AUTOINFLAMMATORY DISORDERS

PERIODIC FEVER SYNDROMES GINO TANN

Copyright 2008 American Society of Hematology. Copyright restrictions may apply.Dale, D. C. et al. Blood 2008;112:935-945Figure 5 Overview of the pattern-recognition receptor system of phagocytes, including the TLR family

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757Temporal Patterns of Fever and Associated Clinical Findings in a Patient with Familial Mediterranean Fever (Panel A), a Patient with the Hyper-IgD Syndrome (Panel B), and a Patient with the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (Panel C)

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757Distinctive Features of Familial Mediterranean Fever, the Hyper-IgD Syndrome, and the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome

Contrast-enhanced chest CT scan showing a left-sided pleural effusion.Katsenos S et al. Chest 2008;133:999-10012008 by American College of Chest Physicians

Tel-Hashomer Criteria for Diagnosis of FMF

Major criteriaRecurrent febrile episodes accompanied by serositis or synovitisAmyloid A amyloidosis without a predisposing causeResponse to continuous colchicine prophylaxisMinor criteriaRecurrent febrile episodesErysipelas-like erythemaFMF in a first-degree relativeDefinite diagnosisTwo major or one major and two minor criteriaProbable diagnosisOne major and one minor criteria

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757Structure of the Gene for Familial Mediterranean Fever (MEFV )PYRINMEFV (MEditerranean FeVer)

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757Petechiae and Purpura on the Lower Right Leg during a Febrile Attack in a Patient with the Hyper-IgD Syndrome

Copyright 2003 American Academy of PediatricsPrietsch, V. et al. Pediatrics 2003;111:258-261Fig 1. MRI of patient 3 at the age of 6 years, showing the severe cerebellar atrophyCEREBELLAR ATROPHY HYPER IgD syndrome

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757Metabolism of Mevalonate and Biosynthesis of Cholesterol in Mammalian Cells

Drenth J and van der Meer J. N Engl J Med 2001;345:1748-1757Hypothesized Pathogenesis of the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome

Copyright 2007 American Physiological SocietySimon, A. et al. Am J Physiol Regul Integr Comp Physiol 292: R86-R98 2007;doi:10.1152/ajpregu.00504.2006Fig. 1. Synthesis and secretion of IL-1beta and formation of the cryopyrin inflammasome

Drenth J and van der Meer J. N Engl J Med 2006;355:730-732The Cryopyrin Inflammasome

NLRs and relevant proteins Journal of Leukocyte Biology. 2008;83:13-30

PYRIN domain and related proteinsStehlik, Reed Journal of Experimental Medicine 2008:200:551-558 2008 Stehlik et.al.

Potential molecular mechanisms underlying PFSsStehlik, Reed Journal of Experimental Medicine 2009:200:551-558 2009 Stehlik et.al.

Copyright 2007 American Physiological SocietySimon, A. et al. Am J Physiol Regul Integr Comp Physiol 292: R86-R98 2007;doi:10.1152/ajpregu.00504.2006Fig. 2. Two current hypotheses on the mechanism of pyrin action

Figure 1. Steps in the processing and secretion of IL-1Dinarello Journal of Experimental Medicine 2008:201:1355-1359 2008 DinarelloLL37

Figure 2. Systemic manifestations of IL-1Dinarello Journal of Experimental Medicine 2008:201:1355-1359 2008 Dinarello

Copyright 2002 American Physiological SocietyLeon, L. R. J Appl Physiol 92: 2648-2655 2002;doi:10.1152/japplphysiol.01005.2001Fig. 1. Pathway of fever development in response to infection, inflammation, or trauma

HEREDITARY PERIODIC-FEVER SYNDROMESHereditary Systemic Autoinflammatory DisordersFamilial cold autoinflammatory syndrome

Muckle-Wells syndrome

Episodes of urticarial rash and systemic inflammationNo bony overgrowthNo CNS abnormalities

Mutations in CIAS1 gene encodes cryopyrin (NALP3)CIAS1-associated diseases

FCASMWS

Hawkins P et al. N Engl J Med 2003;348:2583-2584Serial Measurements of Plasma Concentrations of Serum Amyloid A Protein in Two Patients with the Muckle -Wells Syndrome

