Aggressive multi-combination therapy for anti-MDA5 antibody-positive dermatomyositis-rapidly progressive interstitial lung disease.

OBJECTIVES: To elucidate the efficacy and safety of aggressive multi-combination therapy with mycophenolate mofetil, rituximab, and plasma exchange or polymyxin B immobilized fiber column direct hemoperfusion followed by conventional therapy with corticosteroids, calcineurin inhibitors, and intravenous pulse cyclophosphamide in patients with rapidly progressive interstitial lung disease (RPILD) with anti-melanoma differentiation-associated gene 5 (MDA5)-antibody-positive dermatomyositis (DM). METHODS: A total of 23 patients with anti-MDA5 antibody-positive DM-RPILD were enrolled, with nine patients in Group A (treated conventionally before March 2015) and 14 patients in Group B (received aggressive treatment after April 2015). RESULTS: Pretreatment severity of interstitial lung disease (ILD) did not differ between the two groups. However, Group B exhibited a higher cumulative survival rate at 48 weeks than Group A (64.3% vs. 33.3%). The corticosteroid dose, divided by the initial dose at 3 months and 12 months, was significantly lower in Group B than in Group A (p = .046 and .026, respectively). Among the ILD-related deaths in Group B, there was a tendency toward a higher proportion of males and more severe ILD. The incidence of infection did not differ between the groups, but leukopenia was more common in Group B. CONCLUSION: This aggressive multi-combination therapy may improve the survival outcome of patients with anti-MDA5 antibody-positive DM-RPILD. However, careful management of complications, such as opportunistic infections and leukopenia, is essential. Future refinement through longitudinal investigations tracking the long-term efficacy, safety, and cost-effectiveness of this treatment strategy is needed.

Serum Complement C4 Levels Are a Useful Biomarker for Predicting End-Stage Renal Disease in Microscopic Polyangiitis.

This study aimed to evaluate the risk factors for end-stage renal disease (ESRD) in microscopic polyangiitis (MPA). In total, 74 patients with MPA were enrolled, and we compared the baseline clinical characteristics and disease activity between MPA patients who have progressed to ESRD and those without ESRD to select predictive factors for ESRD. Out of 74 patients, 12 patients (16.2%) had ESRD during follow-up. Serum C4 levels were significantly higher in MPA patients who have progressed to ESRD than in those without ESRD (p = 0.009). Multivariate analyses revealed that high serum creatinine levels (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.25-15.5) and high serum C4 levels (OR 1.24, 95% CI 1.03-1.49) were risk factors for ESRD. Using receiver operating characteristic analysis, the cut-off value for initial serum C4 levels and serum creatinine levels were 29.6 mg/dL and 3.54 mg/dL, respectively. Patients with MPA with a greater number of risk factors (serum C4 levels > 29.6 mg/dL and serum creatinine levels > 3.54 mg/dL) had a higher ESRD progression rate. Serum C4 levels were significantly positively correlated with serum creatinine levels and kidney Birmingham vasculitis activity score (p = 0.02 and 0.04, respectively). These results suggest that serum C4 levels are useful tools for assessing renal disease activity and prognosis in MPA.

Examination of nailfold videocapillaroscopy findings in ANCA-associated vasculitis.

