Progressive fibrosing interstitial lung diseases: A new concept and indication of nintedanib.

Many interstitial lung diseases (ILDs) are characterized by chronic progressive fibrosis. The antifibrotic agents may prevent disease progression of these diseases. Nintedanib is a triple tyrosine kinase inhibitor and has an antifibrotic effect. The proven beneficial effects of nintedanib in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc)-associated ILD, nintedanib was intended for use in many other fibrotic lung diseases consistent with the concept described below. With this trial, the concept and definition of progressive fibrosing ILD (PF-ILD) were created, a type of fibrosing diseases that progresses with fibrosis measured in forced vital capacity and high-resolution CT findings and worsening of respiratory symptoms at a certain rate or faster. PF-ILDs are composed of idiopathic interstial pneumonias such as non-specific interstitial pneumonia and unclassifiable interstitial pneumonia and inhalation lung diseases such as chronic hypersensitivity pneumonia and connective tissue disease-associated ILD such as rheumatoid arthritis-related ILD and SSc-related ILD and sarcoidosis and so on. Nintedanib significantly reduced the annual rate of decline in forced vital capacity over 52 weeks compared with placebo. Nintedanib received marketing approval in the United States and Japan for the treatment of PF-ILDs. This review summarizes the new concept of PF-ILDs and effectiveness of nintedanib to PF-ILDs and discussion points to be solved in the future when using nintedanib for PF-ILDs.

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial.

OBJECTIVE: We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. METHODS: Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. RESULTS: In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was -86.2 mL/year (nintedanib) and -90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, -103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. CONCLUSION: In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

Exploration of pathomechanism using comprehensive analysis of serum cytokines in polymyositis/dermatomyositis-interstitial lung disease.

OBJECTIVES: To elucidate the serum cytokine profile and address the pathomechanism of interstitial lung disease (ILD) complicated with PM/DM. METHODS: Forty patients with PM/DM-ILD were enrolled, and principal components analysis and cluster analysis were performed to classify patients into subgroups. Additionally, we compared cytokine profiles between the survivors and dead patients and between anti-melanoma differentiation-associated gene 5 antibody- and anti-aminoacyl tRNA synthetase antibody-positive ILD patients. We also examined the association of various cytokines with disease activity indicators and prognosis of ILD. RESULTS: The principal components analysis data allowed classification of the cytokine profile into three groups: group 1, neutrophilic and M1-macrophage-driven cytokines; group 2, type 1 Th cell-driven and M2-macrophage-induced cytokines; and group 3, M2-macrophage-driven cytokines. Cluster analysis showed the presence of PM/DM-ILD patient groups with high or low levels of total cytokines. Ninety percent of patients who died of ILD were included in clusters with high cytokine levels. Serum cytokine levels of all groups were significantly higher in the anti-melanoma differentiation-associated gene 5 antibody-positive patients than in the anti-aminoacyl tRNA synthetase antibody-positive patients. Groups 1 and 2 significantly correlated with known factors for poor prognosis, such as serum ferritin levels and alveolar-arterial oxygen difference. Serum cytokine levels of patients in group 1 were significantly higher initially and at 2 and 4 weeks in those who died. CONCLUSION: These findings suggested that the activation of monocytes, macrophages and type 1 Th cells, and neutrophils play roles in the pathomechanism of PM/DM-ILD, and group 1 cytokines could be useful biomarkers for predicting prognosis of PM/DM-ILD.

Asymptomatic rheumatoid meningitis revealed by magnetic resonance imaging, followed by systemic rheumatic vasculitis: A case report and a review of the literature.

We report the case of a 66-year-old man with seropositive rheumatoid arthritis who developed neurologically asymptomatic rheumatoid meningitis (RM) revealed by MRI. RM worsened and chest CT showed pericardial effusion, pleural effusion, and bilateral consolidation, and his serum C3 level was decreased. We diagnosed systemic rheumatic vasculitis based on these findings. After a review of more than 20 previously reported cases of RM, this is the first case of RM without central nerve system symptoms.

A case of scleritis associated rheumatoid arthritis accompanying an intraocular elevated lesion.