Urticaria-like rash in 1st 6 weeks of lifeBony overgrowth in kneesChronic aseptic meningitisIncreased intracranial pressureCerebral atrophyVentriculomegalyChronic papilledemaOptic nerve atrophy with loss of visionMental retardationSeizuresSensorineural hearing lossShort statureHepatosplenomegalyLeukocytosisIncreased serum amyloid A, CRP and ESR20 % mortality before adulthoodSystemic amyloidosis in 25 % casesNeonatal-onset multisystem inflammatory disease (NOMID)Chronic infantile neurologic, cutaneous, articular syndrome (CINCA)Goldbach-Mansky R et al. N Engl J Med 2006, 355: 583-592

Goldbach-Mansky R et al. N Engl J Med 2006;355:581-592Inflammatory Organ Manifestations in Neonatal-Onset Multisystem Inflammatory Disease before (Panels A, C, E, and G) and after (Panels B, D, F, and H) Treatment with Anakinra

Hull K et al. N Engl J Med 2002;346:1415-1416Glomerular Amyloid Deposition in a Renal-Biopsy Specimen (Congo Red, x400)

Mutations in CIAS1 Blood, 1 April 2004, Vol. 103, No. 7, pp. 2809-2815

TABLE 1. Criteria for the diagnosis of adult onset Still's disease (Yamaguchi et al. 1992 [28]). Five or more criteria (including two major) required for diagnosis

Major criteria Minor criteria

ANA, antinuclear antibody; RF, rheumatoid factor. Rheumatology 2002; 41: 216-222

Fever >39CSore throatArthralgiasLymphadenopathy or splenomegalyStill's rashHepatic dysfunctionNeutrophilic leucocytosisNegative RF and ANA

NON EROSIVE CARPAL FUSIONRheumatology 2002; 41: 216-222

TABLE 2. Positive/abnormal tests

Value Rheumatology 2002; 41: 216-222 VARIABLE

Erythrocyte sedimentation rate (mm/h)120(020)C-reactive protein (mg/dl)21.600.8Haemoglobin (g/dl)7.91215White blood cell count (x10/mm3)25.63.410Aspartate transaminase (U/L)881132Alanine transaminase (U/L)65530Lactate dehydrogenase (U/L)317110205Ferritin (ng/ml)984612250

TABLE 3. Negative/normal testsRheumatology 2002; 41: 216-222

Antinuclear antibodiesAnti-double-stranded DNA antibodiesAnti-SmithAnti-RoAnti-LaAnti-RNPC3C4Rheumatoid factorANCASerum protein electrophoresisCreatine kinase

Angiotensin converting enzyme concentrationAnti-cardiolipin antibodyFamilial Mediterranean fever genetic testLyme antibodyVDRL testPurified protein derivativeCytomegalovirus (buffy coat, urine)Human immunodeficiency virus antibodyCultures: blood, urine, cerebrospinal fluid, bone marrow, broncho-alveolar lavage fluid

TABLE 4. Pathology reports

Bone marrowMarked granulocytic hyperplasia; no dysplasiaLiverPatchy periportal inflammation; moderate steatosisCervicalNon-specific reactive histologylymph nodeLacrimal glandNormal histology with no lymphoid infiltrate orevidence of epithelial malignancySpleenFollicular hyperplasia; negative for lymphomaSmall intestineMild villous atrophy; Congo Red stain negative for amyloidRheumatology 2002; 41: 216-222

Acute rash at the onset of SJIAExpression of S100A9 by keratinocytesRheumatology 2008 47(2):121-125

Figure 3. Values of (a) temperature; (b) active joint count; (c) white blood cells (WBC); (d) hemoglobin; (e) platelet count; and (f) ESR in 9 SoJIA patientsPascual et al. Journal of Experimental Medicine 2009:201:1479-1486 2009 Pascual et.al.

