A rare case of ulcerative colitis in a patient who developed acute ischemic colitis associated with Takayasu arteritis.

Intestinal ischemia is a rare complication of Takayasu arteritis (TAK), which often requires colectomy. We report the case of a 27 year-old man with ulcerative colitis (UC), who was admitted to our hospital due to abdominal pain. Computed tomography revealed an edematous wall of the ascending colon with ascites and a thickened aortic wall with mild stenosis of the superior mesenteric artery (SMA), suggesting large vessel vasculitis, especially TAK. Colonoscopy revealed acute ischemic colitis associated with mild stenosis of the SMA caused by TAK, but there was no worsening of UC. The patient was successfully treated with conservative therapy.

An open-label, randomized controlled trial of sulfamethoxazole-trimethoprim for Pneumocystis prophylaxis: results of 52-week follow-up.

OBJECTIVES: The aim was to investigate the long-term prophylactic efficacy, drug retention and safety of low-dose sulfamethoxazole-trimethoprim (SMX/TMP) prophylaxis against Pneumocystis pneumonia (PCP). METHODS: Adult patients with rheumatic diseases receiving prednisolone ≥0.6 mg/kg/day were randomized into the single-strength group (SS; SMX/TMP 400/80 mg daily), the half-strength group (HS; 200/40 mg daily) or the escalation group (ES; starting at 40/8 mg and increasing incrementally to 200/40 mg daily) and treated for 24 weeks, then observed for 52 weeks. The primary endpoint, the PCP non-incidence rate (non-IR) at week 24, has been reported previously. The secondary endpoints were the PCP non-IR at week 52, treatment discontinuation rate and adverse events. RESULTS: Fifty-eight, 59 and 55 patients in the SS, HS and ES, respectively, received SMX/TMP. PCP did not develop in any of the patients by week 52. The estimated PCP non-IR in patients receiving SMX/TMP 200/40 mg daily (HS and ES) was 96.8-100%. Throughout the 52-week observation period, the overall discontinuation rate was significantly lower in HS than in SS (22.7 vs 47.2%, P = 0.004). The discontinuation rates attributable to adverse events were significantly lower in HS (19.1%, P = 0.007) and ES (20.3%, P = 0.007) than in SS (41.8%). The IRs of adverse events requiring SMX/TMP dose reduction before week 52 differed among the three groups, with a significantly higher IR in SS than in HS or ES (P = 0.007). CONCLUSION: SMX/TMP 200/40 mg had a high PCP prevention rate and was superior to SMX/TMP 400/80 mg in terms of drug retention and safety. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000007727.

A Patient with Necrotizing Vasculitis Related to Sarcoidosis, which Was Diagnosed via Immunohistochemical Methods Using Propionibacterium acnes-specific Monoclonal Antibodies.

Propionibacterium acnes (P. acnes) is a commensal bacterium indigenous to the skin. Previous reports have suggested that infection with P. acnes causes sarcoidosis, a systemic granulomatous disease. We present the case of a 63-year-old woman who developed subcutaneous nodules. A skin biopsy revealed necrotizing vasculitis and noncaseating granulomas, which are characteristic of sarcoidosis. Immunohistostaining revealed a P. acnes skin infection, which led to the diagnosis of sarcoidosis. Minocycline treatment resolved the infection and improved the patient's symptoms. We herein report a case in which immunohistochemistry was useful in the diagnosis of sarcoidosis.

Early Detection and Intervention of Coronary Artery Involvement in Immunoglobulin G4-related Disease.

A 59-year-old man with swollen submandibular glands developed an aortic aneurysm requiring aortic prosthesis implantation. Echocardiography performed to evaluate the cardiac function before the surgery incidentally revealed masses around the coronary arteries. The serum IgG4 levels were increased. A post-operational pathological examination of the abdominal aneurysms revealed infiltration of plasma cells, with the ratio of IgG4/IgG-positive cells being >80%. The patient was diagnosed with IgG4-related disease (RD) with coronary artery involvement. He was treated successfully with corticosteroid before any associated cardiovascular events occurred. Given the poor prognosis of IgG4-RD-associated coronary artery involvement, this case emphasizes the importance of the early assessment with echocardiography, even if patients have no cardiovascular symptoms.

