1 Autoinflammatory Diseases in 2 3 4 Pediatrics 5 Q2Q3 Jonathan S. Hausmann, MD*, Fatma Dedeoglu, MD Q4 6 7 KEYWORDS 8  Autoinflammatory diseases  Periodic fever  Pediatrics  Familial Mediterranean fever  PFAPA 9  HIDS  TRAPS  CAPS 10 11 12 KEY POINTS 55 13 56  Viral infections are the most common cause of recurrent fevers in children. 14 57  Autoinflammatory diseases (AIDs) should be considered in a child with recurrent or persistent fever, 15 58 when infectious and malignant causes have been excluded. 16 59  17 AIDs are characterized by recurrent episodes of systemic and organ-specific , and are 60 18 caused by defects in the innate immune system. 61  19 Periodic fevers with , , and cervical adenitis is the most common AID 62 20 in children and occurs at regular intervals. 63 21  Familial Mediterranean fever is the most common monogenic AID and presents with recurrent 64 22 attacks of fever, , arthritis, and rash that last for 1 to 3 days. 65 23 66 24 67 25 68 26 69 27 Q6 INTRODUCTION inborn errors of the innate immune system.1 They 70 28 involve disorders of neutrophils, macrophages, 71 Repeated febrile illnesses are common in young 29 and molecules of innate immunity that evolved to 72 children, especially in those attending daycare 30 protect against external pathogens. These innate 73 and school. Most often, these febrile episodes are 31 immune cells are activated by endogenous or 74 caused by repeated viral infections. However, if 32 exogenous stimuli, so-called pathogen-associated 75 there is continued recurrence of fever and other 33 molecular patterns (PAMPs) and damage- 76 associated symptoms, it is important to maintain a 34 associated molecular patterns (DAMPs), which 77 broad differential that includes primary immuno- 35 lead to inflammation. 78 deficiencies, anatomic and metabolic abnormali- 36 In contrast with most autoimmune diseases, 79 ties, malignancies, and autoinflammatory diseases 37 AIDs usually present during childhood. Many are 80 (AIDs). The diagnosis of an AID may be challenging, 38 characterized by recurrent or persistent fever, 81 because there are numerous diseases, overlapping 39 and they are an important part of the differential 82 signs and symptoms, and lack of specific laboratory 40 diagnosis of the febrile child. It is essential for phy- 83 testing. 41 sicians who care for children to recognize these 84 AIDs are characterized by recurrent episodes of 42 disorders, and to refer these children to specialists 85 systemic and organ-specific inflammation. Unlike 43 who can initiate treatment, improve quality of life, 86 patients with autoimmune disorders such as sys- 44 and avoid long-term complications. temic lupus erythematosus, patients with AIDs 45 Research over the last 10 years has identified do not have the presence of or 46 many of the genes that cause AIDs. Most of these antigen-specific T cells. Instead, AIDs result from 47 diseases are monogenic and inherited in an 48 49 50 51 No disclosures. 52 Program in , Division of Immunology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA Q5 53 * Corresponding author. 54 E-mail address: [email protected]

Dermatol Clin - (2013) -–- http://dx.doi.org/10.1016/j.det.2013.04.003

0733-8635/13/$ – see front matter Ó 2013 Published by Elsevier Inc. derm.theclinics.com DET818_proof ■ 3 May 2013 ■ 10:58 am 2 Hausmann & Dedeoglu

87 autosomal dominant or recessive pattern. How- infections should be evaluated for immunodefi- 144 88 ever, understanding of these diseases continues ciencies, cystic fibrosis, or anatomic abnormal- 145 89 to evolve. Most children with periodic fevers ities. Parasitic infections with Plasmodium may 146 90 (greater than 80% in some studies) do not have mu- occur in children who have traveled to endemic 147 91 tations in known periodic fever syndrome genes.2 areas. 148 92 This article presents the differential diagnosis of Inflammatory bowel disease is a common cause 149 93 recurrent fever in children. It discusses periodic of recurrent fevers, and the fevers may precede 150 94 fevers with aphthous stomatitis, pharyngitis, and other signs of inflammatory bowel disease, such 151 95 cervical adenitis (PFAPA), the most common AID as abdominal pain, bloody stools, poor growth, 152 96 in children. It then focuses on the clinical presenta- and anemia, by weeks or months. 153 97 tion of monogenic AIDs that present with fevers In Behc¸ et disease, children also present with 154 98 in children, including familial Mediterranean fever recurrent oral and genital ulcers, uveitis, or skin 155 99 (FMF), tumor necrosis factor (TNF) receptor–asso- rashes such as erythema nodosum. Systemic ju- 156 100 ciated periodic syndrome (TRAPS), cryopyrin- venile idiopathic arthritis presents with at least 157 101 associated periodic syndromes (CAPS), deficiency 2 weeks of daily fevers, along with a rash, lymph- 158 102 of interleukin-36 receptor antagonist (DITRA), adenopathy, hepatosplenomegaly, or . 159 103 Majeed syndrome, and chronic atypical neutro- These two syndromes share many of the features 160 104 philic dermatosis with lipodystrophy and increased of AIDs but no clear genetic causes have been 161 105 temperature syndrome (CANDLE). Two granulo- identified. 162 106 matous disorders, pyogenic sterile arthritis, pyo- After the diagnoses mentioned earlier have been 163 107 derma gangrenosum, and acne (PAPA) syndrome evaluated, AIDs should be considered, especially 164 108 and Blau syndrome, are also discussed. if there is a family history of recurrent fevers or if 165 109 the child is of certain ethnic groups. One of the 166 110 167 RECURRENT FEVERS characteristics of AIDs is that the fever pattern 111 and associated features are similar between epi- 168 112 Fever is one of the most common reasons for chil- sodes. In most of these diseases, children are 169 113 dren to visit their pediatrician.3 Some children pre- well between episodes, although some of them 170 114 sent with recurrent or periodic fevers, defined as 3 follow a more chronic course and cause significant 171 115 or more episodes of fever in a 6-month period morbidity and mortality unless treated. Fever is not 172 116 without a known illness to explain the fevers, and a part of all of the AIDs, although this article 173 117 with at least 7 days between febrile episodes.4 focuses on the ones in which fever is present, 174 118 The approach to children with recurrent fevers and briefly touch on several without fevers. 175 119 should be different than that for children present- Clinical scoring systems have been created 176 120 ing with fever of unknown origin, because their to determine the likelihood that a child will have 177 121 causes may differ. an AID with a known genetic cause, and may 178 122 To better create a differential diagnosis, the help guide genetic testing (http://www.printo.it/ 179 123 pattern of the fevers should be characterized pre- periodicfever), although this needs to be validated 180 124 cisely, especially whether there is a regularity to in a diverse patient population. 181 125 the intervals of fever. Episodes of fever occurring 182 126 at regular intervals suggest a diagnosis of PFAPA PFAPA 183 127 or cyclic neutropenia. Other characteristics that 184 128 should be noted include the age of fever onset, The syndrome of PFAPA is the most common 185 129 cause of periodic fevers in childhood. First des- 186 height of the fever, and pattern during the day. 5 130 It is important to monitor for associated symp- cribed in 1987, it is characterized by recurrent 187 131 toms during an episode, including rashes, and febrile episodes lasting 3 to 6 days, occurring 188 132 involvement of the mucosa, joints, eyes, lung, or every 3 to 6 weeks, in addition to the presence 189 133 abdomen. of the features that make up the name of this syn- 190 134 Viral infections are the most common causes of drome. Regular intervals (with almost clockwork 191 135 fevers occurring at irregular intervals in children.4 regularity) between episodes are the cardinal 192 136 Although most viral infections cause obvious feature of PFAPA, whereas the presence of asso- 193 137 ciated symptoms is more varied. The disease is 194 symptoms, such as those of upper or lower respi- 6 138 ratory tract infections, many viruses can also common in most ethnic groups. 195 139 cause fevers without any other defining signs or 196 Cause 140 symptoms. 197 141 Most children with occult bacterial infections The cause of PFAPA is unknown. Genetic studies 198 142 present with prolonged rather than recurrent fe- have failed to find a common genetic abnormality 199 143 vers. However, children with repeated bacterial in patients with this syndrome. However, 17% to 200

DET818_proof ■ 3 May 2013 ■ 10:58 am Autoinflammatory Diseases in Pediatrics Q1 3

