Management of oral complications of disease-modifying drugs in rheumatoid arthritis

Stomatitis is a troublesome adverse effect of disease-modifying anti- rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA) patients. This review presents data to examine the incidence, clinical features and consequences of DMARD-related stomatitis, and suggests an algorithm for its clinical management. The specific objectives of the two studies presented here were to determine the incidence of DMARD-related stomatitis and its effect on DMARD continuation, and secondly to identify the clinical and laboratory risk factors. We investigated two cohorts of patients: (i) a retrospective survey of data collected from drug monitoring clinics run for patients on DMARDs from 1987 to 1994 involving 1539 patients and 2394 drug exposures; (ii) a prospective study of 25 consecutive RA patients presenting with DMARD-related stomatitis compared to 29 RA controls with no history of DMARD stomatitis. The retrospective survey showed that 2% of DMARD patients stopped therapy because of stomatitis, but 55% of these were able to resume the same therapy. In the case control study. 24% of patients discontinued temporarily and 8% permanently. Cases of DMARD-related stomatitis differed from controls in that they had a higher incidence of previous mouth ulcers (40% vs 14%), they smoked less (8% vs 31%) and Schirmer's test was more often abnormal (44% vs 21%). There were no differences in RA severity, disease activity or oral hygiene. Haematinic deficiencies were equally common in cases and controls: 30% for iron, 8% for vitamin B12 and 24% for folic acid. Herpes simplex virus was involved in a minority (8%) of cases. In conclusion, the occurrence of stomatitis in RA patients on DMARD should not lead to cessation of drug therapy, but to a careful evaluation so that patients may be maintained on effective treatment.      

Effect of age on cytokine response in an experimental model of osteomyelitis

To study the effect of age on cytokine response in an experimental model of osteomyelitis. Forty adult male Wistar rats received a stainless steel needle, intramedullarly in the left tibia. Young rats (3 months old) and old rats (22 months old) were allotted in: Group A: Sterile implant. Group B: Sterile implant + slime producing S. aureus. Rats were sacrificed 9 weeks after surgery. Determinations: Cytokines (ELISA) in blood and in tibia extract and the number of bacteria in tibia and implant. The Wilcoxon, Mann–Whitney U tests were used (P ≤ 0.01 significant). Infection was detected in every old rat receiving S. aureus, and in 7 of 10 young rats. In blood: prior to surgery, old rats presented higher IL-2 and lower IL-4 levels. Surgery alone did not induce significant changes in old rats; surgery + S. aureus induced significant increases of IL-2 and IL-10 in young rats, and of IL-6 in old rats. Tibia analysis S. aureus group showed increased levels of: IL-10 in young rats, and IL-1β in old rats. In experimentally induced osteomyelitis, significant differences were observed in cytokine response with regard to age.     

Amylin exerts osteogenic actions with different efficacy depending on the diabetic status

Amylin displays osteogenic features, but its role in diabetic osteopenia is unclear. We examined the possible osteogenic action of amylin infusion for 3 days into fructose-induced insulin-resistant (IR) and streptozotocin-induced type 2 diabetic (T2D) and normal (N) rats. Amylin failed to affect glycaemia or parathyroid hormone levels in any group, but reduced hyperinsulinemia in IR rats. In N rats, amylin increased bone formation rate and reduced osteoclast surface and erosive surface in the femoral metaphysis, and increased osteoprotegerin (OPG)/receptor activator of NFκB ligand (RANKL) mRNA ratio in the tibia. In T2D rats, amylin normalized trabecular structure parameters and increased osteoblast number and osteocalcin (OC) expression in long bones. In contrast, in IR rats, no apparent osteogenic effect of amylin in the femur was observed, although both OC and OPG/RANKL ratio were increased in the tibia. Our findings demonstrate a different osteogenic efficacy of amylin in two diabetic settings.     

