Hans-Peter Brezinschek

Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti‐TNF‐α antibody infliximab

Sir, Insulin resistance (IR) is an important component in the pathophysiology of type-II diabetes, hypertension, hyperlipidaemia and finally cardiovascular disease with both genetic and environmental factors contributing to its development. Tumour necrosis factor alpha (TNFα ), a proinflammatory cytokine, may play a prominent role in obesity associated IR as well as β -cell dysfunction [1]. Elevated expression of TNFα in obese insulin resistant rodents and humans was observed along with the indication of elevated plasma TNFα in some studies. TNFα has tissue specific effects on glucose homeostasis and is known to impair insulin receptor signalling experimentally. Furthermore, cytokines that activate (NF)-kB (a nuclear transcription factor closely involved into regulation of cellular inflammatory response), such as TNFα , are thought to be a common denominator for β cell apoptosis in type 1 and type 2 diabetes [2]. In addition, it has been suggested that TNFα is a powerful regulator of adipose tissue [3]. Neutralizing TNFα in obese fa/fa-rats has shown increased insulin sensitivity [4]. So far, in humans two studies failed to demonstrate an effect of acute administration of either a chimeric anti-TNFα antibody [5] or a recombinant soluble human TNFα receptor [6] on insulin sensitivity in obese or type-II diabetic subjects. Prolonged administration of anti–TNFα antibody is used in the treatment of chronic inflammatory diseases such as rheumatic diseases [7] or Crohn’s disease [8]. Here we report observational findings of chronic treatment with infliximab (a chimeric anti-TNFα antibody) on insulin sensitivity as assessed by the homeostasis model assessment (HOMA: fasting plasma glucose (mmol L − 1 ) × fasting serum insulin (mU L − 1 ) divided by 225 [9]), in such patients. Our index case, a 31 years old male with a body-mass-index (BMI) of 31·2 kg m − 2 was diagnosed with type-II diabetes in November 1999 with an HbA 1c of 9·2%. The patient lost weight within 8 months to a BMI of 22·4 kg m − 2 and was treated with insulin (approx. 28 IU per day). As a result stable, good glycaemic control (fasting blood glucose: 6·05 mmol L − 1 ) in the absence of hypoglycaemia could be reached and maintained till 2001. In January 2001 treatment with infliximab (5 mg kg − 1 ) every 8 weeks, was started due to refractory psoriatic arthritis. At this time point he exhibited an unexpectedly severe insulin resistance with a HOMA of 36·98 despite maintenance of normal body weight (In healthy subjects the median HOMA is about 1·4 whereas only 10% of them exhibit a HOMA between 4·5 and 20). After 4–5 months, the patient noticed a decline in insulin requirements and the occurrence of hypoglycaemia. In October 2001, after a severe hypoglycaemic episode, the patient stopped insulin treatment. In July 2002, still on infliximab treatment glucose status was reevaluated. Fasting plasma glucose was 5·17 mmol L − 1 and 2-h after challenge with 75 g glucose 10·56 mmol L − 1 were observed indicating the presence of impaired glucose tolerance instead of insulin requiring diabetes. The respective serum insulin was 32·8 mU L − 1 and 96·4 mU L − 1 , HbA1c was 5·4%. Today the patient is still without insulin therapy. This observation prompted us to evaluate insulin sensitivity retrospectively, using the HOMA, in samples stored from patients treated with infliximab after obtaining informed consent (Fig. 1). Interestingly, with exception of our lean index patient, only the most obese patients (patients 3 and 5), available for analysis (Table 1), showed a pronounced insulin resistance at baseline and improved substantially. In contrast, the other patients (patients 2 and 4) with a lower BMI were insulin sensitive at baseline and did not change during infliximab Division of Rheumatology (B. Yazdani-Biuki, H. P. Brezinschek, J. Hermann, T. Mueller, W. Graninger), Diabetes and Metabolism Clinic (H. Stelzl, T. C. Wascher), and Division of Oncology ( P. Krippl), Department of Internal Medicine, Medical University Graz, Austria.

Immunization of patients with rheumatoid arthritis with antitumor necrosis factor?? therapy and methotrexate

Purpose of reviewThe aim of this study is to highlight the recent findings on the use of methotrexate and/or TNFα-blockers in adult patients with rheumatoid arthritis and their effects on the immune response to various vaccines. Recent findingsRegarding influenza vaccination, methotrexate monotherapy is not associated with a decreased response, whereas the use of etanercept and infliximab in combination with methotrexate may cause lower titers and lower response rates. Concerning pneumococcal vaccination, methotrexate seems to impair responsiveness. The concomitant use of adalimumab and methotrexate is also associated with decreased response, whereas the concomitant use of etanercept or infliximab seems not to have an effect on response rates. As immunological pathways seem to play a major role, T-cell-dependent pneumococcal vaccines are designed to achieve higher response rates and protective titers. SummaryPatients with rheumatic disorders are more likely to develop preventable infectious diseases, which underlines the importance of adequate immunoprotective titers. Several studies have shown that the combination of methotrexate and certain TNFα-blockers are affecting the responsiveness to vaccines. Further findings indicate that the response also depends on what type of vaccine is used.

