Refractory Cases of Adult Onset Still's Disease Successfully Treated with TNF-α Blocker

Adult onset Still`s disease (AOSD) is a systemic inflammatory disorder of unknown etiology characterized by spiking fever, evanescent salmon-colored rash, polyarthritis and leukocytosis. The diagnosis of AOSD remains a challenge to clinicians and requires a high index of suspicion because of its rarity and nonspecific symptoms. Although the etiology and pathogenesis of AOSD is not elucidated clearly, the pathogenetic role of inflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-18 and tumor necrosis factor (TNF)-α were suggested and the correlations of their levels with disease activity were also reported. These results raise a possibility that the blocking of these cytokines may provide a therapeutic benefit in controlling disease activity and relieving the symptoms of AOSD. Recently, we experienced two cases of AOSD, who were refractory to the treatment with high dose glucocorticoid and immunosuppressive agents. Both were treated with TNF- blockers and experienced remissions thereafter. These experiences might support the use of biologic agents in refractory AOSD.ope

Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis

OBJECTIVES: To determine whether osteopontin (OPN) is increased in patients with AS and to investigate its relationship to inflammatory disease activity and bone remodelling process. METHODS: This cross-sectional study included 30 patients with AS and 23 age- and sex-matched healthy controls. We assessed clinical characteristics and laboratory parameters including the ESR, CRP, lipid profiles, the Bath AS disease activity index (BASDAI) and the Bath AS radiographic index (BASRI). To evaluate bone metabolism, we tested ALP, OCN and C-telopeptide of type I collagen (CTX-I). Plasma levels of OPN, TNF-alpha and IL-6 were measured by ELISA, and mRNA expression in peripheral blood mononuclear cells (PBMCs) was performed by RT-PCR. Changes in OPN level were also evaluated in eight patients after the treatment with a TNF-alpha blocker. RESULTS: Patients with AS had significantly higher plasma OPN, TNF-alpha and IL-6 levels and more mRNA expression than healthy controls. Plasma OPN levels were correlated with serum ALP, OCN and CTX-I levels, but not with ESR, CRP, lipid profiles, BASDAI or BASRI. Treatment with a TNF-alpha blocker did not alter OPN levels, although it reduced the disease activity. CONCLUSIONS: Patients with AS had higher levels of OPN compared with controls. The plasma OPN level was correlated with serum ALP, OCN and CTX-I levels, but not with disease activity in AS. OPN might be involved in bone remodelling rather than in inflammation in AS.ope

Longitudinal Myelitis in the Cervical Cord Presenting Weakness of the Lower Extremities, as an Initial Manifestation of SLE

Transverse myelitis is a rare and serious complication of systemic lupus erythematosus (SLE). Magnetic resonance imaging (MRI) shows cord swelling and increased signal intensity in T2-weighted images in a patient with transverse myelitis. We described a 45-year-old man presenting with weakness on the lower extremities without involvement of the upper extremities, as an initial manifestation of SLE. The lesion was involved continuous levels of the cervical spinal cord, a distinctive feature recently named `longitudinal myelitis`. His symptoms and signs responded well to the cyclophosphamide and methylprednisolone pulse therapies. So far, 10 cases of longitudinal myelitis have been reported in the world. But only 2 cases presented lower extremities weakness rather than upper extremities, in spite of cervical spine involvement. We report a patient with longitudinal myelitis in the cervical cord presenting weakness of the lower extremities as an initial manifestation of SLE with literature review.ope

Two Cases of Calcinosis Cutis Combined with Rheumatologic Disease

The calcinosis, dystrophic soft tissue calcification, occurs in damaged or devitalized tissues normal calcium/phosphorus metabolism. It is the subcutaneous tissues of connective tissues disease ??primarily systemic lupus erythematosus, scleroderma, or dermatomyositis ??and may involve a relatively localized area. The calcinotic accumulations may result in muscle atrophy, joint contractures, and skin ulceration complicated by recurrent episodes of local inflammation and infection. Calcinosis may be the source of both pain and disability in connective tissue disease patients. While various therapeutic modality have been used, no treatment has convincingly prevented or reduced calcinosis. We report two cases of calcinosis cutis combined with rheumatic disease.ope

Kikuchi-Fujimoto`s Disease with Adult Onset Still`s Disease

Kikuchi-Fujimoto`s disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare benign and self-limiting disease. KFD are confused with systemic autoimmune disease as they present with localized lymphadenopathy, fever, fatigue, arthritis, leukopenia. Furthermore as KFD can occur associated with other autoimmune disease, we need to diagnose carefully. Here, we describe a case of 27-year-old female patient, diagnosed as KFD, who subsequently developed adult onset Still`s disesase (AOSD). As far as we know, this is the first case of KFD with AOSD in Korea.ope

A Case of Successful Treatments of Venous Leg Ulcers in Secondary Antiphospholipid Syndrome