SWEETS SYNDROME ( Acute Febrile Neutrophilic Dermatosis)

Moderate to high fever Pink eye (conjunctivitis) or sore eyes Tiredness Aching joints and headache Mouth ulcers

PAPA syndrome Rheumatology 2005 44(3):406-408 Syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), also known as CD2-binding protein 1

PYODERMA GANGRENOSUMEcthyma-likePost-surgicalPeristomal-UCSevere

PG

Weenig R et al. N Engl J Med 2002;347:1412-1418Ulceration Resembling Pyoderma Gangrenosum but Due to Antiphospholipid-Antibody Syndrome

Weenig R et al. N Engl J Med 2002;347:1412-1418Frequency of Diagnostic Findings on Initial or Repeated BiopsyDD: PYODERMA GANGRENOSUM

Dinarello C. N Engl J Med 2000;343:732-734The Actions of Interleukin-1 (IL-1) and Interleukin-1-Receptor Antagonist (IL-1Ra)

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437Inflammatory Skin and Bone Manifestations in Patients with Deficiency of Interleukin-1-Receptor Antagonist

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437Mutations in the IL1RN Gene Encoding Interleukin-1-Receptor Antagonist and a Genomic Deletion in the Study Patients

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437Functional Consequences of Deficiency of Interleukin-1-Receptor Antagonist

Aksentijevich I et al. N Engl J Med 2009;360:2426-2437Clinical and Laboratory Response of Patients with Deficiency of Interleukin-1-Receptor Antagonist to Treatment with Anakinra

