DEAR EDITOR, JIA constitutes a heterogeneous group of diseases, where genetic factors are presumed to play an important pathological role. RF-positive polyarticular JIA is the least common subtype of JIA, occurring in about 5% of patients. Most such patients are diagnosed after 8years of age. There is phenotypic resemblance with adult RA, which itself is considered as a polygenic disease [1]. Here, we report a Mendelian cause of RF-positive polyarticular JIA consequent upon a previously unreported mutation in COPA. A female, with a history of hereditary multiple exostoses resulting from a paternally inherited heterozygous mutation in EXT1, presented at age 6years with a symmetric polyarthritis involving the wrists, metacarpophalangeal and interphalangeal proximal joints, knees, ankles and cervical spine. High titres of RF and anti-cyclic citrullinated peptide (anti-CCP) antibodies were detected. Lung function tests, chest computed tomography, serum creatinine, blood urea nitrogen and urine protein were normal. A diagnosis of RF-positive polyarticular JIA was proposed and treatment with methotrexate initiated. Owing to a persistence of active polyarthritis, treatment with rituximab was then introduced, resulting in long-lasting clinical remission beyond 3 years of follow-up. Considering the early onset and the rarity of RF-positive polyarthritis, a monogenic cause was suspected. Whole exome sequencing identified a heterozygous variation in exon 10 of COPA, c. 855G> C; p. Q285H. This variant, which was found to have occurred de novo, is not present in publicly available single-nucleotide polymorphism (SNP) databases (ExAC and gnomAD). Interestingly, this mutation is close to but distinct from the hotspot containing all the known mutations initially associated with COPA syndrome, occurring on the outer surface of the adjacent blade within the seven-bladed b-propellor structure (Fig. 1A)[2]. Moreover, like the previous mutations, this substitution is not predicted to be structurally damaging (DDG= 0.40 kcal/mol calculated with FoldX)[3]. COPA syndrome is an autosomal dominant condition, most typically manifesting in childhood, and variably associating interstitial lung disease and/or pulmonary haemorrhage, inflammatory arthritis, renal glomerular disease and high-titre autoantibodies [2]. Of interest, a severe early onset deforming arthritis associated with interstitial lung disease has been very recently described with a heterozygous missense mutation of COPA (c. 841C> T, p. R281W) also distinct from the initial mutation hotspot (Fig. 1A)[3]. COPA syndrome results from missense mutations in COPA, encoding the subunit alpha of the coatomer complex I (COPI) that ensures the retrograde trafficking of dilysine-tagged proteins from the Golgi to the endoplasmic reticulum (ER)[2]. Loss of COPA function leads to enhanced type I IFN signalling due to a failure of Golgi-to-ER STING retrieval [4]. Thus, to evaluate the relevance of the p. Q285H substitution, we investigated type I IFN signalling. IFN-stimulated gene (ISG) expression was up-regulated in whole blood (Fig. 1B), and IFNa2 protein was measured at 87.38 fg/ml (recorded using an ultra-sensitive digital ELISA). Functional analysis demonstrated that the p. Q285H variant, like other known COPA mutations studied in our laboratory [4], induced type I IFN signalling (Fig. 1C–E). These results provide strong evidence that the identified COPA variant is responsible for the development of the RF-positive polyarticular JIA in our patient. This study was approved by the Comitede Protection des Personnes (ID-RCB/EUDRACT: 2014-A01017-40).

To date, the demonstration of monogenic inheritance in JIA has …