201 45% of children with PFAPA have a family history aphthae (<1 cm or less) or less frequently by a 258 202 of recurrent fevers, and 12% have a family history crop of small aphthae. 259 203 of PFAPA,7,8 suggesting a genetic susceptibility. Associated symptoms may include chills, head- 260 204 Some of these patients have been shown to have ache, nausea, diarrhea, abdominal pain, lethargy, 261 205 heterozygous mutations in various genes known poor appetite, myalgias, and .10,13 Pa- 262 206 to be involved in other monogenic AIDs such as tients are completely well between episodes and 263 207 NRLP3, Mediterranean fever (MEFV), TNFRSF1a, have normal growth and development. 264 208 or mevalonate kinase (MVK).9 Long-term outcome for patients with PFAPA is 265 209 The resolution of PFAPA with tonsillectomy excellent. Most patients have resolution of epi- 266 210 suggests that the tonsils may provide a reser- sodes after 4 to 6 years.8,13,14 Those patients who 267 211 voirforapathogenthatcausesanaugmented are still symptomatic after several years typically 268 212 innate immune response.10,11 These patients have a shortening of febrile days and a decrease 269 213 show increase in molecules of the innate im- in the frequency of the episodes.10,14 Follow-up 270 214 mune system including complement and inter- studies have shown good long-term outcomes in 271 215 leukin (IL)-1b. children diagnosed with PFAPA without increased 272 216 risk for malignancy, autoimmune disorders, or 273 217 Clinical Presentation chronic infectious diseases.13,14 274 218 275 219 PFAPA usually presents in children less than 276 6 Diagnosis 220 5 years of age, although cases have been re- 277 10 221 ported to occur during adolescence and adult- There are no laboratory or genetic tests to confirm 278 12 222 hood. Several studies have noted a slight male the diagnosis of PFAPA. As such, it is a diagnosis 279 6,8,10,13 223 predominance of 1.2:1 to 2.3:1. Character- of exclusion made clinically. However, monoge- 280 224 istics of patients with PFAPA are shown in netic AIDs can often overlap with PFAPA. A recent 281 Table 1 225 . study showed that patients with monogenic AIDs 282 226 The interval between febrile episodes varies from such as hyper- immunoglobulin (Ig) D and periodic 283 6,10 227 21 to 42 days between patients. However, for a fever syndrome (HIDS) or TRAPS, also met criteria 284 2,15 228 particular patient, fevers recur at regular intervals. for PFAPA. 285 229 Many families state that they can predict the onset During attacks, children have leukocytosis with 286 230 of fever with remarkable accuracy. Over a period of increased monocytes and neutrophils, and an in- 287 231 years, the cycles may shorten or lengthen, and may crease in inflammatory markers including erythro- 288 232 even stop for several months before restarting cyte sedimentation rate (ESR), C-reactive protein 289 9 233 again with their usual regularity. (CRP), and serum amyloid A protein (SAA). ESR 290 234 Most patients have a prodrome before the may be normal at the onset of fever, but it in- 291 6 235 episode of fever begins. This prodrome may in- creases within a few days. Between attacks, all 292 236 clude fatigue, headache, abdominal pain, or irrita- inflammatory markers normalize. Neutropenia dur- 293 6 237 bility. Pharyngitis and cervical adenitis are the ing episodes should prompt evaluation for cyclic 294 238 most common features. When aphthous stomatitis neutropenia. Diagnostic criteria are shown in 295 Box 1 239 is present, it is usually limited to 1 to 4 superficial . Q7 296 240 297 241 298 242 Table 1 299 243 Characteristics of patients with PFAPA in various clinical studies 300 244 301 Q14 245 Licamelli 2012 Feder and Salazar 2009 Thomas 1999 302 (n 5 102) (n 5 105) (n 5 94) 246 303 247 Pharyngitis 79% 61% 72% 304 248 Cervical adenitis 84% 46% 88% 305 249 Aphthous stomatitis 44% 21% 70% 306 250 Steroids abort fever 96% 97% 76% 307 251 308 Age at disease onset NA 3.3 y 2.8 y 252 309 Duration of episode NA 4.1 d 4.8 d 253 310 254 Days between episodes NA 29.8 d 28.8 d 311 255 Tonsillectomy aborts PFAPA 97% 100% 64% 312 256 313 Abbreviation: NA, not applicable. 257 Data from Refs.6,10,13 314

DET818_proof ■ 3 May 2013 ■ 10:58 am 4 Hausmann & Dedeoglu

315 372 Box 1 asymptomatic episodes between attacks. The 316 17 373 Modified diagnostic criteria for PFAPA first case was described in 1908, and the first 317 series of patients was published in 1945.18 It 374 318  Regularly recurring fevers with an early age was initially thought to be a disease limited to 375 319 of onset (<5 years) certain populations living in the Mediterranean, 376 320  Constitutional symptoms in the absence of including Sephardic Jews, Turks, Armenians, 377 321 upper respiratory infection with at least 1 of and Arabs. However, the discovery of the gene 378 322 the following clinical signs: responsible for FMF in 199719,20 has allowed the 379 323 380  Aphthous stomatitis identification of mutations in other ethnic groups 324 including Europeans, Americans, Australians, 381  Cervical lymphadenitis 325 Indians, Chinese, and Japanese.21,22 382 326  Pharyngitis Carrier frequencies as high as 1:3 to 1:5 have 383 327 23 384  Exclusion of cyclic neutropenia been described in certain populations. The 328 385  high frequency of carriers of this mutation sug- 329 Completely asymptomatic intervals between 386 episodes gests that heterozygous individuals may have an 330 evolutionary advantage, perhaps by conferring a 387  331 Normal growth and development more potent immune response against certain 388 24,25 332 Data from Thomas KT, Feder HM, Lawton AR, et al. pathogens. 389 333 Periodic fever syndrome in children. J Pediatr 390 334 1999;135(1):15–21. Cause 391 335 392 336 FMF is an autosomal recessive disease caused by 393 337 Treatment mutations in the MEFV gene located in chromo- 394 338 some 16. MEFV codes for the protein pyrin (mare- 395 Prednisone doses of 1 to 2 mg/kg at the beginning 339 nostrin), which is expressed predominantly in 396 of an attack may be sufficient to halt an attack. If 340 neutrophils, although it is also found in eosinophils, 397 the fever does not resolve, a second dose 341 monocytes, dendritic cells, and fibroblasts of the 398 12 hours later may be attempted. A recent study 342 synovium, peritoneum, and skin. The distribution 399 found efficacy with a lower dose of prednisone 343 of expression of pyrin within the body accounts 400 of 0.5 mg/kg.16 Other symptoms may take longer 344 for the sites of inflammation that are affected dur- 401 to resolve.6,13 Although steroids have been effec- 22 345 ing attacks. Mutated pyrin leads to increased 402 tive in aborting episodes, they may paradoxically 346 activation of caspase 1 and uncontrolled release 403 increase their frequency.6,13 b 1 347 of IL-1 from phagocytes. 404 Antipyretics are only partially effective in con- 348 Although it is an autosomal recessive disorder, 405 trolling the fevers.10 Cimetidine has also been 349 genetic sequencing of patients with FMF has re- 406 used for treatment, and seems to be effective in 350 vealed substantial numbers of patients with only 407 resolving fevers in 27% of patients.6 Small case re- 351 1 mutated MEFV allele but full phenotype of the 408 ports have shown good clinical responses with an 26 352 disease, suggesting that FMF could also result 409 IL-1 receptor antagonist ().11 353 from MEFV haploinsufficiency. 410 Tonsillectomy has been shown to be successful 354 411 in causing resolution of symptoms in several 355 Clinical Presentation 412 studies.6,10,13 A recent report on 102 patients 356 413 who underwent tonsillectomy showed excellent FMF is characterized by recurrent, self-limited, 357 414 response in 97% of children without surgical com- febrile episodes of sterile arthritis, peritonitis, 358 415 plications.10 However, tonsillectomy is still an pleuritis, and skin involvement. The episodes 359 416 invasive, expensive procedure, and may be occur suddenly, typically last 12 to 72 hours, and 360 417 considered unnecessary for an illness that is self- resolve spontaneously. They can be triggered by 361 418 limiting and transient. However, the impact of a variety of factors including infections, stress, ex- 362 27 419 monthly fevers on the daily lives of patients and ercise, or menses. The frequency of attacks va- 363 420 families cannot be disregarded. As such, tonsillec- ries, occurring several times per month to once 364 421 tomy can be an acceptable alternative for some yearly. Each attack is associated with leukocytosis 365 422 patients. and increased inflammatory markers including 366 increased ESR, CPR, and fibrinogen. 423 367 424 FMF The disease usually starts during childhood. 368 Thirty percent of patients present at less than 425 369 FMF is the most common monogenic AID in the 2 years of age,28 and 80% of cases present before 426 370 world. It presents as recurrent attacks of fever, 20 years of age.29 Most young patients are homo- 427 371 serositis, arthritis, and rash, with completely zygous for the M694V mutation. Younger children 428