Protection against liver injury by PGE1 or anti‐TNF‐α is associated with a reduction of TNF‐R1 expression in hepatocytes

Background: Tumour necrosis factor‐α (TNF‐α) has been shown to exacerbate or protect against liver injury in different experimental models. In a previous study, we observed that enhancement of TNF‐α expression in hepatocytes by prostaglandin E ₁ (PGE ₁ ) pre‐administration induced iNOS expression and cytoprotection against experimental liver injury in rats. Nevertheless, the reduction of TNF‐α bioactivity by anti‐TNF‐α antibodies also reduced liver injury by D‐GalN. The purpose of the present study was to evaluate whether protection by PGE ₁ or anti‐TNF‐α was related to a common effect on the membrane‐bound TNF‐α receptor expression. Methods: Liver injury was induced in male Wistar rats by intraperitoneal injection of D‐galactosamine (D‐GalN) (1?g/kg). PGE ₁ or anti‐TNF‐α was administered at 30 or 60?min before D‐GalN, respectively. Liver injury was evaluated by alanine aminotransferase (ALT) activity in serum and histological examination in liver sections. TNF‐αwas determined by ELISA in serum. The expression of TNF‐α receptor type 1 (TNF‐R1) and TNF‐α receptor type 2 (TNF‐R2) in hepatocytes was assessed by immunohistochemistry and immunoprecipitation?+?Western‐blot analysis. Results: PGE ₁ or anti‐TNF‐α reduced liver injury induced by D‐GalN. Although PGE ₁ enhanced and anti‐TNF‐α reduced TNF‐α concentration in serum, both protective treatments reduced the expression of TNF‐R1 in hepatocytes. TNF‐R2 was not detected in our experimental conditions. Conclusions: Our study showed that reduction of liver injury by PGE ₁ or anti‐TNF‐α antibodies was related to a reduction of TNF‐R1 expression in hepatocytes.     

Impact of experimental haemodilution on platelet function,thrombin generation and clot firmness: effects of different coagulation factor concentrates

Background

Haemodilution during resuscitation after massive haemorrhage may worsen the coagulopathy and perpetuate bleeding.

Materials and methods

Blood samples from healthy donors were diluted (30 and-60%) using crystalloids (saline, Ringer’s lactate, Plasmalyte^TM) or colloids (6% hydroxyethylstarch [HES130/0.4], 5% human albumin, and gelatin). The effects of haemodilution on platelet adhesion (Impact R), thrombin generation (TG), and thromboelastometry (TEM) parameters were analysed as were the effects of fibrinogen, prothrombin complex concentrates (PCC), activated recombinant factor VII (FVIIa), and cryoprecipates on haemodilution.

Results

Platelet interactions was already significantly reduced at 30% haemodilution. Platelet reactivity was not improved by addition of any of the concentrates tested. A decrease in TG and marked alterations of TEM parameters were noted at 60% haemodilution. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCC whereas rFVIIa only caused a mild acceleration of TG initiation. Fibrinogen restored the alterations of TEM parameters caused by haemodilution including those caused by HES 130/0.4. Cryoprecipitates significantly improved the alterations caused by haemodilution on TG and TEM parameters; the effects on TG disappeared after ultracentrifugation of the cryoprecipitates.

Discussion

The haemostatic alterations caused by haemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 had the most deleterious effect on haemostasis parameters. Coagulation factor concentrates did not improve platelet interactions in the Impact R, but did have favourable effects on coagulation parameters measured by TG and TEM. Fibrinogen notably improved TEM parameters without increasing thrombin generation, suggesting that this concentrate may help to preserve blood clotting abilities during haemodilution without enhancing the prothrombotic risk.     