BACKGROUND: Scleritis and/or uveitis sometimes accompanies patients who suffer from rheumatoid arthritis. However, few studies have reported scleritis and/or uveitis accompanying a fundus elevated lesion, such as an intraocular tumor. In this study, we report a case of rheumatoid uveitis associated with an intraocular elevated lesion. CASE PRESENTATION: A 66-year-old female visited another eye clinic and was diagnosed as bilateral anterior uveitis, and was prescribed steroid eye drops for treatment. She had previously been diagnosed as rheumatoid arthritis at the age of 30 years. Due to vitreous opacity that appeared in her right eye, we increased the instillation of steroid eye drops and the amount of oral prednisolone. Although the inflammation had improved, anterior uveitis relapsed, and an intraocular whitish elevated lesion resembling an intraocular tumor at the superior nasal retina appeared. We speculated this lesion to be a granuloma complicated with rheumatoid arthritis. Thus, we increased the amount of prednisolone administration, and the lesion began to shrink and ultimately fully disappeared. CONCLUSIONS: We strongly believe that our case's lesion was a subretinal granuloma related with rheumatoid arthritis, as it disappeared by increased corticosteroid treatment. Our findings show that we should consider rheumatoid arthritis in a differential diagnosis of such types of fundus elevated lesions.

Eosinophilic granulomatosis with polyangiitis complicated by subarachnoid hemorrhage and coronary vasculitis: a case report and review of the literature.

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by necrotizing vasculitis of small-sized vessels with extravascular granulomas and eosinophilic infiltration. The case of a 48-year-old Japanese woman with EGPA, who presented concurrently with subarachnoid hemorrhage (SAH) and coronary vasculitis, is reported. She initially presented with bronchial asthma, and then 8 months later she developed various symptoms caused by systemic eosinophilic vasculitis and was admitted to our hospital. Three days after admission, she started oral corticosteroid therapy, and her 2009 Five-Factor Score (FFS) was 0. However, she developed an SAH, followed by coronary vasculitis 1 day later. With extensive treatment with a combination of betamethasone, cyclophosphamide, intravenous immunoglobulin, and rituximab, her systemic vasculitis improved dramatically. This seems to be the first case of EGPA with SAH and coronary vasculitis. In previous reports of EGPA with SAH, 4 of 11 cases developed SAH as an exacerbation of systemic vasculitis during remission induction therapy. The present patient also had SAH during remission induction therapy. However, the period between bronchial asthma and SAH was only 8 months. This is the shortest among case reports of EGPA with SAH. In addition, the present patient rapidly developed coronary vasculitis. These findings suggest that EGPA causes SAH and coronary vasculitis as early complications of systemic vasculitis. In EGPA, it is necessary to pay careful attention to rapid changes of disease activity, even when the FFS indicates a good prognosis.

Evaluation of clinical prognostic factors for interstitial pneumonia in anti-MDA5 antibody-positive dermatomyositis patients.

OBJECTIVES: We retrospectively investigated clinical prognostic factors for interstitial pneumonia (IP) in anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive dermatomyositis (DM) patients. METHODS: Subjects comprised 18 patients with anti-MDA5 Ab-positive DM-IP (9 survivors; 9 deaths). RESULTS: Initial serum albumin levels, ferritin levels, and ground-glass opacity (GGO) scores in the right middle lobes were significantly higher in the death group than in the survivor group (p = .033, .013, and .005, respectively). Initial alveolar-arterial oxygen gradient (P[A-a]O2) was also higher in the death group than in the survivor group (p = .064). Initial serum ferritin, P[A-a]O2, and right middle lobe GGO score were found to significantly relate to death. Survival rates after 24 weeks were significantly lower among patients with an initial ferritin level of ≥450 ng/mL (25%), P[A-a]O2 of ≥30 mmHg (31%), and a right middle lobe GGO score of ≥2 (11%) than each of the others (p = .006, .020, and .002, respectively). CONCLUSIONS: An initial serum ferritin level of ≥450 ng/mL, P[A-a]O2 of ≥30 mmHg, and right middle lobe GGO score of ≥2 (GGO ≥5% of the lobe) were identified as poor prognostic factors for anti-MDA5 Ab-positive DM-IP patients.

Add-on iguratimod as a therapeutic strategy to achieve remission in patients with rheumatoid arthritis inadequately responding to biological DMARDs: A retrospective study.