Optimal regimens of sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with systemic rheumatic diseases: results from a non-blinded, randomized controlled trial.

BACKGROUND: Sulfamethoxazole-trimethoprim (SMX/TMP) is a standard drug for the prophylaxis of Pneumocystis pneumonia (PJP) in immunosuppressed patients with systemic rheumatic diseases, but is sometimes discontinued due to adverse events (AEs). The objective of this non-blinded, randomized, 52-week non-inferiority trial was to quest an effective chemoprophylaxis regimen for PJP with a low drug discontinuation rate. Results at week 24 were reported. METHODS: Adult patients with systemic rheumatic diseases who started prednisolone ≥0.6 mg/kg/day were randomized into three dosage groups: a single-strength group (SS, SMX/TMP of 400/80 mg daily), half-strength group (HS, 200/40 mg daily), and escalation group (ES, started with 40/8 mg daily, increasing incrementally to 200/40 mg daily). The primary endpoint was non-incidence rates (non-IR) of PJP at week 24. RESULTS: Of 183 patients randomly allocated at a 1:1:1 ratio into the three groups, 58 patients in SS, 59 in HS, and 55 in ES started SMX/TMP. A total of 172 patients were included in the analysis. No cases of PJP were reported up to week 24. Estimated non-IR of PJP in patients who received daily SMX/TMP of 200/40 mg, either starting at this dose or increasing incrementally, was 96.8-100% using the exact confidence interval as a post-hoc analysis. The overall discontinuation rate was significantly lower with HS compared to SS (p = 0.007). The discontinuation rates due to AEs were significantly lower with HS (p = 0.006) and ES (p = 0.004) compared to SS. The IR of AEs requiring reduction in the dose of SMX/TMP (p = 0.009) and AEs of special interest (p = 0.003) were different among the three groups with significantly higher IR in SS compared to HS and ES. CONCLUSIONS: Although there were no PJP cases, the combined group of HS and ES had an excellent estimated non-IR of PJP and both were superior in safety to SS. From the perspective of feasibility and drug discontinuation rates, the daily half-strength regimen was suggested to be optimal for prophylaxis of PJP in patients with systemic rheumatic diseases. TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry number is UMIN000007727 , registered 10 April 2012.

IgG4-Related Sialoadenitis with a Skin Lesion and Multiple Mononeuropathies Suggesting Coexistent Cryoglobulinemic Vasculitis.

A 68-year-old man was admitted because of weakness of the left leg, dysesthesiae of the extremities and bilateral lower extremity purpura. A neurological examination showed mononeuritis multiplex with laboratory evidence of hypocomplementemia, cryoglobulinemia and leukocytoclastic vasculitis in the biopsy of a skin specimen. The patient also exhibited bilateral submandibular gland swelling, elevated serum IgG4 levels and infiltration of a large number of IgG4-positive plasma cells in the submandibular glands. These findings were consistent with both cryoglobulinemic vasculitis and IgG4-related disease. The administration of oral prednisolone (1 mg/kg/day) resolved the neurological manifestations and the swelling of the submandibular glands and cryoglobulinemia.

[Atherosclerotic and hemorrhagic diseases in a patient with primary immune deficiency].

A 59-year-old man, who suffered from periodic fever with continuous elevation of the C-reactive protein (CRP) level was referred to our hospital. He had frequent respiratory infections and diarrhea since his childhood. The serum immunoglobulin (Ig) G level was low (537 mg/dl) while IgA and IgE were undetectable. The serum IgM level was elevated (737 mg/dl). Based on these clinical features, he was diagnosed with primary immune deficiency, hyper IgM syndrome. He had past histories of aortic aneurysm, which had been repaired surgically in his fifties. His persistent proteinuria made us to perform renal biopsy, which revealed nephrosclerotic changes. During the hospitalization, multiple events of subcortical brain hemorrhage, subarachnoid hemorrhage, and pulmonary alveolar hemorrhage occurred. Bleeding time and coagulation tests were normal. Antinuclear antibody, anti-neutrophil cytoplasmic antibody, or anti-cardiolipin antibody was absent. Herein, we described the first case of the immune deficiency associated with severe arteriosclerosis and hemorrhage.

Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients.

We hypothesized B cells are involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive, restrictive lung disease that is refractory to glucocorticoids and other nonspecific therapies, and almost invariably lethal. Accordingly, we sought to identify clinically associated B cell-related abnormalities in these patients. Phenotypes of circulating B cells were characterized by flow cytometry. Intrapulmonary processes were evaluated by immunohistochemistry. Plasma B lymphocyte stimulating factor (BLyS) was assayed by ELISA. Circulating B cells of IPF subjects were more Ag differentiated, with greater plasmablast proportions (3.1 ± 0.8%) than in normal controls (1.3 ± 0.3%) (p < 0.03), and the extent of this differentiation correlated with IPF patient lung volumes (r = 0.44, p < 0.03). CD20(+) B cell aggregates, diffuse parenchymal and perivascular immune complexes, and complement depositions were all prevalent in IPF lungs, but much less prominent or absent in normal lungs. Plasma concentrations of BLyS, an obligate factor for B cell survival and differentiation, were significantly greater (p < 0.0001) in 110 IPF (2.05 ± 0.05 ng/ml) than among 53 normal (1.40 ± 0.04 ng/ml) and 90 chronic obstructive pulmonary disease subjects (1.59 ± 0.05 ng/ml). BLyS levels were uniquely correlated among IPF patients with pulmonary artery pressures (r = 0.58, p < 0.0001). The 25% of IPF subjects with the greatest BLyS values also had diminished 1-y survival (46 ± 11%), compared with those with lesser BLyS concentrations (81 ± 5%) (hazard ratio = 4.0, 95% confidence interval = 1.8-8.7, p = 0.0002). Abnormalities of B cells and BLyS are common in IPF patients, and highly associated with disease manifestations and patient outcomes. These findings have implications regarding IPF pathogenesis and illuminate the potential for novel treatment regimens that specifically target B cells in patients with this lung disease.

Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses.

RATIONALE: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations. OBJECTIVES: To identify clinically relevant, antigen-specific immune responses in patients with IPF. METHODS: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti-heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies. MEASUREMENTS AND MAIN RESULTS: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0-8.6; P < 0.0001). HSP70 protein, antigen-antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression. CONCLUSIONS: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.

Characterization of TLR4-mediated auto-antibody production in a mouse model of histidyl-tRNA synthetase-induced myositis.

We have previously shown that intramuscular immunization with a recombinant fragment of murine histidyl-tRNA synthetase (HRS) in the absence of exogenous adjuvant generates Ag-specific, IgG class switched Abs a murine model of myositis. Markedly diminished IgG anti-HRS auto-Ab responses in TLR4 signaling-deficient C3H/HeJ mice indicate that TLR4 is required for auto-Ab formation and/or class switching in this system. Comparative time course assessment of HRS-immunized C3H/HeOuJ (wild type) and C3H/HeJ (TLR4 mutant) mice shows here that despite significant impairment of class switched IgG anti-HRS responses in TLR4-deficient C3H/HeJ mice, production of IgM anti-HRS auto-Abs is relatively preserved-suggesting that TLR4-mediated signals modulate IgG class switching rather than auto-Ab formation in this genetic background. In C57BL/6-derived knockout mice lacking either MyD88 (B6.MyD88(-/-)) or TRIF (B6.TRIF(-/-)) adaptor molecules, immunization studies indicate that TRIF exerts a dominant role in the generation of HRS-specific IgG auto-Abs. Complementing these analyses, in vitro stimulation of unfractionated, as well as T cell-depleted, C3H/HeOuJ splenocytes with recombinant murine HRS reveals that TLR4-mediated generation of class switched auto-Abs can occur independently of T cell help. Overall, these findings support a broader role for TLR4 in the breakdown of immune tolerance and development of autoimmunity.

