Przemyslaw J. Kotyla

Infliximab treatment increases left ventricular ejection fraction in patients with rheumatoid arthritis: assessment of heart function by echocardiography, endothelin 1, interleukin 6, and NT-pro brain natriuretic peptide.

Objective. To study the influence of anti-tumor necrosis factor-α (TNF-α) treatment on echocardiographic measures and concentrations of endothelin 1 (ET-1), interleukin 6 (IL-6), and amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) in a cohort of 23 female patients with rheumatoid arthritis (RA). Methods. We recruited 23 patients (mean age 51.3 ± 1.55 yrs) with RA resistant to treatment with disease-modifying antirheumatic drugs and average disease duration of 7.1 ± 1.0 years who had been selected to start treatment with the anti-TNF-α antagonist infliximab. Transthoracic echocardiographic examinations were performed before the first infusion and repeated after 1 year of treatment. Data for age, sex, RA disease activity by Disease Activity Score (DAS28) and echocardiographic data, NT-proBNP, IL-6, ET-1, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and other routine laboratory data were collected before treatment and after 1 year. Results. Twelve months of treatment with infliximab resulted in reduction of RA activity (i.e., reduction of DAS and acute-phase reactants). There was increased left ventricle ejection fraction, from 58.5% before treatment to 63% after. Treatment with infliximab also resulted in significant reduction of ET-1 (1.26 fmol/ml before treatment vs 0.43 fmol/ml after), IL-6 (58.46 pg/ml vs 3.46 pg/ml), and NT-proBNP (43.06 fmol/ml vs 14.78 fmol/ml). These reductions were observed after just 4 months of treatment and remained significant until the termination of the study. Conclusion. In patients with RA, treatment with infliximab contributed significantly to increase in left ventricular ejection fraction. Improvement of cardiac function was shown by conventional echocardiography; there was reduction of biochemical markers of heart failure.

Etanercept increases adiponectin level in woman with rheumatoid arthritis

Dear Editor, We read with interest the paper by Serelis J. et al. “Effect of anti-TNF treatment on body composition and serum adiponectin levels of women with rheumatoid arthritis” [1]. This study gives a new insight into the influence of TNF alpha and its inhibition on fat tissue metabolism in patients with chronic inflammatory polyarthropaty—rheumatoid arthritis (RA). The paper is of special importance in the light of the current studies that highlight the burden of premature atherosclerosis and its fatal complication among RA patients. The results from the study do not only go far beyond assessment of fat tissue metabolism but may also give the new information on pathogenesis of atherosclerosis in RA patients and the role of anti-TNF alpha treatment among the patients with this disease. To support the observation of the authors, we would like to present a similar study in RA patients treated with another TNF inhibitor—etanercept. In the group of 18 women with RA aged 45.5 (range, 21–55), we determine the plasma adiponectin levels before and after 3 months of treatment with etanercept and compare it with healthy age-matched women. The disease activity (DAS28) and serum adiponectin concentration were measured before treatment and after 3 months. The body composition was measured by DEXA only before treatment in patients and compared to controls. The levels of adiponectin were significantly higher in patients before treatment than in the controls—12.3 μg/ml (range, 5.7–21.1) vs 9.2 μg/ml (range, 3.5–15.3). Our results show also marked elevation of adiponectin levels in the patients after the 3-month treatment of etanercept as compared to the period before the treatment, which is in the agreement with the results of authors. Moreover, we found that increment of adiponectin level was not related to changes of disease activity (p>0.05) that support rather the directed influence of pro-inflammatory cytokine cascades on adiponectin concentration than general inflammation state. Taking into account the fact that various antiTNF alpha agents have a different influence on total TNF alpha levels in the patients treated (in some studies, etanercept does not reduce TNF alpha level [2]), we may also postulate that contradictory results reported in the literature reflect various changes in TNF alpha levels in the course of treatment with various anti-TNF alpha agents. We may also suggest that TNF alpha seems to be a key cytokine that regulates adiponectin level in patients with RA. On the other hand, adiponectin exhibits strong anti-inflammatory activity. Adiponectin paradoxically stimulates TNF alpha release from macrophages; however, this is a transient effect followed by TNF-alpha-induced IL-10 elevation [3]. In RA, elevated adiponectin level may reflect anti-inflammatory properties of this adipocytokine and may satisfactorily explain its elevation in comparison to the healthy subjects [4]. The contradictory results in studies using various anti-TNF alpha agents show rather different levels of TNF alpha suppression, with adiponectin level being higher when TNF alpha reduction is not prominent.

