Abstract
Monogenic autoinflammatory syndromes are a rare group of disorders characterized by periodic episodes of systemic inflammation of endogenous origin. Sometimes, these diseases may present with features akin to vasculitis. We conducted a literature review on such vasculitic manifestations in described monogenic autoinflammatory syndromes utilizing the Online Mendelian Inheritance in Man (OMIM), Medline, and Scopus databases. Our search identified that Familial Mediterranean fever (FMF) can manifest with features of either small, medium, large, or variable-vessel vasculitis. Stimulator of interferon gene (STING)-associated vasculopathy of infancy (SAVI) is an interferonopathy that can mimic the presentation of medium-vessel or small-vessel vasculitis, whereas deficiency of adenosine deaminase 2 (DADA2) is another such mimic of medium-vessel vasculitis, associated in a significant number of patients with features of immunodeficiency. Occasional reports exist of vasculitic manifestations in tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) and chronic infantile neurologic cutaneous and articular disorder (CINCA), whereas mevalonate kinase deficiency can also mimic the presentation of small- or medium-vessel vasculitis. Clinicians should be aware of the possibility of autoinflammatory disease presenting as vasculitis to diagnose and treat the same appropriately.
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Abbreviations
- AAV:
-
ANCA-associated small-vessel vasculitis
- AIS:
-
Autoinflammatory syndromes
- ANCA:
-
Anti-neutrophil cytoplasmic antibodies
- AZA:
-
Azathioprine
- BD:
-
Behcet’s disease
- CIAS1:
-
Cold induced autoinflammatory syndrome 1
- CINCA:
-
Chronic infantile neurologic cutaneous and articular disease
- CRP:
-
C-reactive protein
- DADA2:
-
Deficiency of adenosine deaminase 2
- DIRA:
-
Deficiency of IL-1 receptor antagonist
- FMF:
-
Familial Mediterranean fever
- GI:
-
Gastrointestinal
- GPA:
-
Granulomatosis with polyangiitis
- HBV:
-
Hepatitis B virus
- HIDS:
-
Hyper IgD syndrome
- IgAV:
-
Immunoglobulin A vasculitis
- IFN:
-
Interferon
- IL:
-
Interleukin
- IVIG:
-
Intravenous immunoglobulin
- KD:
-
Kawasaki’s disease
- LVV:
-
Large-vessel vasculitis
- MEFV:
-
Mediterranean fever gene
- MKD:
-
Mevalonate kinase deficiency
- MPA:
-
Microscopic polyangiitis
- NFκB:
-
Nuclear factor kappa B
- NOMID:
-
Neonatal onset multisystemic inflammatory disorder
- OMIM:
-
Online Mendelian Inheritance in Man
- PAN:
-
Polyarteritis nodosa
- PAAND:
-
Pyrin-associated autoinflammation with neutrophilic dermatosis
- PAPA:
-
Pyogenic arthritis, pyoderma gangrenosum and acne syndrome
- PBMC:
-
Peripheral blood mononuclear cells
- PFM:
-
Protracted febrile myalgia
- PSTPIP1:
-
Proline serine threonine phosphatase interacting protein 1
- SAVI:
-
STING-associated vasculopathy of infancy
- STING:
-
Stimulator of interferon genes
- TA:
-
Takayasu’s arteritis
- TNF:
-
Tumor necrosis factor
- TNF-α:
-
Tumor necrosis factor alpha
- TNFAIP3:
-
TNF-α-induced protein 3
- TNFRSF1A:
-
TNF receptor superfamily 1 A
- TRAPS:
-
TNF receptor-associated periodic syndrome
References
Manthiram K, Zhou Q, Aksentijevich I, Kastner DL (2017) The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol 18:832–842. doi:10.1038/ni.3777
Jamilloux Y, Belot A, Magnotti F et al (2017) Geoepidemiology and immunologic features of autoinflammatory diseases: a comprehensive review. Clin Rev Allergy Immunol. doi:10.1007/s12016-017-8613-8
