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1.  Treatment continuation in patients receiving biological agents or conventional DMARD therapy 
Annals of the Rheumatic Diseases  2005;64(9):1274-1279.
Objective: To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure.
Methods: Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases.
Results: Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate.
Conclusions: Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.
doi:10.1136/ard.2004.031476
PMCID: PMC1755655  PMID: 15708884
2.  Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2004;64(4):575-581.
Objectives: To analyse the association of interleukin 10 (IL10) promoter polymorphisms, which have been shown to be related to IL10 secretion capacity, with the response to long term treatment with etanercept in patients with rheumatoid arthritis (RA).
Methods: Fifty patients with active RA were treated for up to 4 years (median 39 months, range 3–52) with stable doses of etanercept as monotherapy. Treatment response was assessed as defined by the EULAR criteria in an intention to treat analysis, with the last observation carried forward. IL10 promoter microsatellite polymorphisms IL10.R and IL10.G were genotyped by fragment length analysis in patients and 189 healthy controls matched for ethnicity, age, and sex. Haplotypes were reconstructed using a method based on bayesian, coalescent theory with the PHASE software.
Results: IL10 microsatellite polymorphisms were not associated with susceptibility to RA. When patients with good treatment response (n = 25) were compared with patients with moderate (n = 17) or no response (n = 8), a significantly different distribution of the prevailing alleles R2, R3 and G9, G13, respectively, became evident. Good treatment response was associated with carriage of the R3 allele or R3-G9 haplotype, whereas the allele G13 and the haplotype R2-G13 predominated in patients with moderate or no response.
Conclusion: Genotyping of the IL10 promoter microsatellites may be useful in predicting the clinical response to etanercept in patients with RA. The high prevalence of the presumptive IL10 low producer allele R3 in patients with a favourable response suggests that IL10 promotes disease activity in RA under the specific condition of tumour necrosis factor antagonism.
doi:10.1136/ard.2004.027672
PMCID: PMC1755447  PMID: 15345504
4.  Soluble tumour necrosis factor receptor treatment does not affect raised transforming growth factor ß levels in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2002;61(3):254-256.
Methods: Plasma levels of TGFß1 and TGFß2 were determined in 26 patients with RA during six months of etanercept treatment and compared with disease activity and laboratory parameters, including matrix metalloproteinase-3 (MMP-3) and interleukin 6 (IL6).
Results: Before treatment all patients had raised TGFß1, IL6, and MMP-3 levels. In the course of treatment IL6 and MMP-3 levels decreased significantly, accompanied by a drop in serological markers (C reactive protein and erythrocyte sedimentation rate) and clinical disease activity (visual analogue scale and Thompson joint score). By contrast, high levels of latent TGFß1 were present in all specimens over the entire six months. TGFß2 levels did not change during treatment.
Conclusions: Etanercept treatment induces subtle changes in the cytokine network. Although the proinflammatory cytokine IL6 is down regulated, the persistence of high TGFß plasma levels indicates the existence of as yet unknown mechanisms for TGFß overexpression in RA. This may predispose to severe infections and can cause an altered tumour defence.
doi:10.1136/ard.61.3.254
PMCID: PMC1754023  PMID: 11830433
7.  Bone substitutes as carriers for transforming growth factor-β1 (TGF-β1) 
International Orthopaedics  2002;26(4):203-206.
We studied the suitability of three different hydroxyapatite materials (Endobone, Bio-Oss and Algipore) as carriers for the bone growth promoting factor TGF-β1.The hydroxyapatite materials either were incubated for 24 h or directly loaded with hrTGF-β1 (Diagnostic Products Corporation, DPC) at a concentration of 10 ng hrTGF-β1/mg. For the release experiment the hydroxyapatite materials covered with hrTGF-β1 were either suspended in pure phosphate buffered saline (PBS) or human serum albumin (HSA). The concentration of hrTGF-β1 was measured every 6 h the first day and then daily at the 2nd, 7th, 14th and 28th day. With Bio-Oss and Endobone the release of growth factor in HSA showed a two-phase kinetics. TGF-β1 reached a maximum concentration within the first 24 h and decreased almost linearly until day 28. With Algipore the concentration of growth factor reached a maximum after 12 h and showed a rapid decline until day 2. From day 2 the TGF-β1 concentrations remained low. Significantly, more TGF-β1 was released into HSA than into PBS. Our study suggests that the hydroxyapatite materials are suitable as TGF-β1 carriers.
doi:10.1007/s00264-002-0353-5
PMCID: PMC3620956  PMID: 12185519
8.  Comparison of the antibody responses to the 77 Klebsiella capsular types in ankylosing spondylitis and various rheumatic diseases. 
Infection and Immunity  1994;62(11):4838-4843.
The production of antibodies to Klebsiella capsular polysaccharides was measured in sera from either HLA-B27-positive (HLA-B27+) or HLA-B27-negative (HLA-B27-) patients with classical ankylosing spondylitis (n = 54). These sera were compared with sera from patients with various rheumatic diseases (n = 82) and HLA-B27+ or HLA-B27- healthy individuals (n = 85). All sera were analyzed by means of an enzyme-linked immunosorbent assay specific to each of the 77 Klebsiella serotypes. The sera from HLA-B27+ patients with ankylosing spondylitis showed a significantly higher antibody frequency to the capsular types K26, K36, and K50 than the sera from HLA-B27- ankylosing spondylitis patients, patients with psoriatic arthritis, systemic lupus erythematosus, rheumatoid arthritis, or reactive arthritis after Yersinia enterocolitica infection, or healthy controls (P < 0.02). The antibodies were of the immunoglobulin G type. No significant antibody response to the other 74 Klebsiella serotypes, noncapsulated mutants of K26, K36, and K50, or preparations of Citrobacter, Serratia, Hafnia, or Morganella spp. or Streptococcus pneumoniae could be detected. The results might suggest a specific association between these capsular types and HLA-B27+ ankylosing spondylitis and might imply their predominance in this disease.
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PMCID: PMC303195  PMID: 7927763
9.  Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. 
Journal of Clinical Investigation  1991;87(3):1010-1016.
We reported previously that PBMC from HIV+ patients spontaneously release increased levels of TGF beta 1, contributing to defects in cellular immune responses. This study defines the implications of TGF beta overexpression for humoral immunity in HIV infection. We found that upon Staphylococcus aureus Cowan I (SAC) stimulation of cells from HIV+ donors, B-lymphocyte proliferative responses were decreased. This deficiency correlated closely (r = 0.7, P less than 0.001) with increased TGF beta secretion by PBMC from HIV-infected donors. Conditioned medium from HIV+ PBMC and purified TGF beta 1 had similar inhibitory effects on SAC- or EBV-induced B-cell proliferation, and B cells from HIV-infected donors were as sensitive to inhibition by TGF beta as cells from normal donors. Antibodies to TGF beta 1 neutralized the inhibitory effect of HIV+ culture supernatants on normal B cells and increased low proliferative responses by HIV+ cells. Using PWM as stimulus for B cell differentiation, it was shown that activated TGF beta from HIV+ PBMC is able to significantly reduce the induction of immunoglobulins and this effect was also abrogated by anti-TGF beta. These studies support the concept that in HIV infection, TGF beta is a potent suppressor, not only of the cellular, but of the humoral immune responses as well.
PMCID: PMC329894  PMID: 1999481

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