Arthritis associated with Kawasaki disease: MRI findings and serum matrix metalloproteinase‐3 profiles

Abstract

Kawasaki disease (KD) is a systemic vasculitis predominantly affecting young children.1,2 Arthritis or arthralgia complicates up to one-third of KD patients and has been divided into two types.1–3 Early onset arthritis, which develops during the first 10 days of illness, affects both small and large joints and is often indistinguishable from systemic juvenile idiopathic arthritis (JIA).3,4 Late-onset arthritis, which develops on the 10th day or later of illness, primarily affects weight-bearing joints, similar to oligoarticular JIA, and lasts for 6–8 weeks.2–6 Recently it has been reported that arthritis develops in 2% of KD cases after defervescence following high-dose i.v. immunoglobulin (HD-IVIG) therapy.7 Despite the clinical significance, precise reports characterizing the arthritis particularly on magnetic resonance imaging (MRI) are limited.8 We report MRI findings and serum matrix metalloproteinase-3 (MMP-3) profiles in two patients with KD-associated arthritis. A previously healthy 5-year-old Japanese girl was admitted to Kitami Red Cross Hospital with a 2 day history of fever and right neck pain. All of the six items of the Japanese diagnostic guideline for KD were fulfilled by the fifth day of illness.1 Following the commencement of HD-IVIG therapy (2 g/kg per 24 h) in combination with acetylsalicylic acid (50 mg/kg per day), her fever resolved rapidly. On the 14th day of illness, she complained of arthralgia of her left knee in association with fever of 38.1°C. The joint was warm, and swelling with restricted motion suggested active arthritis, whereas she had no major symptom of KD except for fever. Paracentesis of the joint demonstrated yellowish synovial fluid containing 25 600 cells/mm3 of white blood cells with 65% neutrophils but no pathogenic microbes on either Gram-staining or bacterial culture. In addition, arthritis developed in her left wrist, elbow, and metacarpophalangeal and proximal interphalangeal joints of the index, middle and ring fingers in the subsequent week. Although her fever and arthritis of the left knee resolved gradually following the commencement of ibuprofen (30 mg/kg per day), arthritis of her left fingers and wrist persisted. All of her arthritis clinically subsided in association with normalization of both serum levels of both C-reactive protein (CRP) and MMP-3 following increase of the dose of ibuprofen (40 mg/kg per day). A 2-year-old Japanese girl was admitted to Kitami Red Cross Hospital because of fever and elevated levels of serum CRP. Five of the six items of the Japanese diagnostic guideline for KD were fulfilled.1 Defervescence was achieved on the seventh day of illness following two courses of HD-IVIG therapy combined with 30 mg/kg per day of acetyl salicylate. Membranous desquamation was also noted in her fingers. On the 17th day of illness, fever and swelling of her right knee developed. Serum levels of CRP and MMP-3 were elevated despite administration of ibuprofen (30 mg/kg per day). Two weeks later, the dose of ibuprofen was increased to 40 mg/kg per day. Her arthritis gradually subsided, whereas defervescence was achieved within 2 days. Both serum levels of CRP and MMP-3 returned to normal ranges within 3 months after the onset of arthritis. No other joints were affected. In both patients, gadolinium-enhanced fat-suppressed T1-weighted MRI (Gd-T1 MRI) showed effusion surrounded by abnormal enhancement of the synovium of the affected knee (Fig. 1). There was no erosion, irregular lining of the synovium or bone marrow edema on serial examination. MRI findings improved by the eighth month of illness. Anti-Epstein–Barr virus antibodies, rheumatoid factor and antinuclear antibody were all negative in both patients. Serum levels of CRP and MMP-3 were elevated at the onset of arthritis and thereafter declined to normal levels (Table 1). Both of the patients are recently drug-free without relapse of either KD or arthritis. Sagittal fat-suppressed gadolinium-enhanced T1-weighted magnetic resonance imaging of (a) the left knee of patient 1 and (b) the right knee of patient 2 showing effusion and surrounding enhancement of the synovium (arrows). The arthritis developed 8 and 10 days after defervescence following HD-IVIG therapy in patients 1 and 2, respectively, which is consistent with the previous report.7 Although the present patients responded to the increased dose of non-steroidal anti-inflammatory drugs (NSAIDs), some studies have reported a relapse of arthritis, requiring treatment with corticosteroid or a second course of HD-IVIG.3,5,7 Synovial enhancement on Gd-T1 MRI observed in the present patients possibly reflects hyperemia and inflammation of the synovium, which is commonly observed in rheumatoid arthritis (RA) and JIA but also in other arthritis such as transient arthritis of the hip, reactive arthritis and systemic lupus erythematosus.8 A similar MRI finding has been reported in a case of cervical spine and temporomandibular joint arthritis associated with KD.9 In contrast, there was no other findings characteristic of JIA or RA such as erosions of the bone, irregular lining of the synovium or bone marrow edema despite repeated MRI, although these MRI findings are absent in some JIA patients particularly at an early stage.10 This is consistent with the pathology reported in a KD patient who underwent arthrotomy demonstrating infiltration of leukocytes but not hypertrophy of the synovium.5 Given that both clinical and MRI findings improved within 8 months after onset in the present two patients, the arthritis in KD may not progress to pannus formation and resultant joint destruction as observed in RA or JIA because of its self-limiting nature. Otherwise, NSAIDs could be sufficient to prevent progression of the arthritis. Matrix metalloproteinase-3 is produced by fibroblasts, synovial cells and chondrocytes, and is involved in the destruction of cartilage and remodeling of connective tissues such as synovium and vascular walls. Serum MMP-3 level, a marker of synovitis in RA or JIA, also rises in vascular diseases such as acute phase KD particularly with coronary lesions, although at a lower level compared with the present cases, possibly due to tissue remodeling of the vascular walls.10,11 In the present patients, coronary lesions were not detected on repeated echocardiography, and MMP-3 levels correlated with the presence of arthritis but not with other KD-related symptoms. The mechanisms of arthritis in KD have not been clarified. Although autoimmune mechanisms have been implicated in the development of RA and rheumatoid factor-positive JIA, arthritis is also a major complication of auto-inflammatory diseases such as familial mediterranean fever, which are characterized by activated innate immunity and lack of autoantibodies and autoreactive T cells.12 Because the expression of MMP-3 is induced by growth factors and pro-inflammatory cytokines such as interleukin-1 and tumor necrosis factor-α,13 both synovitis and elevated MMP-3 levels could be associated with hypercytokinemia in KD. MMP-3 levels were higher at the diagnosis of KD than at the remission of arthritis in both cases. Thus, it is possible that arthritis had developed in the early stage of KD and became apparent after defervescence following HD-IVIG therapy. In conclusion, arthritis associated with KD is possibly non-erosive synovitis with excellent outcome but initially indistinguishable from an early stage of JIA. Careful follow up using NSAIDs is necessary in such cases.