Pediatric Granulomatous Arthritis Research Articles

Impaired renal function and fever of unknown origin in a patient with pediatric granulomatous arthritis: Answers.

Impaired renal function and fever of unknown origin in a patient with pediatric granulomatous arthritis: Answers.

Impaired renal function and fever of unknown origin in a patient with pediatric granulomatous arthritis: Questions.

Impaired renal function and fever of unknown origin in a patient with pediatric granulomatous arthritis: Questions.

AB1107 Hereditary autoinflammatory syndromes in brazil: A multicenter study

BackgroundThe most prevalent autoinflammatory syndromes (AIS) with an identified genetic defect are: Familial Mediterranean Fever (FMF); Tumoral necrosis fator (TNF) Receptor Associated Periodic Syndrome (TRAPS); Pediatric Granulomatous Arthritis (PGA); Cryopyrin...

AB1147 Treatment of blau syndrome-related uveitis with the long-acting IL-1 inhibitor CANAKINUMAB: 6 months follow-up

BackgroundPediatric granulomatousarthritis is a very rare conditionthataffectsyoung children and is characterized by the triad of exudative tenosynovitis, maculopapular rash, and uveitis. A genetic form, known as Blau syndrome (BS) is...

Monogenic autoinflammatory diseases: concept and clinical manifestations.

The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.

Clinical and transcriptional response to the long‐acting interleukin‐1 blocker canakinumab in Blau syndrome–related uveitis

To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment. A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month. Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patient's blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes. The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments.

Hereditary Autoinflammatory Syndromes: A Brazilian Multicenter Study

To evaluate the prevalence of genetic defects in clinically suspected autoinflammatory syndromes (AIS) in a Brazilian multicenter study. The study included 102 patients with a clinical diagnosis of Cryopyrin Associated Periodic Syndromes (CAPS), TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD) and Pediatric Granulomatous Arthritis (PGA). One of the five AIS-related genes (NLRP3, TNFRSF1A, MEFV, MVK and NOD2) was evaluated in each patient by direct DNA sequencing, based on the most probable clinical suspect. Clinical diagnoses of the 102 patients were: CAPS (n = 28), TRAPS (n = 31), FMF (n = 17), MKD (n = 17) and PGA (n = 9). Of them, 27/102 (26 %) had a confirmed genetic diagnosis: 6/28 (21 %) CAPS patients, 7/31 (23 %) TRAPS, 3/17 (18 %) FMF, 3/17 (18 %) MKD and 8/9 (89 %) PGA. We have found that approximately one third of the Brazilian patients with a clinical suspicion of AIS have a confirmed genetic diagnosis.

Autoinflammatorische Syndrome/Fiebersyndrome

Hereditary periodic (fever) syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or joint symptoms. Some of these disorders present with organ involvement and serological signs of inflammation without fever. There is a strong serological inflammatory response with an elevation of serum amyloid A (SAA), resulting in an increased risk of secondary amyloidosis. There are monogenic disorders (familial mediterranean fever (FMF), hyper-IgD-syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), "pyogenic arthritis, acne, pyoderma gangrenosum" (PAPA), and "pediatric granulomatous arthritis (PGA) where mutations in genes have been described, which in part by influencing the function of the inflammasome, in part by other means, lead to the induction of the production of IL-1β. In "early-onset of enterocolitis (IBD)", a functional IL-10 receptor is lacking. Therapeutically, above all, the IL-1 receptor antagonist anakinra is used. In case of TRAPS and PGA, TNF-antagonists (etanercept) may also be used; in FMF colchicine is first choice. As additional possible autoinflammatory syndromes, PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis and adenitis), Schnitzler syndrome, Still's disease of adult and pediatric onset, Behçet disease, gout, chronic recurrent multifocal osteomyelitis (CRMO) and Crohn's disease also are mentioned.

