Eugene J. Kucharz

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.

The Relapsing Polychondritis Disease Activity Index: Development of a disease activity score for relapsing polychondritis

OBJECTIVE The rarity of relapsing polychondritis (RP) has hindered the development of standardized tools for clinical assessment. Here, we describe the development of a preliminary score for disease assessing activity in RP, the Relapsing Polychondritis Disease Activity Index (RPDAI). METHODS Twenty-seven RP experts participated in an international collaboration. Selection and definition of items for disease activity were established by consensus during a 4-round internet-based Delphi survey. Twenty-six experts assessed the Physicians Global Assessment (PGA) of disease activity on 43 test cases on a 0-100 scale, yielding a total of 1118 PGA ratings. The weight of each item was estimated by multivariate regression models with generalized estimating equation, using PGA as the dependent variable. RESULTS Experts decided in consensus that the RPDAI should consider the 28-day period before each RPDAI assessment. Inter-rater reliability assessed by the intra-class correlation coefficient for the 1118 PGA ratings was 0.51 (CI95%: 0.41-0.64). The final RPDAI score comprised 27 items with individual weights ranging from 1 to 24 and a maximum theoretical RPDAI score of 265. Correlation between the RPDAI scores calculated based on the weights derived from the final multivariate model, and the 1118 PGA ratings was good (r=0.56, p<0.0001). CONCLUSION We have developed the first consensus scoring system to measure disease activity in relapsing polychondritis (see www.RPDAI.org for online scoring). This tool will be valuable for improving the care of patients with this rare disease.

Influence of short-time application of a low sodium diet on blood pressure in patients with hyperthyroidism or hypothyroidism during therapy.

Hyperthyroidism or hypothyroidism are commonly associated with altered blood pressure (BP). Restriction of sodium in the diet produces a decrease in BP in some individuals. It is also well known that hormones other than thyroid affect BP. The present study was designed to evaluate the influence of a low sodium diet on BP in patients with hyperthyroidism or hypothyroidism during therapy. The occurrence of salt-sensitive or salt-nonsensitive BP was compared with hormonal levels (plasma renin activity, aldosterone, atrial natriuretic peptide, and arginine vasopressin). Patients with hyperthyroidism (75 subjects) were investigated before the initiation of treatment, 2 weeks after the treatment, and after the attainment of euthyroid state. Patients with hypothyroidism (31 subjects) were studied before the treatment and in the euthyroid state. Control values were obtained from 37 healthy individuals. Blood pressure, changes of plasma volume, serum aldosterone, atrial natriuretic peptide, vasopressin levels, and plasma renin activity were measured in all investigated subjects after application of a normal sodium diet and after 3 days on a low sodium diet. Elevated systolic BP was found in patients with hyperthyroidism and hypothyroidism. Mean arterial BP was higher only in the untreated hypothyroid patients. The high incidence of salt-sensitive BP was found only in untreated hypothyroid patients. Also in hypothyroid patients the application of a low sodium diet led to a lower increase in plasma renin activity in subjects with salt-sensitive BP than in individuals with salt-resistant BP. Therefore, different mechanisms are responsible for BP elevation in patients with hyperthyroidism or hypothyroidism.

Dynamics of serum interleukin-6 level in patients with acute myocardial infarction

Background: Interleukin-6 (IL-6) is a key cytokine in the initiation of the acute-phase reaction that accompanies myocardial infarction. The study was designed to evaluate changes in serum IL-6 in patients with myocardial infarction and to compare IL-6 alterations with serum creatine kinase (CK) activity. Methods: Serum IL-6 level and CK activity were measured in 19 males with acute myocardial infarction. Blood was taken on the 1st, 3rd, 5th, 7th and 21st days of the disease. Control values were obtained from 30 age-matched healthy males. IL-6 was determined according to the ELISA method and CK was measured with a routine procedure. Results: Serum IL-6 was found to increase on the 1st and 3rd days of the disease, followed by some decline on days 5-21. However, the last values measured were still higher than those in the controls. Patients with transmural myocardial infarction had higher IL-6 levels than those with non-Q myocardial infarction. There was no difference in serum IL-6 in patients with myocardial infarction of the inferior cardiac wall and of the anterior cardiac wall. A correlation was found between IL-6 level and CK activity in the patients, especially on the 1st and 3rd days of the disease. Conclusion: Serum IL-6 increases in patients with myocardial infarction, and this elevation seems to be related to the mass of the affected myocardium. The highest increase is found during the first days of the disease, although the enhanced IL-6 level lasts for at least 3 weeks, probably reflecting the healing process of the myocardium. The clinical value of IL-6 determination does not seem to exceed that of the indices commonly used.