THANK YOUGT05122009

Figure 1. Temporal Patterns of Fever and Associated Clinical Findings in a Patient with Familial Mediterranean Fever (Panel A), a Patient with the Hyper-IgD Syndrome (Panel B), and a Patient with the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (Panel C). Each panel shows the temperature during an attack of fever in a hospitalized patient and the symptoms that accompanied the febrile attack. The bar graph below each curve shows the number of attacks that the patient had in a year, when they occurred, and their approximate duration. The patient with the TNF-receptor-associated periodic syndrome had long attacks twice in one year, whereas the patient with familial Mediterranean fever and the patient with the hyper-IgD syndrome had shorter but more frequent attacks.Table 1. Distinctive Features of Familial Mediterranean Fever, the Hyper-IgD Syndrome, and the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome.Contrast-enhanced chest CT scan showing a left-sided pleural effusion.Figure 2. Structure of the Gene for Familial Mediterranean Fever (MEFV ). The MEFV gene consists of 10 exons (coding regions). Exon 2 and exon 10 are the largest and most mutation-rich regions of the MEFV gene, but mutations have also been reported in exons 3, 5, and 9. Most mutations in the gene are missense mutations in which one amino acid has been replaced with another in the MEFV gene product, pyrin (marenostrin). The most common mutations in the MEFV gene are M694V (replacement of methionine with valine at codon 694) and V726A (replacement of valine with alanine at codon 726). Because familial Mediterranean fever is autosomal recessive, two MEFV mutations must be present in order for the disease to develop. Most genetic laboratories screen only for the most common mutations in exon 10 and in some cases for the E148Q mutation (replacement of glutamine for glutamic acid at codon 148) in exon 2 as well.Figure 3. Petechiae and Purpura on the Lower Right Leg during a Febrile Attack in a Patient with the Hyper-IgD Syndrome. The skin lesions disappeared a week after the end of the attack. The clinical findings in this patient (Patient 30 in the hyper-IgD syndrome registry in Nijmegen, the Netherlands) have been described in detail elsewhere.42Figure 4. Metabolism of Mevalonate and Biosynthesis of Cholesterol in Mammalian Cells. Mevalonate is the first committed intermediate of the cholesterol metabolic pathway. 3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase, which is the rate-limiting enzyme, can be inhibited by the administration of statins. Mevalonate kinase is the defective enzyme in the hyper-IgD syndrome, and the defect results in an accumulation of trace amounts of mevalonate in the urine of affected patients. The structural formulas corresponding to the intermediates in the branched pathway of cholesterol are shown at the left.Figure 5. Hypothesized Pathogenesis of the Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome. Under normal conditions, activation of the TNF receptor by TNF causes the activation of a protease that can shed the TNF receptor from the cell surface (upper panel). This process results in diminished cellular signaling of TNF. The shed TNF receptor is cleared in the extracellular space, where it can bind free TNF and limit the inflammatory response. It is postulated that in patients with the TNF-receptor-associated periodic syndrome, the TNF receptor is not shed from the cell surface (lower panel). In the absence of shedding, there is continuous signaling by TNF and, consequently, an inflammatory response.Tumor necrosis factor (TNF)-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is caused by an autosomal dominant mutation of the TNF receptor molecule (triangles). This molecule exists both as a transmembrane receptor (shown as a triangle attached to a cell) and as a soluble molecule antagonist to TNF (shown as a triangle in plasma). TNF is depicted by ovals. Control subjects have cells that release soluble TNF receptor molecules when challenged with an inflammatory response. Patients with TRAPS are unable to release a sufficient amount of soluble TNF, thereby they lack the self-regulatory control of the inflammatory process Synthesis and secretion of IL-1 and formation of the cryopyrin inflammasome. a: Toll-like receptor (TLR)-4-stimulated NF- B activation leads to transcription of pro-IL-1 , which then moves to the cytoplasm and to specialized lysosomes. b: upon activation of cryopyrin by ligands such as bacterial RNA, the NACHT-domain (the abbreviation is derived from a combination of NAIP, CIITA, HET-E, and TP1 domain) becomes exposed, and a complex of proteins called the cryopyrin inflammasome is formed. c: formation of the inflammasome activates pro-caspase-1 into caspase-1, which can, in its turn, activate the pro-IL-1 into IL-1 . P2X7-receptor activation, then mediates the secretion of bioactive IL-1 . There are contradictory reports on the effect of the cryopyrin inflammasome on NF- B (see text). PYD, pyrin domain; LRR, leucine-rich repeat