Patient satisfaction and efficacy of switching from weekly bisphosphonates to monthly minodronate for treatment and prevention of glucocorticoid-induced osteoporosis in Japanese patients with systemic rheumatic diseases: a randomized, clinical trial.

The randomized, clinical trial demonstrated that switching to monthly minodronate from weekly alendronate and risedronate provides greater increases in patients' satisfaction and bone mineral density and more substantial decreases in a bone resorption marker than continuing weekly alendronate and risedronate in patients with systemic rheumatic diseases on glucocorticoid therapy. PURPOSE: Osteoporosis and associated fractures are major concerns for patients with systemic rheumatic diseases on long-term glucocorticoid therapy. Bisphosphonates increase bone mineral density (BMD) and reduce the frequency of vertebral fractures, but they are associated with poor adherence. The effects of monthly oral minodronate on patients' satisfaction, BMD, and bone turnover markers were investigated in patients with systemic rheumatic diseases on glucocorticoids and weekly oral alendronate or risedronate. METHODS: Study patients with systemic rheumatic diseases on oral glucocorticoids and weekly alendronate 35 mg or risedronate 17.5 mg were randomly assigned either to switch to minodronate 50 mg every 4 weeks or to continue the currently taking weekly bisphosphonate for 52 weeks after a 24-week run-in period.Patients were stratified by hospital site, sex, and menopausal status in women at enrollment. The primary endpoint was the difference between the proportions of patients who responded very satisfactory or satisfactory for the current bisphosphonate therapy at weeks 48 and 76 between the two groups. Secondary endpoints included percentage changes in lumbar spine BMD and bone turnover markers from the time of starting allocated treatment. RESULTS: Monthly minodronate was superior to weekly alendronate or risedronate for patients' satisfaction, the increase of lumbar spine BMD, and suppression of serum tartrate-resistant acid phosphatase 5b at week 76. CONCLUSIONS: Monthly minodronate is more acceptable and may be more effective than weekly alendronate or risedronate for prevention and treatment of bone loss in patients with systemic rheumatic diseases on glucocorticoid therapy.

Simultaneous Formation and Spatial Patterning of ZnO on ITO Surfaces by Local Laser-Induced Generation of Microbubbles in Aqueous Solutions of [Zn(NH3)4]2.

We demonstrate the simultaneous formation and spatial patterning of ZnO nanocrystals on an indium-tin oxide (ITO) surface upon local heating using a laser (1064 nm) and subsequent formation of microbubbles. Laser irradiation of an ITO surface in aqueous [Zn(NH3)4]2+ solution (1.0 × 10-2 M at pH 12.0) under an optical microscope produced ZnO nanocrystals, the presence of which was confirmed by X-ray diffraction analysis and Raman microspectroscopy. Scanning the focused laser beam over the ITO surface generated a spatial ZnO pattern (height: ∼60 nm, width: ∼1 µm) in the absence of a template or mask. The Marangoni convection generated in the vicinity of the microbubbles resulted in a rapid concentration/accumulation of [Zn(NH3)4]2+ around the microbubbles, which led to the formation of ZnO at the solid-bubble-solution three-phase contact line around the bubbles and thus afforded ZnO nanocrystals on the ITO surface upon local heating with a laser.

Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.

Case report: successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still's disease.

We report on a 64-year-old woman with multirefractory flare of adult-onset Still's disease successfully treated with six-month course of add-on anti-interleukin 6 receptor antibody, tocilizumab. Before administration of tocilizumab, the combination therapy with 80 mg/day of prednisolone and cyclosporine or tacrolimus for five weeks, two courses of pulse methylprednisolone, and high-dose intravenous immunoglobulin could not control the disease. Add-on tocilizumab dramatically improved her disease state and enabled tapering of corticosteroid and tacrolimus. Furthermore remission has been maintained on low-dose corticosteroid and tacrolimus after withdrawal of tocilizumab. This case report suggests that short-term add-on tocilizumab might be a useful therapeutic option for patients with multirefractory flare of polycyclic systemic adult-onset Still's disease.