Pediatric hereditary autoinflammatory syndromes

To describe the most prevalent pediatric hereditary autoinflammatory syndromes. A review of the literature including relevant references from the PubMed and SciELO was carried out using the keywords autoinflammatory syndromes and child. The hereditary autoinflammatory syndromes are caused by monogenic defects of innate immunity and are classified as primary immunodeficiencies. These syndromes are characterized by recurrent or persistent systemic inflammatory symptoms and must be distinguished from infectious diseases, autoimmune diseases, and other primary immunodeficiencies. This review describes the epidemiological, clinical and laboratory features, prognosis, and treatment of the main autoinflammatory syndromes, namely: familial Mediterranean fever; TNF receptor associated periodic syndrome; the cryopyrinopathies; mevalonate kinase deficiency; pediatric granulomatous arthritis; pyogenic arthritis, pyoderma gangrenosum and acne syndrome; Majeed syndrome; and deficiency of interleukin 1 receptor antagonist. The cryopyrinopathies discussed include neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic, cutaneous and articular syndrome), Muckle-Wells syndrome, and familial cold autoinflammatory syndrome. Pediatricians must recognize the clinical features of the most prevalent autoinflammatory syndromes. Early referral to a pediatric rheumatologist may allow early diagnosis and institution of treatment, with improvement in the quality of life of these patients.

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica

OBJECTIVE: To describe the most prevalent pediatric hereditary autoinflammatory syndromes. SOURCES: A review of the literature including relevant references from the PubMed and SciELO was carried out using the keywords autoinflammatory syndromes and child. SUMMARY OF THE FINDINGS: The hereditary autoinflammatory syndromes are caused by monogenic defects of innate immunity and are classified as primary immunodeficiencies. These syndromes are characterized by recurrent or persistent systemic inflammatory symptoms and must be distinguished from infectious diseases, autoimmune diseases, and other primary immunodeficiencies. This review describes the epidemiological, clinical and laboratory features, prognosis, and treatment of the main autoinflammatory syndromes, namely: familial Mediterranean fever; TNF receptor associated periodic syndrome; the cryopyrinopathies; mevalonate kinase deficiency; pediatric granulomatous arthritis; pyogenic arthritis, pyoderma gangrenosum and acne syndrome; Majeed syndrome; and deficiency of interleukin 1 receptor antagonist. The cryopyrinopathies discussed include neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic, cutaneous and articular syndrome) Muckle-Wells syndrome, and familial cold autoinflammatory syndrome. CONCLUSIONS: Pediatricians must recognize the clinical features of the most prevalent autoinflammatory syndromes. Early referral to a pediatric rheumatologist may allow early diagnosis and institution of treatment, with improvement in the quality of life of these patients.

NOD2‐Associated pediatric granulomatous arthritis, an expanding phenotype: Study of an international registry and a national cohort in spain

To study the phenotype characteristics of the largest to date cohort of patients with pediatric granulomatous arthritis (PGA) and documented mutations in the NOD2 gene. We analyzed merged data from 2 prospective cohorts of PGA patients, the International PGA Registry and a Spanish cohort. A systematic review of the medical records of interest was performed to identify phenotype characteristics. Forty-five patients with PGA (23 sporadic cases and 22 from familial pedigrees) and documented NOD2 mutations were identified and formed the basis of the study. Of these 45 patients, 18 had the R334W-encoding mutation, 18 had R334Q, 4 had E383K, 3 had R587C, 1 had C495Y, and 1 had W490L. The majority of patients manifested the typical triad of dermatitis, uveitis, and arthritis. In contrast, in 13 patients, the following "atypical" manifestations were noted: fever, sialadenitis, lymphadenopathy, erythema nodosum, leukocytoclastic vasculitis, transient neuropathy, granulomatous glomerular and interstitial nephritis, interstitial lung disease, arterial hypertension, hypertrophic cardiomyopathy, pericarditis, pulmonary embolism, hepatic granulomatous infiltration, splenic involvement, and chronic renal failure. In addition, 4 individuals who were asymptomatic carriers of a disease-causing mutation were documented. NOD2-associated PGA can be a multisystem disorder with significant visceral involvement. Treating physicians should be aware of the systemic nature of this condition, since some of these manifestations may entail long-term morbidity.

Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 "Blau mutations."