DET818_proof ■ 3 May 2013 ■ 10:58 am Autoinflammatory Diseases in Pediatrics 5

429 may present with recurrent fevers as the only which lasts from a few hours to 2 or 3 days, and re- 486 430 manifestation of FMF, making the diagnosis a solves with rest.40 487 431 challenge and delaying the initiation of treat- Protracted febrile myalgia syndrome is seen in a 488 432 ment.28 The frequency of the initial presenting small percentage of patients with FMF and is char- 489 433 symptom for FMF is shown in Box 2. acterized by high fever and severe, debilitating 490 434 Abdominal attacks occur in 95% of patients.30 myalgias of the extremities.41 It is occasionally 491 435 Pain is usually severe, confining children to bed, accompanied by abdominal pain, diarrhea, arthritis, 492 436 and may be mistaken for appendicitis.31 Radio- or a purpuric rash. Although there is extreme pain 493 437 logic examination may reveal air-fluid levels, lead- and tenderness on examination, laboratory work re- 494 438 ing to the suspicion of acute abdomen and the veals normal creatine phosphokinase and non- Q8 495 439 need for surgery.32 In children, diarrhea is com- specific electromyogram changes.42 Untreated, it 496 440 mon, although constipation can also be seen.30,32 typically lasts for 4 to 6 weeks, but resolves with 497 441 Recurrent abdominal attacks may cause perito- steroids. 498 442 neal adhesions. Other less-frequent features of FMF include or- 499 443 Pleuritis, manifested as chest pain, is found in chitis and scrotal swelling, most commonly during 500 444 23% to 62% of patients.33 Pericarditis is only childhood.43 Splenomegaly may also occur.31,33 501 445 seen in a minority of patients.34 Patients with FMF seem to be at increased risk 502 446 Arthritis is present in 37% to 77% of patients of vasculitis including Henoch-Schonlein purpura, 503 447 and may even be the presenting symptom.30,33,35 polyarteritis nodosa, and Behc¸ et disease.31,34 504 448 The arthritis is of sudden onset, usually monoartic- Secondary is the most severe 505 449 ular, most often affecting the knees, ankles, and complication of FMF. It commonly affects the kid- 506 450 hips.33,35 Joints may be red, swollen, warm, and ney, causing proteinuria or nephrotic syndrome. 507 451 tender, and may be mistaken for septic arthritis.30 However, long-term use of colchicine in children 508 452 Although arthritis usually develops spontaneously, prevents this potentially fatal complication.44 509 453 exertion and insignificant trauma can also precipi- Screening urinalyses are important to detect im- 510 454 tate an attack.35 Short attacks of arthritis are most paired renal function. 511 455 common and usually resolve within 1 week without The clinical presentation of FMF may vary be- 512 456 sequelae. In a minority of patients, a chronic tween individuals, and even among individuals 513 457 arthritis occurs, usually of the knee or hip. Sacro- through their lifetimes, which is likely related to 514 458 iliac involvement, presenting as inflammatory the interplay between genes and the environment. 515 459 back pain, has also been described in several For example, the most common mutation, M694V, 516 460 case series, and is thought to affect 0.4% to 7% is associated with earlier onset and more severe 517 461 of patients with FMF.33,36–39 Sacroiliitis seems to disease, including more frequent attacks, more 518 462 be more common in patients with FMF and human joint disease, higher doses of colchicine required 519 463 leukocyte antigen (HLA)-B27. for control, and higher rates of amyloidosis among 520 464 Skin manifestation of FMF is limited to an erysi- patients not adequately treated.45 521 465 pelaslike rash that occurs in 7% to 34% of children The environment also plays a role. A recent 522 466 with FMF.33 The rash mainly presents in the lower study compared disease severity of Turkish chil- 523 467 extremities, especially around the ankles or dren with FMF living in Turkey, with Turkish chil- 524 468 dorsum of the feet, and usually fades within 1 to dren living in Germany.46 Although there was no 525 469 3 days.31 difference between the increase of acute phase 526 470 Exercise-induced myalgias are also common.33 reactants during attacks, the severity of the at- 527 471 Up to 20% of patients develop lower extremity tacks was significantly higher in children living in 528 472 pain after physical exertion, mostly in the evening, Turkey, suggesting that microbes or other aspects 529 473 of the environment may affect the final disease 530 474 expression. 531 475 Box 2 532 476 Presenting symptoms of FMF 533 477 Diagnosis 534 Symptom Percentage 478 Several clinical diagnostic criteria for FMF have 535 479 Abdominal pain 55 been created; the Tel Hashomer criteria are the 536 Arthritis 26 480 most widely used, and are shown in Box 3. There 537 481 Chest pain 5 538 Fever 3 are efforts to create diagnostic criteria specifically 482 for children, although these have yet to be vali- 539 483 Data from Sohar E, Gafni J, Pras M, et al. Familial 47 540 Mediterranean fever. A survey of 470 cases and review dated in diverse populations. 484 of the literature. Am J Med 1967;43(2):227–53. The use of genetic testing for the MEFV gene in 541 485 countries with a low prevalence of FMF may be 542

DET818_proof ■ 3 May 2013 ■ 10:58 am 6 Hausmann & Dedeoglu

543 Colchicine has been found to be safe and effec- 600 544 Box 3 601 Simplified Tel Hashomer criteria for the tive in children with FMF. Complete remission oc- 545 602 diagnosis of FMF. Diagnosis requires 1 or more curs in up to two-thirds of patients treated with 546 major criteria or 2 or more minor criteria. Typical colchicine; whereas a partial response, character- 603 547 attacks are defined as recurrent (‡3 of the same ized as a significant decrease in frequency and 604 548 type), febrile (‡38C), and short (lasting severity of episodes, occurs in a third of patients.50 605 549 between 12 and 72 hours). Incomplete attacks Multiple studies have shown that amyloidosis can 606 550 differ from typical attacks in lack of fever, being be prevented in children with regular use of colchi- 607 551 of shorter or longer length, lack of abdominal cine, even if it does not completely prevent 608 552 attacks, localized abdominal attacks, or attacks.33,51 609 arthritis in joints other than those specified 553 True colchicine resistance is rare (w5% of pa- 610 554 49,50 611 Tel Hashomer criteria for the diagnosis of FMF tients). In patients who do not respond to 555 colchicine, compliance should be evaluated, and 612 Major criteria: 556 alternative diagnoses should be sought. Newer bi- 613 557 Typical attacks ologics with anti–IL-1 activity (anakinra and cana- 614 558 615  Peritonitis (generalized) kinumab) have shown excellent responses in 559 patients who do not tolerate, or are resistant to, 616  Pleuritis (unilateral) or pericarditis 560 colchicine.52 617  561 Monoarthritis (hip, knee, ankle) Treatment of acute attacks include nonsteroidal 618 562  Fever alone antiinflammatory drugs (NSAIDs) and opiates if 619 563 49 620 Minor criteria pain is severe. Increasing colchicine doses dur- 564 ing attacks does not seem to have any beneficial 621 565 Incomplete attacks involving 1 or more of effects.29 622 566 the following sites: 623 567  624 Chest HIDS/MVK DEFICIENCY 568 625  Joint 569 HIDS is a rare, autosomal recessive AID charac- 626 Q15 570 Exertional leg pain terized by recurrent episodes of systemic inflam- 627 571 Favorable response to colchicines mation that includes fevers, abdominal pain, 628 572 diarrhea, rash, arthralgias, aphthous ulcers, and 629 573 Data from Livneh A, Langevitz P, Zemer D, et al. 630 Criteria for the diagnosis of familial Mediterranean lymphadenopathy. It is caused by mutations in 574 fever. Arthritis Rheum 1997;40(10):1879–85. the MVK gene, an enzyme involved in the synthe- 631 575 sis of cholesterol and isoprenoids. Mutations of 632 576 this gene cause a range of phenotypes, depend- 633 577 ing on the level of functioning enzyme. Reduced 634 helpful. However, even complete sequencing of 578 activity of the enzyme causes HIDS, whereas a 635 the MEFV gene sometimes fails to identify any ab- 579 complete deficiency results in mevalonic aciduria, 636 normalities in a small subset of patients who 580 a syndrome of severe fever episodes and neuro- 637 exhibit symptoms consistent with FMF and res- 581 logic complications including ataxia, mental retar- 638 pond appropriately to colchicine, suggesting that 582 dation, and early death. The exact mechanism of 639 other genes may be involved. 583 how mutations in MVK lead to periodic fevers is 640 584 still unknown, but shortage of a product of the 641 Treatment 585 MVK pathway seems to activate of the inflamma- 642 586 The simultaneous discovery of the efficacy of some and secrete IL-1b.53 643 587 colchicine for FMF by Dr Ozkan in Turkey and Dr Half of the documented cases of HIDS have 644 588 Goldfinger48 in the United States changed the been found in people of Dutch origin,54 although 645 589 landscape of the disease. Before colchicine, up cases have now been identified globally, with 646 590 to 75% of patients developed amyloidosis during most patients being of European ancestry.55 In 647 591 adulthood. However, this has become a rare the largest study of patients with HIDS, the 648 592 outcome. Early introduction of colchicine in chil- average age of onset was 6 months, 78% of pa- 649 593 dren is helpful to prevent painful, febrile attacks, tients had their first attack within the first year, 650 594 avoid unnecessary interventions (laparotomy, anti- and all of them presented during childhood.55 For 651 595 biotics), and prevent amyloidosis.49 The exact most patients, childhood vaccinations precipitated 652 596 mechanism of colchicine efficacy in FMF is un- their first attack. Emotional and physical stress can 653 597 known, although colchicine inhibits leukocyte also precipitate attacks. The frequency of attacks 654 598 chemotaxis and alters the expression of adhesion decreased after age 20 years, although they still 655 599 molecules. occurred at least every other month. 656