Treatment with infliximab may contribute to the development of peripheral neuropathy among the patients with rheumatoid arthritis

Sir, We have read with the interest the paper of Tektonidu et al. [1] reporting the two cases of peripheral neuropathy in patients with rheumatoid arthritis treated with anti-tumor necrosis factor (anti-TNF) alpha monoclonal antibody infliximab. The paper addresses the problem of potential side effects of infliximab upon peripheral nervous system. In spite of the fact that peripheral nervous system damage is not often reported in patients with rheumatoid arthritis on anti-TNF alpha treatment, the observation is of great clinical values when taking into consideration thousands of patients treated with a such an agent [2]. The role of TNF alpha in pathogenesis of nervous system damage is not fully elucidated. TNF alpha is thought to play a significant role in the pathogenesis of inflammatory demyelinating disease of the central nervous system, which was demonstrated in humans and in animal models [3–5]. If it is true, anti-TNF alpha agents would exert protective activity against demyelination of central and peripheral nervous systems. Many facts however suggest otherwise. The study with lenarcept, a soluble dimeric p55 TNFR–IgG fusion protein in patients with multiple sclerosis (MS), was terminated prematurely because of unexpected exacerbation of the disease. The study was designed to verify a good therapeutic response observed in animal model of MS [6]. These facts are instructive into two ways: Firstly, it is difficult to translate the results from animal models directly to man, and secondly, toxic effect of anti-TNF alpha blockers may be due to imbalance of TNF alpha and TNF alpha receptor levels in the patients. Rapid changes in concentrations of TNF alpha may thus potentially evoke or worsen underlying latent demyelinating process. As the problem of peripheral neuropathy in patients receiving anti-TNF alpha agents was not explained well in prospective studies, we undertook the 1 year observational study. During this period of time, 28 patients (26 women and 2 men) with active, refractory to standard diseasemodifying anti-rheumatic drug (DMARD) therapy were investigated. All patients were treated with infliximab within 1 year (cumulative dose, 36 mg/kg of body mass). Before administration of the first dose of infliximab and after 12 months of therapy, electromyography was carried out in all patients. The examination included measurement of motoneuronal conduction velocity and amplitude in the following nerves: median, peroneal, tibial and ulnar and sensory neuronal velocity, and amplitude in the median, sural, and ulnar nerves. Before the first administration of infliximab, all patients were characterized by normal nervous function. There were no disturbances in conduction velocity and amplitude in examined nerves. After 12 months of the treatment with TNF alpha antagonist, we observed statistically significant changes in following electromyographic parameters: an increased motoneuronal amplitude in median nerve (4.93 vs 8.06 mV) and a decrease in conduction velocity in the nerves of lower limbs; tibial and sural 50.88 vs 47.08 m/s, and 48.73 vs 44.93 m/s respectively [7]. These results were still in normal limits, and the patients continued to be asymptomatic. Data obtained from our study suggests, however, that anti-TNF alpha treatment exerts impact on peripheral nervous system function and, in some predisposing circumstances, may result in overt neuropathy. In the light of the Clin Rheumatol (2007) 26:1595–1596 DOI 10.1007/s10067-007-0657-3

Increased Adiponectin Levels in Women with Rheumatoid Arthritis After Etanercept Treatment

To the Editor: We read with great interest the report by Dr. Nagashima, et al , “Increase in plasma levels of adiponectin after administration of anti-tumor necrosis factor (TNF) agents in patients with rheumatoid arthritis”1. The article is of special importance in regard to accelerated atherosclerosis among patients with connective tissue disease, including rheumatoid arthritis (RA). In the study, the elevation of total and high molecular weight adiponectin was observed in patients with RA treated with both etanercept and infliximab. To support the observations of those authors, we share our … Address reprint requests to Dr. Kotyla. E-mail: pkotyla{at}slam.katowice.pl

Pravastatin, a 3-hydroxy-3-methyl-glutharyl coenzyme A inhibitor does not show pleiotropic effects in patients with systemic lupus erythematosus

