. [1] A few have apthous ulcers. Negative ice cube test. Some have headaches, fatigue with fever and flares. It is uncommon to have many other central nervous system symptoms. [1] A few patients have a MWS/NOMID crossover of symptoms. Many have increased sensorineural hearing loss, starting in adolescence. [1] Conjunctivitis (non-infectious) during flares,[1] or corneal haze. [26] MWS/NOMID crossover patients may have more eye involvement. Rare. [1] Some have abdominal pain with flares or other gastrointestinal issues. [1] Rarely noted. [1] Arthralgia, recurrent arthritis, stiffness and swelling with flares. [1] Not noted. [1] Elevated serum amyloid (SAA). >25 % with secondary amyloidosis. [1], [9] High: ESR, CRP, SAA. Leukocytosis with flares. [1]
STING-associated vasculopathy with onset in infancy (SAVI);TMEM173-AID Interferon Mediated Autoinflammatory Diseases TMEM173 Autosomal dominant. Unknown Unknown-rare Continuous, starting in infancy with fevers and progressive skin lesions and vasculitic changes. Cold-induced flares. [98] Infancy-before 8 weeks in most cases. [98] Cold-induced flares. [98] Relapsing malar rash, thin hair. [93] Scaling, pustular, violaceous and/or blistering rashes on the distal fingers, toes, nose, cheeks, & pinnae of the ears that develops into acral necrosis and/or gangrene (leading to amputation of digits). Chilblains. Eschar and painful crusts on ulcerated lesions. Skin lesions worsen in the winter. [92] Skin biopsy: Inflammatory infiltrate of the dermis plus signs of leukocytoclastic vasculitis & microthrombotic angiopathy of the dermal small vessels and leukocytoclasia. Also deposits of IgM or vessels with fibrin. [82] One case of fatal necrotizing facscitis. Telangiectasias, Raynaud's, livedo reticularis, perforated nasal septum. [98] Nail loss or dystrophy. [93] Rare: basal ganglia calcifications. Normal cognitive function.[98] Not noted [98] Not noted [98] Interstitial lung disease and pulmonary fibrosis noted on CT scan in many patients, that in some cases can be fatal. [82] [93] Emphysema [98] Tachypnea at birth [92], abnormal pulmonary-function test (PFT). A few with arterial hypertension. [98] Hilar or paratracheal lymphadenopathy, mixed, scattered lymphocytic inflammatory infiltrate on a lung biopsy. [82] Failure to thrive is common. [82] Abdominal, liver or spleen issues are uncommon. [98] Occasional general lymphadenopathy. [98] Hilar or paratracheal lymphadenopathy noted [82] Seropositive polyarthritis. [82] Arthralgia, myositis. [98] Widespread vasculitis. [82] Damaged small vessels are common, plus nailfold capillary tortuosity and the loss of capillary loops. Telangiectasias noted on the limbs and hard palate. [82] Not noted [82] High: ESR, CRP, IgG, IgA. Hypergammoglobulinema. Anemia, leukopenia, thrombocytosis, T-cell lymphopenia with normal B cells. [92] Normal or low positive ANA, c-ANCA, p-ANCA, antiphospholipid antibodies that later disappear, or are variable. [82] [92] [93]

Main authors:

Karen Durrant RN, BSN–President of The Autoinflammatory Alliance (autoinflammatory.org), & Dr Juan Ignacio Aróstegui MD–Immunologist at the CDB Hospital Clínic in Barcelona, Spain & Director of La Unidad de Enfermedades Autoinflamatorias (autoinflamatorias.com)

Acknowledgements: A special thanks to the many medical doctors who have helped to make voluntary suggestions in regards to the original comparative chart, and suggestions for our new Autoinflammatory Search Database: Dr Juan Ignacio Aróstegui, Dr Hal Hoffman, Dr Raphaela Goldbach-Mansky, Dr Scott Canna, Dr Anna Simon, Dr Polly Ferguson, Dr Rebecca Marsh, Dr Daniel Kastner, Dr Luca Cantarini, Dr Véronique Hentgen, Dr Nico M. Wulffraat, Dr Kieron Leslie, Dr Lori Broderick, Dr Mikail Kostik, Dr Beata Wolska, Dr Joost Frenkel, Dr Dan Kastner, Dr Helen Lachmann, Dr Jonathan Hausmann, Dr Phillip Kahn, Dr Israel Andrews, and to all that have been using our materials to educate others about autoinflammatory diseases worldwide.

Thank you to Black Peacock SE, especially David Schwieler, Tommy Westerberg and Lotti Ungerth Fastmarken for all your amazing work on this database. Also to Nathan Durrant and Jennifer Tousseau for all your help on this, the original chart, and many projects. Our deepest thanks to all of The Autoinflammatory Alliance Board of Directors, & to all the patients & families who have supplied images for this chart, & support for the Autoinflammatory Alliance. You are our greatest inspiration and strength!

Great thanks to all of the doctors from the International Society of Systemic Auto-Inflammatory Diseases (ISSAID) for their research & dedication to patients with autoinflammatory diseases, plus the opportunity to present the original chart in a poster session at the Autoinflammation 2013 Congress. Thanks for the inspiration for this chart also go to: The Translational Autoinflammatory Disease Section at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) & The National Human Genome Research Institute at the National Institutes of Health (NIH); The Spanish Society of Pediatric Rheumatology (SERPE) & La Unidad de Enfermedades Autoinflamatorias; The French Centre de Référence des Maladies Auto-inflammatoires (CeRéMAI) & Le Club Rhumatismes et Inflamations; Dermatology Online Atlas. (DermIS Dermatology Information System), the Pediatric Rheumatology European Society (PReS),European League Against Rheumatism(EULAR), PRINTO, the EUROFEVER Project, the SHARE Consortium, The National Amyloidosis Centre, UK, The Interuniversity autoinflammation workgroup & Nijmegen center for Immunodeficiency and Autoinflammation (NCIA) of the Radboud Nijmegen University Medical Center, Nijmegen, The Netherlands, The American College of Rheumatology (ACR), CARRA, FAVOR & the many other research centers and doctors around the world.

Disclosure: All of the doctors involved in the authorship, review, editing and creation of this chart voluntarily donated their help for this educational reference, & received no financial compensation. Karen Durrant, RN has only received reimbursement only for for out-of-pocket travel costs from SOBI to attend a few meetings as a patient representative, but has received no personal financial compensation from any pharmaceutical company.

Swedish Orphan Biovitrum AB (Sobi), of Stockholm, Sweden provided the Autoinflammatory Alliance with an unrestricted grant in 2014 to support the development of this Autoinflammatory Search Database to help to educate medical professionals, and a future collection of disease-specific websites for patients. This grant, along with donated funds from the general public and patient community has helped to make this monumental project a reality, and we are so thankful!

Novartis Pharmaceuticals Canada Inc. provided The NOMID Alliance (now known as the Autoinflammatory Alliance) with an unrestricted grant in 2012 to help with the initial development & printing costs for the first comparative chart in print. An unrestricted grant from Swedish Orphan Biovitrum AB (Sobi) in 2013 supported many projects, including: the printing of the final comparative chart that we distributed at the 2013 ACR meeting, and 2014 PRYSM meeting, in addition to mailings to doctors worldwide. The NOMID Alliance has received a number of unrestricted grants at various times from Regeneron, Novartis & Sobi for grant-specific projects.

List of abbreviations:

Autoinflammatory Chart References