domain; ASC, apoptosis-associated specklike-like protein with a caspase-recruitment domain (CARD). Figure 1. The Cryopyrin Inflammasome. Cryopyrin, or NALP3, is the central component of the cryopyrin inflammasome. Cryopyrin contains three domains: a pyrin domain (PYD), a nucleoside oligomerization domain (NOD), and a domain of leucine-rich repeats (LRR). The other components of the cryopyrin inflammasome ASC -- apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD), cardinal, and procaspase-1 (Panel A) -- consist of domains that can be assembled only after cryopyrin is activated through the interaction of its LRR domain with either a crystal (urate or calcium pyrophosphate dehydrate) or certain microbial species (Panel B). The assembly of the domains ultimately leads to the release of active caspase-1, which in turn activates interleukin-1beta through the cleavage of pro-interleukin-1beta. On its secretion into the extracellular milieu, interleukin-1beta sets off a series of events that result in inflammation. FIIND denotes the domain with function to find.At present, three human inflammasomes are discerned, named for the NOD-LRR protein involved: the NALP1 inflammasome, activating caspase-5 as well as caspase-1, and the NALP3 (or cryopyrin) inflammasome and Ipaf inflammasome, both activating caspase-1 (104). More variants are expected to emerge, as there is a repertoire available of at least 14 NOD-LRR proteins and 13 caspases. NALP3 [Nacht domain-, leucine-rich repeat- and pyrin domain (PYD)-containing protein] and PYPAF1 (pyrin domain-containing APAF-like protein). NLRs are classified into subfamilies by protein interaction domains such as CARD or pyrin domain (PYD). NACHT (NBD) and LRRs are domains common to all NLRs. Two major subfamilies are the CARD and pyrin subfamilies. Although they are not NLRs, putative helper and adaptor proteins are also shown, including apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC; adaptor for NLRs), Nalp10, and PYRIN (negative regulator of Caspase-1 activation). DEFCAP, ; AD, activation domain; BIR, baculovirus inhibitor of apoptosis repeat; SPRY. ATP-binding region (Walkers A box) or the magnesium-binding region (Walkers B box) PYRIN domain and related proteins. PYRIN domain and some related proteins are presented. Domains shown include: CARD; hematopoietic interferon-inducible nuclear proteins with a 200-amino-acid repeat (HIN200/IFI20); NAIP, CIITA, HET-E, and TP1 (NACHT); LRR; baculovirus inhibitor of apoptosis repeat (BIR); Trp-Asp 40 (WD40); activation domain (AD); NACHT-associated domain (NAD), TIR; coiled-coil (CC); cysteine-rich domain (CYS); transmembrane domain (TM); zinc finger B-box (zf-B-box); Dictyostelium discoideum dual specificity kinase SplA and ryanodyne receptor (SPRY); SPRY associated (PRY); domain with function to find (FIIND).The NOD-LRR proteins form a protein family that seems to be deeply involved in the regulation of immune responses (147). They are also known as CATERPILLER proteins [CARD (caspase-recruitment domain)-transcription enhancer, R-binding, pyrin, lots of leucine repeats], NACHT-LRR proteins (NAIP, CIITA, HET-E and TP1 domain-leucine rich repeats; NACHT is an alternative name for the NOD) or NOD-like receptors (32, 147). The NH2-terminal part of all the proteins in this family consists of a NOD-LRR configuration. The NOD is important for protein-protein interactions; the LRR domain is hypothesized to be involved in the interaction with PAMPs, in analogy with TLRs (147). Some of the NOD-LRR proteins have been shown to be part of an intracellular pathogen-sensing system in the innate immune response. The COOH-terminal part of the NOD-LRR proteins is variable. Pyrin consists of four domains that can facilitate protein interactions. There is a 92-amino acid NH2-terminal pyrin domain (PYD), member of the death domain fold superfamily (17), a B-box zinc finger, a coiled-coil region and a COOH-terminal B30.2/rfp/SPIa and ryanodine receptor (SPRY)/domain (also known as PRYSPRY domain). Potential molecular mechanisms underlying PFSs. (A) PAN family proteins are thought to sense pathogens via their LRR domains, triggering NACHT domainmediated oligomerization, resulting in association with the adaptor protein ASC and activation of downstream effectors, including caspase-1 and IKK complex by the induced proximity mechanism. The ASC-associated Ser/Thr kinase Cardiak might potentially provide the link to IKK. Through PYRINPYRIN interactions, family members such as POP1 may prevent spontaneous activation of these downstream effectors. (B) NALP1, which is a unique PAN in that it contains COOH-terminal FIIND and CARD domains, has been suggested to connect via PYRINPYRIN interaction to ASC, which then links to procaspase-1 by CARDCARD interaction. NALP1 further utilizes its CARD to also recruit procaspase-5 into the inflammasome (45), resulting in activation of both caspases. (C) PANs, including Cryopyrin and NALP2 were recently demonstrated to form inflammasomes that also recruit ASC by PYRINPYRIN interaction, which then links to procaspase-1 