DET818_proof ■ 3 May 2013 ■ 10:59 am Autoinflammatory Diseases in Pediatrics 7

657 Attacks typically last 3 to 7 days and are charac- such as lymphoma and tuberculosis. Thus, genetic 714 658 terized by lymphadenopathy, abdominal pain, testing is probably the best way of diagnosing this 715 659 vomiting or diarrhea, and . Two-thirds disease. 716 660 of patients have a rash, usually maculopapular. Treatment is not standardized, and can in- 717 661 Aphthous ulcers, sometimes with genital ulcers, clude trials of NSAIDs, prednisone, anakinra, or 718 662 occurred in about 50% of patients, mistaking this etanercept.50,59–61 719 663 diagnosis with Behc¸ et disease. Many features of 720 664 721 HIDS are also seen in patients with PFAPA. How- TRAPS 665 ever, HIDS can be differentiated by an earlier age 722 666 of onset, with longer periods of fever, longer inter- TRAPS is the most common autosomal dominant, 723 667 vals between episodes, and more frequent vomit- inherited periodic fever syndrome.62 It is charac- 724 668 ing and abdominal pain. Box 4 shows criteria to terized by prolonged, episodic fevers with sys- 725 669 help make the diagnosis of HIDS. temic inflammation. Previously referred to as 726 670 Leukocytosis and increases in inflammatory familial Hibernian fever because of its first descrip- 727 671 markers including ESR and CRP were seen during tion in an Irish family,63 TRAPS has been found in 728 672 attacks. Urinary levels of mevalonic acid are other populations throughout the world.64,65 729 673 increased during attacks, and are helpful in mak- TRAPS is caused by mutations in the TNF recep- 730 674 ing the diagnosis.56 IgD and IgA concentrations tor (TNFR1a), which is found mainly on monocytes 731 675 were increased in most patients, although 22% and macrophages and responds to the inflamma- 732 676 of patients with HIDS have normal IgD levels. IgD tory cytokine TNF. The pathogenic mechanism 733 677 serum concentrations did not vary during acute by which the mutation results in the phenotype of 734 678 episodes and are not correlated with severity of TRAPS is still not well understood.66 Some muta- 735 679 symptoms or frequency of attacks,57 suggesting tions seem to result in impaired shedding of the 736 680 that the increased levels of IgD may be an epiphe- soluble receptor.62 Other mutations result in mis- 737 681 nomenon of the disease and, despite the name, folding of the protein and retention of the receptor 738 682 not central to the pathogenesis of HIDS. Further- intracellularly.64 The mutant receptor seems to 739 683 more, 50% of patients with other periodic fever accumulate within the cell and sensitizes the cell 740 684 syndromes also have increased IgD levels.58 In- to produce inflammatory cytokines with little 741 685 creases in IgD can also be seen in other conditions stimulation.67 742 686 Patients with TRAPS usually present at a median 743 687 age of 3 years, although cases have been identi- 744 Box 4 688 fied as early as 2 weeks and as late as 53 years.65 745 689 Clinical criteria for the consideration of a 746 diagnosis of HIDS Patients experience recurrent, prolonged epi- 690 sodes of fever, lasting an average of 3 weeks, 747 691 When to consider HIDS but sometimes as long as 6 weeks.26,65,68 Attacks 748 692 749 Recurrent episodes of fever lasting 3 to 7 days may occur every 5 to 6 weeks and usually consist 693 750 for more than 6 months of myalgias, fever, and rash. The rash is usually a 694 centrifugal, migratory, erythematous patch that 751 And 1 or more of the following: 695 overlies the area of myalgia. The rash is tender, 752 696 Sibling with genetically confirmed HIDS warm, and blanchable. There is no increase of 753 697 Increased serum IgD (>100 IU/L) muscle enzymes. 754 698 755 First attack after childhood vaccination Peritonitis causing abdominal pain is common, 699 and may be mistaken for an acute abdomen. Pa- 756 700 Three or more symptoms during attacks: tients may also have arthralgias, conjunctivitis, 757 701  Cervical lymphadenopathy periorbital edema, uveitis, and iritis.65 758 702 759  Abdominal pain Laboratory examinations show increases in acute 703 phase reactants including ESR, CRP, haptoglobin, 760  Vomiting or diarrhea 704 fibrinogen, and ferritin.65 There may be leukocy- 761 705  Arthralgia or arthritis of large peripheral tosis, thrombocytosis, and anemia from the chronic 762 706 joints inflammatory disease.66 Patients may also have 763 707  Aphthous ulcers polyclonal hypergammaglobulinemia. Acute phase 764 708 765  Skin lesions reactants may remain increased while asymptom- 709 atic, although at lower levels than during attacks. 766 710 Data from van der Hilst JC, Bodar EJ, Barron KS, et al. Because of the persistent inflammatory state, 767 711 Long-term follow-up, clinical features, and quality of 768 life in a series of 103 patients with hyperimmunoglo- children with TRAPS are at risk of developing 712 bulinemia D syndrome. Medicine 2008;87(6):301–10. amyloidosis, most commonly involving the 769 713 kidneys.65 Q9 770

DET818_proof ■ 3 May 2013 ■ 10:59 am 8 Hausmann & Dedeoglu

771 Treatment of TRAPS seems to be more chal- The most severe form of the disease, called NO- 828 772 lenging than for other AIDs, possibly due the het- MID or chronic infantile neurologic cutaneous and 829 773 erogeneity of genetic mutations and clinical articular syndrome (CINCA), includes all of the 830 774 phenotypes.66 Treatment of acute attacks can be symptoms of MWS but presents during the 831 775 effective with NSAIDs and corticosteroids, espe- newborn period. Episodes are nearly continuous 832 776 cially if associated with certain mutations.50,66 Eta- and also associated with dysmorphic features, 833 777 nercept has been shown to be beneficial in most chronic aseptic meningitis, blindness, mental 834 778 patients, although a complete response is not al- retardation, and bone deformation.75 Patients 835 779 ways achieved.50,69 Other anti-TNF agents seem with NOMID have significant arthropathy affecting 836 780 to cause exacerbation of the disease.66 Anakinra large joints, resulting in functional disability with 837 781 was shown to produce a complete response in endochondral ossification and calcified masses 838 782 most patients in one observational study.50 in the joints.73 839 783 Laboratory abnormalities include increases in 840 784 841 CAPS CRP and SAA, which usually remain increased 785 even without attacks.73 Urine should be checked 842 786 The CAPS are a set of rare, autosomal dominant for protein, to screen for amyloidosis. Biopsy of 843 787 AIDs that encompass a spectrum of severity from the urticarial lesion shows a sparse interstitial 844 788 mild to severe disease. They are caused by muta- neutrophilic infiltrate in the reticular dermis,74 and 845 789 tions in nucleotide-binding domain, leucine-rich can help in the diagnosis of this syndrome. 846 790 repeat family, pyrin domain containing 3 (NLRP3), Anakinra has been shown to be effective in reso- 847 791 which codes for cryopyrin. NLRP3 is a key compo- lution of fever, rash, conjunctivitis, and joint symp- 848 792 nent of the and is expressed in neu- toms, as well as normalization of inflammatory 849 793 trophils, monocytes, and chondrocytes.70 Most markers.76 It may even be effective in reversing 850 794 patients with CAPS have gain-of-function muta- amyloid deposits.72 Canakinumab77 and rilona- 851 795 tions that activate the inflammasome and cause cept78 also seem to be effective in controlling the 852 796 release of IL-1b, in response to reduced or absent disease, again highlighting the importance of 853 797 stimuli.26 The discovery of NLRP3 in 200171 linked IL-1b in the pathogenesis of this AID. 854 798 3 diseases (familial cold autoinflammatory syn- A similar phenotype to that seen in FCAS, with 855 799 drome [FCAS], Muckle-Wells syndrome [MWS], arthralgias and myalgias in response to cold expo- 856 800 and neonatal-onset multisystem inflammatory dis- sure, has been found as a result of mutations of a 857 801 ease [NOMID]), previously thought to be unrelated. different gene, NLRP12, which also seems to 858 802 Most cases of NOMID are associated with de novo enhance secretion of IL-1b.79 859 803 mutations, whereas the mutated gene is com- 860 804 861 monly inherited in FCAS and MWS. DITRA 805 CAPS is distinguished from other AIDs by the 862 806 presence of an urticarial rash and cold exposure An autosomal recessive disease first described in 863 807 as a trigger for attacks. Unlike other some of the 2011 in several Tunisian families, DITRA is charac- 864 808 AIDs, a third of patients do not have fever accom- terized by generalized pustular psoriasis.80 It is 865 809 panying the episodes.72 caused by mutations in IL36RN, the gene that en- 866 810 FCAS is characterized by recurrent episodes of codes for interleukin-36 receptor antagonist. In the 867 811 fever, urticaria, and arthralgia brought about by wild-type state, IL-36 receptor antagonist works to 868 812 cold exposure. The rash is seen in the trunk and block several proinflammatory signaling path- 869 813 limbs, and individual lesions migrate and last less ways. Most patients present between birth and 870 814 than 24 hours.73 The rash is minimal during the 11 years of age. Patients have repeated flares of 871 815 morning and increases in severity in the evening.74 sudden-onset, high-grade fever of more than 872 816 Amyloidosis is a rare complication of this disease. 40C, malaise, and weakness, in addition to a 873 817 In MWS, in addition to fever, urticarial rash, and diffuse, erythematous rash associated with pus- 874 818 arthralgias, the episodes often lead to progressive tules, leukocytosis, and increased CRP. 875 819 neurosensory hearing loss secondary to cochlear 876 820 26 877 inflammation, which was present in 50% of pa- MAJEED SYNDROME 821 tients in one study.72 The urticaria is present 878 822 most days, and tends not to be pruritic, or only Majeed syndrome, first described in 1989, is a rare, 879 823 mildly pruritic. Other commonly occurring symp- autosomal recessive condition that consists of 3 880 824 toms include conjunctivitis, uveitis, headache, prominent features: chronic recurrent multifocal 881 825 abdominal pain, and diffuse aching of the extrem- osteomyelitis (CRMO), congenital dyserythro- 882 826 ities. Amyloidosis can be seen as a late complica- poietic anemia, and an inflammatory dermatosis.81 883 827 tion in 25% of patients with MWS. It has been identified in Kuwaiti,81 Jordanian,82 and 884