Safety and efficacy of liraglutide in patients with type 2 diabetes with elevated liver enzymes: individual patient data meta-analysis of the LEAD programme

BackgroundFatty liver disease has reached epidemic proportions in type 2 diabetes. Glucagon-like peptide-1 (GLP-1) analogues are licensed for treatment of type 2 diabetes, yet little data exist on efficacy and safety in liver injury. We aimed to assess the safety and efficacy of 26 weeks' liraglutide on liver function compared with an active placebo.MethodsIndividual patient data meta-analysis was done with patient level data combined from six 26-week, phase 3, double-blind randomised controlled trials on type 2 diabetes, which comprise the Liraglutide Effect and Action in Diabetes (LEAD) programme. In addition, the LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis.FindingsOf 4442 patients analysed, 2241 (50·8%) had an abnormal alanine aminotransferase (ALT) at baseline (mean 33·8 IU/L [SD 14·9] in female participants; 47·3 [18·3] in male participants). Liraglutide 1·8 mg reduced ALT in these patients compared with placebo (?8·20 vs ?5·01 IU/L, p=0·003), and was dose dependent (no significant differences vs placebo with liraglutide 0·6 or 1·2 mg). This effect was lost after adjustment for liraglutide's effect on reduction of weight (corrected mean ALT difference vs placebo ?1·41 IU/L, p=0·21) and HbA1c (corrected mean ALT difference vs placebo 0·57 IU/L, p=0·63). Adverse effects with 1·8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In the LEAD-2 sub-study, liraglutide 1·8 mg (26 weeks) improved hepatic steatosis (CT-measured liver:spleen attenuation ratio) from baseline (0·10, p=0·001) and showed a trend towards improvement compared with placebo (0.10 vs 0·00, p=0·07).Interpretation26 weeks of liraglutide (1·8 mg) is safe, well tolerated, and improves liver enzymes compared with placebo in patients with type 2 diabetes.FundingWellcome Trust.     

Therapeutic efficacy of platelet components treated with amotosalen and ultraviolet A pathogen inactivation method: results of a meta‐analysis of randomized controlled trials

Background and Objectives There are conflicting data regarding the therapeutic efficacy of platelets inactivated using amotosalen and ultraviolet A light. We have performed a meta‐analysis to summarize the results of different randomized controlled trials (RCT). Materials and Methods Five RCTs reported through March 2011 met the criteria for meta‐analysis. Weighted mean difference (WMD) in corrected count increment (CCI) at 1 h, CCI‐24 h, and transfusion interval (days) and summary odds ratio (OR) of bleeding in inactivated platelet (I‐P) group vs. noninactivated platelet (C‐P) group were calculated across studies. Results Randomized controlled trials were statistically homogeneous when we analysed CCI‐24 h, and the transfusion of C‐P was associated with a higher CCI‐24 h when compared with the transfusion of I‐P (WMD, 3 × 10³; 95% CI, 2·32 × 10³–3·69 × 10³; P < 0·00001). RCTs were statistically heterogeneous when we analysed CCI‐1 h, transfusion interval and OR of bleeding. Regarding the OR of bleeding in the I‐P and C‐P groups, it varied by as much as a multiple of four among the trials, from 0·66 to 2·66. When we combined double‐blinded and high methodologic quality score RCTs, the use of I‐P was not statistically associated with an increase in the OR of bleeding when compared with the use of C‐P (OR, 0·97; 95% CI, 0·75–1·27; P = 0·84). Conclusion Although the transfusion of I‐P was associated with lower CCI‐24 h when compared with the transfusion of C‐P, this was not associated with differences in the OR of bleeding between I‐P and C‐P.     

