Background/Purpose:

Alagille syndrome is a complex multisystem disease characterized by chronic cholestasis due to a paucity of intrahepatic bile ducts, congenital heart disease and ocular embryotoxon. Skeletal involvement consists mainly of vertebral anomalies and osteoporosis. The association of Alagille syndrome and inflammatory arthritis is exceptional and to date only 4 cases have been described. Our purpose is to collect and describe a cases series of children affected by Alagille syndrome who developed an inflammatory arthritis.

Methods:

This was a retrospective analysis of clinical charts from 6 centres in Italy, USA and France, including the Hospital where Dr. Alagille worked and described the syndrome.

Results:

We collected 9 cases of Alagille syndrome associated with chronic arthritis, 5 females and 4 males, median age 11 years (range 4-18) at last follow up. All patients had neonatal cholestasis; 9/9 cardiac involvement; 8/9 characteristic facies; 8/9 ocular abnormality; 6/9 kidney disease; 3/9 osteoporosis and 2 butterfly vertebrae. Median age at arthritis onset was 6.2 years (range 2-10); the median number of active joints at onset was 3 (range 1-8). The most common site of arthritis was the knee (8/9) followed by ankle (6/9), elbow (4/9), wrist (3/9), small joints of hands or feet (3/9), cervical spine (2/9), temporomandibular (2/9), shoulder (1/9) and hip (1/9). Two patients also had uveitis, one of which with other signs typical of sarcoidosis. Three patients had skin manifestations. Two patients had ANA positivity (³1:160) and 8/9 high inflammatory markers. Synovial fluid examination, performed in 3 patients, revealed mild to moderate leucocytosis (200-15.000 WBC/mm³). Five patients received at least one intraarticular injection of corticosteroids, 7/9 received an anti-TNF, 2/9 ustekinumab, and one patient received consecutively methotrexate, anakinra, abatacept and tocilizumab. Two patients underwent liver transplantation with arthritis resolution in one and partial remission in the other one. One patient died before transplantation; 4 patients still had active arthritis despite treatment, 2 had a mild improvement of arthritis with biologic therapies.

Conclusion: In our series the frequency of chronic arthritis among patients affected by Alagille syndrome (9/150 patients followed in the same centers) was 50 times higher than the expected frequency in the general population (1/1000). All patients had arthritis resistant to conventional treatments and only the patient who underwent liver transplantation reached clinical remission. The etiology of chronic arthritis in Alagille syndrome is not known. The two genes associated with Alagille syndrome, JAG1 and NOTCH2, have a role in regulation of angiogenesis and T cells function, possibly explaining the occurrence of joint inflammation. While the chronic course, the elevated inflammatory markers, the leucocytosis in synovial fluid and the age at onset < 16 years could be suggestive of juvenile idiopathic arthritis, the high incidence among patients with Alagille syndrome, the resistance to common treatments and the resolution with liver transplantation may suggest a role of the underlying disease in the pathogenesis of arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alagille-syndrome-and-chronic-arthritis-an-international-case-series/