Comparison Chart of Systemic Autoinflammatory Diseases (SAID)

Cryopyrin-Associated Periodic Syndromes (CAPS) Pyrin Protein Folding Mevalonate Kinase Deficiencies Inflammatory Bone Diseases Pyogenic Diseases Granulomatous Monarch-1 Proteasome Idiopathic Macrophage Activation Diseases PLCG2-associated SLC29A3 related ADA2 deficiency Familial Cold Muckle-Wells Neonatal-Onset Schnitzler Familial Tumour Necrosis Hyperimmuno- Mevalonate Deficiency of Majeed Syndrome Chronic Recurrent Deficiency of Familial Psoriasis Pyogenic Sterile Juvenile Systemic NLRP12-Associat- Chronic Atypical Behçets Disease Periodic Fever, Systemic-Onset Adult-Onset (Primary) Familial PLCG2-associated Autoinflammation SLC29A3 Spectrum Deficiency of Ad- Autoinflammatory Syndrome* Multisystem Syndrome Mediterranean Factor (TNF)- globulinemia D Aciduria (MA) Interleukin-1ß –aka Chronic Recur- Multifocal Interleukin-36-Re- (PSORS2)–aka Arthritis, Granulomatosis ed Periodic Fever Neutrophilic Aphthous Stoma- Juvenile Idiopathic Stills Disease–aka Hemophagocytic Antibody Defi- & PLCG2-asso- Disorder–aka H. enosine Deami- Syndrome* Autoinflammatory Fever* Associated with Periodic (IL-1ß) Receptor rent Multifocal Osteo- Osteomyelitis–aka ceptor Antagonist CARD14-Mediated Pyoderma –aka Blau syndrome, Syndrome–aka Dermatosis w/ titis, Pharyngitis, Arthritis–aka Still’s, Adult Still’s, Wissler- Lymphohistiocy- ciency & Immune ciated Antibody syndrome; Pigmented nase 2 (DADA2) Hypertrichosis w/IDDM; (Mevalonate Kinase myelitis, Congenital Synovitis, Acne, Pustular Psoriasis Pediatric Granuloma- Familal Cold Autoin- Systemic Juvenile Fanconi Syndrome –aka Fever w/Early Disease–aka Chronic Periodic Sydrome Fever Syndrome Antagonist (DIRA) (DITRA)–aka Gangrenosum, & Lipodystrophy & & Cervical Ad- tosis–aka Familial Dysregulation, Deficiency & Faisalabad Histiocytosis Deficiencies, such as Dyserythropoietic tous Arthritis (PGA), Infantile Neurological –aka Familial Hiber- (HIDS)* –aka Osteomyelitis, Pustulosis, Hyperosto- Generalized Pustular Acne Syndrome flammatory Syndrome Elevated Temper- enitis (PFAPA) Idiopathic Arthritis Erythrophagocytic (PLAID)–aka Familial Immune Dysregu- & Sinus Histiocytosis Onset Stroke (FEOS) HIDS & MA are also Anemia, & Neutro- sis, Osteitis Syndrome Early Onset Sarcoido- 2, or Guadaloupe Cutaneous Articular nian Fever* Sterile Multifocal Psoriasis (GPP) ature–aka Nakajo- –aka Marshall Lymphohistiocytosis Atypical Cold Urticaria lation (APLAID) w/Massive Lymphade- referred to as MKD) philic Dermatosis sis, or Jabs Syndrome Periodic Fever Syndrome (CINCA)* w/Periostitis Pustulosis Nishimura Syndrome Syndrome (FACU) or FCAS3 nopathy ACRONYM FCAS MWS NOMID/CINCA SCHNITZLER FMF TRAPS HIDS MA DIRA/OMPP MAJEED CRMO/SAPHO DITRA/PSORP CAMPS/PSORS2 PAPA BLAU/PGA/EOS NLRP12/FCAS2 CANDLE/PRAAS BEHÇETS/BD PFAPA soJIA/sJIA AOSD 1° HLH/ FHL PLAID/FCAS3 APLAID SLC29A3 DADA2 GENE NLRP3 NLRP3 NLRP3 Currently unknown. MEFV TNFRSF1A MVK MVK IL1RN LPIN2 Currently unknown. IL36RN CARD14 PSTPIP1 NOD2 NLRP12 PSMB8; also ERAP1 (with HLA-B51); Currently unknown. Currently unknown. Currently unknown. PRF1, STX11, STXBP2, Heterozygous genomic PLCG2 mutation SLC29A3 CECR1 (Some pts. w/somatic PSMB4, PSMB9, also variants near: CCR1, HLA-DRB1 in some pts. MUNC13-4 , RAB27A deletions within the NLRP3 mutations.)76 PSMA3, POMP 59 KLRC4, STAT4 42 w/European ancestry57 X link: SH2D1A, BIRC4 PLCG2 gene64 INHERITANCE Autosomal Dominant. Autosomal Dominant. Autosomal Dominant. Unknown. Autosomal Recessive. Autosomal Dominant. Autosomal recessive. Autosomal recessive. Autosomal recessive. Autosomal recessive. Currently unknown. Autosomal recessive. Autosomal Dominant. Autosomal Dominant. Autosomal Dominant. Autosomal Dominant. Autosomal recessive. Complex. Currently unknown. Complex. Currently unknown. Autosomal recessive, Autosomal Dominant. Autosomal Dominant. Autosomal recessive. Autosomal recessive. Large familial groups, Spontaneous mutations, Spontaneous mutations, Some cases are gene- Spontaneous mutations, Some cases w/only one Spontaneous mutations, Spontaneous mutations, Spontaneous mutations, but if X-linked: inheri- some spontaneous some familial groups.1 few familial cases.1 dosage-dependent some familial groups.1 mutation found.33 some familial groups.23 some familial groups.29,30 some familial groups.29,30 tance is dominant. mutations.1 autosomal dominant.10 ETHNICITY Affects all races, but Affects all races, but Any­–present in all Affects all races, but Turk, Armenian, Arab, Affects all races. 2nd Mostly of Dutch descent, Mostly of Dutch Carriers in 0.2% population Currently, the only Affects all races, but the May affect all races. Pts. Most w/European or Currently, the only docu- Affects all races. Unknown. Cases in Gua- Unknown. Caucasian, Rare in the USA. More Affects all races.40 Affects all races. Rare. Affects all races.44 Affects all races. 