The Th17/IL-23 Axis and Natural Immunity in Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory skin disease that causes enthesitis and destructive arthritis and significantly lowers patient quality of life. Recognition of the two target organs (the skin and joints) involved in the immunopathophysiology of PsA helped in elucidating the pathology of various systemic autoimmune diseases targeting multiple organs. Recent advances in immunology and genetics have made it clear that acquired immunity, especially that mediated by the Th17/IL-23 axis, plays an important role in the inflammatory pathology observed in psoriasis and PsA. Additionally, involvement of natural immunity has also been suggested. Microbial infection has been known to trigger psoriasis and PsA. Recent clinical studies using biopharmaceuticals, such as tumor-necrosis-factor- (TNF-) α inhibitors and IL-12/23 p40 antibodies, indicate that studies need not be based only on the immunological phenomena observed in PsA pathology since disease pathology can now be verified using human-based science. Considering this aspect, this paper discusses the immunopathology of PsA compared to psoriasis (cutaneous) and rheumatoid arthritis in humans and immunopathology of PsA with respect to the Th17/IL-23 axis and microbial infection.

Comparison of QuantiFERON-TB Gold and the tuberculin skin test for detecting previous tuberculosis infection evaluated by chest CT findings in Japanese rheumatoid arthritis patients.

The aim of the study was to compare the usefulness of the QuantiFERON-TB Gold (QFT-2G) with that of the tuberculin skin test (TST) for detecting previous infection of tuberculosis (TB) in Japanese rheumatoid arthritis (RA) patients. Before receiving biologic therapy, 97 RA patients were divided into two groups based on their chest computed tomography (CT) findings: the TB past infection group (n = 48), with old inflammatory changes due to prior pulmonary TB; and the non-TB infection group (n = 49), without such findings. The QFT-2G was not affected by methotrexate or prednisolone. Indeterminate results with a positive control had a low incidence (5.2%). A positive QFT-2G for the TB past infection group at cutoffs of 0.35 and 0.1 IU/ml (intermediate range) was seen in 5.8% and 20.8%, respectively. A TST >20 mm was significantly higher in the non-TB infection group (31%) than in the TB past infection group (13%). The correlation between the QFT-2G and TST was poor among all patients. Disagreement between these tests in the non-TB infection group was caused by the false-positive TST induced by previous Bacillus Calmette-Guérin (BCG) vaccination. Only 12 (12.4%) of 97 patients had a positive QFT-2G (≥0.1 IU/ml) and a negative TST (<20 mm), but in this subgroup, a high incidence (10, 83.3%) was detected in the TB past infection group. QFT-2G may be a good alternative to the TST to evaluate previous TB infection when it is necessary to determine whether isoniazid (INH) prophylaxis is needed before biologic therapy is begun.

Serodiagnosis of Mycobacterium avium-complex pulmonary disease with an enzyme immunoassay kit that detects anti-glycopeptidolipid core antigen IgA antibodies in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) has many pulmonary manifestations, including bronchial abnormalities that can develop into Mycobacterium avium-complex (MAC) pulmonary disease (PD). MAC-PD can be lethal in patients receiving tumor necrosis factor-alpha blockers despite administration of antibiotics. Diagnosis of MAC-PD is often difficult, because MAC is an environmental organism. In this study, we investigated the usefulness of serodiagnosis of MAC-PD in RA patients by using an enzyme immunoassay (EIA) kit that detects anti-glycopeptidolipid (GPL) core antigen IgA antibodies. Antibody levels were measured in 63 patients with RA: 14 with MAC-PD plus 3 cultured nontuberculous mycobacteria (NTM) other than MAC, 16 with pulmonary abnormalities characterizing NTM but undetected in sputum culture, and 30 control subjects. RA patients with MAC-PD showed significantly higher antibody levels than controls (p = 0.02). The cutoff point was set at 0.7 IU/l, making the sensitivity and specificity of the antibody in MAC-PD and control patients 43% and 100%, respectively. The EIA kit is useful for diagnosis of MAC-PD in RA patients because of its high specificity. This test is an easier and less invasive form of examination and could therefore replace bronchoscopy as the main diagnostic procedure for RA patients with MAC-PD.

Usefulness and limitations of QuantiFERON-TB Gold in Japanese rheumatoid arthritis patients: proposal to decrease the lower cutoff level for assessing latent tuberculosis infection.