DET818_proof ■ 3 May 2013 ■ 10:59 am Autoinflammatory Diseases in Pediatrics 9

885 Turkish83 families. The gene responsible for this DEFICIENCY OF THE INTERLEUKIN-1 942 886 syndrome is LPIN2, although its function is still RECEPTOR ANTAGONIST 943 887 unclear.82 944 888 First described in 2009 by Aksentjevich and col- 945 Majeed syndrome presents in children less than 86 889 2 years of age. It is characterized by recurrent fe- leagues, deficiency of the interleukin-1 receptor 946 890 vers, occurring every 2 to 4 weeks and lasting 3 to antagonist (DIRA) is an inherited, recessive dis- 947 891 4 days. CRMO has an early age of onset; as many ease caused by mutations in IL1RN, the gene 948 892 as 1 to 3 relapses per month; and short, infrequent that codes for the interleukin-1 receptor antago- 949 893 remissions.81 It eventually leads to delayed nist. The endogenous IL-1 receptor antagonist 950 894 growth, joint contractures, or both.82 Anemia normally inhibits the proinflammatory cytokines 951 b 895 severity can range from mild to severe depending IL-1a and IL-1 . A mutation in IL1RN leads to over- 952 896 on the need for blood transfusions. The inflamma- stimulation by proinflammatory cytokines. Al- 953 897 though the mutation has been found in patients 954 tory dermatosis commonly presents as Sweet 86 898 from Canada, the Netherlands, Lebanon, 955 syndrome. Anakinra and have 87 88 899 been effective in 2 patients,83 highlighting the Brazil, and Turkey, it seems to be particularly 956 900 important role of IL-1 in the pathogenesis of this common in some areas of Puerto Rico as a result 957 901 of a founder mutation, with an incidence as high 958 disease. 86 902 as 1 in 6300 births. DIRA usually presents within 959 903 the first 2 weeks of birth with fetal distress, a pus- 960 CANDLE 904 tular rash, arthritis, oral lesions, and pain with 961 905 CANDLE syndrome is characterized by recurrent movement. Soon after birth, children develop 962 906 fevers, purpuric skin lesions, violaceous swollen cutaneous pustulosis, multifocal aseptic osteomy- 963 907 eyelids, arthralgias, progressive lipodystrophy, elitis, and periostitis. Fever is typically not present, 964 908 anemia, delayed physical development, and in- but inflammatory markers, including ESR and 965 909 crease of acute phase reactants.84 It is caused CRP, are markedly increased. Neutrophilia is pre- 966 910 by mutations in PSMB8, which lead to immuno- sent in the blood and neutrophilic infiltrates can 967 911 be found in skin and bones. DIRA is often confused 968 proteasome dysfunction. The immunoproteasome 87 912 is critical for protein degradation and generation of with infections in the newborn period. Untreated 969 913 disease can lead to death from multiple organ fail- 970 antigenic peptides for major histocompatibility 86 914 complex class I presentation. Mutations within ure ; however, treatment with anakinra has 971 915 shown rapid and complete remission of the 972 this structure cause inability to maintain cell ho- 86,87,89 916 meostasis and results in increased interferon disease. 973 917 signaling. 974 918 975 Previously identified diseases, including Nakajo- PAPA 919 Nishimura syndrome, Japanese autoinflammatory 976 920 syndrome with lipodystrophy, and joint contrac- PAPA is a rare, autosomal dominant, inherited AID 977 921 tures, muscular atrophy, microcytic anemia, and distinguished by painful flares of recurrent sterile 978 922 panniculitis-associated lipodystrophy (JMP) syn- arthritis with a prominent neutrophilic infiltrate.90 979 923 drome, have been shown to result from mutations The disease is caused by missense mutations in 980 924 within this same gene. the proline-serine-threonine phosphatase-inter- 981 925 The onset of this disease usually occurs shortly acting progein 1 gene (PSTPIP1). PSTPIP1 is an 982 926 after birth, and is uniformly present by 6 months of adaptor protein that seems to interact with pyrin 983 927 age.84 Fevers occur daily or almost daily and have and the inflammasome. Mutations are thought to 984 928 poor response to NSAIDs.85 In addition, children cause spontaneous activation of the inflamma- 985 929 develop erythematous and violaceous, annular some and release of IL-1b.90 986 930 cutaneous plaques that last days to weeks and The skin involvement is variable, and may pre- 987 931 leave residual purpura. During infancy, children sent as ulcerations, pyoderma gangrenosum, 988 932 develop persistent periorbital erythema and cystic acne, or pathergy.90,91 Arthritis usually pre- 989 933 edema, finger or toe swelling, and hepatomegaly. sents during early childhood, and may begin after 990 934 During the first year of life, patients lose peripheral minor trauma or sporadically.91 It is characterized 991 935 fat and develop failure to thrive, lymphadenopathy, by recurrent episodes that lead to accumulation 992 936 and anemia. Use of high-dose steroids improved of pyogenic, neutrophil-rich material within af- 993 937 clinical symptoms, but the disease rebounded fected joints, which results in synovial and carti- 994 938 with their tapering. Methotrexate, calcineurin in- lage destruction. It typically affects 1 to 3 joints 995 939 hibitors, TNF inhibitors, anti–IL-1 and anti–IL-6 at a time. By puberty, joint symptoms tend to sub- 996 940 therapy have limited success in managing this side, and cutaneous symptoms become more 997 941 disease.84 prominent. 998