Subtypes of Epstein-Barr virus (EBV) in Hodgkin's disease: association between B-type EBV and immunocompromise [see comments]

Epstein-Barr virus (EBV) has been associated with Hodgkin's disease (HD) in up to 50% of cases, but the subtype of EBV involved has only recently been studied. In this report, biopsy samples from 30 patients with HD were assessed for EBV sequences using both the polymerase chain reaction (PCR) and in situ hybridization (ISH). EBV sequences were localized to the malignant Reed-Sternberg cells and their mononuclear variants (Hodgkin's cells) in 9 of the 30 cases, with 7 demonstrating A- type and 2 B-type EBV sequences. Both of the patients with B-type EBV- associated HD had features to suggest pre-existing immune compromise: one was infected with human immunodeficiency virus (HIV) and had severe CD4+ T-lymphocyte depletion; the other was a debilitated elderly patient with dementia. A previous study suggested that A-type EBV alone is associated with HD and the finding of predominantly A-type EBV in the present series is in keeping with this report. The presence of B- type EBV in the HD of patients with pre-existing immunodeficiency, taken together with the recent report that B-type EBV occurs in HIV- associated non-Hodgkin's lymphoma, suggests that B-type EBV may be an important human pathogen in immunocompromised patients.     

Cooperative effects of interleukin-3 (IL-3), IL-5, and granulocyte- macrophage colony-stimulating factor: a new myeloid cell line inducible to eosinophils

The cytokines interleukin-3 (IL-3); IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are known to contribute to the proliferation and differentiation of eosinophil progenitors. Recently, it was determined that the cellular receptors for these three cytokines share a common beta-chain while having unique alpha-chains. Thus, there is considerable interest in how these cytokines and their receptors interact in promoting production of eosinophils. We have established a cell line (AML14) from a patient with acute myelogenous leukemia that will consistently exhibit eosinophilic differentiation in suspension in response to IL-3, IL-5, and GM-CSF. Proliferation with only modest differentiative effects was observed in response to a single cytokine. Combinations of two cytokines gave variable results, with GM-CSF + IL-3 and IL-3 + IL-5 causing more proliferation than a single cytokine but little more differentiation. The combination of GM-CSF + IL-5 caused marked enhancement of eosinophilic differentiation with only modest augmentation of proliferation. The combination of all three cytokines was most effective in stimulating both proliferation and eosinophilic differentiation (up to 70% of cells) of AML14 cells. Specific binding of GM-CSF and IL-5 to AML14 cells can be conveniently studied by flow cytometric methods, and cross-competition of these two cytokines for their respective receptors was demonstrated. IL-3 was shown to partially compete for IL-5 binding on AML14 cells. Although specific IL- 3 binding could not be demonstrated by flow cytometry, mRNA for the alpha-chains of the IL-3, IL-5, and GM-CSF receptors and the beta-chain common to all three receptors was detected in AML14 cells. The AML14 cell line may be a useful model for the study of cooperative interactions of IL-3, IL-5, GM-CSF, and their respective receptors in the promotion of eosinophil progenitor growth and differentiation.     

A point mutation in the GYPC gene results in the expression of the blood group Ana antigen on glycophorin D but not on glycophorin C: further evidence that glycophorin D is a product of the GYPC gene

Glycophorin C (GPC) and glycophorin D (GPD) are homologous sialoglycoproteins in the human red blood cell membrane. Both are thought to be encoded by the GPC gene (GYPC). We report that the rare blood group antigen, Ana, is expressed on GPD but not on GPC. cDNA was synthesized from total RNA obtained from two unrelated, heterozygous Ana+ blood donors and analyzed by the polymerase chain reaction using primers that spanned sequences encoded by the GYPC gene. The expected 412-bp fragment was generated, and sequencing of the amplified product showed a G-->T substitution at nucleotide 67 of the coding sequence, resulting in the substitution of alanine by serine at amino acid residue 23 of GPC and, presumably, residue 2 of GPD. To explain the expression of Ana on GPD but not on GPC, we postulate that the conformation of the amino acid residues at the N-terminal region of GPD determines the antigenic expression as this conformation would be different from that of the same sequence of amino acids occurring within GPC. Other possible reasons for antigen expression on a shorter protein product but not on the full-length protein product of the same gene are discussed. We extrapolate this reasoning to account for the expression of the common GE2 blood group antigen on GPD but not on GPC.