Sumiaki Tanaka

Rapid induction of neutrophil apoptosis by sulfasalazine: implications of reactive oxygen species in the apoptotic process.

Accumulating evidence indicates that neutrophils are crucially involved in the pathogenesis of inflammatory bowel diseases and rheumatoid arthritis. We therefore investigated the effect of sulfasalazine (SSZ), which is widely used in the treatment of these diseases, on neutrophil apoptosis in vitro. The apoptosis of neutrophils was determined by morphology, a DNA histogram of propidium iodide‐stained nuclei, and DNA fragmentation. SSZ rapidly accelerated the rate of spontaneous neutrophil apoptosis within clinically relevant concentrations. This effect is unique to neutrophils because other types of leukocytes and a number of leukocyte cell lines are resistant to SSZ. Neutrophil apoptosis caused by SSZ was abrogated by a tyrosine kinase inhibitor, a protein kinase A inhibitor, and antioxidants. The subsequent results provided pharmacological evidence that the phosphorylation of tyrosine kinase and protein kinase A and generation of reactive oxygen species are involved in SSZ‐mediated neutrophil apoptosis. These data suggest that SSZ‐induced neutrophil apoptosis may account, in part, for the clinical benefits of SSZ on inflammatory bowel diseases and rheumatoid arthritis. J. Leukoc. Biol. 62: 817–826; 1997.

Predictors of Survival and Causes of Death in Japanese Patients with Systemic Sclerosis

Objective. To clarify the mortality rates, causes of death, and contributing clinical factors in Japanese patients with systemic sclerosis (SSc). Methods. A cohort of 405 patients with SSc, who attended our institution during the period 1973 to 2008, was retrospectively analyzed until the end of 2009. Clinical data were obtained from medical records or autopsy reports. Results. The 405 patients with SSc consisted of 310 (76.5%) survivors, 86 (21.2%) who died, and 9 who were lost to followup. Diffuse cutaneous SSc and involvement of organs other than the gastrointestinal tract were more frequent in patients who died, and were associated with a worse prognosis according to Kaplan-Meier analysis. Female sex, limited cutaneous SSc, anticentromere antibody (ACA), and overlap with Sjögren’s syndrome (SS) were factors favoring a better prognosis, while overlap with myositis contributed to a poor prognosis. The overall 10-year survival rate was 88%. The patients with SSc had a significantly higher mortality than the general population (standardized mortality ratio 2.76), but the patients with ACA or overlapping SS did not. The most common causes of death were unknown ones including sudden death, followed by malignancy and infection. In patients with pulmonary arterial hypertension, sudden death was the most common cause of mortality. Conclusion. The overall mortality rate of patients with SSc was higher than that of the general population, probably because of poor prognostic factors including organ involvement. These factors should be carefully monitored during followup.

Serum adhesion molecule levels as prognostic markers in patients with early systemic sclerosis: A multicentre, prospective, observational study

Objective To assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. Methods Ninety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) −1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically. Results At their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters. Conclusion In patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

Brain MRI in patients with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

Background Manifestations in neuropsychiatric systemic lupus erythematosus (NPSLE), especially active diffuse NPSLE syndromes, are some of the most difficult complications of the disease. For the evaluation and the diagnosis of central nervous system manifestations, including NPSLE, MRI is a very useful tool to detect the various abnormalities. However, the relationship between brain MRI findings and clinical variables has not yet been clarified in patients with diffuse NPSLE. Objectives The aim of this study is to investigate the pathogenesis of diffuse NPSLE, by comparing various parameters such as serum autoantibodies and cytokines in cerebrospinal fluid (CSF) with abnormal findings revealed on brain MRIs in patients with diffuse NPSLE. Methods Fifty-three patients with diffuse NPSLE admitted to our University Hospital from 1992 to 2012 were exhaustively enrolled in this study. Their medical charts and brain MRI scans were reviewed. The relationship of MRI abnormalities with various parameters was analysed. Results As many as 25 of 53 patients (47.2%) had abnormal MRI findings. MRI findings improved after treatment in 10 of 17 patients for whom follow-up studies were available. MRI abnormalities were not correlated with age at the onset of diffuse NPSLE. However, the disease duration of SLE was significantly longer in patients with abnormal MRI findings (p=0.0009). MRI abnormalities were not significantly associated with serum autoantibodies. However, there were significant elevations of the CSF protein level (p=0.0106) and the CSF interleukin 6 level (p=0.0225) in patients with abnormal MRI findings. Patients with MRI abnormalities showed significantly higher overall mortality (p=0.0348). Conclusions The results revealed that MRI abnormalities in diffuse NPSLE might be heterogeneous with regard to their reversibility. These data also indicate that patients with diffuse NPSLE and MRI abnormalities have more severe inflammation in the central nervous system related to the activity of diffuse NPSLE, as evidenced by poorer prognosis.