Antiphospholipid syndrome is an autoimmune disorder characterized by recurrent arterial or venous thrombosis, and pregnancy loss. A 57-year-old woman was admitted for aggravation of both leg ulcers. Venogram showed chronic venous obstructions at both lower extremities, and chest x-ray and computed tomography revealed serositis in pericardium and pleura. The laboratory tests revealed pancytopenia, and positive tests for antinuclear antibody, anti-dsDNA antibody, lupus anticoagulant and anticardiolipin antibody, which led to a diagnosis of antiphospholipid syndrome secondary to systemic lupus erythematous. After medical treatments by anticoagulation and immunosuppression, and surgical managements including subtotal skin graft and local flap surgery, leg ulcers had been successfully treated without recurrence. Recognition of antiphospholipid syndrome as a cause of venous ulcer and the treatment plans including anticoagulation and surgical management is important in proper managementsope

강직성척추염의 말초혈액단핵구에서 오스테오폰틴 mRNA의 발현과 질병 활성도와의 연관성

Dept. of Medicine/석사[한글]연구배경 및 목적: 강직성척추염은 골 감소와 함께 새로운 골 형성을 특징으로 하는 만성 염증성 질환이다. 그러나 아직까지 그 병인이 명확히 밝혀져 있지 않다. 오스테오폰틴은 골재형성 과정에 중요한 역할을 할 뿐만 아니라 염증성 사이토카인으로서 작용한다. 이 연구에서는 강직성척추염 환자의 혈액 내의 오스테오폰틴의 농도와 말초혈액단핵구에서 발현되는 오스테오폰틴 mRNA 정도를 조사하였다. 또한 질병 활성도 및 골 형성에 관여하는 표지자들과의 상관 관계를 알아보고, 강직성척추염에서 발현이 증가되는 다른 염증성 사이토카인들과의 상관 관계에 대하여 조사하였다.연구재료 및 방법: 이 연구는 20명의 강직성척추염 20명의 건강한 대조군을 대상으로하여 단면조사연구로 진행되었다. 혈청 내 오스테오폰틴과 종양괴사인자-알파, 인터루킨-6의 농도는 효소면역측정법을 통하여 측정하였고, 말초혈액단핵구에서 mRNA의 발현 정도를 알아보기 위해 역전사효소-중합효소연쇄반응을 시행하였다. 환자의 임상적인 특징들을 조사하고, 적혈구침강속도와 C-반응단백, 알칼리성 포스파타제를 측정하였으며 BASDAI와 BASRI를 평가하였다. 그리고 이들 항목들과 오스테오폰틴과의 연관성에 대하여 조사하였다.연구 결과: 혈청 오스테오폰틴과 종양괴사인자-알파, 인터루킨-6 농도는 강직성척추염 환자군에서 정상 대조군에 비하여 모두 유의하게 높게 측정되었다 (오스테오폰틴; 76.92±16.60 ng/ml vs 26.00±7.23 ng/ml, p<0.01, 종양괴사인자-알파; 63.59±14.15 pg/ml vs 18.59±4.97 pg/ml, p<0.01, 인터루킨-6; 40.26±3.80 ng/ml vs 11.30±1.52 ng/ml, p<0.01). mRNA의 발현 정도 또한 오스테오폰틴과 종양괴사인자-알파, 인터루킨-6 모두 정상 대조군에 비하여 강직성척추염 환자군에서 유의한 차이를 보이며 높게 나타났다 (오스테오폰틴; 118.83±19.05 vs 82.64±17.28, p<0.01, 종양괴사인자-알파; 117.25±15.03 vs 77.23±22.37, p<0.01, 인터루킨-6; 128.24±16.97 vs 62.49±16.75, p<0.01). 오스테오폰틴 mRNA의 발현 정도는 종양괴사인자-알파와 인터루킨-6 mRNA의 발현과 유의한 상관관계가 있었다 (rho = 0.555, p<0.01; rho = 0.655, p<0.01). 또한 오스테오폰틴 mRNA의 발현 정도는 적혈구침강속도, C-반응단백, BASDAI와도 유의한 상관관계를 나타냈으나 (rho = 0.435, p = 0.03; rho = 0.388, p = 0.04; rho = 0.520, p<0.01), 알칼리성 포스파타제나 BASRI와는 통계적 유의성을 보이지 않았다.결론: 강직성척추염 환자군은 정상 대조군에 비해 혈청 오스테오폰틴 농도와 말초혈액단핵구에서 오스테오폰틴 mRNA의 발현 정도가 증가되어 있었다. 강직성척추염에서 오스테오폰틴의 mRNA 발현은 종양괴사인자-알파, 인터루킨-6 mRNA의 발현 및 강직성척추염에서 질병활성도를 나타내는 표지자인 적혈구침강속도, C-반응단백, BASDAI와 유의한 상관관계를 나타냈다. 결론적으로 오스테오폰틴은 강직성척추염의 활동성에 관여하는 생물학적 표지자로 생각된다. [영문]Objective: Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown etiology that is characterized by new bone formation, syndesmophytes, as well as osteopenia. Osteopontin (OPN) plays an important role in the regulation of bone remodeling and acts as an inflammatory cytokine. In this study, we investigated the level of serum OPN protein and the expression of OPN mRNA in PBMC in patients with AS. We also assessed the association between the expression of OPN and disease activity or bone formation parameters, and the expression of other inflammatory cytokines that were increased in AS.Methods: This cross-sectional study included 20 patients with AS and 20 age and sex matched healthy controls. The serum levels of OPN, TNF-α and IL-6 were determined by ELISA, and the expression of their mRNA was performed by RT-PCR. We assessed clinical characteristics and laboratory parameters including ESR, CRP, alkaline phosphatase, BASDAI and BASRI, and evaluated their relationship to the expression of OPN.Results: When compared to controls, patients with AS had significantly higher mean serum OPN, TNF-α and IL-6 levels (OPN; 76.92±16.60 ng/ml vs 26.00±7.23 ng/ml, p<0.01, TNF-α; 63.59±14.15 pg/ml vs 18.59±4.97 pg/ml, p<0.01, IL-6; 40.26±3.80 ng/ml vs 11.30±1.52 ng/ml, p<0.01), as well as increased mRNA expression (OPN; 118.83±19.05 vs 82.64±17.28, p<0.01, TNF-α; 117.25±15.03 vs 77.23±22.37, p<0.01, IL-6; 128.24±16.97 vs 62.49±16.75, p<0.01). The expression of OPN mRNA was associated with the expression of TNF-α and IL-6 mRNA (rho = 0.555, p<0.01; rho = 0.655, p<0.01, respectively). The expression of OPN mRNA also had association with ESR, CRP and BASDAI (rho = 0.435, p = 0.03; rho = 0.388, p = 0.04; rho = 0.520, p<0.01, respectively), but no association with alkaline phosphatase and BASRI.Conclusion: Patients with AS had higher levels of serum OPN protein and the OPN mRNA expression in PBMC compared to controls. The expression of OPN mRNA was associated with other inflammatory cytokines, such as TNF-α and IL-6, which were increased in AS, as well as ESR, CRP and BASDAI, disease activity markers in AS.ope