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

A review of glucosamine for knee osteoarthritis: why patented crystalline glucosamine sulfate should be differentiated from other glucosamines to maximize clinical outcomes.

Abstract The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for knee osteoarthritis (OA) recommends symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) first line for the medium to long term management of OA, due to their ability to control pain, improve function, and delay joint structural changes. Among SYSADOAs, glucosamine is probably the most widely used intervention. In the present review of glucosamine for knee OA, we have investigated whether the evidence is greater for the patented crystalline glucosamine sulfate (pCGS) preparation (Rottapharm/Meda) than for other glucosamine formulations. Glucosamine is actually widely available in many forms, as the prescription-grade pCGS preparation, generic and over-the-counter formulations of glucosamine sulfate (GS) and food supplements containing glucosamine hydrochloride (GH), which vary substantially in molecular form, pharmaceutical formulation and dose regimens. Only pCGS is given as a highly bioavailable once daily dose (1500 mg) with a proven pharmacological effect. pCGS consistently reaches the plasma levels of around 10 μM required to inhibit interleukin-1 induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction, compared with sub-therapeutic levels achieved with GH. It is evident, from careful consideration of the evidence base, that only the pCGS formulation of glucosamine reliably provides an effect size on pain that is higher than that of paracetamol and equivalent to that provided by non-steroidal anti-inflammatory drugs. In comparison, the effect size on pain of non-crystalline GS preparations and GH from randomized controlled trials is repeatedly demonstrated to be zero. In addition, there is evidence that chronic administration of pCGS has disease-modifying effects, with a reduction in the need for total joint replacement surgery lasting for at least 5 years after treatment cessation. Consequently, the pCGS preparation (Rottapharm/Meda) is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression.