by CARDCARD association. In addition, the CARD containing protein Cardinal, which resembles the COOH-terminal FIIND and CARD domain structure of NALP1, associates with these PANs via FIINDNACHT interaction and then recruits caspase-1 by CARDCARD association, leading to activation of this caspase and secretion of bioactive IL-1. Consistent with an inhibitory role for the LRR domain, this domain suppresses association of PANs and Cardinal, suggesting that LRR ligands might be required to induce this interaction. (D) Theoretically, PANs might also link via Cardinal to the IKK complex.Steps in the processing and secretion of IL-1. (A) TLR ligands such as endotoxin trigger gene expression and synthesis of the IL-1 precursor, which remains diffusely in the cytosol. In the same cell, inactive procaspase-1 is bound to components of the IL-1 inflammasome, which contains the products of the NALP-3 gene. The IL-1 inflammasome is kept in an inactive state by binding to a large molecular weight putative inhibitor. (B) After TLR signals, there is a transient uncoupling of the inhibitor and NALP-3 gene products from procaspase-1, which then colocalizes with the IL-1 in secretory lysosomes. (C) Activation of the nucleotide receptor P2X7 by ATP or LL37 initiates the efflux of potassium from the cell via a potassium channel. The efflux of potassium activates the autocatalytic processing of procaspase-1. Active caspase-1 cleaves the IL-1 precursor in an active cytokine. (D) The efflux of potassium ions results in the influx of calcium ions, which in turn activate phospholipases. Phosphatidylcholine-specific phospholipase C (PC-PLA-2) facilitates lysosomal exocytosis and secretion of IL-1. Calcium-independent phospholipase A2 is required for caspase-1 processing in the specialized lysosomes, whereas phosphatidylcholine-specific phospholipase C is required for lysosomal exocytosis and release Systemic manifestations of IL-1. Active IL-1 is secreted by many cell types including monocytes and macrophages (center). IL-1 enters the circulation and triggers IL-1 receptors on the hypothalamic vascular network resulting in synthesis of cyclooxygenase-2, which causes brain levels of prostaglandin E2 to rise, thus activating the thermoregulatory center for fever production (reference 27). In the periphery, IL-1 activates IL-1 receptors on the endothelium resulting in rashes and the production of IL-6. Circulating IL-6 stimulates liver hepatocytes to synthesize several acute phase proteins, which accounts for the increase in erythrocyte sedimentation rate in SoJIA. IL-1 also acts on the bone marrow to increase mobilization of granulocyte progenitors and mature neutrophils, resulting in peripheral neutrophilia. IL-1induced IL-6 increases platelet production, which results in thrombocytosis. IL-1 also causes decreased response to erythropoietin, which causes anemia.Figure 1. Serial Measurements of Plasma Concentrations of Serum Amyloid A Protein in Two Patients with the Muckle -Wells Syndrome. The arrows indicate when treatment with the recombinant human interleukin-1-receptor antagonist began. The median plasma concentration of serum amyloid A protein in Patient 1 between May 1998 and October 2002 was 22 mg per liter (interquartile range, 12 to 56), and the median concentration in Patient 2 between August 1998 and November 2002 was 48 mg per liter (interquartile range, 14 to 82).Figure 1. Inflammatory Organ Manifestations in Neonatal-Onset Multisystem Inflammatory Disease before (Panels A, C, E, and G) and after (Panels B, D, F, and H) Treatment with Anakinra. The severity of rash, conjunctivitis, and leptomeningeal and cochlear enhancement on MRI is shown at baseline (Panels A, C, E, and G [arrow], respectively) and after three months (Panels B, D, F, and H) of anakinra therapy.Figure 1. Glomerular Amyloid Deposition in a Renal-Biopsy Specimen (Congo Red, x400). Panel A shows amyloid deposits, predominantly in mesangial nodules. Panel B shows the same specimen as in Panel A, viewed under polarized light; the characteristic yellow-green birefringence of amyloid deposits is visible.Locations of the mutations in CIAS1 encoding protein. All the mutations identified to date in CIAS1 that cause FCU, MWS, or CINCA/NOMID syndromes are located in exon 3, which encodes the NACHT domain and its flanking regions. Mutations previously reported are indicated above the protein structure, whereas new mutations identified in this study appear below the protein structure. NALP/PYPAF (PYRIN-containing Apaf-1-like protein) CATERPILLER (CARD, transcription enhancer, R(purine)-binding, pyrin, lots of LRR). NALP (NACHT-, LRR-, and PYD-containing proteins) (A) Acute rash at the onset of SJIA. (B) Expression of S100A9 by keratinocytes and infiltrating phagocytes (immunoperoxidase staining, red) in skin biopsy of the acute rash in active SJIA. S100A12 seems to be a member of a novel inflammatory signalling pathway involving RAGE (receptor for advanced glycation end products) as a receptor transducing pro-inflammatory signals in endothelial cells and