Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in one rheumatological center: two years’ drug survival

The aim of the present study was to determine the drug survival during 2 years’ follow-up in patients (n = 104) with active rheumatoid arthritis (RA) or spondyloarthropathy (SpA) who were treated with infliximab as their first biological anti-rheumatic drug in a single rheumatological center. According to the national guidelines, infliximab was added to the treatment with combinations of traditional disease-modifying anti-rheumatic drugs (DMARD). Patients’ records were analyzed at baseline and after 2 years of follow-up. The response to treatment was determined inadequate if the response was lower than ACR50 (American College of Rheumatology 50) in RA or the reduction of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was lower than 50% or 2 cm in SpA. Drug survival in infliximab-treated patients after 2 years was 40%, and among those who continued with the therapy the prednisolone dose has been reduced by 52%. Discontinuation rate was 60% during 2 years of follow-up, where 7% achieved remission and 22% of the patients were regarded as poor responders. As much as 24% of the patients discontinued due to an adverse event, mainly infections and hypersensitivity reactions. Two drug-related leukopenias were diagnosed. In the present study, infliximab therapy was initiated in RA or SpA patients who had active disease despite ongoing treatment with combinations of DMARDs. The drug survival with infliximab was 40% after 2 years of follow-up. During the 2-year follow-up, 60% discontinued infliximab treatment, mainly due to unsatisfactory or waning efficacy or a severe adverse event.     

Liposomal Targeting of Bcl-2 Antisense Oligonucleotides with Enhanced Stability into Human Myeloma Cell Lines

Cationic liposomes improve the delivery of antisense oligonucleotides (ODNs) into cells. However, there is marked variability in the cellular uptake of ODNs into different cell lines. We used liposomes containing dimethyloctadecylammonium bromide (DDAB) and dioleoylphosphatidylethanolamine (DOPE) to increase the delivery of phosphodiester ODNs into four different myeloma cell lines. The delivery by cationic liposomes increased the delivery of bcl-2 antisense ODNs by a factor of 9 to 45 as compared to plain ODNs. The stability of ODNs was increased with liposomes both in the culture medium and within the cells. Intact liposomal ODNs were detected inside the cells up to 24 hours with gel electrophoresis and phosphor imager analysis. Antisense ODNs had no effect on bcl-2 mRNA levels. Also the proliferation of myeloma cells remained unchanged during the 3-day incubation period. Our study shows that liposomal antisense ODNs targeting bcl-2 of human myeloma cells result in increased stability of ODNs with minimal toxicity. However, further modifications are needed to gain biological effects of antisense ODNs on human myeloma cells.     

Variability gene effects of DNA polymorphisms at the apo B, apo AI/C III and apo E loci on serum lipids: the Cardiovascular Risk in Young Finns Study

We studied the influence of selected genetic markers on the intra-individual long-term variability in serum lipid levels. The study cohort consisted of a sub-sample from a large follow-up study of atherosclerosis precursors in children and young adults. A total of 320 subjects had determinations of apo B XbaI RFLP genotypes, 305 subjects had apo AI/CIII SstI RFLP genotype determinations and 1581 subjects had their apo E phenotypes determined. Complete data on serum lipids were available at 3-year intervals over a 6-year follow-up period. The subjects were healthy and aged 3–18 years at baseline. Intra-individual variability was assessed with a nested analysis of variance procedure. Each of the genetic markers studied here significantly affected intra-individual variability of serum lipid levels. No clear sex influence was observed, although the differences in variability tended to be more significant in males. Apo B XbaI genotypes significantly influenced intra-individual variability of total and LDL-cholesterol levels in both sexes. A marked effect of the XbaI geno-type was also found on triglyceride variability. In males the standardized intra-individual triglyceride variances were 0.71 and 0.34 in genotypes X1X1 and X2X2, respectively (p < 0.001), with a clear gene dosage effect. The apo AI/CIII genotype had an influence only on the variability of total cholesterol and LDL-cholesterol levels and only in males. The apo E phenotypes were associated with intra-individual variability in total and LDL-cholesterol levels but again, only in males. The lowest variability was observed in the phenotype E4/3 where high mean values were also observed. We also examined the effect of combined genetic markers. Up to 7 times greater variability was found in the combination E3/2 + S1S1 compared to combination E4/3 + S1S2 (p < 0.001). In addition, mean levels of, e.g., LDL-cholesterol were 70% greater in the combination of E4/3 +S1S2 compared to E3/2 + S1S1. This implies that subjects with both these genetic markers have high LDL-cholesterol values that also tend to remain constantly elevated. In conclusion, it is evident that many of the presently known DNA polymorphisms of the coronary heart disease candidate gene loci also influence intraindividual variability of serum lipid or lipoprotein levels. These findings can be used to further refine our ability to predict the risk of a cardiovascular event.     

Distinct ligand binding properties of Mac‐2‐binding protein and mouse cyclophilin C‐associated protein*

Human Mac‐2‐binding protein (Mac‐2‐BP) is a secreted glycoprotein that is widely expressed. It binds to the human macrophage‐associated lectin Mac‐2 and has been suggested to have a role in host defence. Mouse cyclophilin C‐associated protein (mCyCAP) is also a secreted glycoprotein that binds with high affinity to cyclophilin C in the absence of the immunosuppresive drug cyclosporin A. The two proteins share a similar domain structure and considerable sequence identity, including a highly conserved scavenger receptor cysteine‐rich domain, and both of them exert their function within the immune system. To elucidate whether these molecules are also functional homologues, we compared their ligand binding properties using cell lines which express Mac‐2‐BP or mCyCAP as well as transfected cell lines stably expressing mCyCAP or a mutant version lacking the scavenger domain. These experiments show that Mac‐2‐BP is unable to bind to either human or mouse cyclophilin C and thatmCyCAP cannot bind to Mac‐2. The scavenger domain is not required for the interaction between mCyCAP and cyclophilin C. We conclude that these proteins may be part of a larger family of proteins of immunological importance in which closer functional homologues might exists.