Summary
Granulomatous arthritis of childhood designates a chronic inflammatory disease characterized by granulomatous polyarthritis, uveitis and rash with a typical onset before 5 years. It can present in a familial form, called Blau Syndrome (BS), and a sporadic from, known as early onset sarcoidosis. The prevalence is unknown, but in total the sporadic and familial forms of the disease have been reported in around 40 pedigrees. The disease starts with a finely scaly, pink-red or tan-colored papulo-erythematous rash on the dorsum of the trunk and extremities. Shortly after, or simultaneously, a polyarticular symmetrical (rarely oligoarticular) synovitis of large and small joints and tendon sheaths ensues. Synovitis is remarkably proliferative and described as ``boggy'' or cyst-like. Preservation of range of motion and absence of erosive radiographic changes are characteristic. Early involvement of the proximal interphalangeal joints of the hands leads to contractures described as camptodactyly. Pan-uveitis (less frequently anterior uveitis) is mostly bilateral and granulomatous (clumpy) by biomicroscopy. It appears within a year of the other symptoms. In addition to this classic triad, other phenotype features are: 1-large vessel vasculitis mimicking Takayasu's arteritis, renal artery stenosis with severe hypertension and aortitis; 2-interstitial granulomatous nephritis and 3-hepatic and splenic granulomas. Mild anemia, elevated sedimentation rate, variable elevation of angiotensin-converting enzyme (ACE) levels, and absent antinuclear antibodies and rheumatoid factor are characteristic. Chest radiographs lack hilar adenopathy and joint films show para-atrticular osteopenia but rarely erosions or narrowing. Both BS and early onset sarcoidosis are associated with mutations in the gene encoding NOD2/CARD15 (located on chromosome 16; 16q12). BS is inherited as an autosomal dominant trait. To date, ten different genetic mutations leading to amino acid substitutions in or near the NBS/NACHT domain of CARD15 have been documented in affected patients with either the familial or the sporadic forms of the disease. Of those, R334W and R334Q are the most prevalent. Mutations are found in 50-100% of familial forms and 90% of the sporadic cases. Downstream effects of these mutations are under intense investigation. Up-regulation of NF-kB has been documented by in vitro studies, suggesting that dysregulation of cytokines occurs. Diagnosis may be confirmed through skin, synovial or conjunctival biopsy, as well as by genetic testing. Histologically, there is synovial proliferation with non-caseating giant cell granulomas, mimicking adult sarcoidosis, Granulomas can be found in the dermis of affected skin and in conjunctiva. The differential diagnosis should include polyarticular juvenile idiopathic arthritis, sarcoidosis and spondyloarthropathy. Anti-inflammatories (both steroidal and non-steroidal) as well as tumor necrosis factor (TNF) blockers have been widely used, but their efficacy has not been evaluated systematically. Uveitis can be treated topically but often requires systemic therapy and surgery to treat the complications (cataracts, glaucoma, retinal detachment). Compromise of the optic nerve is not unusual. The uveitis leads to irreversible visual impairment in up to 40% of the cases and can be very severe, being without a doubt the most important contributor to morbidity. Articular functional studies are not yet available but the arthritis is difficult to control with antirheumatic drugs, including biological agents. The rash may disappear with time but the rest of the symptoms tend to persist and many patients become corticosteroid dependent over time. *Authors: Drs C. Rose and C. Wouters (October 2006)*.