DET818_proof ■ 3 May 2013 ■ 10:59 am 10 Hausmann & Dedeoglu

999 Laboratory findings reflect systemic inflamma- genetics and molecular biology have focused 1056 1000 tion. Treatment has been successful with ana- attention on AIDs, and the pathways responsible 1057 1001 kinra92,93 and infliximab.94 for these rare syndromes have also been impli- 1058 1002 cated to play a role in a variety of more common 1059 1003 1060 BLAU SYNDROME/EARLY-ONSET conditions such as gout, diabetes mellitus, and 1004 1061 SARCOIDOSIS atherosclerosis. By continuing to study and im- 1005 prove the treatment of children with AIDs, treat- 1062 1006 The familial Blau syndrome is an autosomal domi- ments may be discovered for many of the 1063 1007 nant AID manifested as a triad of granulomatous diseases that affect people in the modern world. 1064 1008 dermatitis, arthritis, and uveitis. In 2001, mutations 1065 1009 95 1066 in NOD2 were found in Blau syndrome and sub- REFERENCES 1010 sequently discovered in patients with early-onset 1067 1011 sarcoidosis, now known to be the sporadic form 1. Masters SL, Simon A, Aksentijevich I, et al. Horror 1068 1012 of the same disease.96 NOD2 acts as an intracel- autoinflammaticus: the molecular pathophysiology 1069 1013 lular sensor of bacterial cell wall components and of autoinflammatory disease*. Annu Rev Immunol 1070 1014 Q10 activates nuclear factor kappa B (NF-kB) and 2009;27(1):621–68. 1071 1015 enhanced autophagy. Gain-of-function mutations, 2. Gattorno M, Sormani MP, D’Osualdo A, et al. 1072 1016 as seen in Blau syndrome, lead to increased A diagnostic score for molecular analysis of he- 1073 1017 NF-kB activity and possibly to the release of reditary autoinflammatory syndromes with periodic 1074 1018 inflammatory cytokines. fever in children. Arthritis Rheum 2008;58(6): 1075 1019 The average age of onset of the disease is be- 1823–32. 1076 1020 tween 2 and 3 years. Arthritis is polyarticular, often 3. Finkelstein JA, Christiansen CL, Platt R. Fever in 1077 1021 affecting the hands and feet, and produces a pediatric primary care: occurrence, management, 1078 1022 boggy synovitis and tenosynovitis as a result of and outcomes. Pediatrics 2000;105(1 Pt 3):260–6. 1079 1023 granulomatous inflammation.97,98 4. John CC, Gilsdorf JR. Recurrent fever in children. 1080 1024 The dermatitis is described as a tan, maculo- Pediatr Infect Dis J 2002;21(11):1071–7. 1081 1025 papular rash with ichthyosiform desquamation 5. Marshall GS, Edwards KM, Butler J, et al. Syn- 1082 1026 and the presence of dermal granulomas.99 Bilat- drome of periodic fever, pharyngitis, and aphthous 1083 1027 eral uveitis occurs in most patients between 7 stomatitis. J Pediatr 1987;110(1):43–6. 1084 1028 and 12 years of age.97 It presents as anterior uve- 6. Feder HM, Salazar JC. A clinical review of 105 pa- 1085 1029 itis with eye pain, photophobia, and blurred vision. tients with PFAPA (a periodic fever syndrome). 1086 1030 Over time, eye inflammation can cause severe vi- Acta Paediatr 2010;99(2):178–84. 1087 1031 sual impairment and blindness. About one-third 7. Cochard M, Clet J, Le L, et al. PFAPA syndrome is 1088 1032 of patients also have other prominent features not a sporadic disease. Rheumatology (Oxford) 1089 1033 including fever, sialadenitis, lymphadenopathy, er- 2010;49(10):1984–7. 1090 1034 ythema nodosum, and vasculitis. 8. Førsvoll J, Kristoffersen EK, Oymar K. Incidence, 1091 1035 Diagnosis is made by finding noncaseating clinical characteristics and outcome in Norwegian 1092 1036 granulomas in skin, synovium, or conjunctiva.99 children with PFAPA syndrome; a population- 1093 1037 Genetic testing for the NOD2 mutation has based study. Acta Paediatr 2013;102(2):187–92. 1094 1038 increasingly helped to make the diagnosis. There 9. Kolly L, Busso N, Scheven-Gete von A, et al. Peri- 1095 1039 are no studies on the optimal treatment of the dis- odic fever, aphthous stomatitis, pharyngitis, cervi- 1096 1040 ease, but methotrexate, thalidomide, corticoste- cal adenitis syndrome is linked to dysregulated 1097 1041 roids, TNF inhibitors, and IL-1 inhibitors have monocyte IL-1b production. J Allergy Clin Immunol 1098 1042 been tried with various levels of success.98 2012. http://dx.doi.org/10.1016/j.jaci.2012.07.043. 1099 1043 10. Licameli G, Lawton M, Kenna M, et al. Long-term 1100 1044 1101 SUMMARY surgical outcomes of adenotonsillectomy for 1045 PFAPA syndrome. Arch Otolaryngol Head Neck 1102 1046 Fever is one of the most common reasons for a Surg 2012;138(10):902–6. 1103 1047 child to present to a pediatrician. Repeated febrile 11. Stojanov S, Lapidus S, Chitkara P, et al. Periodic fe- 1104 1048 episodes are most commonly caused by viral in- ver, aphthous stomatitis, pharyngitis, and adenitis 1105 1049 fections. However, in a child with recurrent fevers (PFAPA) is a disorder of innate immunity and Th1 1106 1050 and other features of inflammation, AIDs should activation responsive to IL-1 blockade. Proc Natl 1107 1051 be considered. Although these diseases are rare, Acad Sci U S A 2011;108(17):7148–53. 1108 1052 they have helped clinicians to understand the 12. Padeh S, Stoffman N, Berkun Y. Periodic fever 1109 1053 role of the innate immune system and inflamma- accompanied by aphthous stomatitis, pharyngitis 1110 1054 tory pathways that are ubiquitous in health and and cervical adenitis syndrome (PFAPA syndrome) 1111 1055 disease. Over the last decade, advances in in adults. Isr Med Assoc J 2008;10(5):358–60. 1112

DET818_proof ■ 3 May 2013 ■ 10:59 am Autoinflammatory Diseases in Pediatrics 11

1113 13. Thomas KT, Feder HM, Lawton AR, et al. Periodic 29. Sohar E, Gafni J, Pras M, et al. Familial Mediterra- 1170 1114 fever syndrome in children. J Pediatr 1999;135(1): nean fever. A survey of 470 cases and review of the 1171 1115 15–21. literature. Am J Med 1967;43(2):227–53. 1172 1116 14. Wurster VM, Carlucci JG, Feder HM, et al. Long- 30. Onen F. Familial Mediterranean fever. Rheumatol 1173 1117 term follow-up of children with periodic fever, aph- Int 2005;26(6):489–96. 1174 1118 thous stomatitis, pharyngitis, and cervical adenitis 31. Ozen S. Familial Mediterranean fever: revisiting an 1175 1119 syndrome. J Pediatr 2011;159(6):958–64. ancient disease. Eur J Pediatr 2003;162(7–8):449–54. 1176 1120 15. Gattorno M, Caorsi R, Meini A, et al. Differentiating 32. Bhat A, Naguwa SM, Gershwin ME. Genetics and 1177 1121 PFAPA syndrome from monogenic periodic fevers. new treatment modalities for familial Mediterranean 1178 1122 Pediatrics 2009;124(4):e721–8. fever. Ann N Y Acad Sci 2007;1110(1):201–8. 1179 1123 16. Yazgan H, Gu¨ltekin E, Yazıcılar O, et al. Com- 33. Majeed HA, Rawashdeh M, Shanti El H, et al. 1180 1124 parison of conventional and low dose steroid Familial Mediterranean fever in children: the 1181 1125 in the treatment of PFAPA syndrome: preliminary expanded clinical profile. QJM 1999;92(6):309–18. 1182 1126 study. Int J Pediatr Otorhinolaryngol 2012; 34. Group TFS. Familial Mediterranean fever (FMF) in 1183 1127 76(11):1588–90. Turkey. Medicine 2005;84(1):1–11. 1184 1128 17. Janeway TC, Mosenthal HO. An unusual parox- 35. Heller H, Gafni J, Michaeli D, et al. The arthritis of 1185 1129 ysmal syndrome, probably allied to recurrent vom- familial Mediterranean fever (FMF). Arthritis Rheum 1186 1130 iting, with a study of the nitrogen metabolism. Arch 1966;9(1):1–17. 1187 1131 Intern Med 1908;2(3):214. 36. Lehman TJ, Hanson V, Kornreich H, et al. HLA-B27- 1188 1132 18. Siegal S. Benign paroxysmal peritonitis. Ann Intern negative sacroiliitis: a manifestation of familial Med- 1189 1133 Med 1945;23(1):1–21. iterranean fever in childhood. Pediatrics 1978; 1190 1134 19. Consortium TIF. Ancient missense mutations in 61(3):423–6. 1191 1135 a new member of the RoRet gene family are 37. Balaban B, Yasar E, Ozgul A, et al. Sacroiliitis in fa- 1192 1136 likely to cause familial Mediterranean fever. milial Mediterranean fever and seronegative spon- 1193 1137 The International FMF Consortium. Cell 1997; dyloarthropathy: importance of differential 1194 1138 90(4):797–807. diagnosis. Rheumatol Int 2005;25(8):641–4. 1195 1139 20. French F. A candidate gene for familial Mediterra- 38. Langevitz P, Livneh A, Zemer D, et al. Seronegative 1196 1140 nean fever. Nat Genet 1997;17(1):25. spondyloarthropathy in familial Mediterranean fe- 1197 1141 21. Ben-Chetrit E, Touitou I. Familial Mediterranean fe- ver. Semin Arthritis Rheum 1997;27(2):67–72. 1198 1142 ver in the world. Arthritis Rheum 2009;61(10): 39. Kas‚ ifoglu T, Calis‚ ir C, Cansu DU, et al. The fre- 1199 1143 1447–53. quency of sacroiliitis in familial Mediterranean fever 1200 1144 22. Chae JJ, Aksentijevich I, Kastner DL. Advances in and the role of HLA-B27 and MEFV mutations in the 1201 1145 the understanding of familial Mediterranean fever development of sacroiliitis. Clin Rheumatol 2009; 1202 1146 and possibilities for targeted therapy. Br J Haema- 28(1):41–6. 1203 1147 tol 2009;146(5):467–78. 40. Cassidy JT, Petty RE, Laxer R, et al. Textbook of pe- 1204 1148 23. Touitou I. The spectrum of familial Mediterranean diatric rheumatology E-Book. Saunders; 2010. Q11 1205 1149 fever (FMF) mutations. Eur J Hum Genet 2001; 41. Senel K, Melikoglu MA, Baykal T, et al. Protracted 1206 1150 9(7):473–83. febrile myalgia syndrome in familial Mediterranean 1207 1151 24. Fumagalli M, Cagliani R, Pozzoli U, et al. fever. Mod Rheumatol 2010;20(4):410–2. 1208 1152 A population genetics study of the familial Mediter- 42. Majeed HA, Al-Qudah AK, Qubain H, et al. The 1209 1153 ranean fever gene: evidence of balancing selection clinical patterns of myalgia in children with familial 1210 1154 under an overdominance regime. Genes Immun Mediterranean fever. Semin Arthritis Rheum 2000; 1211 1155 2009;10(8):678–86. 30(2):138–43. 1212 1156 25. Lachmann HJ. Clinical and subclinical inflamma- 43. Leung DY, Sampson H, Geha R, et al. Pediatric 1213 1157 tion in patients with familial Mediterranean fever allergy: principles and practice E-Book. Saunders; 1214 1158 and in heterozygous carriers of MEFV mutations. 2010. 1215 1159 Rheumatology (Oxford) 2006;45(6):746–50. 44. Zemer D, Livneh A, Danon YL, et al. Long-term 1216 1160 26. Park H, Bourla AB, Kastner DL, et al. Lighting the colchicine treatment in children with familial 1217 1161 fires within: the cell biology of autoinflammatory Mediterranean fever. Arthritis Rheum 1991;34(8): 1218 1162 diseases. Nat Rev Immunol 2012;12(8):570–80. 973–7. 1219 1163 27. Rigante D. The fresco of autoinflammatory dis- 45. Dewalle M, Domingo C, Rozenbaum M, et al. 1220 1164 eases from the pediatric perspective. Autoimmun Phenotype-genotype correlation in Jewish patients 1221 1165 Rev 2012;11(5):348–56. suffering from familial Mediterranean fever (FMF). 1222 1166 28. Padeh S, Livneh A, Pras E, et al. Familial Mediterra- Eur J Hum Genet 1998;6(1):95. 1223 1167 nean fever in the first two years of life: a unique 46. Ozen S, Aktay N, Lainka E, et al. Disease severity 1224 1168 phenotype of disease in evolution. J Pediatr 2010; in children and adolescents with familial Mediter- 1225 1169 156(6):985–9. ranean fever: a comparative study to explore 1226