OBJECTIVE: The objective of this study was to evaluate nailfold videocapillaroscopy (NVC) as a useful tool for assessing the disease activity of ANCA-associated vasculitis (AAV). METHODS: This study enrolled 51 patients with AAV and 21 healthy controls. We scored NVC findings semiquantitatively, and compared them between AAV patients and controls. We examined the association of NVC findings with disease activity indicators, histopathological findings of skin biopsies, and high-resolution CT (HRCT) scores in AAV. Additionally, we repeatedly rated the NVC findings 3 months after immunosuppressive therapy. RESULTS: Of the 51 enrolled patients, 36 (70.6%) showed a microangiopathy pattern and 4 (7.8%) showed a scleroderma pattern in AAV. The scores for microhaemorrhage, capillary loss, neoangiogenesis, and tortuosity were significantly higher in the AAV group than in the control group. NVC abnormalities correlated with the severity of skin, lung and kidney involvement. The scores of giant capillaries significantly correlated with the total BVAS and the chest BVAS; the scores of capillary loss correlated with the chest BVAS and the renal BVAS. The scores of microhaemorrhage significantly correlated with perivascular inflammatory cell infiltrations in the upper dermis of the purpura and tended to correlate with the total ground-glass opacity and consolidation scores on HRCT. In addition, capillary loss scores had a significant positive correlation with serum creatinine levels. Additionally, the microhaemorrhage scores were significantly reduced after 3 months of immunosuppressive therapy. CONCLUSION: In AAV patients, NVC abnormalities are significantly associated with disease severity. This result suggests that NVC is a useful tool for assessing the disease activity and treatment response in AAV.

Association of M2 Macrophages, Th2, and B Cells With Pathomechanism in Microscopic Polyangiitis Complicated by Interstitial Lung Disease.

OBJECTIVE: To address the pathomechanism of microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using serum biomarker profile and pulmonary histopathology. METHODS: Serum biomarkers from patients with MPA-ILD (n = 32), MPA without ILD (n = 17), and healthy controls (n = 10) were examined. Based on the biomarker profiles, principal component analysis (PCA) and cluster analysis were performed to classify patients with MPA-ILD into subgroups. Clinical characteristics and prognosis were assessed for each subgroup. Two lung biopsies were examined following H&E staining and immunostaining. RESULTS: T cell and macrophage polarization was skewed toward the T helper (Th) 2 cells and M2 macrophages in the MPA-ILD group relative to that in MPA without ILD group. The PCA allowed classification of the 19 biomarker profiles into 3 groups: (1) B cell- and neutrophil-related cytokines, vascular angiogenesis-related factors, extracellular matrix-producing factors; (2) Th1-driven cytokines, M1 macrophage-driven cytokines, and Th2-driven cytokines; and (3) M2 macrophage-induced and driven cytokines. The cluster analysis stratified the patients with MPA-ILD into clinically fibrotic-dominant (CFD) and clinically inflammatory-dominant (CID) groups. Notably, severe infections were significantly higher in the CFD group than in the CID group. Immunohistochemical staining demonstrated intense CXC motif chemokine ligand 13 staining in B cells and Th2 cells in the interstitium of the lungs of patients with MPA-ILD. CONCLUSION: The activation of M2 macrophages, Th2 cells, and B cells plays a key role in the pathomechanism of MPA-ILD. Classification of MPA-ILD based on serum biomarker profile would be useful in predicting the disease activity and the complications of severe infection in MPA-ILD.

Comparison of therapeutic effects of combination therapy with prednisolone and tacrolimus or azathioprine on progressive interstitial pneumonia with systemic sclerosis.

OBJECTIVES: We retrospectively compared the therapeutic effects of combination therapy with prednisolone (PSL) and oral tacrolimus (TAC) or azathioprine (AZA) on progressive interstitial pneumonia with systemic sclerosis (SSc-PIP). METHODS: The effects of PSL (0.2-0.5 mg/kg/day) and TAC (3 mg/day) or AZA (1-2 mg/kg/day) therapies (n = 18) were evaluated for short (12 months) and long (36 months or more) periods. RESULTS: In the short period, IP improved in 6 and 5 patients and was stable in 12 and 13 patients in the TAC and AZA groups, respectively. In the long period, 11 patients were followed up in the TAC group and 12 in the AZA group. IP improved in 4 and 2 patients and was stable in seven and nine in the TAC and AZA groups, respectively. The rates of evolution of total fibrosis score, and those corrected by disease duration for the long period, in the TAC group were significantly lower than those in the AZA group (p = .017 and .025, respectively). CONCLUSION: The inhibitory effect of PSL and TAC combination therapy on the progression of fibrosis in SSc-PIP may be superior to that of PSL and AZA in the long period.

CCL2 produced by CD68+/CD163+ macrophages as a promising clinical biomarker of microscopic polyangiitis-interstitial lung disease.