High frequencies and co-existing of myositis-specific autoantibodies in patients with idiopathic inflammatory myopathies overlapped to rheumatoid arthritis.

A small proportion of patients with rheumatoid arthritis (RA) develop idiopathic inflammatory myopathies (IIM); however, the clinical and immunological characteristics of these patients have not been elucidated. In the present study, we evaluate the frequency of autoantibodies and the accompanying clinical features in patients with IIM overlapped to RA (IIM-RA) and in patients with IIM without RA. Twelve patients with IIM-RA were selected from 142 patients with IIM who were admitted to our hospital. Clinical and laboratory data, including autoantibody test results, were collected from patient medical records. Myositis-specific antibodies (MSAs) were analyzed by immunoprecipitation. Clinically, patients with IIM-RA were more likely to be male, to have polymyositis, and to be older at the time of IIM onset than patients with IIM without RA. Patients with IIM-RA had been treated for 2-25 years prior to the onset of IIM with more than two disease-modifying antirheumatic drugs (DMARDs). Patients with IIM-RA had a high frequency (75.0%) of positivity for MSAs, including anti-Jo-1, anti-PL-7, anti-PL-12, or anti-signal recognition particle (SRP) antibodies; anti-Jo-1 antibody was detected in 4 patients (33.3%). In addition, 2 out of 12 patients with IIM-RA were concurrently positive for two different MSAs, anti-Jo-1, and anti-PL-7 antibodies. In 3 other patients with IIM-RA, anti-Jo-1 antibody, or anti-PL-7 antibody was detected in serum samples collected 6-18 months prior to development of myositis. High frequency and coexistence of MSAs were detected in patients with IIM-RA. MSAs detected in patients with RA even without symptoms of myositis may indicate possible future development of myositis.

Role of innate immunity in a murine model of histidyl-transfer RNA synthetase (Jo-1)-mediated myositis.

OBJECTIVE: Previous studies in humans and in animal models support a key role of histidyl-transfer RNA synthetase (HisRS; also known as Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HisRS to trigger adaptive immune responses, in vitro studies clearly indicate that HisRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HisRS to direct innate immune responses in a murine model of myositis. METHODS: Following intramuscular immunization with soluble HisRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. Enzyme-linked immunosorbent assay-based assessment of autoantibody formation and carboxyfluorescein succinimidyl ester proliferation studies provided complementary measures of B cell and T cell responses triggered by HisRS immunization. RESULTS: Compared to appropriate control proteins, a murine HisRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days postimmunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/RAG-2(-/-) and C3H/HeJ (TLR-4(-/-) ) mice indicated that the ability of murine HisRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require Toll-like receptor 4 signaling. CONCLUSION: Collectively, the findings of these experiments support a model in which HisRS can trigger both innate and adaptive immune responses that culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy.

Increased HGF and c-Met in muscle tissues of polymyositis and dermatomyositis patients: beneficial roles of HGF in muscle regeneration.

We investigated the expression of hepatocyte growth factor (HGF), which has mitogenic and anti-fibrotic activities, in muscle tissue of polymyositis/dermatomyositis (PM/DM) patients, as well as its functional roles in cultured myoblasts. Immunohistochemistry in muscle from PM/DM patients revealed that HGF was expressed predominantly on infiltrating mononuclear cells and that muscle cells expressed the receptor c-met. Cultured myoblasts produced HGF; which was increased by IL-1alpha but suppressed by TGF-beta and dexamethasone. Exogenous HGF induced myoblast proliferation and reduced procollagen type I production. Furthermore, HGF enhanced the gene expression of muscle regulatory factors MyoD and Myf5, while suppressing expression of fibrosis-related genes, connective tissue growth factor and alpha-smooth muscle actin. Although dexamethasone showed contrasting effects to HGF on the expression of these genes, co-treatment with HGF ameliorated the effects of dexamethasone. Taking the beneficial roles of HGF into consideration, administration of HGF might contribute to muscle regeneration in PM/DM especially under corticosteroid treatment.

Diagnostic reliability of magnetic resonance imaging for central nervous system syndromes in systemic lupus erythematosus: a prospective cohort study.