80% of Unknown. Most reported Unknown. Unknown. Many pts. w/ Unknown. many are of European many are of European races.1 most cases are in Sephardic Jew, Italian.1 most common inherited or Northern European.1 descent, or Northern of Newfoundland & 1.3% documented cases are majority of patients have w/Caucasian, Spanish, Asian ancestry. Pts. in US, mented cases are from deloupe, US, Martinique, Hispanic, Japanese common in the Middle soJIA accounts for 10% African Americans, & 20% cases w/European Middle Eastern ancestry. descent.1 descent.1 Europe.13 More men than Most common inherited SAID (after FMF.)1 European.1 in Puerto Rico. Also Dutch of Middle Eastern European ancestry; more Asian, African, Algerian EU, Canada (Newfound- Europe, New Zealand & France, Italy, & Armenia. pts. & one case in East, Asia & Japan. of all JIA.45 of pts. w/European decent ancestry. Some from India, Paki- women are affected. periodic fever syndrome. Brazilian & Lebanese pts.16 ancestry.18 female pts. than males.21,22 & Tunisian ancestry.58,75,77 land), Haiti, & Taiwan.23 the USA.30 38,39,75 South Africa.27,60 (Silk Road Route.)42,43 have PRF1 mutations.47,48 stan, Spain, Bulgaria.70 FREQUENCY IN 1:1 million, or more. In 1:1 million, maybe more. Estimated frequency Unknown. Over 150 In specific ethnic Unknown. TRAPS affects Unknown, but very rare. Unknown, but very rare. Unknown, but very Unknown, but very rare. Unknown, but rare. Unknown but rare. 1% of Unknown, but rare. Unknown, but rare. Unknown, but rare. Unknown, but rare. Unknown, but rare. Prevalence is 80- Unknown. Most common Uncommon. 0.4–0.9 France: estimated that 1° HLH affects 1:50,000 Unknown but rare. Unknown but rare. Unknown but rare. Unknown but rare. USA 300+ diagnosed– Some large family 1:1 million, mostly due known cases, mostly in groups, the carrier 0.01:10,000 people in the >200-300 known patients <100 known patients rare. In some regions of Very few documented Sfax, Tunisians are car- 370:100,000 people in non-infectious recurrent cases per 100,000 0.16:100,000 people have people worldwide.48 THE WORLD most cases are from groups.5 Frequency of to spontaneous genetic Europe.13 frequency of MEFV vari- European Union.51 >1000 worldwide, (>300, when worldwide.11 Aricibo, Puerto Rico cases at this time.18,53 riers, w/ a 0.52% chance Turkey, 10:100,000 in fever disorder.40 people, per year.46 AOSD. AOSD affects large family groups.2,5 CAPS in France is mutations.5 ants is up to 1:5 people.1 pts. worldwide.52 suspected cases are w/more DIRA carriers, of having the disease in Japan & 0.6:100,000 in more women than men.44 1:360,000.55 also included.)12 DIRA may occur 1:6300.16 this population.58 Yorkshire, UK.3 TIMING OF 12-24 hours, or longer. Often lasts 2-3 days. Continuous w/increased 12-36 hours. Rash is 12-72 hours.1,9 Days to weeks. 3-7 days. Recurrent bouts 4-5 days. Recurrent Continuous inflamma- Flares last for a few At least 6 months Flares last days–weeks. Continuous chronic Early-onset, destructive, Intermittent-persistent 1-3, to up to 7-15 days of Frequent fevers w/dis- Mouth ulcers are pres- Periodic fevers & symp- Fevers often > 39°C 1-2 High fevers > 39°C that Fevers often > 39°C 1-2 Onset <5 minutes after Recurrent skin lesions, Fever 39°C w/flares that Intermittent, recurrent Onset of fever & flares Random onset–flares of symptoms & fever present first. Intermit- Recurrent fever & flares Average flare is 3 of fever & flares every flares & fever every 2-3 tion from birth/fetal days, w/1-4 exacerba- w/chronic or relapsing Some w/chronic symp- pustular or plaque recurrent inflamma- daily fevers, rash & fevers 39–40°C, rash & ease flares. Inflammatory ent in almost all patients toms lasting 3-6 days, times/day for >2 weeks, last for <4 hours, times/day for >2 weeks, exposure to cold air chronic inflammation, last 7-10 days w/joint & fevers, livedo reticularis SYMPTOMS is often 1-3 hours after fever & symptoms are during flares.1 Chronic tent fevers, that often can occur weekly, or weeks.1,9 2-12 weeks.1,9 Some weeks. Patients have development. Untreated tions a month of high symptoms. Often 7-25 toms. Most flare w/infec- psoriasis, triggered by tion of the joints, skin & arthritis. pain. Onset after expo- flares & symptoms are during flares, for around recurring every 21-28 most often occuring in recurring more than most often occurring in (evaporative cooling).64 & progressive eye abdominal pain; peri- rash, vasculopathy, & exposure to cold or often triggered by cold inflammation noted occur separately from only a few times a year. flares occur after vac- chronic inflammation DIRA can lead to death fevers, severe pain, & yrs. of symptoms. Many tions, stress, medication inflammatory stimuli. muscle. Flares often sure to cold or cooling often present before the 10 days w/inflammation days. Pts. are symptom- the evening w/arthralgia, once a week, w/ a the evening w/arthralgia, Frequent sinus/lung complications from this carditis & sometimes high risk for early-onset OR ATTACKS cooling temperatures.1 or cooling temperature.1 between flares. the rash.13 cines.9 noted between flares.11 in infancy–childhood.16 joint swelling.18,53 bone lesions heal changes, during preg- Some cases w/psoriatic occur after mild injury, temperatures.38,39 age of 6 months.26,27 in the eye, & arthritis.42,43 free between flares.40 rash & other symptoms. maculopapular rash & rash & other symp- infections. Concurrent disease.66,67,68 diarrhea. Flares occur lacunar stroke.73,74 completely.19,22 nancy or menstruation.58 arthritis.23,24 or injections.29 45,46 arthralgia.44 toms.47,48 autoimmune