Jennette JC, Falk RJ, Bacon PA et al (2013) 2012 revised international chapel hill consensus conference nomenclature of vasculitides. Arthritis Rheumatol 65:1–11. doi:10.1002/art.37715
Liu Y, Jesus AA, Marrero B et al (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518. doi:10.1056/NEJMoa1312625
Navon Elkan P, Pierce SB, Segel R et al (2014) Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 370:921–931. doi:10.1056/NEJMoa1307362
Federici S, Sormani MP, Ozen S et al (2015) Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis 74:799–805. doi:10.1136/annrheumdis-2014-206580
Gul A (2015) Pathogenesis of Behcet’s disease: autoinflammatory features and beyond. Semin Immunopathol 37:413–418. doi:10.1007/s00281-015-0502-8
Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writing a narrative biomedical review: considerations for authors, peer reviewers, and editors. Rheumatol Int 31:1409–1417. doi:10.1007/s00296-011-1999-3
Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227–253
Schlesinger M, Kopolovic J, Viskoper RJ, Ron N (1983) A case of Familial Mediterranean fever with cutaneous vasculitis and immune complex nephritis: light, electron, and immunofluorescent study of renal biopsy. Am J Clin Pathol 80:511–514
Sachs D, Langevitz P, Morag B, Pras M (1987) Polyarteritis nodosa and Familial Mediterranean fever. Br J Rheumatol 26:139–141
Glikson M, Galun E, Schlesinger M et al (1989) Polyarteritis nodosa and Familial Mediterranean fever: a report of 2 cases and review of the literature. J Rheumatol 16:536–539
Henckes M, Roskams T, Vanneste S, Van Damme B, Vanrenterghem Y (1994) Polyarteritis nodosa type vasculitis in a patient with Familial Mediterranean fever treated with cyclosporin A. Transpl Int 7:292–296
Kocak H, Cakar N, Hekimoglu B et al (1996) The coexistence of Familial Mediterranean fever and polyarteritis nodosa; report of a case. Pediatr Nephrol 10:631–633
Ozdogan H, Arisoy N, Kasapcapur O et al (1997) Vasculitis in Familial Mediterranean fever. J Rheumatol 24:323–327
Serrano R, Martinez MA, Andres A, Morales JM, Samartin R (1998) Familial mediterranean fever and acute myocardial infarction secondary to coronary vasculitis. Histopathology 33:163–167
Tekin M, Yalcinkaya F, Tumer N et al (2000) Clinical, laboratory and molecular characteristics of children with Familial Mediterranean fever-associated vasculitis. Acta Paediatr 89:177–182
Ozen S, Bakkaloglu A, Yilmaz E et al (2003) Mutations in the gene for Familial Mediterranean fever: do they predispose to inflammation? J Rheumatol 30:2014–2018
Bosacki C, Richard O, Freycon F, Mosnier JF, Cathebras P (2003) The association of polyarteritis nodosa and Familial Mediterranean fever. Presse Med 32:24–26
Braun E, Schapira D, Guralnik L, Azzam ZS (2003) Acute vasculitis with multiorgan involvement in a patient with Familial Mediterranean fever. Am J Med Sci 325:363–364
Hatemi G, Masatlioglu S, Gogus F, Ozdogan H (2004) Necrotizing vasculitis associated with Familial Mediterranean fever. Am J Med 117:516–519. doi:10.1016/j.amjmed.2004.02.050
Topaloglu R, Ozaltin F, Yilmaz E et al (2005) E148Q is a disease-causing MEFV mutation: a phenotypic evaluation in patients with Familial Mediterranean fever. Ann Rheum Dis 64:750–752. doi:10.1136/ard.2004.026963
Ozkaya O, Bek K, Alaca N et al (2007) Cerebral vasculitis in a child with Henoch-Schonlein purpura and Familial Mediterranean fever. Clin Rheumatol 26:1729–1732. doi:10.1007/s10067-006-0485-x
Balbir-Gurman A, Nahir AM, Braun-Moscovici Y (2007) Vasculitis in siblings with Familial Mediterranean fever: a report of three cases and review of the literature. Clin Rheumatol 26:1183–1185. doi:10.1007/s10067-006-0323-1