BACKGROUND: Previous studies of magnetic resonance imaging (MRI) as a diagnostic tool for central nervous system (CNS) syndromes in systemic lupus erythematosus (SLE) contained several limitations such as study design, number of enrolled patients, and definition of CNS syndromes. We overcame these problems and statistically evaluated the diagnostic values of abnormal MRI signals and their chronological changes in CNS syndromes of SLE. METHODS: We prospectively studied 191 patients with SLE, comparing those with (n = 57) and without (n = 134) CNS syndrome. CNS syndromes were characterized using the American College of Rheumatology case definitions. RESULTS: Any abnormal MRI signals were more frequently observed in subjects in the CNS group (n = 25) than in the non-CNS group (n = 32) [relative risk (RR), 1.7; 95% confidence interval (CI), 1.1-2.7; p = 0.016] and the positive and negative predictive values for the diagnosis of CNS syndrome were 42% and 76%, respectively. Large abnormal MRI signals (ø >or= 10 mm) were seen only in the CNS group (n = 7; RR, 3.7; CI, 2.9-4.7; p = 0.0002), whereas small abnormal MRI signals (ø < 10 mm) were seen in both groups with no statistical difference. Large signals always paralleled clinical outcome (p = 0.029), whereas small signals did not (p = 1.000). CONCLUSIONS: Abnormal MRI signals, which showed statistical associations with CNS syndrome, had insufficient diagnostic values. A large MRI signal was, however, useful as a diagnostic and surrogate marker for CNS syndrome of SLE, although it was less common.

Successful treatment for sympathetic storms in a patient with neuro-Behçet's disease.

Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behçet's disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient's symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

Therapeutic efficacy of intravenous cyclophosphamide concomitant with moderate- to high-dose prednisolone in two patients with fasciitis panniculitis syndrome.

Fasciitis panniculitis syndrome (FPS) has been proposed as a new category of 'fasciitis' and includes the well-established eosinophilic fasciitis (EF). Unlike EF, FPS exhibits inconsistent eosinophilia and/or eosinophilic infiltration of the lesions. Principal histological FPS findings include dermal thickening, inflammation and thickening of the subcutaneous fat tissue, fibrous thickening of the fascia and inflammation of the adjacent muscle. FPS is commonly resistant to corticosteroids, and cimetidine is effective in approximately 80% of FPS patients. A new therapy for FPS is required for cases refractory to treatment or intolerant to cimetidine because of adverse drug reaction. In this report, two FPS patients were resistant to corticosteroids. Both received intravenous cyclophosphamide (IVCY) concomitant with moderate- to high-dose prednisolone (PSL), and this effectively treated the induration of the FPS lesions. Patient 1 was a 50-year-old woman who had been diagnosed with fasciitis following en bloc muscle biopsy of the thigh. She had been treated with high-dose PSL for 6 years, but the fasciitis was refractory. Induration of the neck, thorax and thighs resulted in impaired neck rotation, restrictive respiratory failure and impaired walking. A diagnosis of FPS was made by re-assessing the en bloc muscle biopsy. Although PSL (40 mg/day) for 18 days was ineffective, the addition of IVCY (400 mg) dramatically improved the disease manifestations. Patient 2 was a 68-year-old man who was diagnosed with fasciitis based on en bloc muscle biopsy of the left foot. He had been treated with PSL for 16 years, but the fasciitis was refractory. He exhibited lower limb induration and a refractory skin ulcer of the left foot. A diagnosis of FPS was made by re-assessing the en bloc muscle biopsy. Although PSL (40 mg/day) for 2 weeks was ineffective, the addition of IVCY (450 mg) improved both the lower limb induration and the skin ulcer. FPS may cause both entrapment vasculopathy of subcutis and perivasculitis of the subcutaneous fat tissue such that the skin ulcer might be closely related with the ischemic mechanism triggered by FPS. According to the clinical courses of our cases, IVCY combined with moderate- to high-dose PSL may be a new therapeutic choice for corticosteroid-resistant FPS patients.