OBJECTIVES: Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance. METHODS: We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining. RESULTS: Initial serum C-C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs. CONCLUSION: CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD.

Evaluation of poor prognostic factors of respiratory related death in microscopic polyangiitis complicated by interstitial lung disease.

The prognosis of microscopic polyangiitis (MPA) with interstitial lung disease (ILD) is significantly worse than that of MPA without ILD. However, the clinical characteristics in MPA-ILD, especially poor prognostic factors, are not elucidated. We evaluated demographic, clinical, laboratory, and radiological findings, treatments, and outcomes of 80 patients with MPA, and investigated prognostic factors of respiratory-related death in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive MPA-ILD. Ground-glass opacity and fibrosis were evaluated as scores on high-resolution computed tomography (HRCT). The presence of ILD was consistent with a high risk of respiratory-related death (hazard ratio, 4.8; P = 0.04). Multivariable logistic regression analyses using propensity scoring showed right or left lower lobe fibrosis score to be significantly associated with respiratory-related death (P = 0.0005 and 0.0045, respectively). A right or left lower lobe fibrosis score ≥ 2, indicating the presence of honeycombing at 1 cm above the diaphragm, was determined to be the best cut-off value indicating a poor prognosis. The 5-year survival rate was significantly lower in patients with right or left lower lobe fibrosis score ≥ 2 (survival rates: 37% and 19%, respectively) than those with a score < 2 (71% and 68%, respectively) (P = 0.002 and 0.0007, respectively). These findings suggest that the presence of honeycomb lesions in bilateral lower lobes on chest HRCT was associated with respiratory-related death in patients with MPO-ANCA positive MPA-ILD.

The comparison of nailfold videocapillaroscopy findings between anti-melanoma differentiation-associated gene 5 antibody and anti-aminoacyl tRNA synthetase antibody in patients with dermatomyositis complicated by interstitial lung disease.

Dermatomyositis (DM) is frequently complicated by interstitial lung disease (ILD), which increases mortality. This study aims to elucidate the clinical significance of nailfold videocapillaroscopy (NVC) on assessing the disease activity and prognosis of DM-ILD. We compared the NVC findings between anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive and anti-aminoacyl tRNA synthetase (anti-ARS) antibody-positive patients, the survival and ILD-related death groups, and examined the association of NVC findings with prognostic factors of DM-ILD. The median scores of microhemorrhage and capillary disorganization in the anti-MDA5 antibody-positive group were significantly higher than those in the anti-ARS antibody-positive group (P = 0.012 and 0.044, respectively). In contrast, the median scores of tortuous capillaries in the anti-ARS antibody-positive group were significantly higher than those in the anti-MDA5 antibody-positive group (P = 0.002). The median scores of microhemorrhage was significantly higher in the ILD-related death group than the survival group (P = 0.02). The scores of microhemorrhage, capillary disorganization, and neoangiogenesis correlated with known poor prognosis factors of DM-ILD. Additionally, the scores of microhemorrhage and capillary loss correlated significantly with the total fibrosis scores of chest high-resolution computed tomography. These findings suggest that NVC is a useful tool for assessing the disease activity and prognosis of DM-ILD.

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.

Efficacy and safety of oral high-trough level tacrolimus in acute/subacute interstitial pneumonia with dermatomyositis.