phagocytes. In contrast to S100A12, S100A8 and S100A9 have not been shown to bind to RAGE. After release by activated phagocytes complexes of both proteins bind specifically to endothelial cells. Potential ligands on endothelial cells (ECs) are heparansulphate proteoglycans or carboxylated N-glycans expressed by ECs after activation. S100-proteins are not processed by caspase 1 prior to release Molecular pathogenesis of SJIA. During the early course of SJIA so far unknown factors and signalling mechanisms (signal X) activate preferentially cells of the innate immune system like monocytes, macrophages or neutrophils. These signals result in activation of a multi-protein complex called inflammasome, which processes inactive pre-IL-1 and pre-IL18 to active cytokines by caspase-1-dependent proteolytic cleavage (left dotted circle). Mutations in proteins regulating the function of the inflammasome lead to well-defined auto-inflammatory syndromes. Beside IL-1 and IL-18 phagocyte-specific S100-proteins like the complex S100A8/S100A9 and S100A12 are significantly higher expressed in patients with SJIA compared with all other inflammatory diseases investigated so far. Like IL-1 and IL-18 these S100-proteins are released via a so-called alternative secretory pathway independent of the classical route via endoplasmatic reticulum and Golgi complex. However, S100-proteins are not activated by proteolytic cleavage by caspase-1. It therefore seems to be conceivable that a loss of regulation downstream of caspase-1 activation in the alternative secretory pathway is involved in the pathogenesis of SJIA (second dotted circle). However, the molecular mechanisms that are involved in intracellular trafficking and transmembraneous secretion of Il-1, IL-18 and S100-proteins are not identified so far. Values of (a) temperature; (b) active joint count; (c) white blood cells (WBC); (d) hemoglobin; (e) platelet count; and (f) ESR in 9 SoJIA patients. Values on the x axis represent months before (2) initiation of Anakinra treatment (0) and up to 212 mo of follow up (average, 6.6 mo). Arrows indicate the time of treatment initiation. p-values were calculated at time 0 and at 2-mo follow-up (paired, two-tailed t test). Color codes for individual patients (from Table I) are represented at the bottom.(a) Clinical symptoms described as pain, swelling, restricted flexion and extension of the right ankle in relation to treatment and laboratory findings. 1 = start of symptoms; 2 = first intra-articular depot (40 mg triamcinolone hexacetonide); 3 = second intra-articular depot; 4 = start of anakinra (1 mg/kg). (b) Right knee at presentation. (c) Right knee 1 week after starting treatment with anakinra. The mutations described in PAPA syndrome result in a mutated CD2BP1 (CD2 binding protein 1, also known as PSTPIP1; prolineserinethreonine phosphatase interacting protein). The function of CD2BP1 is not completely understood, but mutations can lead to decreased apoptosis, explaining the observed accumulation of neutrophil-rich material. This 416-amino acid protein contains three known domains: an NH2-terminal Fer-CIP4 domain, a coiled-coil domain, and an SH3 domain.. the coiled-coil domain is important for protein-protein interactions (84). Through this domain, PSTPIP1 binds to pyrin (the SH3 domain is also necessary for this interaction) (84) and to protein tyrosine phosphatase with a PEST (proline, glutamate, serine, threonine) domain (PTP-PEST) Figure 1. Ulceration Resembling Pyoderma Gangrenosum but Due to Antiphospholipid-Antibody Syndrome. A 27-year-old woman presented with a nine-year history of systemic lupus erythematosus and debilitating leg ulcers. The ulcers were refractory to treatment with 80 mg of prednisone daily, cyclophosphamide, and dapsone. A circulating anticardiolipin antibody was identified. Definitive treatment consisted of a two-week course of low-dose tissue plasminogen activator, followed by maintenance therapy with aspirin. The ulcers healed completely and did not recur during 10 years of follow-up.Table 2. Frequency of Diagnostic Findings on Initial or Repeated Biopsy.Figure 1. The Actions of Interleukin-1 (IL-1) and Interleukin-1-Receptor Antagonist (IL-1Ra). Interleukin-1 activates its receptor on cells with various functions, which results in the production of secondary substances that mediate inflammatory events as well as tissue remodeling. In endothelial cells, interleukin-1 induces the release of platelet-activating factor (PAF), nitric oxide, and prostaglandin E (PGE), which reduce vascular resistance. Chemokines and the expression of adhesion molecules on the endothelial surface facilitate the emigration of circulating leukocytes into the tissues. Lymphocytes stimulated by interleukin-1 release lymphocyte growth factors that activate lymphocytes and promote expansion. Chondrocytes respond to interleukin-1 by producing collagenases that contribute to the breakdown of cartilage. The action of interleukin-1 on smooth muscle results in the production of growth factors. Interleukin-1-stimulated macrophages