Kone-Paut I, Hentgen V, Guillaume-Czitrom S et al (2009) The clinical spectrum of 94 patients carrying a single mutated MEFV allele. Rheumatology (Oxford) 48:840–842. doi:10.1093/rheumatology/kep121
Zihni FY, Kalfa M, Ocakçi PT et al (2012) Coexistence of Takayasu’s arteritis with Familial Mediterranean fever. Rheumatol Int 32:1675–1678. doi:10.1007/s00296-011-1853-7
Luger S, Harter PN, Mittelbronn M, Wagner M, Foerch C (2013) Brain stem infarction associated with Familial Mediterranean fever and central nervous system vasculitis. Clin Exp Rheumatol 31:93–95
Ebrahimi-Fakhari D, Schonland SO, Hegenbart U et al (2013) Familial Mediterranean fever in Germany: clinical presentation and amyloidosis risk. Scand J Rheumatol 42:52–58. doi:10.3109/03009742.2012.714796
Moradian MM, Sarkisian T, Amaryan G et al (2014) Patient management and the association of less common Familial Mediterranean fever symptoms with other disorders. Genet Med 16:258–263. doi:10.1038/gim.2013.112
Komatsu S, Honma M, Igawa S et al (2014) Cutaneous necrotizing vasculitis as a manifestation of Familial Mediterranean fever. J Dermatol. doi:10.1111/1346-8138.12588
Taylan A, Yildiz Y, Sari I, Ozkok G (2014) Vasculitis and long standing ankylosing spondylitis in a patient with Familial Mediterranean fever. J Res Med Sci 19:1009–1011
Jarjour RA, Al-Berrawi S (2015) Familial Mediterranean fever in Syrian children: phenotype-genotype correlation. Rheumatol Int 35:629–634. doi:10.1007/s00296-014-3116-x
Amaryan G, Sarkisian T, Tadevosyan A (2015) Clinical and genetic peculiarities of vasculitis associated with Familial Mediterranean fever in Armenian children. Pediatr Rheumatol Online J 13:P91–P91. doi:10.1186/1546-0096-13-S1-P91
Abbara S, Fain O, Saadoun D et al (2015) Vasculitis associated with familial Mediterranean fever: a study on 16 French adult cases. Pediatr Rheumatol Online J 13:P128–P128. doi:10.1186/1546-0096-13-S1-P128
Ugan Y, Dogru A, Sencan H, Sahin M, Ercan Tunc S (2016) Sacroiliitis and polyarteritis nodosa in a patient with Familial Mediterranean fever. Case Rep Med 2016:5134546. doi:10.1155/2016/5134546
Ozcakar ZB, Cakar N, Uncu N, Celikel BA, Yalcinkaya F (2017) Familial Mediterranean fever-associated diseases in children. QJM 110:287–290. doi:10.1093/qjmed/hcw230
Luger S, Harter PN, Mittelbronn M, Wagner M, Foerch C (2013) Brain stem infarction associated with Familial mediterranean fever and central nervous system vasculitis. Clin Exp Rheumatol 31:S93–S95
Masters SL, Lagou V, Jéru I et al (2016) Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci Transl Med 8:332ra45. doi:10.1126/scitranslmed.aaf1471
Cashen K, Kamat D (2009) Recurrent fever and rash. Clin Pediatr (Phila) 48:679–682. doi:10.1177/0009922809333090
Lamprecht P, Moosig F, Adam-Klages S et al (2004) Small vessel vasculitis and relapsing panniculitis in tumour necrosis factor receptor associated periodic syndrome (TRAPS). Ann Rheum Dis 63:1518–1520. doi:10.1136/ard.2003.016733
Hernandez-Rodriguez J, Ruiz-Ortiz E, Tome A et al (2016) Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center. Autoimmun Rev 15:9–15. doi:10.1016/j.autrev.2015.08.008
Zhou Q, Wang H, Schwartz DM et al (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet 48:67–73. doi:10.1038/ng.3459
Zhou Q, Yu X, Demirkaya E et al (2016) Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci USA 113:10127–10132. doi:10.1073/pnas.1612594113