diseases.64,65 once every 2-3 months.70 AGE OF ONSET Infancy, but a few pres- Infancy, but a few Neonatal/early infancy. Most cases start in Infancy, to under 20 Most first attacks by 3 >90% present w/symp- Most present w/symp- Most have symptoms at Most present w/symp- Mostly affects children– Variable age of onset. Variable age of onset First symptoms of Rash often develops by Neonatal/early infancy. Onset at birth or in Most show symptoms Early childhood, usually Onset before the age of First onset of symptoms Onset <1yr: often by 6 Onset in infancy-under 6 Onset in infancy Onset in infancy-starts Onset of symptoms in ent w/symptoms later present w/symptoms Rash, symptoms, & middle age, over 35-50 years of age for the first yrs, & almost all begin by toms in infancy.9 toms at birth, or in early birth, or as a neonate: toms in infancy to early some adult onset. Peak Many have symptoms from infancy–childhood arthritis develop by 1-10 4 months of age, fevers Rash, fevers, symptoms, infancy. Progressive in early adulthood between 2-5 years of 16–most often by 2 years occurs between 16-35 months–early childhood. months of age. Lifelong w/recurrent skin lesions, w/recurrent fevers infancy–early childhood. in childhood or adoles- later in childhood or abnormal labs are often yrs. Youngest pt. was 13 symptoms.9 20 yrs. of age; a few start infancy. Most have facial pustular rash, bone pain, childhood, between 3 incidence of flares is starting in childhood. to adulthood w/pustular yrs old, & skin lesions and other symptoms may be present at damage from chronic (20’s-30’s) but the onset age. A few adult-onset of age, or between 0-5 yrs. of age. Affects all Some in utero or late symptoms, but some arthralgia, eye inflamma- & flares. Chronic & w/recurrent fevers, cence.1 adolescence.1 present at birth.1,6 yrs old. Symptoms start later in life.9 features noted at birth.11 swollen joints, & oral weeks to 2 years of age.18 around 10 years of age.22 Some have symptoms psoriasis.23,24 develop during adoles- present by 4 yrs. of age.34 birth.38,39 inflammation noted as can be in childhood, or cases. Many teens yrs. of age.46 ages.44 childhood. A few adult- find the symptoms less tion, & infections. Some progressive systemic livedo reticularis rash, & w/the rash.13 ulcers.16 beginning in adulthood.58 cence.29,32 the child grows.26,27 any age.42,43 outgrow it.40 onset cases.47,48,49 severe in adulthood.64,65 w/ intestinal symptoms.68 symptoms develop.69,70,71 vasculopathy.73,74 SYSTEMIC FINDINGS: SKIN/ Cold induced urticaria- Urticaria-like rash Ever-present1 Urticaria- Maculopapular rash, Erysipeloid erythema Migrating rash w/deep Diffuse maculopapular Diffuse maculopapular Epidermal neutrophilic Most patients have Some patients have Recurrent, generalized Generalized pustular Pathergy. Pyoderma First symptom: scaly Present during flares: Annular cutaneous Pathergy. Pseudofol- Some have a rash with Rash: Fleeting, evanes- Evanescent, salmon- 40% w/transient Cold urticaria, erythema Erythematous plaques & Hyperpigmentation Livedo reticularis rash, like rash w/increased w/increased neutrophils like rash w/increased & plaques (sometimes on the ankle–foot–be- pain under rash areas. rash. Some w/petechiae or morbilliform rash. pustules at hair folicles. inflammatory dermatosis, acne, &/or pustulosis pustular psoriasis & high psoriasis (can be gangrenosum ulcerative plaques. The rash often Cold-induced urticarial plaques w/residual liculitis, erythema flares. Aphthous stoma- cent, migratory, bright pink, mildly pruritic maculopapular, nodular & itching post cold expo- vesiculopustular blister- w/hypertrichosis.69,70 ,71,72 few w/polyarteritis nodo- CUTANEOUS neutrophils at the ec- at the eccrine coils.4 neutrophils at the itchy) on the chest low knee region–lasts Severe pain follows the or purpura present. A Some w/petechiae or Oral ulcers, pathergy, Sweet’s syndrome, on the palms &/or soles fevers after erythema- severe), &/or plaque lesions, &/or severe starts on the face, then or malar rash39 noted in purpura. Lipodsystrophy: nodosum-like &/or titis, & pharygitis w/ salmon-pink, morbilli- maculopapular rash on or purpuric skin rashes sure (air, wet skin, cold ing rash that intensifies Some w/notable varicose sa. Diffuse vasculopathy, crine coils.4 Almost daily Most w/daily rash that eccrine coils. Rash & limbs. Dermis has 2-3 days during flares rash path from the trunk few w/apthous ulcers.1,9 purpura present. A few hyperkeratosis, acan- pustular skin lesions, of their extremities (w/ tous rash. Some w/acral psoriasis. Sometimes cystic acne. Affected on the torso. Biopsies w/ some pts. Some with first on face & around acneiform nodules. 98% exudate, (but no form, macular rash often the proximal limbs & during bouts of high food). Some w/angioede- w/heat & sun exposure. veins on the legs.69 w/impaired endothelial rash that increases increases w/flares.1 increases w/flares.4 neutrophillic infiltrate. of symptoms.1 out to the limbs.9 w/apthous ulcers.1,9,11 thosis; high neutrophil psoriasis. Intra-epidermal SAPHO). 