OBJECTIVES: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. METHODS: RA patients who fulfilled the following criteria were included: (i) ≥ 24-week of bDMARDs; (ii) 2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1 or the presence of synovitis with a power Doppler (PD) score ≥2 in at least 1 of the 28 joints on joint ultrasonography. Disease activity and joint ultrasound findings were evaluated at baseline and at 12 and 24 weeks. RESULTS: DAS assessing 28 joints with ESR (DAS28-ESR) decreased significantly from 3.45 ± 0.92 at baseline to 2.85 ± 1.13 at 24 weeks (p < .001). Overall, 38.3% achieved clinical remission (c-remission). The total PD score decreased significantly from 8.7 ± 6.1 at baseline to 5.5 ± 5.0 at 24 weeks (p < .001). A lower baseline DAS28-ESR was related to c-remission after 24 weeks (p =.002). Shorter duration of disease (p =.020) was related to ultrasound remission, in addition to a lower baseline DAS28-ESR (p < .001). CONCLUSIONS: IGU add-on therapy can be a therapeutic strategy to achieve remission in RA patients inadequately responding to ≥24-week treatment with bDMARDs.

Efficacy and safety of combination therapy with prednisolone and oral tacrolimus for progressive interstitial pneumonia with systemic sclerosis: A retrospective study.

OBJECTIVES: We retrospectively investigated efficacy and safety of combination therapy with prednisolone (PSL) and tacrolimus (TAC) for progressive interstitial pneumonitis with systemic sclerosis (SSc-PIP). METHODS: We studied 11 patients with SSc-PIP who received combination therapy with PSL (0.5 mg/kg/d) and TAC (3 mg/d). RESULTS: Baseline Hugh-Jones grades were I, II, III, and IV in 2, 6, 2, and 1 patients, respectively. Krebs von den Lungen-6 (KL-6) values were elevated to 914 (range 300-2614) U/mL. % Diffusing capacity of carbon monoxide (%DLco) remarkably decreased to 47.4 (range 9.7-64.4) %. All patients were alive at 1 year after therapy. In response to treatment, interstitial pneumonia (IP) improved in three patients, stable in seven patients, and deteriorated in one patient. Total ground-glass opacity (GGO) score improved (p = .005). No significant changes occurred in values of KL-6, % forced vital capacity (%FVC), and %DLco. Presently, all seven patients who could be followed up were alive. IP improved in three patients and stable in four patients. Total GGO score improved (p = .016). KL-6, %FVC, and %DLco did not change. Mild cytomegalovirus or herpes zoster infection occurred in two patients. Grade I renal injuries were observed in three and one patient at 1 year and present, respectively. CONCLUSION: Combination therapy with PSL and TAC appeared to be well tolerated and effective in suppressing the disease activity of SSc-PIP.

Comparison of long-term prognosis and relapse of dermatomyositis complicated with interstitial pneumonia according to autoantibodies: anti-aminoacyl tRNA synthetase antibodies versus anti-melanoma differentiation-associated gene 5 antibody.

The aim of this study was to investigate long-term prognosis and relapse of dermatomyositis complicated with interstitial pneumonia (DMIP) according to anti-aminoacyl tRNA synthetase (ARS) antibodies and anti-melanoma differentiation-associated gene 5 (MDA5) antibody. This retrospective study comprised 36 patients with DMIP who were divided into the anti-ARS antibody-positive group (ARS+) (n = 12), anti MDA5 antibody-positive group (MDA5+) (n = 11), double-negative group (ARS-/MDA5-) (n = 11), and double-positive group (ARS+/MDA5+) (n = 1). Clinical features, treatment, prognoses, and relapses during the 2 years after initiation of treatment were compared between three groups excluding ARS+/MDA5+ group. Although short-term (24-week) mortality in MDA+ was higher than that in ARS+ or ARS-/MDA5- (P = 0.004), there was no difference in long-term (2-year) mortality between the three groups. Relapse rate in ARS+ was higher than that in MDA5+ and ARS-/MDA5- during the 2 years after initiation of treatment (P = 0.044). There was no difference in serum KL-6 levels at the initiation of treatment between ARS+ and MDA5+, but serum ferritin levels in MDA5+ were significantly higher than those in ARS+ (P = 0.406, 0.042, respectively). Serum KL-6 and ferritin levels at 2 years after initiation of treatment in ARS+ were significantly higher than those in MDA5+ (P = 0.008, 0.034, respectively). We found that in MDA5+ DMIP, acute alveolar inflammation caused a poor prognosis early in the disease course, and in ARS+ DMIP, chronic injury to the alveolar epithelial cells or basement membrane caused long-term recurrence.