We aimed to determine the sensitivity and specificity of QuantiFERON-TB Gold (QFT-G) in Japanese rheumatoid arthritis (RA) patients with a past history of tuberculosis (TB). We assessed whether it is possible to decrease the cutoff using receiver operating characteristic (ROC) analysis. We evaluated chest computed tomography (CT) findings, prior history of treatment, and contact with active TB in 370 RA patients. Forty-nine patients before initiation of treatment with tumor necrosis factor (TNF) inhibitors were divided into two groups: 22 with a past history of TB and 27 without. We estimated the efficacy of QFT-G compared with the tuberculin skin test and antituberculosis (anti-TB) glycolipid antigen antibody. QFT-G was positive (>or=0.35 IU/ml) in 13.6% with a past history of TB, increasing to 27.3% at the intermediate range cutoff of 0.1 IU/ml. The sensitivity and specificity of QFT-G was 0.27 and 1.00, respectively, at 0.1 IU/ml. Using ROC analysis, the area under the curve (AUC) of QFT-G but not for the other two tests was significantly large. QFT-G is a useful diagnostic method due to its superior specificity, but the use of a cutoff value of 0.35 IU/ml will likely result in an underestimate. We propose that a lower interferon-gamma (IFN-gamma) titer of 0.1 IU/ml be adopted when deciding to administer anti-TB drugs before initiation of TNF inhibitors.

Alendronate-induced esophagitis: possible pathogenic role of hypersensitivity to alendronate.

Upper gastrointestinal tract mucosal irritations, such as esophagitis, have been reported as rare adverse events due to a variety of aminobisphosphonates, including alendronate sodium, which have been widely used to treat osteoporosis. Although the pathogenesis of aminobisphosphonate-induced esophageal mucosal irritation has not been clearly understood, direct chemical esophageal irritation with prolonged local mucosal exposure to the drug with gastric contents might be the most plausible mechanism according to the previously reported literature. Here we report a young adult man with severe ulcerative esophagitis due to alendronate who demonstrated a strongly positive result on a drug lymphocyte stimulation test against alendronate. This case report provides the new concept that T-cell mediated delayed hypersensitivity to the drug may be involved in the pathogenesis of alendronate-induced esophagitis.

Drug-induced hypersensitivity syndrome associated with a marked increase in anti-paramyxovirus antibody titers in a scleroderma patient.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is characterized by a severe multiorgan hypersensitivity reaction that usually appears after prolonged exposure to certain drugs and may be related to reactivation of herpes viruses. There have been few reports regarding the clinical association of DIHS with pathogens other than herpes viruses. CASE SUMMARY: We report a case of scleroderma with DIHS associated with paramyxovirus infection. A 61-year-old man with early diffuse cutaneous scleroderma with myositis and progressive interstitial pneumonia developed generalized erythema with high fever 3 weeks after taking sulfamethoxazole/trimethoprim. The diagnosis of DIHS was made based on the patient's history of using an offending drug, clinical manifestations and laboratory data showing peripheral eosinophilia with the presence of atypical lymphocytes. Virological tests showed significant increases of antibody titers against mumps virus and parainfluenza virus type 2, which strongly suggested that paramyxovirus infection occurred during the clinical course of DIHS. DISCUSSION: These findings suggest that paramyxovirus infection had contributed to the development of DIHS in this patient and that there is a need to seek evidence of other viral infections in some cases of DIHS, especially those without herpes virus reactivation/infection.

Pulmonary-renal syndrome in systemic sclerosis: a report of three cases and review of the literature.

We describe three cases of acute renal failure with diffuse alveolar hemorrhage, which is designated pulmonary-renal syndrome (PRS), in systemic sclerosis (SSc) and review the literature to better define this rare but severe complication of SSc. The clinical course of three SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage are reported, and the literature published between 1967 and 2005 is reviewed following a PubMed search. Including our cases, a total of 19 SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage have been reported. Pulmonary-renal syndrome developing in SSc patients can be categorized clinicopathologically into three entities: PRS with thrombotic microangiopathy, PRS with small vessel vasculitides accompanied with SSc, and d-penicillamine-induced Goodpasture-like syndrome. Patients with scleroderma PRS with thrombotic microangiopathy, to which group our all patients belong, often developed diffuse alveolar hemorrhage after receiving high-dose corticosteroid therapy. Pulmonary-renal syndrome is a fatal complication of SSc and results from different pathogenic processes. Prompt differential diagnosis between the subsets is critical, because therapeutic strategy may differ in the use of high-dose corticosteroid and plasma exchange between the subsets of PRS. Clinical courses of the patients with PRS with thrombotic microangiopathy suggest that high-dose corticosteroid therapy is a trigger of diffuse alveolar hemorrhage in patients with diffuse SSc with signs of thrombotic microangiopathy.