Investigation of prognostic factors for skin sclerosis and lung function in Japanese patients with early systemic sclerosis: a multicentre prospective observational study

OBJECTIVE To clarify the clinical course of SSc in Japanese patients with early-onset disease. It is well known that ethnic variations exist in the clinical features and severity of SSc. However, neither the clinical course nor prognostic factors have been thoroughly investigated in the Japanese population. METHODS Ninety-three Japanese patients of early-onset SSc (disease duration: <3 years) with diffuse skin sclerosis and/or interstitial lung disease were registered in a multi-centre observational study. All patients had a physical examination with laboratory tests at their first visit and at each of the three subsequent years. Factors that could predict the severity of skin sclerosis and lung involvement were examined statistically by multiple regression analysis. RESULTS Two patients died from SSc-related myocardial involvement and four patients died from other complications during the 3-year study. Among various clinical data assessed, the initial modified Rodnan total skin thickness score (MRSS) and maximal oral aperture were associated positively and negatively with MRSS at Year 3, respectively. Additionally, initial ESR tended to be associated with final MRSS. Pulmonary vital capacity (VC) in the third year was significantly associated with initial %VC. Furthermore, patients with anti-topo I antibody tended to show reduced %VC at Year 3. CONCLUSIONS Several possible prognostic factors for skin sclerosis and lung function were detected in Japanese patients with early SSc. Further longitudinal studies of larger populations will be needed to confirm these findings.

Reversible focal neurological deficits in systemic lupus erythematosus: Report of 2 cases and review of the literature

We report two cases presenting focal neurological deficits with high intensity lesions in fluid attenuated inversion recovery (FLAIR) images on brain magnetic resonance imaging (MRI), which almost completely improved by corticosteroid therapy. Marked elevation of cerebrospinal fluid IL-6 was also noted when these patients showed neurological deficits. As far as we explored, there have been thirteen published case reports of systemic lupus erythematosus patients with reversible focal neurological deficits. The neurological symptoms varied from case to case, but could be attributed to the lesions on MRI scans. The completely reversible feature of neurological manifestations as well as MRI findings on corticosteroid therapy is distinct from any other disorder, including cerebrovascular disease and demyelinating syndrome, in the 1999 American College of Rheumatology nomenclature. Therefore, we propose that reversible focal neurological deficits should be added to the 1999 nomenclature and classification and case definitions.

Henoch-Schönlein pupura complicated by perforation of the gallbladder

Henoch-Schönlein purpura is a systemic vasculitis of small vessels characterized by purpura, arthralgias, glomerulonephritis and gastrointestinal involvements which can cause intestinal perforation. A 75-year-old man with renal dysfunction and palpable purpura (petechiae) of which dermal specimen showed leukocytoclastic vasculitis was diagnosed as Henoch-Schönlein purpura. Corticosteroid and cyclosporine were effective, but subsequently he developed pneumocystis pneumonia. After he improved by treatment with trimethoprim-sulfamethoxazole, he presented sudden abdominal pain, caused by perforation of the gallbladder. Histological analysis revealed infiltration of inflammatory cells with bleeding in the gallbladder wall at the site of perforation. It is suggested that inflammatory disruption of capillary walls might lead to the perforation of the gallbladder.

A case of primary Sjögren’s syndrome complicated by Graves’ disease and primary biliary cirrhosis

A patient with primary Sjögren’s syndrome (SS) who developed Graves’ disease and primary biliary cirrhosis (PBC) is described. Co-existence of these three organ-specific autoimmune diseases has been identified based on the findings of clinical and pathological examination. Although the association of SS with Hashimoto’s thyroiditis or PBC has been well recognized, the association of SS with Graves’ disease is quite rare. Therefore, this may be the first report describing the coexistence of these three organ-specific autoimmune diseases in the same patient.

Safety and tolerability of bosentan for digital ulcers in Japanese patients with systemic sclerosis: Prospective, multicenter, open‐label study

A multicenter, open‐label study was performed to investigate the safety and tolerability of bosentan in Japanese patients with systemic sclerosis (SSc) and secondary digital ulcers. Twenty‐eight patients were enrolled. The safety and tolerability of bosentan was monitored over 52 weeks of study treatment (primary end‐point), while incidence and healing of digital ulcers were also assessed up to week 16. The following adverse events occurred in 5% or more of patients during the 52‐week treatment period: upper respiratory tract infection (50.0%), abnormal liver function tests (42.9%), digital ulcers (25.0%), anemia (17.9%), peripheral edema (14.3%), diarrhea (10.7%), urinary tract infection (7.1%), arthralgia (7.1%), constipation (7.1%) and herpes zoster (7.1%). Eight patients experienced at least one serious adverse event, including drug‐related serious adverse events in two patients, which were abnormal liver function tests and fluid retention (pericardial effusion) in one patient each. During the 16‐week observation period, seven out of 28 patients (25%) developed new digital ulcers. In this study, adverse events were comparable with those previously reported with bosentan. Approximately half of the patients had adverse events associated with abnormal liver function tests, thus we conclude that liver function should be monitored regularly during treatment with bosentan.

Transverse myelitis extended to disseminated encephalitis in systemic lupus erythematosus: Histological evidence for vasculitis

A 42-year-old woman was admitted due to systemic lupus erythematosus complicated with glomerulonephritis and pulmonary hypertension. During the treatment for these complications, she presented motor paresis and sensory loss caused by transverse myelitis. In spite of methyl prednisolone pulse therapy, she further developed acute confusional state due to disseminated encephalitis and fell into respiratory arrest. On laboratory examination, elevation of anti-NR2 antibodies in serum as well as in cerebrospinal fluid was noted. Although she recovered from the disseminated encephalitis after extensive treatment with high doses of corticosteroid and intravenous cyclophosphamide, she suddenly died of pulmonary hypertension. Autopsy findings confirmed the presence of liquefaction necrosis in the entire circumference of the whole spinal cord along with intimal hyperplasia and obliteration of the small arteries, accompanied by mononuclear cell infiltration and disruption of internal elastic lamina. It is therefore most likely that our patient developed longitudinal transverse myelitis through spinal cord vasculitis, which extended to brainstem and brain parenchyma, leading to the development of disseminated encephalitis.