Therapeutic effect of anti-vascular endothelial growth factor receptor I antibody in the established collagen-induced arthritis mouse model

Synovial angiogenesis plays an important role in the inflammation in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) is a key molecule in angiogenesis and binds to specific receptors, known as vascular endothelial growth factor receptor I (VEGF RI). In this study, we investigated the therapeutic efficacy of anti-VEGF RI antibody (Ab) on RA using a collagen-induced arthritis (CIA) mouse model. Twelve DBA/1 mice were divided into three groups. All mice except controls were injected with type II collagen. Mice in the anti-VEGF-RI-Ab-treated groups were injected on one posterior paw with 50 microg anti-VEGF RI Ab twice weekly for 3 weeks. Arthritis score and paw thickness were measured and histopathologic assessment of joint sections was performed by hematoxylin-eosin. The infiltration of CD45+ inflammatory cells and neovascularization were evaluated by immunohistochemical staining. Anti-VEGF RI Ab significantly attenuated the arthritis severity and histopathologic findings in the CIA mice model. The infiltration of CD45+ cells decreased in anti-VEGF-RI-Ab-treated joint tissues. Staining for CD31 revealed reduced synovial neovascularization after anti-VEGF RI Ab treatment. The data showing that in vivo administration of anti-VEGF RI Ab suppressed arthritis in established CIA mice suggest anti-VEGF RI Ab treatment may serve as a new therapeutic modality for RA.ope

Serum leptin levels correlate with interleukin‐6 levels and disease activity in patients with ankylosing spondylitis

OBJECTIVE: To determine whether serum leptin levels are elevated in men with ankylosing spondylitis (AS) and whether the levels correlate with serum cytokine profiles and disease activity of AS. METHODS: Forty-two male patients with newly diagnosed AS were enrolled. Their Bath AS Disease Activity Index (BASDAI), body mass index (BMI), and acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, were assessed. Serum leptin levels were determined using radioimmunoassay (RIA) and serum cytokine profiles, including tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, and interferon (IFN)-gamma, were determined using enzyme-linked immunosorbent assay (ELISA). These results were compared with those from 42 age-matched healthy men. After a follow-up period of 31.0+/-20.1 months, clinical and biochemical variables were reassessed in the men with AS. RESULTS: At baseline, patients with AS had significantly elevated serum levels of leptin, leptin adjusted for BMI (leptin/BMI), TNFalpha, and IL-6, but not IFN-gamma, as compared to the controls. Serum leptin/BMI levels correlated well with IL-6 levels, and both leptin/BMI and IL-6 levels correlated well with BASDAI and CRP levels in patients with AS. The changes in leptin/BMI and IL-6 levels between the baseline and follow-up measurements correlated well with one another (p<0.05) and both correlated well with the changes in BASDAI (p<0.05). CONCLUSION: Serum leptin/BMI levels were increased and significantly associated with IL-6 levels and disease activity in men with AS, suggesting a possible role for leptin in the inflammatory reactions of AS.ope