DET818_proof ■ 3 May 2013 ■ 10:59 am 12 Hausmann & Dedeoglu

1227 environmental effects on a monogenic disease. 61. Bodar EJ, van der Hilst JC, Drenth JP, et al. Effect 1284 1228 Ann Rheum Dis 2009;68(2):246–8. of etanercept and anakinra on inflammatory attacks 1285 1229 47. Yalcinkaya F, Ozen S, Ozcakar ZB, et al. A new set in the hyper-IgD syndrome: introducing a vaccina- 1286 1230 of criteria for the diagnosis of familial Mediterra- tion provocation model. Neth J Med 2005;63(7): 1287 1231 nean fever in childhood. Rheumatology (Oxford) 260–4. 1288 1232 2009;48(4):395–8. 62. McDermott MF, Aksentijevich I, Galon J, et al. 1289 1233 48. Goldfinger SE. Colchicine for familial Mediterra- Germline mutations in the extracellular domains of 1290 1234 nean fever. N Engl J Med 1972;287(25):1302. the 55 kDa TNF receptor, TNFR1, define a family 1291 1235 49. Kallinich T, Haffner D, Niehues T, et al. Colchicine of dominantly inherited autoinflammatory syn- 1292 1236 use in children and adolescents with familial Med- dromes. Cell 1999;97(1):133–44. 1293 1237 iterranean fever: literature review and consensus 63. Williamson LM, Hull D, Mehta R, et al. Familial Hi- 1294 1238 statement. Pediatrics 2007;119(2):e474–83. bernian fever. QJM 1982;51(204):469–80. 1295 1239 50. Haar Ter N, Lachmann H, Ozen S, et al. Treatment 64. Kimberley FC, Lobito AA, Siegel RM. Falling into 1296 1240 of autoinflammatory diseases: results from the TRAPS-receptor misfolding in the TNF receptor 1- 1297 1241 Eurofever Registry and a literature review. Ann associated periodic fever syndrome. Arthritis Res 1298 1242 Rheum Dis 2012;72(5):678–85. Ther 2007;9(4):217. 1299 1243 51. Zemer D, Pras M, Sohar E, et al. Colchicine in the 65. Galeazzi M, Gasbarrini G, Ghirardello A, et al. 1300 1244 prevention and treatment of the amyloidosis of fa- Autoinflammatory syndromes. Clin Exp Rheumatol 1301 1245 milial Mediterranean fever. N Engl J Med 1986; 2006;24(1 Suppl 40):S79–80. 1302 1246 314(16):1001–5. 66. Cantarini L, Lucherini OM, Muscari I, et al. Tumour 1303 1247 52. Caorsi R, Federici S, Gattorno M. Biologic drugs in necrosis factor receptor-associated periodic syn- 1304 1248 autoinflammatory syndromes. Autoimmun Rev drome (TRAPS): state of the art and future per- 1305 1249 2012;12(1):81–6. spectives. Autoimmun Rev 2012;12(1):38–43. 1306 1250 53. van der Burgh R, Haar ter NM, Boes ML, et al. Meval- 67. Simon A, Park H, Maddipati R, et al. Concerted 1307 1251 onate kinase deficiency, a metabolic autoinflamma- action of wild-type and mutant TNF receptors en- 1308 1252 tory disease. Clin Immunol 2012. http://dx.doi.org/ hances inflammation in TNF receptor 1-associated 1309 1253 10.1016/j.clim.2012.09.011. periodic fever syndrome. Proc Natl Acad Sci 1310 1254 54. Korppi M, van Gijn ME, Antila K. Hyperimmunoglo- U S A 2010;107(21):9801–6. 1311 1255 bulinemia D and periodic fever syndrome in chil- 68. Stojanov S, Dejaco C, Lohse P, et al. Clinical and 1312 1256 dren. Review on therapy with biological drugs functional characterisation of a novel TNFRSF1A 1313 1257 and case report. Acta Paediatr 2010;100(1):21–5. c.605T>A/V173D cleavage site mutation associated 1314 1258 55. van der Hilst JC, Bodar EJ, Barron KS, et al. Long- with tumour necrosis factor receptor-associated pe- 1315 1259 term follow-up, clinical features, and quality of life riodic fever syndrome (TRAPS), cardiovascular 1316 1260 in a series of 103 patients with hyperimmunoglobu- complications and excellent response to etanercept 1317 1261 linemia D syndrome. Medicine 2008;87(6):301–10. treatment. Ann Rheum Dis 2007;67(9):1292–8. 1318 1262 56. Ryan JG, Kastner DL. Fevers, genes, and innate 69. Bulua AC, Mogul DB, Aksentijevich I, et al. Efficacy 1319 1263 immunity. Curr Top Microbiol Immunol 2008;321: of etanercept in the tumor necrosis factor receptor- 1320 1264 169–84. associated periodic syndrome: a prospective, 1321 1265 57. Simon A, Bijzet J, Voorbij HA, et al. Effect of inflam- open-label, dose-escalation study. Arthritis Rheum 1322 1266 matory attacks in the classical type hyper-IgD syn- 2012;64(3):908–13. 1323 1267 drome on immunoglobulin D, cholesterol and 70. Feldmann J, Prieur AM, Quartier P, et al. Chronic 1324 1268 parameters of the acute phase response. J Intern infantile neurological cutaneous and articular 1325 1269 Med 2004;256(3):247–53. syndrome is caused by mutations in CIAS1, a 1326 1270 58. Ammouri W, Cuisset L, Rouaghe S, et al. Diag- gene highly expressed in polymorphonuclear 1327 1271 nostic value of serum immunoglobulinaemia D level cells and chondrocytes. Am J Hum Genet 1328 1272 in patients with a clinical suspicion of hyper IgD 2002;71(1):198–203. 1329 1273 syndrome. Rheumatology (Oxford) 2007;46(10): 71. Hoffman HM, Mueller JL, Broide DH, et al. Mutation 1330 1274 1597–600. of a new gene encoding a putative pyrin-like pro- 1331 1275 59. Demirkaya E, Caglar MK, Waterham HR, et al. tein causes familial cold autoinflammatory syn- 1332 1276 A patient with hyper-IgD syndrome responding to drome and Muckle-Wells syndrome. Nat Genet 1333 1277 anti-TNF treatment. Clin Rheumatol 2007;26(10): 2001;29(3):301–5. 1334 1278 1757–9. 72. Leslie KS, Lachmann HJ, Bruning E, et al. Pheno- 1335 1279 60. Topaloglu R, Ayaz NA, Waterham HR, et al. Hyper- type, genotype, and sustained response to ana- 1336 1280 immunoglobulinemia D and periodic fever syn- kinra in 22 patients with autoinflammatory disease 1337 1281 drome; treatment with etanercept and follow-up. associated with CIAS-1/NALP3 mutations. Arch 1338 1282 Clin Rheumatol 2008;27(10):1317–20. Dermatol 2006;142(12):1591. 1339 1283 1340

