Diagnosis and treatment of primary biliary cholangitis.

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study.

BACKGROUND: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking. METHODS: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated. RESULTS: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days. CONCLUSIONS: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality.

Non-musculoskeletal benefits of vitamin D.

The aim of this study is to determine and critically evaluate the plausible relationships of vitamin D with extra-skeletal tissues in humans. Severe vitamin D deficiency results in rickets in children and osteomalacia in adults; these beneficial effects in the musculoskeletal system and certain physiological functions are well understood. Nevertheless, mounting reports support additional beneficial effects of vitamin D, outside the musculoskeletal system. This review explores the recent advances in knowledge about the non-skeletal effects of vitamin D. Peer-reviewed papers were extracted from research databases using key words, to assess correlations between vitamin D and extra-skeletal diseases and conditions. As per the guidelines of the Preferred Reporting Items for Systematic Reviews (PRISMA); general interpretations of results are included; taking into consideration the broader evidence and implications. This review summarizes current knowledge of the effects of vitamin D status on extra-skeletal tissues with special attention given to relationships between vitamin D status and various diseases commonly affecting adults; the effects of intervention with vitamin D and exposure to sunlight. Evidence suggests that vitamin D facilitates the regulation of blood pressure; and cardiac; endothelial; and smooth muscle cell functions; playing an important role in cardiovascular protection. In addition; 1,25(OH)2D improves immunity; subdues inflammation; and reduces the incidence and severity of common cancers; autoimmune diseases and infectious diseases. Almost all adequately powered; epidemiological and biological studies that use; adequate doses of vitamin D supplementation in D-deficient populations have reported favorable outcomes. These studies have concluded that optimizing 25(OH)D status improves the functionality of bodily systems; reduces comorbidities; improves the quality of life; and increases survival. Although accumulating evidence supports biological associations of vitamin D sufficiency with improved physical and mental functions; no definitive evidence exists from well-designed; statistically powered; randomized controlled clinical trials. Nevertheless, most studies point to significant protective effects of vitamin D in humans when the minimum 25(OH)D serum level exceeds 30ng/mL and is maintained throughout the year.

The Big Vitamin D Mistake.

Since 2006, type 1 diabetes in Finland has plateaued and then decreased after the authorities' decision to fortify dietary milk products with cholecalciferol. The role of vitamin D in innate and adaptive immunity is critical. A statistical error in the estimation of the recommended dietary allowance (RDA) for vitamin D was recently discovered; in a correct analysis of the data used by the Institute of Medicine, it was found that 8895 IU/d was needed for 97.5% of individuals to achieve values ≥50 nmol/L. Another study confirmed that 6201 IU/d was needed to achieve 75 nmol/L and 9122 IU/d was needed to reach 100 nmol/L. The largest meta-analysis ever conducted of studies published between 1966 and 2013 showed that 25-hydroxyvitamin D levels <75 nmol/L may be too low for safety and associated with higher all-cause mortality, demolishing the previously presumed U-shape curve of mortality associated with vitamin D levels. Since all-disease mortality is reduced to 1.0 with serum vitamin D levels ≥100 nmol/L, we call public health authorities to consider designating as the RDA at least three-fourths of the levels proposed by the Endocrine Society Expert Committee as safe upper tolerable daily intake doses. This could lead to a recommendation of 1000 IU for children <1 year on enriched formula and 1500 IU for breastfed children older than 6 months, 3000 IU for children >1 year of age, and around 8000 IU for young adults and thereafter. Actions are urgently needed to protect the global population from vitamin D deficiency.

An evaluation of the association between C-reactive protein, the change in C-reactive protein over one year, and all-cause mortality in chronic immune-mediated inflammatory disease managed in UK general practice.