OBJECTIVES: We assessed the efficacy and safety of combination therapy with glucocorticoids and high-trough level tacrolimus (TAC) for the treatment of acute/subacute interstitial pneumonia (A/SIP) in patients with dermatomyositis (DM). METHODS: Eleven DM-A/SIP patients were enrolled. The combination therapy with glucocorticoids and TAC was started as early as possible after DM-A/SIP was diagnosed. We monitored the trough concentration of TAC. In the initial 3 months, we maintained the trough concentration of TAC at relatively high levels within a range of 15-20 ng/mL. Then, we decreased the TAC doses stepwise to keep the trough concentration at 10-15 ng/mL in the next 3 months and 5-10 ng/mL as a maintenance dose. RESULTS: Seven patients had clinically amyopathic DM. Six patients were positive for anti-aminoacyl-tRNA synthetase antibody and two were positive for anti-melanoma differentiation-associated gene 5 antibody. Ten patients survived for the period of the 24-week follow up. One patient died under a tentative diagnosis of viral encephalitis at 4 months after the treatment. In the 10 surviving patients, interstitial pneumonia improved in eight patients and was not worse in two patients. Clinical examinations, including the Krebs von den Lungen-6 levels, % forced vital capacity, and chest computed tomography score, were significantly improved by this combination therapy. Although grade 1 and 2 renal damage occurred in 4 and 2 patients, respectively. CONCLUSIONS: The present findings suggest that early therapeutic intervention by a combination with glucocorticoids and initial high-trough level TAC is effective for DM-A/SIP although consideration of the risks of infection and renal damage is required.

Potential of Krebs von den Lungen-6 as a predictor of relapse in interstitial pneumonia with anti-aminoacyl tRNA synthetase antibodies-positive dermatomyositis.

OBJECTIVE: To identify a predictor of relapse in interstitial pneumonia (IP) in patients with anti-aminoacyl tRNA synthetase antibodies-positive dermatomyositis (ARS-DMIP). METHODS: This retrospective cohort study comprised 27 ARS-DMIP patients. We compared clinical and laboratory findings between the relapse and non-relapse groups during 2 years after treatment initiation to find predictors of relapse in IP. Candidate predictors were further assessed by analysing the relationship with the relapse of IP. RESULTS: One patient with ARS-DMIP died. About 7 (26.9%) of the remaining 26 patients with ARS-DMIP had a relapse of IP. We found that the levels of serum Krebs von den Lungen-6 (KL-6) in the relapse group were significantly higher than those in the non-relapse group at the time points before treatment (P = .046) and after treatments, including 6 (P = .004), 12 (P = .013), 18 (P = .003) and 24 months (P < .001). The KL-6 values that maximised the area under the ROC curve were 2347 U/mL before treatment, 622 U/mL after 6 months and 468 U/mL after 12 months. The relapse rates after 104 weeks were significantly higher in patients with KL-6 levels ≥2400 U/mL before treatment (P = .014), ≥600 ng/mL after 6 months (P < .005) and ≥470 U/mL after 12 months (P = .010). CONCLUSION: These findings suggest that the levels of KL-6 before and after treatment in ARS-DMIP may represent the disease activity of IP, and they may be useful as the predictor of relapse in IP in patients with ARS-DMIP.

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.

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.

[Granulomatosis with Polyangiitis Complicated with Gastrointestinal Perforation: A Case Report and Review of Literature].

  A 51-year-old man was detected nasal bleeding, multiple pulmonary nodule and mass, urinalysis abnormality, renal involvement and high titer of proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA), and was suspected of granulomatosis with polyangiitis and initiated with steroid pulse therapy. On the day after the start of steroid pulse therapy, generalized peritonitis due to ileal perforation occurred, and emergency ileectomy and peritonitis surgery were performed. Induction therapy with steroid pulse therapy, plasma exchange and intravenous cyclophosphamide therapy (IVCY) and maintenance therapy with glucocorticoid and azathioprine led to good therapeutic outcomes. Gastrointestinal perforation in GPA is a rare complication, and we examined the clinical features, treatment contents, and prognosis of GPA with gastrointestinal perforation from this case and previous reports. Lung involvements were complicated in all reported cases. Gastrointestinal perforations in GPA were frequent in the small intestine, occurred just before and immediately after the start of treatment, and were severe involvement with poor prognosis because of the high mortality rate (46.7%). The frequency of ear, nose and upper respiratory tract lesions in the surviving group was significantly higher than in the dead group (survival 87.5%, death 28.3%, P = 0.041). IVCY were more frequently used in the surviving group (62.5%) than the death group (16.7%), but it was not significantly. GPA complicated with gastrointestinal perforation is a severe condition with poor prognosis, but there is a possibility to improve prognosis by early diagnosis and early initiation of strong treatment.