Dear Sir, We read with interest the paper of Costenbader et al. [1] regarding the inXuence of statins therapy upon lipid parameters in patients with systemic lupus erythematosus (SLE). The paper addresses the very important issue of lipid lowering therapy among the patients with SLE. Although the SLE alone is nowadays recognized as an independent risk factor for the development of premature atherosclerosis, and statins therapy is recommended as a valuable concomitant therapy, drugs are rarely started in patients with SLE and the other connective tissue diseases [2]. 3-Hydroxy-3-methyl-glutharyl coenzyme A inhibitors (statins) are potent lipid lowering agents that showed their eYcacy in the primary and secondary prevention of cardiac events. Treatment with these agents contributes signiWcantly to the improvement of endothelial function that is believed to be the main anti-atherosclerotic mechanism. And what is of particular interest is that the therapeutic eVect of statins often proceeds lipid lowering activity. For that purpose it is often underlined that the mode of statins action comprises at least two mechanism; lipid lowering properties and activity that is separated from inXuence on lipids metabolism. The second one is often called pleiotropic eVect and includes inXuence of statins on atherosclerosis progression, atherosclerotic plaque formation, cytokine synthesis and release and immune response [3]. To support authors observation we would like to underline that in the very similar preliminary study with simvastatin given in the dose of 20 mg daily for 28 days we observed the similar reduction of LDL and total cholesterol levels. Additionally we observed marked suppression of TNF alpha level and reduction of disease activity measured by the SLEDAI index [4]. Quite recently similar reduction of disease activity and improvement of endothelial function were reported in SLE patients treated with another compound atorvastatin [5]. Statin therapy attracts high attention since the addition of this compound to the patients regimen may result not only with cholesterol reduction but also may exert the beneWcial eVect on disease activity. At the moment, however it is not clear whether all statins exert their pleiotropic eVects in SLE patients. The promising results after administration of simvastatin and atorvastatin lead to the conclusion that statins may decrease the disease activity and this eVect is rather a class of drug eVect. Two dose of a pravastatin, however, failed to aVect disease activity but exerted their cholesterol lowering properties. This may led to the thesis that not all statins are equal in regard to the pleiotropic eVect in systemic lupus erythematosus. If it is true this observation has the very important impact normalization of lipid disturbances in SLE (but perhaps also in the other connective tissue disease) should be achieved with statins that have disease modifying potential (e.g., simvastatin and atorvastatin).

Short course of simvastatin has no effect on markers of endothelial activation in normolipidemic patients with systemic sclerosis

Objective Statins, a class of 3-hydroxy-3 methyl-glutaryl-coenzyme A reductase inhibitors, are widely used for the treatment of atherosclerosis. Less is known about the role of statins in the treatment of vascular complication in systemic sclerosis (SSc). We therefore performed a short-term interventional study with simvastatin in patients with the diffuse variant of SSc and normal lipid profiles. Methods Twenty-five patients with diffuse SSc were enrolled and received simvastatin at a daily dose of 20 mg for 28 days. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble P-, E- and L-selectins were assessed by ELISA prior to treatment and at day 28. Results No statistically significant changes in the levels of adhesion molecules were observed: sICAM-1 1011 vs. 1032 ng/mL, sVCAM-1 1225 vs. 1570 ng/mL, sP-selectin 66.7 vs. 66.0 ng/mL, sE-selectin 276 vs. 253 ng/mL and sL-selectin 887 vs. 927 ng/mL prior to treatment and at day 28, respectively. Conclusions Markers characterizing vascular activation were not affected by short treatment with low-dose simvastatin in SSc patients, indicating that the endothelial-protective effect of statins may be related to treatment duration and dose.

Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients

The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response. JAK kinase blockade offers a unique opportunity to block most of the key cytokines enabling the deep interaction into immune system functioning. Following discovery first Jakinibs were intensively studied in various forms of autoimmune diseases, including rheumatoid arthritis, and finally two Jakinibs tofacitinib and Baricitinib have been approved for the treatment of rheumatoid arthritis. Some clinical data indicated that under special circumstances Jakinibs may be even superior to biologics in the treatment of RA; however this suggestion should be verified in large clinical and observational studies.

The effects of clinical, epidemiological and economic aspects of changes in classification criteria of selected rheumatic diseases

W pracy przedstawiono epidemiologię i aspekty socjoekonomiczne trzech najczęstszych chorób reumatycznych: reumatoidalnego zapalenia stawów (RZS), tocznia rumieniowatego układowego (TRU) oraz twardziny układowej (TU). Częstość występowania chorób reumatycznych w populacji szacuje się na 4–5%. Współczynnik chorobowości dla RZS w Polsce wynosi 0,45% populacji dorosłej i jest zbliżony do współczynnika w Unii Europejskiej, który wynosi 0,49%. Szacuje się, że średnia częstość występowania tocznia rumieniowatego układowego wynosi 40–55/100 tys. osób. Roczna zapadalność na TU wynosi 19–35 przypadków na milion mieszkańców (w zależności od kraju, w którym przeprowadzono badania). W Polsce blisko 18% wszystkich hospitalizacji jest związanych ze schorzeniami reumatycznymi. Wprowadzenie nowych kryteriów klasyfikacyjnych dla RZS, umożliwiających klasyfikowanie wczesnych postaci choroby i szersze ich zastosowanie w praktyce klinicznej, wpłynie zapewne na zmianę oceny częstości występowania tej choroby w populacji. S u m m a r y