OBJECTIVES: To evaluate the association between systemic inflammation, as measured by CRP, and all-cause mortality. To also evaluate the association between change in CRP status (sub-acute, < or =10 mg/l and acute >10 mg/l) and all-cause mortality. METHODS: A cohort of patients was selected from The Health Improvement Network (THIN) data set of anonymized patient-level data from UK general practice. Patients were selected if they had a diagnosis of RA, psoriasis, AS or PsA. Survival was evaluated using Cox proportional hazards regression models (CPHMs). RESULTS: A total of 11 362 cases had at least one CRP measurement. Analysis grouped by each additional unit increase in log-CRP (range 1-6) across the observed range was associated with a 21% increase in the hazard ratio (HR) of death, after controlling for cardiovascular risk factors (P < 0.001). This observation was consistent in separate analysis of cases with either RA or psoriasis. Repeated CRP observations around 1 yr apart were recorded in 2802 subjects. After controlling for confounding factors, in cases whose CRP changed from sub-acute (< or =10 mg/l) to acute (>10 mg/l), the HR for death increased 2-fold (P < 0.001) relative to cases whose CRP remained sub-acute. In comparison, among those subjects whose CRP was reduced from acute to sub-acute, the HR was virtually identical to those who stayed sub-acute (P = 0.571). CONCLUSIONS: CRP level predicted all-cause mortality after standardization for traditional risk factors, as did change in CRP status from sub-acute to acute observed over 1 yr.

Epidemiology of disease risks in relation to vitamin D insufficiency.

Vitamin D from ultraviolet-B (UVB) irradiance, food, and supplements is receiving increased attention lately for its role in maintaining optimal health. Although the calcemic effects of vitamin D have been known for about a century, the non-calcemic effects have been studied intently only during the past two-three decades. The strongest links to the beneficial roles of UVB and vitamin D to date are for bone and muscle conditions and diseases. There is also a preponderance of evidence from a variety of studies that vitamin D reduces the risk of colon cancer, with 1000 IU/day of vitamin D or serum 25-hydroxyvitamin D levels >33 ng/mL (82 nmol/L) associated with a 50% lower incidence of colorectal cancer. There is also reasonable evidence that vitamin D reduces the risk of breast, lung, ovarian, and prostate cancer and non-Hodgkin's lymphoma. There is weaker, primarily ecologic, evidence for the role of vitamin D in reducing the risk of an additional dozen types of cancer. There is reasonably strong ecologic and case-control evidence that vitamin D reduces the risk of autoimmune diseases including such as multiple sclerosis and type 1 diabetes mellitus, and weaker evidence for rheumatoid arthritis, osteoarthritis, type 2 diabetes mellitus, hypertension and stroke. It is noted that mechanisms whereby vitamin D exerts its effect are generally well understood for the various conditions and diseases discussed here.

Inhibitory effects of autoimmune disease by green tea in MRL-Faslprcg/Faslprcg mice.

To investigate whether green tea has inhibitory effects on the development of autoimmune disease (AID), one-month-old MRL-Faslprcg/Faslprcg mice were fed diets containing 2% green tea powder (GTP) for 3 months. At the end of GTP feeding, the weights of body, subcutaneous (s.c.) and intraperitoneal (i.p.) lymph nodes (LN), kidneys, spleen and intraperitoneal adipose tissue (IPAT), serological abnormalities and renal lesions were compared between GTP-fed and control mice. SCLN, IPLN, kidneys and IPAT weights in both sexes, spleen weight in males and body weight increase in males were significantly lower in GTP-fed mice. Particularly, LN hyperplasia and fatty accumulation were markedly reduced by GTP. Serum levels of anti-DNA antibodies and immune complexes (IC) were significantly lowered and proteinuria and blood urea nitrogen tended to be improved by GTP. The incidence of serious glomerulonephritis was significantly lower and nephric vasculitis was almost completely prevented in GTP-fed mice. Moreover, the survival of mice was significantly prolonged by GTP feeding for 6 months. These results indicate that the progression of lupus-like syndrome including glomerulonephritis was significantly delayed by reduced production of autoantibodies and IC in GTP-fed MRL-Faslprcg/Faslprcg mice, which led to the prolonged survival.

Kidney disease and arthritis in a cohort study of workers exposed to silica.

