Ultrasonographic assessment reveals detailed distribution of synovial inflammation in Blau syndrome

Abstract

IntroductionArthritis is the most frequent manifestation of Blau syndrome, an autoinflammatory disorder caused by the genetic mutation of NOD2. However, detailed information on arthritis in Blau syndrome on which the therapeutic strategy should be based on is lacking. This multi-center study aimed to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome.MethodsPatients who had been diagnosed with Blau syndrome by genetic analysis of NOD2 were recruited. A total of 102 synovial sites in 40 joints were assessed semiquantitatively by ultrasound for gray-scale synovitis and synovial power Doppler (PD) signal.ResultsIn total, 10 patients whose age ranged from 10 months to 37 years enrolled in this study. Although only 4 joints (0.8%) were tender on physical examination, 81 joints (16.9%) were clinically swollen. Moreover, 240 (50.0%), and 124 (25.8%) joints showed gray-scale (GS) synovitis and synovial PD signal on ultrasound, respectively. Importantly, GS synovitis was present in 168 out of 399 non-swollen joints, in which 61 also exhibited synovial PD signal. Among 40 joint regions, the ankle, the wrist, and the proximal interphalangeal joints were the most frequently and severely affected joints. Comparisons between different synovial tissues demonstrated a significantly higher proportion of the joints with tenosynovitis as compared with that with intra-articular synovitis (41.5% versus 27.9%, P < 0.0001). In respect of age and treatment, synovial PD signals were minimal in the youngest patient and in the oldest two patients, and were relatively mild in patients receiving treatment with methotrexate plus TNF antagonists. In two patients who underwent the second ultrasound examination, total PD scores markedly decreased after initiating the treatment with a tumor necrosis factor (TNF) antagonist.ConclusionsThe detailed information on synovial inflammation obtained by ultrasound confirms the dissociation between pain and inflammation and the frequently involved joint regions and synovial tissue in the arthritis of Blau syndrome. Our data also demonstrate that ultrasonography can be a potent tool in monitoring the activity of synovial inflammation and in investigating the pathophysiology of arthritis in this rare but archetypical autoinflammatory condition.

Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early onset sarcoidosis

“…In regard to pathophysiology, the effects of NOD2 mutations are not extensively known and remain somewhat ambiguous. After the first clinical reports on the disease [4,[30][31][32][33], and the discovery of NOD2 locus [38] and its mutations [46,52], more significant contributions to the knowledge of BS and EOS have come from case reports or illustrative case series [99] and international registries [60,64,72]. The rarity and heterogeneity of BS and EOS have not allowed for the determination of treatment guidelines, therefore prospective clinical trials are clearly needed in the near future.…”

“…Normocytic anemia can occur as expression of chronic systemic inflammation [85]. Vascular inflammation involves large vessels [47,99], and Takayasu arteritis has been reported both in the familial [89] and sporadic forms of disease [88]. Arterial hypertension has often been described [60,72].…”

“…High temperature is a frequent finding [37,60], either in the form of intermittent low-grade fever [59] or persistent fever [80,99], sometimes associated with headache or even seizures [88]. Normocytic anemia can occur as expression of chronic systemic inflammation [85].…”

Granulomatous skin involvement in a patient with an unusual NOD2 mutation

“…Soft tissue swelling can occur due to inflammation in the intra‐articular synovium and tenosynovium. However, joint destruction is not commonly reported …”

Monogenic autoinflammatory diseases in children: single center experience with clinical, genetic, and imaging review

“…In Ikeda’s study, ultrasound was used to assess the swollen joints in ten patients with Blau syndrome [ 35 ]. These authors reported a high proportion of involved joints presenting with tenosynovitis rather than intra-articular synovitis (41.5% versus 27.9%).…”