23% w/psoria- pustules & nail damage, nails are affected w/ tissues w/high neutrophil non-caseating granu- buccal aphthosis.38,39 joints. Lips swell w/flares. w/mouth ulcers, & 65% infection) is a classic presents w/onset of trunk.44 fever. Jaundice.47,48 ma; chronic granulomata. Cellulitis often develops integrity & endothelial w/flares.1 Dermographism.13 infiltrate of dermis.16,26 neutrophils.18,53 sis.19,22,54 or chronic plaques.58,61 psoriasis.23, 24 infiltration.29 lomatous dermatitis.34 Purple-red eyelids.26,27 have genital ulcers.43 finding.40,41 fevers.45,46 Ice cube test negative.64 w/rashes.66,67 cellular activation.73,74 NEUROLOGIC Some have headaches, Some have headaches, Headaches, fever, Intermittent fevers can Fevers. Acute aseptic Fevers lasting >3 days at Headaches & fevers Fevers w/flares. Micro- High fevers are not High fevers last for a few Fevers affect a number Sudden onset high fever Not seen.23, 24 Fevers can accompany Intermittent-persistent Fevers 39–40°C myalgia, Aseptic meningitis & 20-40% have Neuro- High fevers for 3-6 days, High fevers >39°C 1-2 >95% have high, spiking High fevers. Increased Not noted.64,65 Not noted.66,67,68 Fever 39°C w/flares Recurrent fevers & early- fatigue w/fever after fatigue w/fever & flares. fatigue, chronic aseptic rise > 40°C. Chills are meningitis is rare & can over 38°C w/flares. w/flares of symptoms cephaly, dolichoceph- common, or noted in days w/flares & severe of patients during flares >40°C w/chills. Some pts. flares of joint inflam- daily fevers. Some have- headaches w/flares. systemic inflammation. Behçets w/headaches, w/chills & malaise. times/day for >2 weeks. fevers, fatigue and CSF protein. High ICP. No fevers noted w/cold- No fevers noted as a part lasting over a week.69,70 onset lacunar strokes. cold exposure. Uncommon to have meningitis, & high CNS uncommon. Fatigue & occur during flares, but Some have headaches are common.1,9 More aly, mental retardation, the neonatal period. pain. Other neurological of CRMO. Other neuro- have a headache w/the mation and pain. Other cranial neuropathies. Other neurological symp- Growth delays–low aseptic meningitis or Some patients have Other neurological myalgia w/flares. Multifocal inflammation induced urticaria.64,65 of this disease (but fevers Psychomotor delays, Possible adult stroke Unknown if there are many other CNS pressure (ICP). Many headaches are common is never chronic.1 Other w/flares of symptoms.1,9 severe neurological developmental delays, Neurological complica- symptoms are not noted. logical symptoms are not onset of the rash & fever, neurological symptoms 80% have vision damage toms are not noted.31 height & weight. Devel- meningoencephalitis, headaches w/flares. symptoms are rare. A Other neurological of the gray & white may be present w/infec- dysmorphic facial risk. Brain biopsies: notable CNS affects at symptoms.1 A few pts. with mental &/or cogni- w/fevers. Temperature neurological involve- symptoms are rarely cerebellar ataxia, tions are not common. Growth delays in height, noted. Some w/impaired plus muscle weakness & are not noted.31 & joint deformities if opmental delays.26,27 seizures, hemiplegia, or Other neurological few cases w/seizures, symptoms are very rarely matter, intracranial tions).66,67,68 features noted.69,70 diffuse vasculopathy, this time.1 have MWS/NOMID tive impairments. Papille- changes, stress & exer- ment is very rarely seen present in HIDS.9 cerebellar atrophy & A few cases of cerebral & chronic pain are com- bone growth, or overall elevated heart rate. 58,,61 untreated. Some cases cranial nerve palsies. symptoms are meningismus, irritabil- seen.44 bleeding, generalized w/impaired endothelial crossover of symptoms. dema is common.6 cise can trigger flares.13 in FMF. epilepsy often develop vasculitis noted.16,26 mon.18,53 impaired growth.19,22,54 have peripheral nerves Cerebral venous throm- not noted.41 ity & decreased level of atrophy or brain edema, integrity & endothelial over time.11 affected.34 bosis w/high ICP noted.43 consciousness.46 seizures &/or coma.47 cellular activation.73,74 AUDITORY Some pts have mild Many have increased Many have increased Uncommon.13 Uncommon–not be- Uncommon–not believed Uncommon–not be- Uncommon–not believed Not noted.15,16 Not noted.18,53 Not noted.19,21,22,54 Not noted.58,61,62 Not seen.23, 24 Not noted.29,30,31 Not noted.34 Many have increased Some have frequent Not noted.42,43 Not noted.40,41 Not noted to be from Not noted.44 Not noted.47,48,49 Not noted.64,65 Not noted.66 Sensorineural hearing Unknown.73,74 hearing loss–not cur- sensorineural hearing sensorineural hearing lieved to be caused by a to be caused by TRAPS.1 lieved to be caused by to be caused by MA.1,9,11 sensorineural hearing otitis &/or recurrent soJIA.45,46 loss, from early infancy/ rently known if it‘s from loss, starting in adoles- loss, from infancy/child- FMF disorder.1 HIDS.1,9 loss.38,39 sinusitis.27 childhood.69,70 CAPS inflammation.1 cence.1 hood.1,6 OPHTHALMIC Conjunctivitis Conjunctivitis Papilledema, uveitis, Not noted.13 Very rare to uncommon.1 Conjunctivitis, & peri- Very rare to uncommon.9 Uveitis, central cataracts, Eye issues are rare. Not noted.18,53 Some cases of uveitis.19 Not noted.58,61,62 Not seen.23, 24 Not noted.29,30,31 Uveitis (some w/blind- Not noted.38,39 Nodular episcleritis (in- Frequent anterior &/or Not noted.40,41 Uveitis can be a compli- Not noted.44 Blindness