Chemokine profiles of interstitial pneumonia in patients with dermatomyositis: a case control study.

Chemokines play an important role in the pathophysiology of dermatomyositis (DM) with interstitial pneumonia (IP). However, the relation between chemokines and the disease activity or prognosis of DM-IP has not been elucidated. We evaluated the serum C-C motif chemokine ligand (CCL) 2, Th1 chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11), and Th2 chemokine (CCL17) profiles of 30 patients, and examined the relation between these chemokines and the disease activity or prognosis of DM-IP. Initial serum CCL2 level was higher in the death group (P = 0.007). To determine the cut-off points effective as poor prognostic factors of DM-IP, ROC curve analysis was carried out on initial serum CCL2 level. The value that maximized the area under the ROC curve was 894 pg/mL (sensitivity: 100%, specificity: 70.8%). Serum CCL2, CXCL9, CXCL10, and CXCL11 levels were lower at 2 weeks after treatment initiation than before treatment. Serum CCL2, CXCL10, and CXCL11 levels at 2 weeks after treatment initiation were higher in the death group. Serum levels of chemokines such as CCL2, CXCL10, and CXCL11 may be possible biomarkers of disease activity and prognosis in DM-IP, and serum CCL2 level may be useful when deciding initial treatment.

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.

Chylothorax in dermatomyositis complicated with interstitial pneumonia.

Chylothorax is a disease in which chyle leaks and accumulates in the thoracic cavity. Interstitial pneumonia and pneumomediastinum are common thoracic manifestations of dermatomyositis, but chylothorax complicated with dermatomyositis is not reported. We report a case of dermatomyositis with interstitial pneumonia complicated by chylothorax. A 77-year-old woman was diagnosed as dermatomyositis with Gottron's papules, skin ulcers, anti-MDA5 antibody and rapid progressive interstitial pneumonia. Treatment with betamethasone, tacrolimus and intravenous high-dose cyclophosphamide was initiated, and her skin symptoms and interstitial pneumonia improved once. However, right-sided chylothorax began to accumulate and gradually increase, and at the same time, her interstitial pneumonia began to exacerbate, and skin ulcers began to reappear on her fingers and auricles. Although her chylothorax improved by fasting and parenteral nutrition, she died due to further exacerbations of dermatomyositis and interstitial pneumonia in spite of steroid pulse therapy, increase in the betamethasone dosage, additional intravenous high-dose cyclophosphamide and plasma pheresis. An autopsy showed no lesions such as malignant tumors in the thoracic cavity. This is the first report of chylothorax complicated by dermatomyositis with interstitial pneumonia.

The proton pump inhibitor lansoprazole, but not rabeprazole, the increased blood concentrations of calcineurin inhibitors in Japanese patients with connective tissue diseases.

OBJECTIVE: Proton pump inhibitors (PPIs) are frequently coadministered with calcineurin inhibitors (CNIs) such as tacrolimus (TAC) and cyclosporin A (CSA), to treat or prevent upper gastrointestinal complications in Japanese patients with connective tissue diseases (CTDs). The coadministration of PPIs increases the blood concentration of TAC due to drug interaction. We retrospectively investigated the influence of the coadministration of PPIs and CNIs, as well as the influence of the cytochrome P450 (CYP) 2C19 gene polymorphism status, on the blood concentrations of TAC and CSA in patients with CTDs. METHODS: Patients treated with TAC (n=35) or CSA (n=30) were enrolled and divided into three groups according to the PPI they received: lansoprazole (LPZ)-combined, rabeprazole (RPZ)-combined, and non-PPI-combined groups. We compared the blood concentrations of TAC or CSA and the incidences of adverse events among the three groups. CYP2C19 gene polymorphisms were also assessed to investigate its influence on the blood concentration of TAC or CSA. RESULTS: LPZ significantly increased the blood concentration of TAC 12 hours after TAC administration (p=0.030 and p=0.003, respectively) and CSA (p=0.047 and p=0.014, respectively) in comparison with RPZ and non-PPI-combined treatment. There were no significant differences in the mean CSA blood concentration two hours after administration in patients with or without PPI treatment, in the incidence of adverse events, or in the CYP2C19 gene polymorphism status among the three groups. CONCLUSION: Combining agents that are mainly metabolized by CYP3A4 such as LPZ elevates the blood concentrations of TAC and CSA, which could leading to adverse events.