Silica exposure has been associated with kidney disease and rheumatoid arthritis; an autoimmune mechanism has been proposed. Approximately 2 million people are occupationally exposed to silica in the United States, 100,000 at more than twice the National Institute for Occupational Safety and Health recommended exposure limit of 0.05 mg/m(3). We examined renal disease morbidity and mortality, as well as arthritis mortality, in a cohort of 4,626 silica-exposed workers in the industrial sand industry (an industry previously unstudied). We compared the cohort with the U.S. population and also conducted internal exposure-response analyses using a job-exposure matrix based on more than 4,000 industrial hygiene samples. We found excess mortality from acute renal disease [standardized mortality ratio (SMR) = 2.61, 95% confidence intervals (95% CIs) = 1.49--4.24; 16 deaths], chronic renal disease (SMR = 1.61, 95% CI = 1.13--2.22; 36 deaths), and arthritis (SMR = 4.36, 95% CI = 2.76--6.54; 23 deaths) on the basis of multiple-cause mortality data, which considered any mention of disease on a death certificate. Linking the cohort with the U.S. registry of end-stage renal disease for the years 1977-1996, we found an excess of end-stage renal disease incidence (standardized incidence ratio = 1.97, 95% CI = 1.25--2.96; 23 cases), which was highest for glomerulonephritis (standardized incidence ratio = 3.85, 95% CI = 1.55--7.93; 7 cases). We found increasing end-stage renal disease incidence with increasing cumulative exposure; standardized rate ratios by quartile of cumulative exposure were 1.00, 3.09, 5.22, and 7.79. A positive exposure-response trend was also observed for rheumatoid arthritis on the basis of death certificate data. These data represent the largest number of kidney disease cases analyzed to date in a cohort with well-defined silica exposure and suggest a causal link between silica and kidney disease. Excess risk of end-stage renal disease due to a lifetime of occupational exposure at currently recommended limits is estimated to be 14%, above a background end-stage renal disease risk of 2%.

Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis).

In previous studies we observed that human umbilical cord blood (HUCB) could have a protective effect on the onset of disease and time of death in MRL Lpr/Lpr mice which have an autoimmune disease that may be considered similar to human lupus. We believed a temporary xenograph may have occurred in these animals with the disease process delayed and the life span markedly increased. When HUCB is stored at 4 degrees C in gas permeable bags, there is a decrease of the cell reaction in mixed lymphocyte cultures. The blood, however, maintains a significant number of cells capable of producing replatable colonies. This study attempted to determine the effect of HUCB on SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR), which have a mutation of the human transgene, (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis. We previously developed evidence that the survival of lethally irradiated mice was related to the number of human mononuclear cells administered. In the present study, we decided to investigate the effect of a relatively large dose of human mononuclear cord blood cells on SOD1 mice subjected to a sublethal dose of irradiation preceded by antikiller sera (rabbit anti-asialo). The SOD1 mice show evidence of paralysis at 4 to 5 months. The average expected lifetime of these mice is reported to be 130 days (Jackson Laboratory). In this experiment, there were 23 mice. Two mice died before the onset of paralysis. The remainder were divided into three groups: group I: control group of 4 untreated mice; group II: an experimental group of 6 mice treated with antikiller sera, 800 cGy irradiation plus 5 x 10(6) congenic bone marrow mononuclear cells; group III: another experimental group of 11 mice treated with antikiller sera, 800 cGy irradiation plus 34.2-35.6 x 10(6) HUCB mononuclear cells, previously stored for 17-20 days at 4 degrees C in gas permeable bags. The results were as follows: the average age at death was: (I) 127 days for the untreated control group, (II) 138 days for the group that received 800 cGy of irradiation and congenic bone marrow (BM) and (III) 148 days for the group that received irradiation and HUCB. (P < 0.001 HUCB vs control, p < 0.01 HUCB vs BM). The longest surviving mouse in each group was 131, 153, and 182 days old respectively. In summary, large doses of HUCB mononuclear cells produced considerable delay in the onset of symptoms and death of SOD1 mice. These preliminary results may not only indicate that amyotrophic lateral sclerosis is an autoimmune disease, but may also indicate a possible treatment for a devastating disease and possibly others.

Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor beta mRNA and protein expression.

