Introduction
Blau syndrome (MIM #186580) is a rare autoinflammatory disorder, which was first described in 1985 by the pediatrician Edward Blau as a dominantly inherited, chronic inflammatory syndrome characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis and recurrent uveitis[
1]. In 2001, Miceli-Richard
et al. identified the gene that confers susceptibility for Blau syndrome, discovering three mis-sense mutations (R334Q, R334W and L469F) in the region encoding the nucleotide-binding oligomerization domain (NOD) of the caspase recruitment domain gene (
CARD15/NOD2) in four French and German affected families[
2]. In spite of the striking clinical similarities with Blau syndrome, early onset sarcoidosis (EOS, MIM #609464) was originally considered a distinct disease entity. However, subsequent genetic analyses have shown that many patients with EOS have mutations in
NOD2[
3‐
6] and these two diseases and other variant forms are now considered to represent a pathophysiologically identical condition in which increased NFκB activity driven by mutated
NOD2 gene plays a significant role[
3,
6‐
11].
Arthritis is the most frequent manifestation of Blau syndrome and usually becomes clinically apparent within the first decade of life[
1,
5,
7,
11‐
15]. Joint manifestation in Blau syndrome has been reported to be chronic, symmetrical, and mostly painless polyarthritis. Marked soft-tissue swelling can occur due to granulomatous inflammation in both intra-articular synovium and tenosynovium, which can cause characteristic camptodactyly (that is, flexion contracture of fingers and toes) and, occasionally, subsequent impairment of physical function. However, the precise location and severity of joint inflammation in patients with Blau syndrome have not been systematically evaluated because of the difficulty to accurately determine with physical examination the activity of current inflammation in mostly non-tender joints in children.
Musculoskeletal ultrasound is a relatively inexpensive imaging modality, which enables more accurate assessment of synovial inflammation than physical examination does[
16‐
19] and, therefore, provides improved accuracy in the diagnosis[
20‐
24] and the disease activity monitoring[
19,
23‐
29] of rheumatoid arthritis (RA). As ultrasound is a non-invasive technique, which patients can undergo with minimal restriction, its use in pediatric inflammatory conditions such as juvenile idiopathic arthritis (JIA) has been increasingly studied[
30‐
33]. We recently reported representative ultrasound images that clearly visualized the tenosynovitis in a patient with Blau syndrome[
34]; however, no other papers have reported the use of ultrasound in the assessment of synovial inflammation in Blau syndrome.
In this pilot, multicenter study, 10 patients with Blau syndrome whose NOD2 mutation had been confirmed underwent comprehensive ultrasound examination of 102 synovial sites, aiming to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome.
Discussion
In this multi-center study, ultrasonographic assessment of 102 synovial sites provided detailed information on the anatomical distribution of synovial inflammation in patients with Blau syndrome. Our data demonstrate that a wide range of synovial sites can be affected mostly in a symmetrical manner in patients with Blau syndrome. Most frequently involved joints identified in this study are consistent with the previous reports[
1,
7,
13‐
15]. However, our data provide novel and more specific information on the anatomical site (intra-articular synovium versus tenosynovium versus bursa), the chronicity (currently active inflammation versus chronic swelling versus subsequent contracture), and the severity (mild versus severe). As a result, the data in the form of a heat map (Figures
1 and
2) readily provide clinicians and researchers with valuable information. Furthermore, our data for the first time demonstrate the predominance of tenosynovitis over intra-articular synovitis in Blau syndrome. Although frequent involvement of the tenosynovium has been reported descriptively[
1,
7,
13‐
15], no studies had provided objective data on the predominance of tenosynovitis.
Although this is a cross-sectional study except for patient 5 and 6, comprehensive and detailed data from patients at a wide range of ages who share the same underlying molecular pathophysiology let us speculate on the natural history of synovial inflammation in Blau syndrome. Comparing the siblings (patients 1 and 2), we assume that mild GS tenosynovitis precedes clinically detectable joint swelling and full-blown PD-positive tenosynovitis; we also assume that tenosynovitis precedes intra-articular synovitis. Given the minimal PD activity of synovial inflammation in patient 10, who carries the same NOD2 mutation as patient 2 but has never received treatment, we also speculate that active synovial inflammation can spontaneously ameliorate, at least in some patients with Blau syndrome, at some point after their adolescence. These hypotheses, however, need to be confirmed in a large-scale observational study.
The marked improvement in PD scores in patients 5 and 6 after treatment with methotrexate plus infliximab and relatively low total PD scores in patients receiving treatment with methotrexate plus TNF antagonists (patients 3, 4, 7, and 9) support the notion that a methotrexate plus TNF antagonist regimen is efficacious not only for RA[
40,
41] and JIA[
42] but also for arthritis in patients with Blau syndrome[
43]. On the other hand, the effectiveness of methotrexate monotherapy was not obvious in our small group of patients. We do not exclude the possible influence of genotypes on the severity of arthritis in patient 3 (D382E) and 4 (R587C), both of which were not included in the previous analysis of the association between genotype and phenotype[
6]. A future investigation on the association between
NOD2 genotypes and ultrasound-defined severity of arthritis in a larger number of patients may identify the high-risk genotypes for severe synovial inflammation.