Pre-treatment ferritin level and alveolar-arterial oxygen gradient can predict mortality rate due to acute/subacute interstitial pneumonia in dermatomyositis treated by cyclosporine a/glucocorticosteroid combination therapy: a case control study [corrected].

BACKGROUND: Acute/subacute interstitial pneumonia in dermatomyositis (DM-A/SIP) is a disease associated with a poor prognosis that resists treatment with glucocorticosteroids (GC) and progresses rapidly in a period of weeks to months to death. We retrospectively studied outcomes, prognostic factors, and their relations with survival rate in patients with DM-A/SIP treated with early cyclosporine A (CSA)/GC combination therapy and 2-hour postdose blood concentration monitoring. METHODS: This study comprised 32 DM-A/SIP patients who were simultaneously treated with CSA and prednisolone. Clinical and laboratory findings were compared between those who died due to DM-A/SIP and those surviving 24 weeks after beginning of therapy. Prognostic factors were extracted, and their relations with the survival rate were evaluated. RESULTS: Of the 32 DM-A/SIP patients, 25 survived, 5 died of DM-A/SIP, and 2 died of infections. In those who died due to DM-A/SIP, ferritin level and the alveolar-arterial oxygen gradient were significantly increased compared with the survivors (P<0.001 and P = 0.002, respectively). Multivariate analyses showed that ferritin and alveolar-arterial oxygen gradient were independent prognostic factors of poor outcome. The survival rate 24 weeks after beginning of treatment was significantly lower in those with a ferritin level of ≥ 600 ng/ml and alveolar-arterial oxygen gradient of ≥ 45 Torr (P<0.001 and P<0.001, respectively). All patients with both prognostic factors died, and the outcome was significantly poorer in these patients than in those with one or neither of the prognostic factors (P<0.001). CONCLUSIONS: We identified pre-treatment high serum ferritin level and high alveolar-arterial oxygen gradient as poor prognostic factors in DM-A/SIP patients undergoing early CSA/GC combination therapy and showed that the outcomes were poor in patients with both factors.

Ultrasound evaluation of the effects of leukocytapheresis on rheumatoid arthritis.

Leukocytapheresis (LCAP) is effective in treating rheumatoid arthritis (RA). Ultrasound (US) examination of joints is useful for evaluating disease activity and therapeutic effects in RA, but the clinical assessment of LCAP therapy with US has been little reported. We investigated the usefulness of US for evaluating the effects of LCAP in patients with RA. US examination was performed in six patients (total of seven cases) who underwent LCAP. Twenty-eight joints (bilateral shoulders, elbows, wrists, 1st to 5th metacarpophalangeal joints, 1st to 5th proximal interphalangeal joints, and knee joints) were evaluated by a systematic multiplanar grey-scale and power Doppler (PD) examination. Disease activity of RA was evaluated using the 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR). Moderate or good responses to LCAP based on the DAS28-ESR were observed in four of the seven cases although C-reactive protein (CRP) and ESR did not decrease. LCAP significantly reduced the mean total PD score 17.3 ± 11.6 to 13.0 ± 10.5 (P = 0.0469). The total PD score decreased in six of the seven cases, and the number of joints with PD score ≥ 2 decreased in five of the seven cases. The rate of decrease in the number of joints with PD score ≥ 2 correlated strongly with the DAS28-ESR and its components, especially swollen joint counts and evaluator's global assessment, but not with the rate of decrease in CRP and ESR. US imaging of joints may be useful for evaluating the therapeutic effects of LCAP on RA compared to other inflammatory parameters.