The present study was carried out to test whether transforming growth factor beta (TGF beta) plays a pathological role in the induction or progression of glomerulonephritis in a murine model of systemic lupus erythematosus (SLE), and whether dietary supplementation with fish oil (FO) can modulate the expression of TGF beta. Weanling female (NZB x NZW) F1 (B/W) mice were divided into three groups. One group was fed an unmanipulated diet (lab. chow; LC) and the other two groups were fed a nutritionally adequate semipurified diet supplemented with 10% CO or FO. Both water and food were provided ad libitum. Proteinuria and serum anti-dsDNA antibody levels were measured to assess disease progression. Mice were killed at 3.5 and 6.5 months of age and renal mRNA levels for TGF beta isoforms, fibronectin-1 (FN-1) and intercellular adhesion molecule-1 (ICAM-1) were studied by Northern blot analysis. TGF beta 1 protein levels were also examined in kidneys by Western blot analysis. Our results indicate that at 3.5 months of age, when urinary protein levels were undetectable and very low levels of anti-dsDNA were detected, no mRNA signal could be detected for TGF beta isoforms, ICAM-1 and FN-1 in either dietary group. However, at 6.5 months, the FO-fed mice, compared to LC and CO, had [1] greatly reduced proteinuria (LC: 2-3+, CO: 2-3+; FO: trace -1+) and serum anti-dsDNA antibodies; [2] improved survival (CO: 100% death (15/15) occurred by 8 months; FO: 50% were alive at 12 months (8/15) and [3] reduced renal TGF beta 1 mRNA and protein levels. TGF beta 2 and beta 3 were not significantly affected by FO diet. Similarly, lower levels of renal FN-1 and ICAM-1 mRNA were observed in FO fed mice. These data indicate that in B/W mice on a FO diet, prolonged survival and amelioration of renal disease may be attributed at least in part to lower levels of TGF beta 1 mRNA and protein in the kidneys.

Diethyldithiocarbamate, a novel immunomodulator, prolongs survival in autoimmune MRL-lpr/lpr mice.

MRL-lpr/lpr mice die at an early age from a spontaneously developing systemic lupus erythematosus-like disease and are characterized by massive lymphadenopathy, hyperproliferation of Lyt-2/L3T4 (null) T cells, decreased responses to mitogens, thymic atrophy, and very high serum autoantibody levels. Diethyldithiocarbamate (DTC), an immunomodulator suggested to enhance T cells, was used to treat 12-week-old female MRL-lpr/lpr mice (25 mg/kg/week). DTC treatment significantly prolonged survival (50% mortality, 43 weeks vs 20 weeks). Increased survival was associated with decreased lymphadenopathy, decreased proliferation of null cells, restoration of impaired mitogen responses, decreased thymic atrophy, and decreased serum levels of anti-DNA and anti-histone antibodies. Studies of cell surface antigen phenotype demonstrated increased expression of Lyt-2 and macrophage surface antigens. No effect on L3T4 single staining cells was observed. These results show that DTC significantly alters the disease course in these mice and suggest that DTC may be a useful treatment for autoimmune disease.

Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes.

MRL/l mice develop progressive, virulent autoimmune disease that has many of the features of systemic lupus erythematosus. Prophylactic treatment of MRL/l mice with syngeneic photoinactivated autoimmune splenocytes improves survival and inhibits the fulminant hyperproliferation of abnormal T cells and the production of high titer anti-DNA antibody invariably found in untreated mice. The proliferation of Thy 1+ splenic T cells was significantly decreased, and prolonged retention of the response to T-cell mitogen was found in treated mice. Treatment with unmodified cells induced a partial inhibition of disease features which did not prolong survival rates. These results suggest that phototherapy potentiates a normal immunoregulatory process which enables suppression of the development of abnormal cell populations in young MRL/l mice with relatively intact immune systems.

Ribavirin treatment in murine autoimmune disease. I. Therapeutic efficacy and effect on the immune response.

NZB/W F1 female mice were treated from 20 weeks of age with ribavirin (a broad spectrum antiviral drug), cyclophosphamide, or saline. Treatment with ribavirin (250 mg/kg twice weekly) prolonged survival from 9.8 to 18.5 months, reduced anti-DNA antibodies, and prevented proteinuria. Ability of ribavirin to prolong survival was dose related when given on a twice weekly schedule. However, daily ribavirin (25 mg/kg/day) was as effective as higher intermittent doses. Optimal ribavirin therapy was equal to cyclophosphamide treatment with regard to prolongation of survival. Ribavirin treatment did not significantly alter the body weight, hematocrit, WBC count, serum immunoglobulins, or Coombs reactivity. No alterations in either cellular or humoral immune responses were noted in NZB/W F1 or BALB/c mice treated for prolonged periods with ribavirin. The impressive therapeutic response to a broad spectrum antiviral agent seen in mice already manifesting immune complex nephritis provides a new therapeutic approach to the treatment of autoimmunity.