Kolivras A, Theunis A, Ferster A et al (2011) Cryopyrin-associated periodic syndrome: an autoinflammatory disease manifested as neutrophilic urticarial dermatosis with additional perieccrine involvement. J Cutan Pathol 38:202–208. doi:10.1111/j.1600-0560.2010.01638.x
Russo RA, Katsicas MM (2001) Chronic infantile neurological cutaneous and articular syndrome: two new cases with rare manifestations. Acta Paediatr 90:1076–1079
Khemani C, Khubchandani R (2007) CINCA syndrome. Indian Pediatr 44:933–936
Dollfus H, Hafner R, Hofmann HM et al (2000) Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome: ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol 118:1386–1392
Niv D, Ramirez JA, Fivenson DP (2017) Pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome with recurrent vasculitis. JAAD Case Rep 3:70–73. doi:10.1016/j.jdcr.2016.11.006
Khatibi K, Heit JJ, Telischak NA, Elbers JM, Do HM (2016) Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm. J Neurointerv Surg 8:e29. doi:10.1136/neurintsurg-2015-011753.rep
Shepherd J, Nicklin MJ (2005) Elastic-vessel arteritis in interleukin-1 receptor antagonist-deficient mice involves effector Th1 cells and requires interleukin-1 receptor. Circulation 111:3135–3140. doi:10.1161/circulationaha.104.519132
Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW (2000) Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med 191:303–312
Matsuki T, Isoda K, Horai R et al (2005) Involvement of tumor necrosis factor-alpha in the development of T cell-dependent aortitis in interleukin-1 receptor antagonist-deficient mice. Circulation 112:1323–1331. doi:10.1161/circulationaha.105.564658
Pace S, Bingham J, Royer M (2015) Histopathologic features in a case of hyperimmunoglobulinemia D syndrome. Indian Dermatol Online J 6:S33–S36. doi:10.4103/2229-5178.171059
Berody S, Galeotti C, Kone-Paut I, Piram M (2015) A retrospective survey of patients’ journey before the diagnosis of mevalonate kinase deficiency. Joint Bone Spine 82:240–244. doi:10.1016/j.jbspin.2014.12.011
Durel CA, Aouba A, Bienvenu B et al (2016) Observational study of a French and Belgian multicenter cohort of 23 patients diagnosed in adulthood with mevalonate kinase deficiency. Medicine (Baltimore) 95:e3027. doi:10.1097/md.0000000000003027
Kaustio M, Haapaniemi E, Göös H et al (2016) Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes. J Allergy Clin Immunol 140:782–796
Jeremiah N, Neven B, Gentili M et al (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Investig 124:5516–5520. doi:10.1172/jci79100
Omoyinmi E, Melo Gomes S, Nanthapisal S et al (2015) Stimulator of interferon genes-associated vasculitis of infancy. Arthritis Rheumatol 67:808. doi:10.1002/art.38998
Munoz J, Rodiere M, Jeremiah N et al (2015) Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol 151:872–877. doi:10.1001/jamadermatol.2015.0251
Picard C, Thouvenin G, Kannengiesser C et al (2016) Severe pulmonary fibrosis as the first manifestation of interferonopathy (TMEM173 mutation). Chest 150:e65–e71. doi:10.1016/j.chest.2016.02.682
Chia J, Eroglu FK, Ozen S et al (2016) Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy. J Am Acad Dermatol 74:186–189. doi:10.1016/j.jaad.2015.10.007
Kalunian KC (2016) Interferon-targeted therapy in systemic lupus erythematosus: is this an alternative to targeting B and T cells? Lupus 25:1097–1101. doi:10.1177/0961203316652495
Caorsi R, Penco F, Schena F, Gattorno M (2016) Monogenic polyarteritis: the lesson of ADA2 deficiency. Pediatr Rheumatol Online J 14:51. doi:10.1186/s12969-016-0111-7