DET818_proof ■ 3 May 2013 ■ 10:59 am Autoinflammatory Diseases in Pediatrics 13

1341 73. Yu JR, Leslie KS. Cryopyrin-associated periodic 85. Torrelo A, Patel S, Colmenero I, et al. Chronic atyp- 1402 1342 syndrome: an update on diagnosis and treatment ical neutrophilic dermatosis with lipodystrophy and 1403 1343 response. Curr Allergy Asthma Rep 2010;11(1): elevated temperature (CANDLE) syndrome. J Am 1404 1344 1405 12–20. Acad Dermatol 2010;62(3):489–95. 1345 1406 1346 74. Shinkai K, McCalmont TH, Leslie KS. Cryopyrin- 86. Aksentijevich I, Masters SL, Ferguson PJ, et al. An 1407 1347 associated periodic syndromes and autoinflam- autoinflammatory disease with deficiency of the 1408 1348 mation. Clin Exp Dermatol 2008;33(1):1–9, interleukin-1–receptor antagonist. N Engl J Med 1409 1349 071010075526003–??? 2009;360(23):2426–37. 1410 1350 75. Cuisset L, Jeru I, Dumont B, et al. Mutations in the 87. Jesus AA, Osman M, Silva CA, et al. A novel muta- 1411 1351 autoinflammatory cryopyrin-associated periodic tion of IL1RN in the deficiency of interleukin-1 re- 1412 1352 syndrome gene: epidemiological study and les- ceptor antagonist syndrome: description of two 1413 1353 sons from eight years of genetic analysis in France. unrelated cases from Brazil. Arthritis Rheum 1414 1354 Ann Rheum Dis 2011;70(3):495–9. 2011;63(12):4007–17. 1415 1355 1416 76. Hawkins PN, Lachmann HJ, Aganna E, et al. Spec- 88. Altiok E, Aksoy F, Perk Y, et al. A novel mutation in 1356 1417 1357 trum of clinical features in Muckle-Wells syndrome the interleukin-1 receptor antagonist associated 1418 1358 and response to anakinra. Arthritis Rheum 2004; with intrauterine disease onset. Clin Immunol 1419 1359 50(2):607–12. 2012;145(1):77–81. 1420 1360 77. Lachmann HJ, Kone´-Paut I, Kuemmerle- 89. Schnellbacher C, Ciocca G, Menendez R, et al. Defi- 1421 1361 Deschner JB, et al. Use of canakinumab in the ciency of interleukin-1 receptor antagonist respon- 1422 1362 cryopyrin-associated periodic syndrome. N Engl J sive to anakinra. Pediatr Dermatol 2012. http:// 1423 1363 Med 2009;360(23):2416–25. dx.doi.org/10.1111/j.1525-1470.2012.01725.x. 1424 1364 78. Hoffman HM, Throne ML, Amar NJ, et al. Efficacy 90. Smith EJ, Allantaz F, Bennett L, et al. Clinical, mo- 1425 1365 and safety of (interleukin-1 trap) in lecular, and genetic characteristics of PAPA syn- 1426 1366 1427 patients with cryopyrin-associated periodic syn- drome: a review. Curr Genomics 2010;11(7): 1367 1428 1368 dromes: results from two sequential placebo- 519–27. 1429 1369 controlled studies. Arthritis Rheum 2008;58(8): 91. Demidowich AP, Freeman AF, Kuhns DB, et al. Brief 1430 1370 2443–52. report: genotype, phenotype, and clinical course in 1431 1371 79. Borghini S, Tassi S, Chiesa S, et al. Clinical presen- five patients with PAPA syndrome (pyogenic sterile 1432 1372 tation and pathogenesis of cold-induced autoin- arthritis, pyoderma gangrenosum, and acne). 1433 1373 flammatory disease in a family with recurrence of Arthritis Rheum 2012;64(6):2022–7. 1434 1374 an NLRP12 mutation. Arthritis Rheum 2011;63(3): 92. Schellevis MA, Stoffels M, Hoppenreijs EP, et al. 1435 1375 830–9. Variable expression and treatment of PAPA syn- 1436 1376 80. Marrakchi S, Guigue P, Renshaw BR, et al. Inter- drome. Ann Rheum Dis 2011;70(6):1168–70. 1437 1377 1438 leukin-36-receptor antagonist deficiency and gene- 93. Dierselhuis MP, Frenkel J, Wulffraat NM, et al. Ana- 1378 1439 1379 ralized pustular psoriasis. N Engl J Med 2011; kinra for flares of pyogenic arthritis in PAPA syn- 1440 1380 365(7):620–8. drome. 2005. Q13 1441 1381 81. Majeed HA, Kalaawi M, Mohanty D, et al. 94. Stichweh DS, Punaro M, Pascual V. Dramatic 1442 1382 Congenital dyserythropoietic anemia and chronic improvement of pyoderma gangrenosum with in- 1443 1383 recurrent multifocal osteomyelitis in three related fliximab in a patient with PAPA syndrome. Pediatr 1444 1384 children and the association with Sweet synd- Dermatol 2005;22(3):262–5. 1445 1385 rome in two siblings. J Pediatr 1989;115(5 Pt 1): 95. Miceli-Richard C, Lesage S, Rybojad M, et al. 1446 1386 730–4. CARD15 mutations in Blau syndrome. Nat Genet 1447 1387 82. Ferguson PJ. Homozygous mutations in LPIN2 are 2001;29(1):19–20. 1448 1388 1449 responsible for the syndrome of chronic recurrent 96. Borzutzky A, Fried A, Chou J, et al. NOD2-associ- 1389 1450 1390 multifocal osteomyelitis and congenital dyserythro- ated diseases: bridging innate immunity and auto- 1451 1391 poietic anaemia (Majeed syndrome). J Med Genet inflammation. Clin Immunol 2010;134(3):251–61. 1452 1392 2005;42(7):551–7. 97. Sfriso P, Caso F, Tognon S, et al. Blau syndrome, 1453 1393 83. Herlin T, Fiirgaard B, Bjerre M, et al. Efficacy of anti- clinical and genetic aspects. Autoimmun Rev 1454 1394 IL-1 treatment in Majeed syndrome. Ann Rheum 2012;12(1):44–51. 1455 1395 Dis 2012;72(3):410–3. 98. Rose CD, Martin TM, Wouters CH. Blau syndrome 1456 1396 84. Liu Y, Ramot Y, Torrelo A, et al. Mutations in protea- revisited. Curr Opin Rheumatol 2011;23(5):411–8. 1457 1397 some subunit b type 8 cause chronic atypical 99. Rose CD, Arostegui JI, Martin TM, et al. NOD2- 1458 1398 neutrophilic dermatosis with lipodystrophy and associated pediatric granulomatous arthritis, an 1459 1399 1460 elevated temperature with evidence of genetic expanding phenotype: study of an international 1400 1461 1401 and phenotypic heterogeneity. Arthritis Rheum registry and a national cohort in Spain. Arthritis 1462 Q12 2012;64(3):895–907. Rheum 2009;60(6):1797–803.

DET818_proof ■ 3 May 2013 ■ 10:59 am Our reference: DET 818 P-authorquery-v9

AUTHOR QUERY FORM

Journal: DET

Article Number: 818

Dear Author,

Please check your proof carefully and mark all corrections at the appropriate place in the proof (e.g., by using on-screen annotation in the PDF file) or compile them in a separate list. Note: if you opt to annotate the file with software other than Adobe Reader then please also highlight the appropriate place in the PDF file. To ensure fast publication of your paper please return your corrections within 48 hours.

For correction or revision of any artwork, please consult http://www.elsevier.com/artworkinstructions.

Any queries or remarks that have arisen during the processing of your manuscript are listed below and highlighted by flags in the proof.

Location Query / Remark: Click on the Q link to find the query’s location in text in article Please insert your reply or correction at the corresponding line in the proof Q1 Please approve the short title to be used in the running head at the top of each right-hand page. Q2 This is how your name will appear on the contributor’s list. Please add your academic title and any other necessary titles and professional affiliations, verify the information, and OK JONATHAN S. HAUSMANN, MD, Fellow in Rheumatology, Program in Rheumatology, Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts FATMA DEDEOGLU, MD, Assistant Professor, Program in Rheumatology, Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts Q3 Are the author names and order of authors OK as set? Q4 The following synopsis is the one that you supplied, but edited down to less than 100 words. Please confirm OK, or submit a replacement (also less than 100 words). Please note that the synopsis will appear in PubMed: Autoinflammatory diseases (AIDs) are characterized by recurrent episodes of systemic and organ-specific inflammation. Many of these diseases share fever as a common presenting feature. Physicians need to consider AIDs in children with recurrent, unexplained fevers, when infectious and malignant causes have been discarded. This article discusses the differential diagnosis of recurrent fever in children, with a focus on AIDs. It discusses periodic fevers with aphthous stomatitis, pharyngitis, and cervical adenitis, and the monogenic AIDs that cause recurrent fevers. In addition, deficiency of the interleukin-36 receptor antagonist and 2 monogenic granulomatous disorders are discussed. Q5 Please verify the affiliation address. Q6 If there are any drug dosages in your article, please verify them and indicate that you have done so by initialing this query. Q7 As per the editorial remarks, “Tables 2e5 have been converted to Boxes 1e4.” Please verify. Q8 Please verify the expansion that has been added for the abbreviation “CPK.” Q9 This query was raised by guest editor, “The authors need to mention rq2q vs cysteine mutations.” Please verify. Q10 Please verify the abbreviation “NF-kB” as retained. Q11 Please provide the publishers’ locations in Refs. 40 and 43. Q12 Originally Refs.85 (now 84) and 86 were identical, so Ref. 86 has been removed from the reference list and subsequent references have been renumbered. Q13 Please provide the complete publication details for Ref. 93. Q14 Please provide superscript reference numbers for the studies cited in Table 1. If necessary, please add the appropriate details to the Reference list, renumber the list sequentially, and add the appropriate superscript number at the citations. Q15 The numbers “3” and “4” in Box 3 has been deleted because there are no numbers “1” and “2.” Are these points minor criteria in addtion to “Incomplete attacks involving 1 or more of the following sites”? Please clarify.

Please check this box or indicate your approval if you have no , corrections to make to the PDF file

Thank you for your assistance.