Normotensive scleroderma renal crisis with diffuse alveolar damage after corticosteroid therapy.

A 68-year-old woman with systemic sclerosis developed acute respiratory failure due to diffuse alveolar hemorrhage and normotensive scleroderma renal crisis (SRC) shortly after the initiation of corticosteroid therapy. Treatment with angiotensin-converting enzyme inhibitor and plasmapheresis had failed in this patient. Autopsy showed diffuse alveolar damage and thrombotic micro-angiopathy. The sequence of events in this patient clarifies the pathologic process of normotensive SRC, and suggests a causative role of corticosteroid therapy and normotensive SRC.

Microscopic polyangiitis associated with diffuse panbronchiolitis.

There are several case reports of systemic vasculitis associated with chronic suppurative lung diseases. We describe a 46-year-old female, previously diagnosed as having diffuse panbronchiolitis (DPB), presenting with hemosputum and dyspnea. Her serum titer of MPO-ANCA was positive together with a high titer of BPI-ANCA. Chest X-ray and chest CT scan showed pulmonary hemorrhage, and the renal biopsy specimen revealed necrotizing, crescentic glomerulonephritis. She was diagnosed as having ANCA-associated vasculitis, and more specifically, microscopic polyangiitis accompanied by DPB. She was treated with methylprednisolone pulse therapy, followed by intravenous cyclophosphamide. This case suggested a possible association with chronic bacterial infection, which may play a role in the pathogenesis of ANCA-associated vasculitis.

Transforming growth factor beta1 gene polymorphism in patients with systemic sclerosis.

OBJECTIVE: To determine whether transforming growth factor beta1 (TGFbeta1) gene DNA polymorphism is associated with pathogenesis in the fibrosis of patients with systemic sclerosis (SSc). METHODS: Eighty-seven Japanese patients with SSc including 30 with diffuse type and 57 with limited type together with 110 unrelated controls were investigated. Pulmonary fibrosis was determined in 34 SSc patients using high-resolution chest computed tomography. TGFbeta1 genetic polymorphisms were analyzed in 2 loci; T869C (Leu10Pro) in codon 10 at exon 1, and C-509T in the promoter region using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Neither the genotype of T/C polymorphism in T869C nor C/T polymorphism in C-509T revealed any difference in distribution between SSc and controls. In the group of SSc patients with pulmonary fibrosis, a weak but significantly high frequency (p = 0.05) of TC+CC (the presence of C allele) in T869C, and CT+TT (the presence of T allele) in C-509T was found. Compared with controls, the pulmonary fibrosis group showed no difference in the highly frequent alleles. CONCLUSION: Our results suggest that TGFbeta1 polymorphisms do not play a role in the pathogenesis of SSc, even though there remains the possibility of a risk factor for genetic susceptibility to pulmonary fibrosis.

Superior mesenteric venous thrombosis associated with a familial missense mutation (Pro626Leu) in the SHBG-like domain of the protein S molecule.

A 76-year-old Japanese woman was hospitalized for ileus symptoms caused by extensive thrombosis of the superior mesenteric vein. Because laboratory test results suggested type III protein S (PS) deficiency, molecular changes in PS were investigated. A single-base transition, CCG to CTG at codon 626 in exon XV, resulting in the missense mutation Pro626Leu, was identified in an allele of the patient and in her son. Reverse transcriptase polymerase chain reaction analysis indicated the presence of both normal and mutant types of PS messages in platelet-derived messenger RNAs. Our findings thus suggest that Pro626 in SHBG-like domain 7 may be crucial for in vivo antithrombotic activity of the PS molecule.