Rheumatoid Arthritis: Wolbink G

Aarden L, Ruuls SR, Wolbink G. · Sanquin Research at Central Laboratory for Blood Transfusion and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Plesmanlaan 125, Amsterdam, The Netherlands. · Curr Opin Immunol. · Pubmed #18619538 No free full text.

Abstract: To date, millions of people have been treated with therapeutic monoclonal antibodies (TmAbs) for various indications. It is becoming increasingly clear that TmAbs can be immunogenic, which may reduce efficacy or induce adverse effects. Over the years, the importance of antibody formation has been questioned and sometimes minimized, as few antibody responses to TmAbs (HACA or HAHA) were reported. However, the methods to detect and quantify such antibodies used in the past have been problematic. Only recently, methods have been developed that have adequate sensitivity and are not seriously disturbed by false-positive reactions caused by rheumatoid factors, natural antibodies to Fab or F(ab')2 fragments, or Fc interactions of IgG4. The large number of treated patients, in combination with these new assays, presents a unique opportunity to study the anti-antibody immune response in man, possibly allowing us to manipulate immunogenicity in the future.

Vis M, Bos WH, Wolbink G, Voskuyl AE, Twisk JW, Van de Stadt R, Hamann D, Dijkmans BA, Lems WF. · VU University Medical Center, Sanquin Research, and Jan van Breemen Institute, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #18322974 No free full text.

Abstract: OBJECTIVE: To investigate the effect of treatment with infliximab on serum levels of rheumatoid factor (IgM-RF), antibodies against cyclic citrullinated peptide (anti-CCP), and antibodies against deiminated human fibrinogen, a specific citrullinated peptide (ACF), and their association with disease activity and disease duration in patients with rheumatoid arthritis (RA). METHODS: The study sample included 62 consecutive patients who were treated with infliximab for at least one year. IgM-RF, anti-CCP, and ACF were measured at 0, 14, 30, and 46 weeks. RESULTS: Patients had a mean age of 54 years and median disease duration of 10 years and were predominantly female (81%). At baseline 63%, 77%, and 82% of patients were positive for IgM-RF, anti-CCP, and ACF, respectively. In terms of percentages, the levels of IgM-RF were reduced by 64% at 46 weeks, while anti-CCP and ACF levels were reduced by roughly 25%. The decrease in serum levels of these autoantibodies was not associated with the decrease in disease activity. The change in ACF was significantly related to disease duration, while the changes in IgM-RF or anti-CCP were not. CONCLUSION: In a cohort of patients with RA who responded to infliximab therapy, all autoantibodies decreased significantly, but IgM-RF showed a larger decrease than anti-CCP or ACF. These changes in levels of autoantibodies are not directly related to the change in disease activity. Early in the disease, ACF levels were best influenced by treatment with infliximab.

van Schaardenburg D, Wolbink G, Nurmohamed MT, Dijkmans BA. · Department of Rheumatology, Jan van Breemen Institute, VU University Medical Center, Amsterdam, The Netherlands. · Nat Clin Pract Rheumatol. · Pubmed #17437031 No free full text.

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van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, Wolbink G, Dijkmans BA, Aarden LA. · Department of Rheumatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16793840 No free full text.

Abstract: BACKGROUND: Many patients with rheumatoid arthritis are currently successfully treated with infliximab (anti-tumour necrosis factor); however, about 30% of the patients do not respond to infliximab. One of the postulated hypotheses of not responding is the fast clearance of infliximab due to the development of infliximab-anti-infliximab complexes. OBJECTIVE: To investigate the in vivo mechanism of not responding and the role of human anti-chimeric antibodies (HACAs) by using radiolabelled infliximab. METHODS: Two responding and two non-responding patients with rheumatoid arthritis, infused with radiolabelled infliximab, were investigated by both imaging and serum analysis. RESULTS: Images showed predominant presence of infliximab in blood up to 24 h, with a trend of faster blood clearance and of higher liver/spleen uptake in a non-responding patient. Clinically inflamed joints showed uptake of the drug. The HACA level in the non-responders was high (1641 and 1008 U/ml), but low or not detectable in responders. Sucrose gradients of serum showed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in a non-responder who developed a serious infusion reaction. CONCLUSION: Formation of infliximab-anti-infliximab complexes were found in non-responders due to the presence of large amounts of HACA. This finding, supported by both imaging and serum analysis data, may explain failure of infliximab treatment.

Vis M, Nurmohamed MT, Wolbink G, Voskuyl AE, de Koning M, van de Stadt R, Twisk JW, Dijkmans BA, Lems WF. · Department of Rheumatology, VU University Medical Centre, Jan van Breemen Institute, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #15693084 No free full text.

Abstract: OBJECTIVE: Cardiovascular morbidity and mortality appear to be enhanced in rheumatoid arthritis (RA), which might be due to an increased prevalence of cardiovascular risk factors such as dyslipidemia. It was recently shown that effective disease modifying antirheumatic drug treatment had a favorable influence on the lipid profile in patients with active RA. As infliximab markedly reduces disease activity in RA, we investigated the effects of infliximab on the lipid profile. METHODS: Infliximab was administered at baseline and at 2 and 6 weeks in patients with active RA. Total cholesterol and HDL-cholesterol concentrations were measured and their ratio, the atherogenic index (an important cardiovascular risk factor indicator), was assessed. RESULTS: Sixty-nine patients were enrolled. The Disease Activity Index score (DAS-28) was 5.9 (SD +/- 1.4) at baseline and decreased to 4.6 (+/- 1.4) after 2 weeks and further to 4.1 (+/- 1.5) after 6 weeks. Total cholesterol level was 5.2 mmol/l at baseline and increased to 5.7 mmol/l (p < 0.001) at 2 weeks, and was 5.6 mmol/l (p < 0.001 vs baseline) at Week 6. For HDL-cholesterol these values were 1.5, 1.6 (p < 0.001), and 1.6 mmol/l (p < 0.001 vs baseline), respectively. Changes in disease activity were significantly inversely associated with changes in total cholesterol and HDL-cholesterol levels. The atherogenic index, however, remained constant. Corticosteroid use at baseline was associated with significantly higher total cholesterol and HDL-cholesterol levels and a lower (more favorable) atherogenic index at baseline. CONCLUSION: Infliximab treatment was associated with a significant increase of both total cholesterol and HDL-cholesterol levels, which correlated with decreasing disease activity. However, this was not accompanied by a favorable effect on the atherogenic index. The favorable effect of infliximab on cardiovascular comorbidity might not be mediated by effects on lipid metabolism, but longterm investigations are needed to confirm this.