Relapse of Diabetes After Interruption of Chronic Administration of Anti–Tumor Necrosis Factor-α Antibody Infliximab: A case observation

Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a prominent role in obesity-associated insulin resistance and β-cell dysfunction (1) and, therefore, in the development of diabetes. An association between obesity and elevated TNF-α levels and, furthermore, the substantial decline of TNF-α levels with the simultaneous restoration of insulin sensitivity during weight loss was reported by Dandona et al. (2). Recently, we found evidence that prolonged administration of anti–TNF-α antibody is able to improve insulin sensitivity in …

Cell-type specific response of peripheral blood lymphocytes to methotrexate in the treatment of rheumatoid arthritis

The mode of action of methotrexate in the treatment of rheumatoid arthritis is still questionable. Although in vitro results suggest an immunosuppressive effect of methotrexate, several clinical studies have failed to confirm these effects in patients treated with oral low-dose methotrexate. With respect to the highly variable bioavailability of methotrexate, we investigated the effects of an intravenous administration of 15 mg methotrexate per week on peripheral blood lymphocyte subsets in eight patients with rheumatoid arthritis. Methotrexate after 12 weeks significantly (P<0.01) reduced total peripheral blood lymphocytes and led to a pronounced redistribution of lymphocyte subsets with a preferred reductive effect on B-lymphocytes (P<0.005) and T-lymphocytes (P<0.05). Natural killer cells and killer cell-like T cells, on the other hand, were unaffected by the treatment. Our results suggest a cell-type specific effect of intravenously administered low-dose methotrexate on peripheral blood lymphocytes. This effect, in our opinion, may contribute to the mode of action of methotrexate as an immunosuppressive drug in the treatment of rheumatoid arthritis.

B lymphocyte-typing for prediction of clinical response to rituximab

IntroductionThe prediction of therapeutic response to rituximab in rheumatoid arthritis is desirable. We evaluated whether analysis of B lymphocyte subsets by flow cytometry would be useful to identify non-responders to rituximab ahead of time.MethodsFifty-two patients with active rheumatoid arthritis despite therapy with TNF-inhibitors were included in the national rituximab registry. DAS28 was determined before and 24 weeks after rituximab application. B cell subsets were analyzed by high-sensitive flow cytometry before and 2 weeks after rituximab administration. Complete depletion of B cells was defined as CD19-values below 0.0001 x109 cells/liter.ResultsAt 6 months 19 patients had a good (37%), 23 a moderate (44%) and 10 (19%) had no EULAR-response. The extent of B lymphocyte depletion in peripheral blood did not predict the success of rituximab therapy. Incomplete depletion was found at almost the same frequency in EULAR responders and non-responders. In comparison to healthy controls, non-responders had elevated baseline CD95+ pre-switch B cells, whereas responders had a lower frequency of plasmablasts.ConclusionsThe baseline enumeration of B lymphocyte subsets is still of limited clinical value for the prediction of response to anti-CD20 therapy. However, differences at the level of CD95+ pre switch B cells or plasmablasts were noticed with regard to treatment response. The criterion of complete depletion of peripheral B cells after rituximab administration did not predict the success of this therapy in rheumatoid arthritis.

Serum levels of interleukin‐6 and tumour‐necrosis‐factor‐alpha are not correlated to disease activity in patients with rheumatoid arthritis after treatment with low‐dose methotrexate

Abstract. Cytokines are major mediators of inflammatory responses in rheumatoid arthritis. Some of them have been shown to correlate with the disease activity and thus are proposed to be used for monitoring patients. Therefore the effects of a low‐dose therapy with methotrexate on serum concentrations of interleukin‐6 (IL‐6) and tumour‐necrosis‐factor‐alpha (TNF‐α) were examined in eight patients with seropositive rheumatoid arthritis. Serum levels of IL‐6 and TNF‐α were significantly elevated in patients compared to healthy controls. Before the onset of MTX treatment IL‐6 concentrations were correlated to the c‐reactive protein (P < 0·05) but the correlation was abolished after treatment. For TNF‐α no correlations neither before nor after treatment were observed. Both cytokines remained substantially elevated after MTX treatment despite a clear reduction in disease activity. Thus we suggest that one of the effects of MTX might be the inhibition of some of the actions of IL‐6 and TNF‐α.

Relapse of diabetes after interruption of chronic administration of anti-tumor necrosis factor-alpha antibody infliximab: a case observation.

Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a prominent role in obesity-associated insulin resistance and β-cell dysfunction (1) and, therefore, in the development of diabetes. An association between obesity and elevated TNF-α levels and, furthermore, the substantial decline of TNF-α levels with the simultaneous restoration of insulin sensitivity during weight loss was reported by Dandona et al. (2). Recently, we found evidence that prolonged administration of anti–TNF-α antibody is able to improve insulin sensitivity in …

The Functional Promoter Polymorphism of the Coagulation Factor XII Gene is not Associated With Peripheral Arterial Disease

Coagulation factor XII (FXII) plays a key role in both coagulation and fibrinolysis and has been associated with cardiovascular disease in some studies. Plasma FXIIa levels are strongly determined by a common functional polymorphism in the promoter of the FXII gene (F12-4C>T). To investigate the potential association of this polymorphism with peripheral arterial disease (PAD), we performed a case-control study including 668 patients with PAD and 762 controls participants without cardiovascular disease. F12 genotype frequencies were not significantly different between patients with PAD and control participants. After adjustment for classical risk factors, the odds ratio of carriers of a F12 -4T allele for PAD was 1.06 (95% confidence interval 0.86—1.32). F12 genotypes were associated with a modest increase of the mean-activated partial thromboplastin time but not with PAD stage or severity. We conclude that the functional F124C>T polymorphism is not associated with PAD.

Treatment of rheumatoid arthritis in the 21st century: targeting B-lymphocytes

SummaryRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent inflammation of synovial tissue. Although the initiating event of RA is still unknown, recent research has demonstrated the importance of the increased production of tumor necrosis factor (TNF) alpha in the perpetuation of the inflammatory process of this disease. Targeting this molecule with soluble receptors, i.e., etanercept, or antibodies, like infliximab or adalimumab, a new class of highly effective anti rheumatic drugs has been developed. Unfortunately, not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents. Targeting B-lymphocytes in these patients has opened a new therapeutic window. It has been demonstrated that B-lymphocytes have an important impact in the pathophysiology of RA. These cells produce not only a variety of autoantibodies, but directly stimulate autoaggressive T lymphocytes in the synovium. Furthermore, B-lymphocytes produce a variety of proinflammatory cytokines that also activate monocytes and synoviocytes. Several placebo-controlled clinical trials have demonstrated the efficacy of B-lymphocyte-directed therapy in patients that have responded poorly to conventional disease-modifying drugs or TNF blockade. In addition, several other B-cell specific antigens are potential targets in different autoimmune diseases.ZusammenfassungDie rheumatoide Arthritis (RA) ist eine chronisch entzündliche Erkrankung, die durch Inflammation des Synovialgewebes gekennzeichnet ist. Obwohl das auslösende Ereignis immer noch unbekannt ist, konnte in letzter Zeit gezeigt werden, dass die vermehrte Produktion von Tumor-Nekrose-Faktor (TNF) alpha für die Aufrechterhaltung des entzündlichen Prozesses wichtig ist. Durch lösliche Rezeptoren wie Etanercept oder Antikörper wie Infliximab oder Adalimumab, die an TNF alpha binden und es dadurch neutralisieren, konnte eine neue Klasse von hocheffektiven anti-rheumatischen Medikamenten entwickelt werden. Es gibt aber leider Patienten, die nur ungenügend ansprechen oder bei denen die Wirkung nachlässt. Bei diesen Patienten kann eine gegen B-Lymphozyten gerichtete Therapie neue Möglichkeiten bieten. Es konnte nämlich gezeigt werden, dass diese Zellgruppe eine wichtige Rolle in der RA spielt. B-Lymphozyten produzieren nicht nur eine Vielzahl von Autoantikörpern, sondern stimulieren direkt autoaggressive T-Lymphozyten im Synovium. Weiters sezernieren B-Lymphozyten verschiedene proinflammatorische Zytokine, die auch Monozyten und Synoviozyten aktivieren. In mehreren Plazebo-kontrollierten Studien konnte die Effektivität der gegen B-Lymphozyten gerichteten Therapie bei Patienten mit ungenügendem Ansprechen auf klassische Basistherapeutika oder TNF-Blockade gezeigt werden. Die verschiedensten B-Lymphozyten-Antigene werden derzeit auf ihr therapeutisches Potential untersucht.

Relapse of Diabetes After Interruption of Chronic Administration of Anti–Tumor Necrosis Factor-α Antibody Infliximab

Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, plays a prominent role in obesity-associated insulin resistance and β-cell dysfunction (1) and, therefore, in the development of diabetes. An association between obesity and elevated TNF-α levels and, furthermore, the substantial decline of TNF-α levels with the simultaneous restoration of insulin sensitivity during weight loss was reported by Dandona et al. (2). Recently, we found evidence that prolonged administration of anti–TNF-α antibody is able to improve insulin sensitivity in …