Zhou Q, Yang D, Ombrello AK et al (2014) Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 370:911–920. doi:10.1056/NEJMoa1307361
Batu ED, Karadag O, Taskiran EZ et al (2015) A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. J Rheumatol 42:1532–1534. doi:10.3899/jrheum.150024
Schepp J, Proietti M, Frede N et al (2017) Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood. Arthritis Rheumatol 69:1689–1700. doi:10.1002/art.40147
Nanthapisal S, Murphy C, Omoyinmi E et al (2016) Deficiency of adenosine deaminase type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol 68:2314–2322. doi:10.1002/art.39699
Ben-Ami T, Revel-Vilk S, Brooks R et al (2016) Extending the clinical phenotype of adenosine deaminase 2 deficiency. J Pediatr 177:316–320. doi:10.1016/j.jpeds.2016.06.058
Van Montfrans JM, Hartman EA, Braun KP et al (2016) Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford) 55:902–910. doi:10.1093/rheumatology/kev439
Sahin S, Adrovic A, Barut K et al (2017) Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency. Rheumatol Int. doi:10.1007/s00296-017-3740-3
Caorsi R, Penco F, Grossi A et al (2017) ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. doi:10.1136/annrheumdis-2016-210802
Garg N, Kasapcopur O, Foster J 2nd et al (2014) Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr 173:827–830. doi:10.1007/s00431-014-2320-8
Van Eyck L Jr, Hershfield MS, Pombal D et al (2015) Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. J Allergy Clin Immunol 135(283–287):e285. doi:10.1016/j.jaci.2014.10.010
Gonzalez Santiago TM, Zavialov A, Saarela J et al (2015) Dermatologic features of ADA2 deficiency in cutaneous polyarteritis nodosa. JAMA Dermatol 151:1230–1234. doi:10.1001/jamadermatol.2015.1635
Fellmann F, Angelini F, Wassenberg J et al (2016) IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation. J Allergy Clin Immunol 137(1189–1196):e1181–e1182. doi:10.1016/j.jaci.2015.07.053
Elbracht M, Mull M, Wagner N et al (2017) Stroke as initial manifestation of adenosine deaminase 2 deficiency. Neuropediatrics 48:111–114. doi:10.1055/s-0036-1597611
Hsu AP, West RR, Calvo KR et al (2016) Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: successful hematopoietic stem cell transplantation. J Allergy Clin Immunol 138(628–630):e622. doi:10.1016/j.jaci.2016.03.016
Poswar Fde O, da Fonseca RM, de Albuquerque LC et al (2016) Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis. J Neurol 263:818–820. doi:10.1007/s00415-016-8070-y
Nihira H, Nakagawa K, Izawa K et al (2017) Fever of unknown origin with rashes in early infancy is indicative of adenosine deaminase type 2 deficiency. Scand J Rheumatol. doi:10.1080/03009742.2017.1324912
Hashem H, Egler R, Dalal J (2017) Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase 2. J Pediatr Hematol Oncol 39:e293–e296. doi:10.1097/mph.0000000000000805
Ginsberg S, Rosner I, Rozenbaum M et al (2016) Autoinflammatory associated vasculitis. Semin Arthritis Rheum 46:367–371. doi:10.1016/j.semarthrit.2016.07.007
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Avinash Jain, Durga Prasanna Misra, Aman Sharma, Anupam Wakhlu, Vikas Agarwal, and Vir Singh Negi declare that they have no conflict of interest.
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Jain, A., Misra, D.P., Sharma, A. et al. Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes. Rheumatol Int 38, 13–24 (2018). https://doi.org/10.1007/s00296-017-3839-6
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DOI: https://doi.org/10.1007/s00296-017-3839-6