The symmetrical involvement of synovial tissues and the effectiveness of methotrexate plus infliximab in our patients with Blau syndrome support the argument that autoinflammatory diseases such as Blau syndrome and autoimmune diseases such as RA share some phenotypic manifestations and cytokine pathways that maintain arthritis even though the contribution of innate/acquired immunity to pathogenesis is quite different between these two categories of disease[
44]. However, our study also confirms the painless nature of arthritis in Blau syndrome, which contrasts with RA. Our patients exhibited surprisingly little tenderness or pain (Table
2) in the presence of active inflammation in both the intra-articular- and teno-synovium (Figures
1 and
2). In addition, the elevation of acute inflammatory responses was infrequent and mild, which is consistent with some of the previous reports[
1,
14]. These data were reflected in the poor correlations of total ultrasound scores with tender joint count, patients’/parents’ global VAS, ESR, and CRP (Table
3), indicating that these measures do not reflect synovial inflammation in Blau syndrome. The reasons for this absence of canonical features of inflammation in the presence of synovial inflammation, along with the predominance of tenosynovitis, caused by
NOD2 mutations are intriguing research questions in understanding the molecular mechanisms of inflammation.
On the other hand, the swollen joint count tended to correlate with total ultrasound scores (Table
3), suggesting that the swollen joint count is the most reliable conventional measure that can reflect the global severity of synovial inflammation in patients with Blau syndrome. At a joint level, however, active synovial inflammation was frequently detected by ultrasound in joints without swelling (Table
4). These data indicate that clinically detected joint swelling is not as sensitive as ultrasound findings to represent synovial inflammation.
Given the significant improvement of clinical parameters after treatment in patient 5 (Table
2), these measures may reflect the therapeutic effect of potent therapy on arthritis when disease activity is very high. However, in order to prevent structural damage and late-onset functional impairment, treating patients to a minimal disease activity state, which can be only evaluated by ultrasound, may be important. Since the impact of synovial inflammation on structural and functional deterioration in Blau syndrome can be substantially different from that in RA and JIA, longitudinal assessment of arthritis in Blau syndrome using quantitative measures for structural damage (for example, radiographic score) is urgently needed to determine the threshold of acceptable activity of synovial inflammation. In the future, clinical studies to establish optimized treatment strategies (for example, treatment agent, treatment target) for arthritis in Blau syndrome, ultrasound may play a significant role in decreasing the sample size needed by providing better quantification and sensitivity to change.
One of the major limitations of our study is the very small sample size. However, Blau syndrome is a much more homogeneous condition as compared with RA or JIA, especially when the genetic mutation of
NOD2 is confirmed. Also given the quantitative capability and the excellent reproducibility of ultrasonographic assessment of synovial inflammation in the recent reports[
22,
29,
36,
37], the comprehensive data obtained in this study are likely to represent the pathophysiology of arthritis in Blau syndrome and provide more reliable information than the mostly descriptive one in the previous reports.
Another major limitation of our study is that ultrasonographic synovial pathologies were graded subjectively due to the lack of currently available standardized measures for children. Although our data support the use of ultrasound in monitoring the disease activity of Blau syndrome, our data cannot be readily generalizable and need to be confirmed in future studies when standardized methods are established. Furthermore, performing the comprehensive ultrasound assessment we employed in this study is not feasible in daily practice. The essential synovial sites to be scanned should be determined not only by the frequency of involvement, but also by the impact on structural and functional deterioration in Blau syndrome. Although we assume that PD signal is more essential than GS synovitis in monitoring disease activity, careful gray-scale assessment is fundamentally important to distinguish between the inflammatory angiogenesis in synovial hypertrophy and the feeding vessels in unossified cartilage in children.
Competing interests
KI, NaK, ST, TK, NoK, RN, HM, and HN have received speaking fees and KI, ST, HM, and HN have also received research grant support from Mitsubishi-Tanabe Pharma Corporation. KI, ST, and HN have received speaking fees and ST and HN have also received research grant support from Takeda Pharmaceutical. KI, ST, HM have received speaking fees and HM has also received research grant support from Pfizer Japan. Other authors declared no competing interests in relation to this work.
Authors’ contributions
KI, NaK, and ST designed the study. KI performed ultrasound examination. NaK, ST, TN, YI, MT, NO, TS, TY, TK collected the clinical information. NaK, YI, IO, NoK, and RN collected the genetic information. KI, NaK, ST, NS, HM, and HN coordinated the study and analyzed and interpreted the data. KI wrote the first draft of the manuscript. All authors critically revised the first draft and approved the final version.