Internal medicine: yesterday, today, and tomorrow

For more than 100 years, internal medicine has been ‘innerlichen krankheiten’ (Fig. 1). In the first chapter, he considered ‘the queen of medicine’. In recent decades, wrote: ‘Und wiewol es ist, so aus den innerlichen kranhowever, talk of its decay has appeared in the medical kheiten auswending am leib etwas anstehet, der chirurgic literature, while others have proposed a new role for it in besolen wird, aber der kleinen’ (original spelling). This health care delivery [1]. This paper reviews the history of translates as ‘and though it is that due to the internal the term ‘internal medicine’, its development as a separate diseases something has to be done externally to the body, entity in medicine, and its definition. On the basis of this surgery should be applied; but only small surgery’ [3]. historical analysis, the present state of internal medicine The Dutch physician and philosopher Hermann Boercan be discussed. haave (1668–1738), during his work as a chair of mediThe art of healing had been divided into surgery and cine and botany at the University of Leiden, published the medicine by the 8th century BC [2]. In the epic poem medical handbook entitled ‘Aphorismi de cognoscendis et ‘Aithiopis’, composed by a contemporary of Homer, curandis morbis’ (‘Aphorisms on the Diagnosis and Cure Asklepios had two twin sons honored by Poseidon: of Diseases’) in 1709. Aphorisms had been the traditional Machaeon was a surgeon and Podaleirios was a physician. form of medical books since the most famous Aphorisms In his famous work ‘History’ (Istoria, book II, 84), the by Hippocrates. One of the chapters in Boerhaave’s book great ancient Greek historian Herodotos (6485 BC–425 was entitled ‘De morbis internis, et de febribus in genere’ BC) described a group of Egyptian physicians as (‘On internal diseases and on fever in general’). This ‘ihtroi . . . tvnaw an vn’ (doctors . . . of invisible dischapter may be considered the oldest monograph in which eases). Whilst the activities of these physicians can only be the term internal medicine is named (Fig. 2). Until the guessed at, this may be the earliest reference to the medical beginning of the 19th century, the field of medicine now specialty that more than 2000 years later would be known known as internal medicine was variously called ‘Praxis as internal medicine. generalis’, ‘Cursus medicus’, ‘Pathologia et therapia’, or The term ‘internal diseases’ was used for the first time ‘Medicina clinica’ in the curricula of university medical in the medical literature by Aureolus Philippus Paracelsus training [4]. (real name: Theophrastus Bombastus von Hohenheim, For centuries, all diseases had been attributed to imbal1493–1541), a Swiss physician and alchemist. In chapter 9 ances in body fluids or humors. It was not until the 17th of his book ‘Theophrasti Paracelsi von Chemy und heilung century when the great English physician Thomas der Franzosen’ (‘Das neunt buch von blatern, leme, beulen Sydenham (1624–1689), known to his contemporaries as u. tractirt von der heilung der chirurgischen krankheiten the English Hippocrates, described a variety of distinct der franzosen’), Paracelsus, in 1528, used the words diseases or diagnoses based on symptoms, signs and other clinical observations. This approach was different from the Hippocratic concept of ‘general disease’ resulting from the imbalance of body humors and was the basis for further *Fax: 148-32-202-9933. E-mail address: ekucharz@slam.katowice.pl (E.J. Kucharz). work on the classification of diseases. The first nosological

Free radical activity and antioxidative systems in patients with systemic sclerosis

Abstract Background: Free radicals have been said to contribute to vascular damage in patients with systemic sclerosis. The aim of the study was to determine the level of lipid peroxidation products and antioxidative enzyme activity in patients with systemic sclerosis and in healthy controls. Methods: 10 women with definite systemic sclerosis and 10 age-matched healthy women were studied. Results: A significant increase in serum lipid peroxidation product levels (i.e. diene conjugates and thiobarbituric acid-reactive substances) was found in patients with systemic sclerosis. These changes were accompanied by a decrease in superoxide dismutase, catalase, and glutathione peroxidase activity in erythrocyte lysate. Furthermore, there was diminished activity of glutathione reductase and a depressed total serum level of antioxidants compared to the controls. Blood thiol group concentration in patients with systemic sclerosis was also found to be decreased. Conclusions: The results obtained indicate increased oxidative stress in patients with systemic sclerosis.

Chronic inflammation-enhanced atherosclerosis: Can we consider it as a new clinical syndrome?

Incidence of cardiovascular disease in patients with chronic autoimmune disorder like rheumatoid arthritis is much higher than in general population. Cardiovascular events (e.g. myocardial infarction or stroke) are caused by premature accelerated development of atherosclerosis. Chronic inflammation-enhanced atherosclerosis syndrome is proposed as a separate syndrome occurring in patients suffering of chronic inflammation. It is suggested that atherosclerosis as an inflammatory disease and long-lasting extravascular inflammation have common mechanisms resulting in an increase in atherosclerosis and its sequellae, cardiovascular diseases.

Serum human cartilage glycoprotein-39 in patients with systemic sclerosis: relationship to skin and articular manifestation

Human cartilage glycoprotein-39 (HC gp-30) is a secretory protein of several types of cells including chondrocytes. It has been suggested to be a laboratory index of joint damage. Thirty-two patients with systemic sclerosis (SSc) and 22 age-matched controls were investigated. An increased serum HC gp-39 level was shown in SSc patients and was found to correlate with inflammatory indices. There was no correlation with modified Rodnan score, joint involvement, or duration of symptoms of SSc. The obtained results indicate for possible relationship of HCgp-39 to inflammation but do not suggest determination of HC gp-39 as clinically applicable index of articular involvement in SSc patients.