Infantile Onset Panniculitis with Uveitis and Systemic Granulomatosis: immunohistochemical findings

Infantile-Onset Panniculitis with Systemic Granulomatosis is a recently described clinicopathologic entity, considered part of the spectrum of pediatric granulomatous inflammatory diseases. Through the International Registry of Pediatric Granulomatous Arthritis (PGA), we now identified 5 children with this disorder, all manifesting from very young age panniculitis, fever, hepatosplenomegaly, arthritis, uveitis and acute phase response. Underlying infections, immune deficiency and autoimmune disease, were excluded. No CARD15 or CIAS1 mutations were found. Histologically, the subcutaneous nodules showed a non-vasculitic non-cytophagic lobular panniculits. Giant and epitheloid cell granulomas were found in liver (pt 1, 5), synovium (pt 2), lymph node (pt 3, 5), colon (pt 3), subcutaneous fat (pt 3), dermis and lung (pt 4). Immunohistochemical study of the granulomas revealed the presence of abundant CD68+ macrophages, numerous CD4+ T lymphocytes and few CD8+ cells. TNF stainings were only weakly positive, conversely abundant IL-6 staining was apparent, especially in the corona of lymphocytes. Despite steroid and cyclosporin treatment, the course was progressive in patient 1 with severe lung involvement and death from respiratory insufficiency at age 14. In patients 2, 3, 4 and 5, therapy with anti-TNF MoAbs allowed better disease control. Infantile onset Panniculitis with Systemic Granulomatosis may be a potentially fatal granulomatous disease in children. Although the response to anti-TNF MoAbs in four of our patients is of note, the paucity of TNF with overwhelming presence of IL-6 in situ in granulomas suggest the implication of alternative immune-inflammatory pathways. The role of the Th17 pthway is currently under investigation

Infantile Onset Panniculitis with Uveitis and Systemic Granulomatosis: A New Clinicopathologic Entity

We report on 4 children with infantile-onset lobular panniculitis, high fever, uveitis, and systemic granulomatous inflammation, recruited through the International Registry of Pediatric Granulomatous Arthritis. Neither CARD15 nor CIAS1 mutations were found. Despite immunosuppressive therapy, disease course was progressive. Response to anti-tumor necrosis factor monoclonal antibody in 3 patients is of note.

NOD2 gene–associated pediatric granulomatous arthritis: Clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin‐1 blockade in a Spanish cohort

Blau syndrome and early-onset sarcoidosis are NOD2 gene-associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/early-onset sarcoidosis. Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex-Set cytokine bead array. The classic Blau syndrome/early-onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized. These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin-1-mediated events.

Pediatric granulomatous arthritis: An international registry

Blau syndrome and its sporadic counterpart, early-onset sarcoidosis, share an identical phenotype featuring the classic triad of arthritis, dermatitis, and uveitis and are associated with mutations of CARD15 in 50-90% of cases. We chose the term "pediatric granulomatous arthritis" to refer to both. An international registry was established in the spring of 2005 to define the phenotype spectrum and establish the mutation frequency and variants. Histologically confirmed granuloma and arthritis were required for inclusion. Probands and relatives were genotyped for CARD15. Deidentified clinical information was collected. One year after the inception of the registry, 61 individuals from 22 pedigrees had been entered. Seven pedigrees with 19 individuals (8 affected, 11 unaffected) had clinical disease that was atypical, and none of the individuals in those pedigrees showed mutations. There were 9 classic simplex pediatric granulomatous arthritis pedigrees including 19 individuals (9 affected, 10 unaffected) and 6 classic multiplex pedigrees with 22 individuals (17 affected, 5 unaffected). Cutaneous presentation was the most common. Arthritis was polyarticular in 96% of patients. Isolated eye disease was never the presenting symptom, but significant/severe visual impairment was observed in 41% of patients. Eye disease was bilateral in 21 of 22 patients and was complicated by glaucoma in 6 of 22 patients and by cataracts in 50% of patients. Skin biopsy was the best diagnostic approach (because of accuracy and low invasiveness). In this series, the first combining familial and sporadic pedigrees and, to our knowledge, the largest, we further defined the phenotype and showed that all affected classic (and no nonclassic) pedigrees carry a mutation and that there is no asymptomatic carriage. If these data are confirmed, mutation analysis rather than tissue sampling may prove to be the most efficient diagnostic procedure.