Coatomer-associated protein subunit alpha syndrome: abnormal trafficking between the Golgi complex and the endoplasmic reticulum
- 1 Pneumology, Groupe Hospitalier UNEOS, Metz, Grand Est, France
- 2 Rheumatology, Groupe Hospitalier UNEOS, Metz, Grand Est, France
- 3 Médecine Interne, Groupe Hospitalier UNEOS, Metz, Grand Est, France
- Correspondence to Dr François Maurier; francois.maurier@hp-metz.fr
Abstract
A 25-year-old woman with a history of juvenile idiopathic arthritis and rheumatoid factor-positive polyarthritis developed dyspnoea. Progressive cystic lung disease was diagnosed. Biomarkers of autoimmunity, such as antinuclear antibodies, antiextractable nuclear antigen antibodies, anti-SCL-70, rheumatoid factor, cyclic citrullinated peptide antibodies, c-antineutrophil cytoplasmic antibody and MPO, were found. No familial disease was reported. Despite lack of kidney manifestations, coatomer-associated protein subunit alpha syndrome was suggested. Type 1 interferon signature score was 40.8 (range, <2.3). A class 4 heterozygous mutation (c.725T>G, p.Val242Gly) was confirmed. Due to abnormal trafficking between the Golgi complex and the endoplasmic reticulum, a Mendelian monogenic autosomal dominant syndrome associating inflammatory arthritis with interstitial lung disease, with several high-titre autoantibodies, was identified. Treatment with tyrosine kinase inhibitors, Janus kinases-signal transducers and activators of transduction, may be beneficial.
Background
Coatomer-associated protein subunit alpha (COPA) syndrome was recently described in 2015 as an autosomal dominant immune dysregulatory disease. This syndrome, a sporadic association between juvenile idiopathic arthritis (JIA), cystic lung disease and undifferentiated signs of autoimmunity, is suspected and confirmed during adulthood.
Case presentation
A 25-year-old Moroccan woman with a history of JIA sought medical advice for pain in the wrists and fingers. She could not walk for distances >5 m without help and moved about in a rolling chair. She belonged to a pure Moroccan family with no history of disease. At 8 years of age, she developed polyarthritis and seropositivity for rheumatoid factor (RF) (figures 1–3) and was treated successively with corticoids, ciclosporin, methotrexate, etanercept and infliximab. No pulmonary symptoms were noted and no roentgen image could be obtained. Ineffective immunosuppressive therapies at the final stage of the inflammatory disease were discontinued at 19 years of age. Arthroplasty was considered at 21 years of age. Prosthesis was implanted on the left knee (figure 4); however, this did not produce the desired effects due to a lesion in the sciatic popliteal nerve. A presurgery roentgen image of the lung indicated interstitial lung disease (ILD). Physical examination indicated a woman of small stature, with height of 150 cm and body weight of 42 kg, without fever, with blood pressure of 123/77 mm Hg and pulse of 82 beats per minute, and with upper and lower limb joint deformities. Her fingers, wrists and toes were distorted. Flessums of the hips and knee were present. Her heart, lungs, bowel, lymph node sites and skin were normal. Neurological and sensorial examinations were normal. Her treatment included first-level analgesics as well as non-steroidal anti-inflammatory drugs. Thoracic CT scans revealed pulmonary cystic fibrosis (figures 5 and 6).
Right hand.
Right knee.
Hips in 2015.
Prosthesis on the left knee.
Apical thoracic CT scan of the cystic pins.
Basal thoracic CT scan of the cystic pins.
Bronchoalveolar lavage fluid revealed lymphocytic alveolitis with 870 000 elements/mm3: 63% macrophagic cells and 34% lymphocytes (CD4/CD8: 1.5), without germs. Blood gas measurements, in open air, were as follows: pH, 7.42; PaCO2, 34 mm Hg; PaO2, 74 mm Hg; and HCO3, 24 mmol/L. Functional lung exploration revealed the following: VEMS, 1.1 (41%); CVF, 1.8 (57%); CPT, 3.2 (79%); and DLCO, 33%. Articular echography revealed active synovitis on the patient’s wrists. Antinuclear antibodies (ANA) 1/1280 homogeneous without anti-DNA native, antiextractable nuclear antigen antibodies (anti-ENA), anti-SCL-70 3.4, RF +59 UI/mL, ACPA antibodies +85 UI/mL, c-antineutrophil cytoplasmic antibody (c-ANCA) +1/320 type and MPO 435 in ELISA were identified. Serum protein electrophoresis revealed polyclonal immunoglobulin level of up to 21.2 g/L. Alpha-1 antitrypsin level was normal. Creatine was 35 µmol/L, with blood urea nitrogen of 0.50 g/L, proteinuria of 0.08 g/L and C reactive protein of 5 mg/L. The patient’s haemogram was normal, and the lymphocytic phenotype indicated a significant deficit in the number of natural killer cells (0.04 G/L). Her type 1 interferon signature score was determined to be 40.8 (reference range, <2.3) using molecular hybridisation (nCounter, NanoString), based on six interferon-stimulated genes: IFIT1, ISG15, RSAD2, IFI27, SIGLEC1 and IFI44L. A heterozygous mutation, c.725T>G, p.Val242Gly, was identified in COPA.