due to CNS Uncommon.66 Many develop corneal Uveitis. Blindness can Unknown.73,74 (non-infectious) during (non-infectious) during iritis, conjunctivitis. orbital edema during blue sclerae & tape- Non-infectious conjunc- ness) 50% w/cataracts, flammation on the eye.) posterior uveitis. Cata- cation from soJIA.46 inflammation.48 erosions, blisters, occur from anterior Strokes have the poten- flares.1 flares,1 or corneal haze.26 Some w/retinal scarring, flares.1,9 toretinal degeneration tivitis can be caused by 1:3 pts. get 2° glaucoma, Conjunctivitis. Keratitis. ract, retinal vasculitis ulcerations, intraocular uveitis & glaucoma. Pto- tial to cause blindness. MWS/NOMID crossover corneal haze or vision are often present, even DIRA.15,16 inflamed conjunctiva, Periorbital edema. <30% risk for blindness. hypertension, &/or sis, eyelid swelling from pts. may have more eye loss.6,26 in less severe cases.11 lacrimal glands, retina & Purple-red eyelids.26,27 Papilledema w/CNS cataracts.66,67,68 histiocytic deposits.69,70,71 involvement. optic nerves.34 involvement.43 CARDIO- Not noted.1 Rare.1 Some have clubbing of Not noted.13 45% have pleuritis, pain- Common, including Rare.1 Some pts. have Rare.1,11 Some w/resp. distress. Not noted.18,53 Not common–some pa- Elevated heart rate. Elec- Not noted.23, 24 Not noted.29,30,31 Some have atrial hyper- Not noted.38,39 Clubbing of the fingers Myocarditis, endocarditis Flares of fevers, stoma- Serositis (especially <25% have pleuritis, High risk for respiratory 44% w/recurrent sinus Mild humoral immune Pericarditis w/flares. Unknown.73,74 fingers. Some cases of ful respiration, w/flares. pleurisy.1 developed severe respi- 1 case: Pulmonary hemo- tients also have ANCA+ trolyte imbalances during tension &/or pericarditis. &/or toes. At risk for w/aortic or mitral insuffi- titis & pharygitis are not pericarditis) is often pericarditis (a few infections triggering &/or respiratory infec- deficiency w/increased Cardiac defects noted: PULMONARY pericardial effusions, or Some w/pericarditis.1 ratory infections. Higher siderosis & progressive Vasculitis that can fever & onset of pustular Some cases with lung cardiac arrythmias & ciency, arterial aneurysm, associated w/respiratory seen. Pleuritis, pleural w/tamponade.) Some fevers, systemic inflam- tions, >50% w/allergies, frequency of sinus &/or ASD, VSD, PDA, mitral pericarditis.1 risk for issues w/S. interstitial fibrosis.15,16,17 affect the lungs.18,54 rash; Risk for cardiac ar- involvement.34,35 dilated cardiomyopa- pulmonary embolism.43 illness.40,41 effusions can occur. myocarditis, pleural mation & MAS. Edema.49 asthma &/or autoimmune respiratory infections or valve prolapse, cardio- pneumoniae infections.78 rest, & septicemia.58,61 thy.26,27 Risk for MAS.46 effusions, ARDS.44 diseases.65 interstitial pneumonia.66,67 megaly & others.69,70 ABDOMINAL Uncommon.1 Some have abdominal Nausea, vomiting & GI symptoms are uncom- Sterile peritonitis, pain, Peritonitis, diarrhea, & Extreme pain, vomiting Enlarged liver &/or Rarely have GI issues. Enlarged liver & chole- Some patients also have Nausea during flares. At Not noted.23,24 Some patients also Enlarged liver &/or Some patients have ab- Loose bowels w/flares. Ulcers from mouth to Abdominal pain, diarrhea Peritonitis rarely occurs. 50-75% w/enlarged liver, Liver disease is common. Not noted. Some have Some w/bouts of Diabetes Mellitus. En- Enlarged liver & spleen; pain w/flares or other abdominal pain w/flares, mon. Enlarged liver &/or and/or constipation with constipation w/flares.1 & diarrhea w/flares.1,9 spleen. Cholestatic liver Mouth ulcers, stomatitis, static jaundice in the inflammatory bowel risk for loss of appetite.58,60 have irritable bowel spleen. Some w/ GI pain, dominal pain w/flares.39 Enlarged liver & abdo- anus. Nausea, abdominal are often present w/ 50% have an enlarged abnormal LFTs. 43% High risk of death from concurrent autoim- abdominal pain, bloody larged liver/spleen. Abd. diffuse vasculopathy gastrointestinal issues.1 or w/high CNS pressure.6 spleen is common.13 flares.1 Some w/enlarged liver/ disease. Pain, vomiting & failure to thrive are neonatal period, but it is diseases.19 Infant case w/failure to syndrome.29 higher risk for kidney &/ men. Delayed or slow pain, anorexia, diarrhea, flares.40,41 spleen, some w/an w/enlarged spleen. multi-organ failure in 2+ mune diseases that may diarrhea, enterocolitis, pain, diarrhea, failure to noted in the liver.73,74 spleen, other GI issues.78 & diarrhea w/flares.1,9,11 common.16 transient.18,53 thrive, diarrhea.63 or liver issues.34,35,36 growth.26,27 (may be bloody).43 enlarged liver.46 Renal disease is rare.44 months if untreated.49 involve other organs.65 or ulcerative colitis.67,68 thrive. Hypogonadism.69,70 LYMPHATIC Not noted.1 Rarely noted.1 Some pts. with enlarged <20% w/lymphoma, IgM Enlarged spleen is Enlarged spleen is Enlarged cervical lymph Enlarged spleen, &/or Enlarged liver and/or Neonates: enlarged liver Some cases of ANCA+ Risk for renal and liver Not seen.23, 24 Not noted.29,30,31 Enlarged liver &/or Some patients with Enlarged liver, with Some w/enlarged liver Cervical adenopathy Many w/generalized Lymphadenopathy is Lymphoma. Hemophago- Not noted. Some