Gastrointestinal involvement at the onset of granulomatosis with polyangiitis: A case report.

A 30-year-old man had developed fever, bloody stools, and oral aphtha. Proteinase 3-antineutrophil cytoplasmic antibody level was 31 EU. Lower intestinal endoscopy revealed edematous mucosa with hemorrhage in the transverse colon. Biopsies of oral aphtha showed necrotizing angiitis with granuloma. Based on these findings, he was diagnosed with granulomatosis with polyangiitis (GPA). Digestive symptoms were remitted by treatment with prednisolone and azathioprine. GPA with digestive symptoms as the initial development is rare.

Initial limited three-level thin-section computed tomography scorings predict the prognosis of acute/subacute interstitial pneumonia in patients with dermatomyositis.

OBJECTIVES: We investigated the prediction of outcomes of patients with dermatomyositis with acute/subacute interstitial pneumonia (DM-A/SIP) on the basis of chest computed tomography (CT) images. METHODS: In 20 patients with DM-A/SIP (13 survivors; seven deaths), the relationships between prognostic outcomes and chest high-resolution CT (HRCT) findings or limited three-level thin-section CT scoring on the first examination were retrospectively investigated. RESULTS: No significant difference was noted in chest HRCT findings between the survivor group and death group. The ground-glass opacity (GGO) scores of the right upper and middle lobes and left upper lobe, and the fibrosis score of the right middle lobe were significantly higher in the death group than in the survivor group (p = 0.01, 0.001, 0.02, and 0.02, respectively). The influence of the GGO score of the right middle lobe on death from IP was the strongest among the items examined, and it was independently significant (p = 0.01). A right middle lobe GGO score of ≥3 (GGO ≥ 25% of the lobe) was determined to be the best cut-off value for a poor prognosis (sensitivity: 85.7%, specificity: 85.7%), and the survival rate after 24 weeks was significantly lower in patients with a right middle lobe GGO score of ≥3 (survival rate: 0.0%) than in those with a score of< 3 (92.9%) (p < 0.0001). CONCLUSIONS: The prognosis of patients with DM-A/SIP was poor when the range of right middle lobe GGO was 25% or higher on limited three-level thin-section CT.

Periodontal pathogens participate in synovitis in patients with rheumatoid arthritis in clinical remission: a retrospective case-control study.

OBJECTIVE: The objective of this study was to investigate the role of periodontal pathogens in RA in remission. METHODS: Twenty-one patients with active RA and 70 patients in clinical remission, including 48 patients with synovitis [US power Doppler (USPD)(+) group] and 22 patients without synovitis [USPD(-) group] were clinically assessed by US. CRP, ESR, haemoglobin, MMP-3, RF and ACPA were measured. Antibody titres against four types of periodontal pathogen [Aggregatibacter actinomycetemcomitans, Eikenella corrodens (Ec), Porphyromonas gingivalis and Prevotella intermedia (Pi)] were analysed using ELISA. RESULTS: Musculoskeletal US examination showed that 68.6% of patients with RA in clinical remission exhibited synovitis. CRP, ESR, haemoglobin, MMP-3 and RF levels in both the USPD(+) and USPD(-) groups were clearly lower compared with the RA group in non-remission. The IgG serum antibody titre against Ec in the non-remission RA(+) group was significantly greater than that in the USPD(+) group, and the IgG antibody titre against Pi in the non-remission RA and USPD(+) groups was greater than in the USPD(-) group. CONCLUSION: More than half of RA patients in remission showed persistent synovitis. This synovitis may be associated with periodontal disease-causing Pi. Thus, treating periodontal disease should also be considered in order to achieve more profound remission of RA.

Therapeutic drug monitoring of cyclosporine microemulsion in patients with corticosteroid-resistant systemic lupus erythematosus.

