Background/Purpose:

Farber disease (Farber lipogranulomatosis; acid ceramidase deficiency) is a rare lysosomal storage disorder resulting from the inherited deficiency of the enzyme acid ceramidase due to mutations in the ASAH1 gene. Inheritance is autosomal recessive. The enzyme deficiency leads to accumulation of the potent pro-inflammatory and pro-apoptotic lipid substrate, ceramide. This, in turn, induces macrophage-driven inflammation in tissues, including synovitis and lipogranuloma formation. The phenotype generally includes joint swelling, contractures and pain. Farber patients do not usually have organomegaly and none have coarse facial features. The clinical similarity of the moderate Farber phenotypes to polyarticular juvenile idiopathic arthritis (JIA) can lead to misdiagnosis. Differential diagnosis can be made by accounting for progressive symmetric arthritis, presence of subcutaneous nodules, and an unusual, hoarse voice (due to nodule formation on the larynx) in Farber disease patients. 

Methods: A cohort of 19 Farber disease patients who have not undergone hematopoietic stem cell transplantation (HSCT) provides insight into the phenotypic spectrum of the disease, as well as the clinical history, diagnostic evaluations, symptomatic treatments and their effects. Retrospectively, whenever possible, the presenting symptoms, clinical history, biochemical, and genetic diagnostic evaluations were recorded. Treatment modalities and response to treatment were registered. 

Results: Patients in the cohort vary in age from 5 months to 25 years of age. Phenotypes range from infantile onset with systemic inflammation, to late childhood onset and very mild disease. All patients demonstrated the three typical symptoms of Farber disease (arthritis, subcutaneous nodules, dysphonia). However, in several cases years passed between the appearance of the individual symptoms. Treatment varied from biologics (incl. anti-TNFa and anti-IL-6), joint injections with corticosteroids, DMARDs, NSAIDs, intensive pain relief, to no chronic treatment at all.

Conclusion: This study represents the largest collection of clinical data on Farber disease to date. It is clear that the spectrum of phenotypes includes mild presentations not previously associated with Farber, and that in most cases a pediatric rheumatologist is involved in patient care. The fact that 19 patients can be referenced and potentially followed prospectively (30 patients including those who have undergone HSCT) implies that the disease is not as rare as earlier supposed. These results also suggest that acid ceramidase deficiency may likely account for a larger number of polyarticular JIA patients than previously thought, with mild disease even possibly diagnosed in adulthood. Therapy with biologics may improve some symptoms, but will not resolve them completely. This shows that lack of adequate response to biologics can also contribute to the indication for Farber testing. It is therefore important to increase awareness of Farber disease among rheumatologists. Clinical screening studies and a natural history study are planned for the near future. Enzyme replacement therapy for Farber is currently under development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/farber-disease-important-differential-diagnostic-information-for-jia-and-other-inflammatory-arthritis-phenotypes-is-revealed-by-data-from-the-largest-clinical-cohort-to-date/