need Not noted.67,68 Lymphadenopathy. Not noted.73,74 liver and/or spleen, myeloma, or Walden- common, some have common; some have nodes w/flares.1 Few lymph nodes are spleen is common. & neutropenia; anemia is Vasculitis that can affect impairment & systemic spleen, enlarged lymph adenopathy.39 elevated liver enzymes; &/or spleen; enlarged during flares.40,41 lymphadenopathy. Some common. Many cytosis–spleen/lymph IVIG for low immuno- Rosai-Dorfman sinus many have enlarged ströms. >45% w/enlarged enlarged lymph nodes.1 enlarged lymph nodes.1 w/enlarged spleen.78 common.1,11 Risk of organ failure if common–can be severe.18 the kidneys.19 infection w/severe nodes.34,35,36 enlarged lymph nodes.26,27 lymph nodes.43 w/mesenteric adenitis.45,46 w/enlarged liver &/or nodes. Enlarged liver &/ globulins & frequent histiocytosis w/massive lymph nodes.1 lymph nodes.13 untreated.16 flares.58,61 spleen.44 or spleen.49 infections. Few w/CVID.65 lymphadenopathy.69,70,71 JOINTS/BONES Arthralgias, stiffness & Arthralgias, recurrent Joint pain, knee valgus 80% have muscle, bone Mono/Polyarthritis, Intermittent or chronic Arthralgias common, Congenital defects are Joint swelling, severe Periarticular tender soft Joint swelling, limp, Muscle weakness during Intermittent joint pain, Episodic inflamma- Symmetrical chronic Myalgia, arthralgia, fa- Joint Contractures, 45% have arthralgias Arthralgias, fatigue and Arthralgias may come Myalgias, arthralgias &/ Hemophagocytosis in the Not noted.64,65 Not noted.67,68 Short stature. Arthralgias. Not noted.73,74 swelling with flares.1 arthritis, stiffness & or varus. Some w/frontal &/or joint pain; arthri- oligoarthritis & clubbing arthritis in large joints symmetric polyarthritis often noted: micro- bone pain. Bone biopsy tissue swelling. Bone severe bone pain over af- fevers & flares. Risk for psoriatic arthritis. 30% tory arthritis, often to polyarthritis or oligoar- tigue & malaise w/flares. muscle atrophy, pan- &/or arthritis–often the malaise. No permanent before the arthritis. 88% or arthritis are common. bone marrow. Delayed Some have concurrent Dysmorphic facial MUSCLES & swelling with flares.1 bossing, saddleback tis. Bone pain is most are common. Ankle w/muscle pain & swell- frequently noted.1 cephaly, dolichocephaly, shows no infection. biopsy shows no infec- fected bones (mostly long inflammatory arthritis.59,61 of affected patients in one joint at a time that thritis of the wrists, Permanent bone or joint niculitis induced knees &/or ankles, but joint or bone issues have polyarticular or Wrist changes after 6 closure of the bones of autoimmune diseases features: Triangular face, nose, contractures, common in the iliac arthralgias are common. ing.1 wide irregular fontanels, Common: Balloon-like tion. Early-onset Chronic bones). 2-18 bone lesions one European family w/ doesn’t resolve on it’s knees, ankles w/ a boggy damage not noted.39 lipodystrophy, myositis, other joints can be noted, and patients are oligoarticular arthritis, months. 41% develop the skull in infants, bulg- that may involve the rotated ears, macrocrania, CARTILAGE clubbing.1 <50% of and tibia. <40% have Severe arthritis of the low set and posteriorly widening of the ante- Recurrent Multifocal are commonly found. PSORS2 also had psori- own. Intermittent sterile appearance is usually fatigue and malaise. affected. May be the first symptom-free between most often in the wrists, intercarpal and carpo- ing fontanel often noted. joints, such as inflamma- exophtalmia. Pectus exca- patients knees have bone lesions. Some w/ hip or ankle is rare.1 rotated ears, downslant- rior rib ends, periosteal Osteomyelitis (CRMO), Earlier age of onset & atic arthritis.24 pauciarticular, peripher- caused by an exuberant Inflammed nose & ear sign of Behçets. X ray is PFAPA flares.40,41 knees, &/or ankles. metacarpal joint space Neck stiffness, abnormal tory arthritis or undif- vatum, wide-set nipples, bony overgrowth. Short osteocondensation & ed palpebral fissures. elevation along multiple periarticular tender soft many bone lesions=more al erosive arthritis. Joint tenosynovitis.34,35,36 cartilage (chondritis). normal but synovium of- Some w/cervical spine, narrowing a few yrs. muscle tone, impaired ferenciated connective widened ribs, long bone stature, growth delays sclerotic bone mar- Hypotonia, myopathy, long bones, multifocal tissue swelling, short severe disease. Bone damage & destruction Growth delays–low ten has high neutrophils hip, temporomandibular after onset of AOSD–25% muscle coordination, tissue diseases.65 changes, short, square failure to thrive, arthritis, row involvement in the & failure to thrive are osteolytic lesions. Other stature, delayed bone biopsy/cultures show no can often develop from height & weight.26,27 or mononuclear cells & joint arthritis or synovial then develop pericapitate paralysis.48,49 hands, sacrococcygal & osteopenia noted.1,26 legs.13 common.11 bones affected.16 age, contractures.18 infection. 19,22 the arthritis.29,30,31,32,55 a vasculitis process.43 cysts.45,46 ankylosis.44 dimple, contractures.69,70 VASCULITIS Not noted.1 Not noted.1 Vasculitis rarely Vasculitis noted in 20% HSP, polyarteritis HSP, lymphocytic Cutaneous vasculitis Not noted.11 A few w/localized or Not noted.18,53 Some w/Takayasu arteri- Not noted.59,60 Not seen.23, 24 Not noted.29 Some w/vasculitis, leuko- Not noted.38,39 Not noted.26,27 Extensive vasculits. 