OBJECTIVES: We retrospectively examined how the cyclosporine-A (CSA) microemulsion administration mode affected blood CSA levels, as well as how the dose and blood levels of CSA affected its therapeutic effect against systemic lupus erythematosus (SLE). METHODS: We calculated the area under the blood concentration time curve (AUC) of CSA in 16 patients with corticosteroid-resistant SLE, and analyzed its correlation with CSA levels at the blood sampling time points to investigate the optimum monitoring and dosing regimen. RESULTS: The blood CSA level peaked at 2 h after administration (C2) in all patients. AUC0-6, which most markedly reflects the immunosuppressive effect, significantly correlated with C2 (R2 = 0.905), but not with the trough (C0). In concentration/dose ratio (C/D) of CSA, C2/D level was significantly higher when administered once daily before breakfast than when administered in the divided dose after meals (R2 = 0.355, P = 0.015), but not C0/D. During the 6-month follow-up, the CSA C2 tended to correlate with improvement in SLE disease activity index 2000 (R2 = 0.633, P = 0.067). CONCLUSIONS: The treatment with a single dose of CSA before breakfast, followed by monitoring of C2, may be useful for improving the therapeutic effect in patients with corticosteroid-resistant SLE.

Predictive value of bone destruction and duration of clinical remission for subclinical synovitis in rheumatoid arthritis patients.

OBJECTIVES: Treatment for rheumatoid arthritis (RA) should aim to achieve full remission. The aim of this study was to investigate predictors of persistent subclinical synovitis and whether longer clinical remission is effective in reducing subclinical synovitis. METHODS: Forty-four RA patients who achieved DAS28ESR clinical remission for at least 3 months were enrolled in this study and underwent ultrasound examination of 22 joints (bilateral proximal interphalangeal joints, metacarpophalangeal joints, and wrists); bilateral hand X-ray; and blood examination. The severity of synovial effusion, synovial hypertrophy, and blood flow were semi-quantitatively graded from 0 to 3 using gray-scale (GS) and power Doppler (PD) modes. RESULTS: Among patients with DAS28ESR-defined clinical remission, 59.1% (26/44) demonstrated residual synovitis (≥ PD1) in at least one joint. Genant-modified total Sharp score (TSS) demonstrated the highest statistical difference between patients with and without residual subclinical synovitis (p = 0.0057), and full remission was only observed in patients with low TSS. A nonsignificant trend for decreased residual synovitis with longer sustained clinical remission was also observed (p = 0.724). CONCLUSION: Residual synovitis can persist during clinical remission, particularly in patients with progressive bone destruction. Early treatment and longer sustained clinical remission prior to bone destruction are critical for full remission.

Dermatomyositis as a complication of interferon-α therapy: a case report and review of the literature.

Autoimmune disorder is one of the important side effects of interferon-α therapy. Some polymyositis cases as complication of interferon-α therapy were reported, but dermatomyositis were rarely. We report a case of dermatomyositis as a complication of interferon-α therapy for hepatitis C. A 52-year-old Japanese man was treated by combination therapy with pegylated interferon-α-2b and ribavirin for hepatitis C. Three months after the initiation of therapy, he showed erythema in the posterior cervical to dorsal and anterior cervical to thoracic regions, weight loss, general malaise, muscle pain, and severe increase in levels of muscle enzymes. We made a diagnosis of dermatomyositis according to these clinical features, proximal muscle-predominant myogenic change on electromyography, and infiltration of monocytes and CD4+-dominant lymphocytes on skin biopsy, although myositis-associated antibodies were absent. He was successfully treated with intravenous immunoglobulin and tacrolimus in addition to glucocorticoid. This is a very rare case of dermatomyositis associated with interferon-α therapy. We reviewed several similar published cases and the association of dermatomyositis and type I interferon.

Successful treatment with tocilizumab of pericarditis associated with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disease often complicated by vasculitis. Pericarditis is a serious complication caused by vasculitis, resulting in retention of pericardial effusion that sometimes induces cardiac tamponade. We report a patient with RA in whom pericarditis improved after tocilizumab administration. A male patient was diagnosed with RA and chronic renal failure in 1980 and was treated with salazosulfapyridine, but disease activity remained high. In January 2012, at the age of 73 years, he developed organizing pneumonia as a complication and was admitted to our hospital. Treatment with prednisolone 30 mg/day was initiated. However, 20 days after initiation of treatment, chest pain and palpitation developed, and chest computed tomography (CT) and echocardiography (ECG) revealed retention of pericardial effusion without cardiac tamponade. Rheumatoid nodules and interstitial pneumonia were also observed, and serum C3 level was decreased. A diagnosis of pericarditis caused by vasculitis was made based on these findings, and tocilizumab 8 mg/kg was administered. His symptoms improved gradually, and chest CT and ECG showed no pericardial effusion after about 3 weeks. No adverse effects of tocilizumab were observed during the clinical course. Although there are only a few reports of the effects of tocilizumab on vasculitis associated with RA, tocilizumab administration appears worthwhile in RA patients with vasculitis who do not respond to conventional treatment.