lead to the activation of osteoclast precursor cells and result in increased bone resorption. Fibroblasts activated by interleukin-1 release inflammatory mediators. When interleukin-1 receptors are occupied by the interleukin-1-receptor antagonist, interleukin-1 cannot bind and thus cannot elicit a biologic response. There is a natural balance between the proinflammatory activities of interleukin-1 and the ability of interleukin-1-receptor antagonist to keep those activities in check by occupying interleukin-1 receptors.Figure 1. Inflammatory Skin and Bone Manifestations in Patients with Deficiency of Interleukin-1-Receptor Antagonist. The skin manifestations range from groupings of small pustules (Panel A) to a generalized pustulosis (Panel B). The bone manifestations include epiphyseal ballooning of multiple distal and proximal long bones, in the single patient from Puerto Rico (Panel C); the more typical radiographic manifestations included widening of multiple ribs (with affected ribs indicated with asterisks) and the clavicle (arrows) (Panel D), heterotopic ossification or periosteal cloaking of the proximal femoral metaphysis (arrows) and periosteal elevation of the diaphysis (arrowheads) (Panel E), and an osteolytic lesion with a sclerotic rim (Panel F, arrow).Figure 2. Mutations in the IL1RN Gene Encoding Interleukin-1-Receptor Antagonist and a Genomic Deletion in the Study Patients. The pedigrees of six families with deficiency of interleukin-1-receptor antagonist are presented in Panel A, according to the country or region of ancestry and the amino acid mutation. Solid symbols indicate Patients 1 through 9, open symbols unaffected relatives, squares male subjects, circles female subjects, and slashes deceased patients. For the subjects for whom the IL1RN genotype was determined, H denotes heterozygous mutant, W wild type, and M homozygous mutant. Panel B shows the structure of IL1RN (isoform 1) exons (black boxes) and the sequences of the homozygous mutations (which are named under the plots, along with the resultant amino acid mutation). A genetic isolate in northwestern Puerto Rico is a founder population for a 175-kb genomic deletion between bases 113,434,601 and 113,609,824 on chromosome 2. This deletes genes encoding six interleukin-1-related genes: IL1RN and the genes encoding interleukin-1 family, members 9 (IL1F9), 6 (IL1F6), 8 (IL1F8), 5 (IL1F5), and 10 (IL1F10) (Panel C). The centromere and the region of interest are shown in red.Figure 4. Functional Consequences of Deficiency of Interleukin-1-Receptor Antagonist. Peripheral-blood granulocytes and leukocytes were obtained from seven controls with wild-type interleukin-1-receptor antagonist, six heterozygous carriers of mutant interleukin-1-receptor antagonist, and three homozygotes with mutant interleukin-1-receptor antagonist. The monocytes were stimulated with recombinant interleukin-1{beta} for 18 hours. Panel A shows the mean production of five selected chemokines and cytokines, which were significantly up-regulated in samples from patients homozygous for mutations resulting in deficiency of interleukin-1-receptor antagonist as compared with those from heterozygotes and controls. (P values are shown for comparisons of patients with the wild-type controls for each chemokine or cytokine.) T bars indicate the standard deviations. MIP-1{alpha} denotes macrophage inflammatory protein 1{alpha}, and TNF-{alpha} tumor necrosis factor {alpha}. Panel B shows the results of cytohistochemical analysis of interleukin-17 expression in skin specimens (alkaline phosphatase stain). The interleukin was markedly up-regulated in a patient with deficiency of interleukin-1-receptor antagonist as compared with a control.Figure 5. Clinical and Laboratory Response of Patients with Deficiency of Interleukin-1-Receptor Antagonist to Treatment with Anakinra. Laboratory values before and after treatment with the recombinant interleukin-1-receptor antagonist anakinra are shown in Panel A for each of the six patients who received the drug. Treatment with anakinra resulted in a rapid and sustained decline in the C-reactive protein level, erythrocyte sedimentation rate, and white-cell count; the platelet count normalized more slowly. The pink star in each plot indicates the time at which the Dutch Patient 6 had discontinuation of the therapy and a resultant flare-up of disease. Reinitiation of anakinra led to normalization of all four measures. Panel B shows an example of the clinical improvement in skin and bone manifestations after anakinra treatment was begun. Before treatment there was extensive pustulosis, diffuse erythema, and crusting on the skin of an affected child that nearly completely resolved just days after initiation of anakinra, with exfoliation of the skin occurring 7 days after (shown here). Improvement in bone findings was similarly dramatic, as seen on radiography, with osteolytic lesions (arrows) present in the proximal and distal tibial metaphysis and periosteal elevation (asterisk) before treatment and resolution 5 months after treatment.