Investigations
The patient was referred to our institution due to rheumatic disease. Her joints were destroyed and the deformations confirmed the final stage of the disease. The joint deformation confined the patient to limited footsteps, a bed and a rolling chair. Pain and loss of autonomy were the main drawbacks. A chest roentgenogram performed in Morocco in 2013 was available and indicated abnormal findings. The patient did not complain of respiratory trouble, yet a lung specialist was consulted and a diffuse, interstitial cystic lung disease was identified. Immunology was confusing, with too many positive tests. A multidisciplinary approach involving a rheumatologist, a pneumologist and an immunologist was adopted. The presence of JIA, severe lung disease and several positive autoimmunity test results without kidney disease suggested a COPA syndrome.1–3
Differential diagnosis
Pulmonary manifestation is not listed as an extra-articular feature in JIA and is considered among the exclusion criteria. The International League of Associations for Rheumatology (ILAR) criteria for JIA may recommend its classification as the seventh criteria, undifferentiated arthritis despite being RF-positive. Environmental, infectious and toxic pulmonary manifestations induced by corticoids, methotrexate and biotherapeutic drugs were ruled out. Monogenic JIA was described, with a mutation in LACC1. JIA and familial Mediterranean fever were described, with an MEFV mutation, introducing the idea of monogenic or polygenic autoinflammatory disorders in JIA. Lymphangioleiomyomatosis associating pulmonary cysts, renal angiomyolipoma was described with a mutation in TSC2. Autoimmunity is identified in JIA. ANCA and ANA may support the pulmonary manifestations of necrotising vasculitis or lupus. Pulmonary cysts have not yet been described in the lungs of patients with lupus or vasculitis, primary Sjögren syndrome may develop cysts in lung but clinical presentation and negative biological data (anti-ENA antibodies) were not in favor of this syndrome. Isolated anti-SCL-70 antibodies and clinical presentation tackled systemic diffuse scleroderma. STING (stimulator of interferon genes)-associated vasculopathy with onset in infancy (SAVI) showed no lung cysts.
Treatment
Physical therapy and an orthopaedic surgeon’s opinion were implicated. No pharmacological treatment was initiated despite reports on the recent successful use of baricitinib in COPA syndrome.4
Outcome and follow-up
Within half a year of kinesitherapy, the patient showed improvement and benefited from further physical therapy. She also procured a job as an engineer at her academic institution.
Discussion
This case underlines the moving complexity of the classification of JIA according to the ILAR or the Paediatric Rheumatology European Society. In 2019, the Paediatric Rheumatology International Trials Organization revised the criteria of classification for JIA, highlighting the presence of routine laboratory measures available worldwide, such as ANA positivity and the striking response to interleukin 1 and interleukin 6 inhibitors, whereupon a new entity in paediatric medical practice was defined as early-onset, ANA-positive JIA. Systemic JIA with recurring fever introduced the term autoinflammatory disease, including fever in the criteria for JIA, although interferon 1 has not yet been considered a cytokinic criterion in JIA.
Our case described COPA syndrome. According to the ILAR classification, it may be categorised as an unclassified type of JIA caused by lung disease associated with excessive signs of autoimmunity downgrading RF positivity. ILD with a different variant, usual interstitial pneumonia and non-specific interstitial pneumonia, may be associated with various pathologies: rheumatoid arthritis, ANCA-associated vasculitis and systemic lupus erythematosus. Cystic lesions were abundant and unusual in our case and were above the typical classification of ILD.
The elevated levels of various biological markers of autoimmunity may hinder diagnosis. The COPA syndrome is a new entity that has affected 31 patients so far according to published reports, with eight mutations described to date. Cytokine interleukin 6 and complement levels were not measured due to the higher index of suspicion for SAVI or other autoinflammatory disorders driven by chronically active type 1 interferon.
The association between JIA and cystic lung disease associated with undifferentiated signs of autoimmunity triggered a COPA syndrome de novo.1 2 Molecular studies involving a large panel of genes implicated in the pathologies caused by surfactant protein C were initiated. The variant Val242Gly, localised in WD40 domain containing eight other COPA mutations, has never been previously described, and bioinformatics algorithms have predicted a probable class 4 pathogenic mutation.5 A segregation study in a patient’s parents should be conducted to confirm the pathogenic role of this mutation. High titres of several autoantibodies suggested immune dysregulation and autoimmunity.
The COPA syndrome, a Mendelian monogenic missense mutation in COPA, was recently described as an autosomal dominant immune dysregulatory disease (OMIM 601924).1–3
The hypomorphic case described herein, associating JIA with ILD, with the p.Val242Gly mutation not yet described in databases and probably pathogenic, occurred de novo in adolescence and not in the neonatal stage. Treatment with tyrosine kinase inhibitors may be useful due to the high type 1 interferon signature score.
Patient’s perspective
I benefited from active kinesitherapy and regained autonomy. However, the doctors proposed no treatment for my illness.
Learning points
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Presence of several antibodies not clearly correlated to pathology evoke an immune dysregulatory disease.
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Coatomer-associated protein subunit alpha is a Mendelian autosomal dominant immune dysregulatory disease associated with autoimmune interstitial lung, joint and kidney disease.
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A high type 1 interferon signature score warrants consideration of treatment with tyrosine kinase inhibitors.
Acknowledgments
The authors would like to acknowledge Professor P Fanen of the Genetic Department at Mondor Hospital, Créteil France, and Professor J Cadranel of the Department of Pneumology, Tenon Hospital, APHP, Paris, France.
Footnotes
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Contributors JP, NR and FM contributed to the design and implementation of the research, analysis of the results and writing of the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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