30% Not noted.40,41 Not noted.45,46 Not noted.44 Not noted.47,48,49 Not noted.64,65 Not noted.67,68 Not noted. Some w/vari- Diffuse vasculopathy in develops.1 of patients.13 nodosa.1 vasculitis.1 common, HSP is rare.1 cerebral vasculitis.16 tis, or ANCA+ Vasculitis.54 cytoclastic vasculitis.34 w/venous thrombosis.43 cose veins on legs.69 the skin, liver & brain.73,74 AMYLOIDOSIS Elevated serum amy- Elevated SAA. Elevated SAA. Second- A few patients have Common >50% in 10-20% occurrence– <5-10%–uncommon.9 Not noted-unknown.9,11 Not noted.15,16,17 Not noted.18,53 Not noted.19,22 ,54 Not noted.59,60 Not noted.23, 24 Not noted.29 Not noted.34 Not noted.39 Not noted.26,27 Not noted.42,43 Not noted.40,41 Amyloidosis occurs in Very rare.44 Not noted.47,48,49 Not noted.64,65 Not noted.67,68 Not noted.69,70,71,72 Not noted.73,74 loid (SAA). Secondary >25 % w/secondary ary amyloidosis in <2% developed secondary untreated patients, it higher risk w/cysteine 7.4% of pts. in the USA, amyloidosis in some amyloidosis.1,9 pts.1,6 amyloidosis.13 depends on genotype.9 mutation.9 and 16% in Turkey.46 patients.1,9 ABNORMAL High: ESR, CRP, SAA. High: ESR, CRP, SAA. Chronically high: ESR, Monoclonal IgM &/or High: ESR, CRP, SAA High: ESR, CRP, SAA. High: ESR, CRP, SAA Anemia, leukocytosis, High: ESR, CRP, leukocy- Congenital dyserythro- Whole body MRI can High during flares (most Mildly elevated WBC, Cultures of bone & skin High CRP & ESR, ACE, Elevated CRP may be Hypochromic or normo- Leukocytosis common. High: ESR, CRP, WBC High: ESR, CRP, WBC, High: ESR, CRP, LFTs, High: ESR, CRP, triglycer- High IgE. Low serum IgA, Low circulating IgA, IgM Chronically elevated, High: CRP, ESR w/flares. Leukocytosis with Leukocytosis,with CRP, SAA, anemia, IgG gammopathy. High: between flares. Elevated PMNs, w/flares. High IgD w/IgA thrombocytopenia. High: tosis, chronic anemia.16,56 poietic anemia (CDA). reveal multifocal bone pts.): ESR, CRP, neu- CRP & ESR rarely are negative. Purulent immunoglobulins. noted during flares. But cytic anemia. High CRP, Normal–rarely elevated during flares–normal SAA, ferritin, aldolase. ferritin. Low glycosy- ides, LFTs, soluble CD25, IgG, IgM. Decreased cir- antibodies, decreased but increase during Cytopenia. Blood: 10-fold LABS flares.1 flares.1 granulocyte ESR, CRP. Leukocytosis. Fibrinogen, Leukocyto- polyclonal gammopathy, in 80% pts. Mevalonate ESR, CRP, SAA, CK, IgD, High ESR. WBC can be lesions.20 Normal or trophils, lactate levels, elevated–only during synovial fluid full of neu- Anemia, leukopenia, some pts. do not have ESR, triglycerides. Some ESR or CRP. Some cryo- levels when not flar- Elevated LFT’s. Leuko- lated ferritin. Leukocy- ferritin. Low: platelets, culating CD19+ B cells, class-switched memory flares: CRP, ESR, WBC. decrease in ADA2. Low leukocytosis.1,6 Complement normal to sis present with flares.1 leukocytosis.1 aciduria noted during IgA. IgE; chronically high normal, or elevated– elevated WBC, ESR, Low: plasma albumin, flares of symptoms.56 trophils. High w/flares: eosinophilia, hematu- elevated CRP w/ flares.39 w/elevated platelets, globulinemia, elevated ing.40,41 cytosis, thrombocytosis tosis, anemia common fibrinogen. Low NK cell IgG+ & IgA+ memory B cells & NK T cells. High during flares: IgG, ADA2-specific adenosine elevated. 50% w/inflam- flares.1 Mevalonate aciduria.1,11 neutropenia in infancy. CRP.19,22,54 calcium, zinc. Risk for CRP, ESR, WBC.29,30,32 ria, proteinuria, pyuria, TSH, &/or LDL.26,27 factor VIII, fibrinolysis.43 Anemia.45,46 w/flares. Prolonged PTT cytotoxic function, B cells, NK cells. >60% ANA negative.67,68 Ig A. Pts. can become deaminase activity: blood matory anemia.13 Cultures negative.18 infections w/flares.59,60 abnormal LFTs (LF).34,36 (DIC risk.)44 neutropenia, anemia.49 +ANA. WBC normal.64,65 very anemic.69,70,71,72 & CD14+ monocytes.73,74

The rash can vary in size, The CAPS rash is often NOMID pt. w/rash, frontal Schnitzler syndrome: Urti- FMF: Erysipelas-like erythe- TRAPS rash on the chest HIDS: Maculopapular rash MA: 21 month old pt. w/ DIRA: Generalized pustulo- Sweet’s Syndrome is often Palmar pustulosis SAPHO 3 yr. old w/generalized Pustular psoriasis–seen w/ PAPA: Pyoderma gangreno- Blau syndrome: Reddish- Urticarial rash w/flares CANDLE: Child w/facial lip- Behçet’s Disease: Oral PFAPA: Aphthous stomatitis. soJIA: Salmon-pink rash AOSD: Salmon trunk erup- Generalized purpuric ma- Cold-induced urticarial APLAID vesiculopustular Pt. w/hyperpigmentation. Livedo reticularis type rash & intensity in all forms of more pronounced during bossing, & saddleback carial skin rash on the arm. ma around the ankle. (Arthritis of a child. (Swiss Med Wkly. on the hand. (cri-net.com Auto facial dysmorphism. (Orphanet sis. (NOMID Alliance pt. image) present w/Majeed. (pbase. (CRMO). (cri-net.com SAPHO Syn- pustular psoriasis. (dermis.net/ CAMPS. (dermatlas.med.jhmi.edu/ sum. (dermatlas.med.jhmi.edu/image/ brown papules. (Dermatology after cold exposure. odystrophy, rash & swollen ulcers. (dermis.net/dermisroot/ (drpaulose.com; blog.timesunion.com/ on abdomen. (Joint Bone Spine, tion on a young adult pt. cules in Familial HLH. (Arch rash. (NOMID Alliance pt. image) rash. (sciencedirect.com/science/ (onlinelibrary.wiley.com/doi/10.1111/ is seen on DADA2 pts. CAPS. (NOMID Alliance pt. image) flares.