Efficacy and safety of liposomal amphotericin B for deep mycosis in patients with connective tissue disease.

The efficacy and safety of liposomal amphotericin B (L-AMB) in the treatment of invasive fungal infections (IFIs) were retrospectively evaluated for patients with connective tissue diseases (CTDs) during treatment with immunosuppressive therapy. Subjects were 13 patients with CTDs complicated by IFI, on the basis of clinical symptoms, imaging findings, and microbiological and histological examinations. All patients were treated with L-AMB. Efficacy and safety were evaluated before and after administration of L-AMB. Underlying diseases were systemic lupus erythematosus for 4 patients, rheumatoid arthritis for 3, microscopic polyangiitis for 2, adult-onset Still disease for 1, dermatomyositis for 1, and mixed connective tissue disease for 1. Eight patients were resistant to other antifungal drugs. Prednisolone was given to 11 patients and the median dose was 10 mg/day. Immunosuppressants were used for 8 patients. The median duration of administration of L-AMB was 8.5 days (range 4-38 days). In proven and probable diagnosis patients (n = 5), the treatment was effective for 3 patients and ineffective for 2 (efficacy rate 60 %). Serum 1,3-ß-D-glucan antigenemia (BG) levels decreased after treatment in the 2 patients who were positive for BG. Serum Aspergillus galactomannan antigen levels decreased in 3 of 4 patients with Aspergillus infection. No patient died of IFI. Regarding potential adverse reactions, there were no significant changes in serum creatinine and potassium levels. L-AMB is effective and well-tolerated for treatment of IFI in patients with CTDs.

Serum levels of matrix metalloproteinase (MMP) 9, a risk factor for acute coronary syndrome, are reduced independently of serum MMP-3 by anti-TNF-α antibody (infliximab) therapy in patients with rheumatoid arthritis.

Matrix metalloproteinase 9 (MMP-9) is a risk factor for cardiovascular events. The serum MMP-9 levels were measured before and 2 weeks after treatment with infliximab (3 mg/kg) in 12 rheumatoid arthritis (RA) patients. The serum average MMP-9 level was 238.5 ng/ml before treatment with infliximab in RA patients (normal range: less than 43.8 ng/ml). Infliximab reduced the serum average MMP-9 level significantly (161.66 ng/ml, P = 0.0425). The serum MMP-9 level was high in the RA patients with active disease, and it was reduced by infliximab independently of the reduction in disease activity. Thus, infliximab may reduce the risk of cardiovascular events directly.

Good response to infliximab in a patient with deep vein thrombosis associated with Behçet disease.

Vascular involvement is a lethal complication in Behçet disease. It is often refractory to conventional therapy such as steroids and immunosuppressants in addition to anticoagulants. We describe here successful treatment with the anti-tumor necrosis factor-alpha (anti-TNF-α) antibody, infliximab, in a patient with Behçet disease presenting with deep vein thrombosis. A 60-year-old man with Behçet disease complained of edema and pain in the lower extremities. Computed tomography revealed a thrombosis extending from the popliteal vein to the inferior vena cava at the level of the renal vein and which recurred despite combination therapy of steroid and immunosuppressants such as cyclosporine, azathioprine, and methotrexate. The patient was then administered infliximab (5 mg/kg) in weeks 0 and 2 and every 4 weeks thereafter. Clinical and laboratory findings improved after the infliximab therapy. Computed tomography of the abdomen and lower extremities showed a reduction of the thrombosis. No severe adverse events occurred during the clinical course. Although further studies are needed to confirm the efficacy and safety of its use, anti-TNF-α antibody may be worth considering as treatment for refractory venous thrombosis in patients with Behçet disease.