(NOMID Alliance pt. image) nose. (NOMID Alliance pt. image) (cri-net.com Schnitzler image 6) Research & Therapy 2009 11:212) 2012;142:w13602) Inflammatory Diseases image 23) Journal of Rare Diseases 2006 1:13) com/leobarco/image/69914524) drome image 29: Spondylarthropathies) dermisroot/en/32493/image.htm) image/pustular_psoriasis_1_061124) pyoderma_gangrenosum_1_020918) Online Journal 15 (12): 5) (NOMID Alliance pt. image) lips. (NOMID Alliance pt. image) en/17101/image.htm Behçet’s disease) mdtobe Mystery Monday 125) Volume 74, Issue 5, Pages 500-503) (cri-net.com AOSD image 1) Dermatol. 2002;138(9):1208-1212) article/pii/S0002929712004181) pde.12085/full#pde12085-fig-0001)

Main authors: Karen Durrant RN, BSN–President of The NOMID Alliance, & Dr Juan Ignacio Aróstegui MD–Immunologist at the CDB Hospital Clínic in Barcelona, Spain & Director of La Unidad de Enfermedades Autoinflamatorias (autoinflamatorias.com) List of abbreviations: All Cited References & Full Image Credits are Listed on the Back Side The NOMID Alliance is a 501(c)(3) non-profit Acknowledgements: A special thanks to the many medical doctors who have helped to make voluntary suggestions in regards to this reference chart: Dr Juan Ignacio Aróstegui, Dr Hal Hoffman, Dr Raphaela Goldbach-Mansky, Dr Anna Simon, Dr Polly Ferguson, Dr Rebecca Marsh, Dr Daniel Kastner, Dr Luca Cantarini, Dr Véronique Hentgen, Dr Nico M. Wulffraat, Dr Kieron ACE: Angiotensin-converting enzyme (lab test) CRP: C-reactive protein (lab test); NK cells: Natural killer cells of this Chart. organization dedicated to improving aware- ADA2: Adenosine deaminase 2 DIC: Disseminated intravascular coagulation PMNs: Polymorphonuclear leukocytes (on lab tests w/ WBC count) ness, care and treatment for patients with Leslie & Dr Lori Broderick. Thank you Nathan Durrant for donating your graphic design services. Our deepest thanks to The NOMID Alliance Board of Directors, & to all the patients & families who have supplied images for this chart, & support for The NOMID Alliance. You are our greatest inspiration and strength! A special thanks to all of the doctors from the International This chart is an educational reference to increase awareness about Society of Systemic Auto-Inflammatory Diseases (ISSAID) for their research & dedication to patients with autoinflammatory diseases, plus the opportunity to present this 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 ANCA+ Vasculitis: Granulomatosis w/polyangiitis (GPA); Wegener’s ESR: Erythrocyte sedimentation rate (lab test); Westergren ESR pt.: abbreviation for the word “patient” CAPS or other autoinflammatory diseases. GI: Gastrointestinal (organs in the abdomen) PTT: Partial thromboplastin time (lab test) autoinflammatory diseases. 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; Der- ARDS: Acute Respiratory Distress Syndrome P.O. Box 590354 HSP: Henoch–Schönlein purpura, anaphylactoid purpura SAA: Serum amyloid A protein (lab test) matology Online Atlas. (DermIS Dermatology Information System), the Pediatric Rheumatology European Society (PReS), PRINTO, the EUROFEVER Project, EULAR, CARRA & the many other research centers and doctors around the world. Thanks to The American College of Rheumatology (ACR) for their efforts & for our non-profit rate booth at ACR 2013 Annual Meeting. CD14+ monocytes: Cluster of differentiation 14 positive monocytes This document is not intended to replace professional medical care, diag- San Francisco, CA 94159 ICP: Intracranial pressure TSH: Thyroid-stimulating hormone (lab test); thyrotropin CD19: B-lymphocyte antigen CD19-aka Cluster of Differentiation 19 nosis and/or treatment by a qualified specialist. It is to be used only for 1-415-831-8782 IDDM: Insulin-Dependent Diabetes Mellitus w/: abbreviation for the word “with” 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. Novartis Pharmaceuticals Canada Inc. provided The NOMID Alliance with an unrestricted grant in 2012 to help with the initial development & printing costs for this chart. A CD25: Soluble interleukin-2-receptor non-commercial, educational purposes. © 2013 The NOMID Alliance. [email protected] generous unrestricted grant from Swedish Orphan Biovitrum AB (Sobi) in 2013 is currently supporting many projects, including: the printing of this chart for the ACR meeting, patient picnics in 2014, & an educational grant for our injection tips guide for families, and some other projects that will be developed in 2014. The NOMID Alliance has received a number of unrestricted CNS: Central Nervous System (involving the brain, spinal cord) LFTs: Liver function tests (lab test): AST, ALT, GGT, ALK Phos, Bilirubin WBC: White Blood Count (lab test) grants at various times from Regeneron, Novartis & Sobi for grant-specific projects. Karen Durrant has received reimbursement 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. *These noted diseases are also referred to as “Classic” Hereditary Periodic Fever Syndromes (CAPS, FMF, HIDS, & TRAPS)