Correction to: Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

In the Original Publication, the e-mail address of the author Milan Petronijevic is incorrect. The correct e-mail address is milanpetronijevic@yahoo.com.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

Etanercept increases tumor necrosis factor-alpha level but not sFas level in patients with rheumatoid arthritis.

BACKGROUND: Targeted anti-tumor necrosis factor-alpha (TNFα) therapy in patients with rheumatoid arthritis (RA) has resulted in dramatic improvement in the disease course and prognosis. One of the features of RA is hyperplasia of synovial cells, particularly RA synovial fibroblasts (RA-SF), caused partially by impaired apoptosis of RA-SF cells. It has been shown that TNFα may inhibit apoptosis in RA-SF cells and this process may be reversed by the use of TNFα antagonists. OBJECTIVES: To determine the influence of etanercept, an anti-TNFα agent, on sFas (CD 95) receptor. METHODS: We analyzed serum levels of sFaS and TNFα in a group of 26 patients with high RA disease activity who were selected to start treatment with etanercept. Assessment of sFas receptor and TNFα levels was performed before and 6 months after treatment with etanercept. RESULTS: Treatment with etanercept resulted in increased TNFα levels (log TNFα 0.602 vs. 1.17, P < 0.05) but no change in sFas levels (log sFas 3.17 vs. 3.11, P = 0.37). As expected, treatment resulted in significant reduction in both disease activity and levels of inflammatory markers. CONCLUSIONS: Etanercept may increase TNFα levels in patients with RA. We also speculate that the Fas pathway is not the main apoptotic pathway in patients with RA treated with etenercept, since sFas, a marker of apoptotic activity, remained unchanged and was not influenced by disease activity and concomitant treatment.

Does regression of skin thickening predict improvement of internal organ involvement and survival in patients with diffuse cutaneous systemic sclerosis? A EUSTAR analysis.

OBJECTIVE: Patients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and ≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis. RESULTS: Of 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations. CONCLUSION: We found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials.

Opinion of patients with ankylosing spondylitis on risk factors impairing their quality of life.

We studied 54 patients with ankylosing spondylitis with questionnaire in order to determine their view on threat to quality of their life related to the disease. We have show that pain and significant disability are the main threats associated with the disease in view of the patients. Social aspects (losing of job or decreasing of income) are also important for the patients, while management of the disease is not considered as arduous. The results of patients' opinion may be helpful in designing of educational programs for them.

Serum ghrelin in female patients with rheumatoid arthritis during treatment with infliximab.

Ghrelin is a gastric hormone that posses multiple functions, including induction of growth hormone release, regulation of proinflammatory cytokines and control of food intake and energy homeostasis. A few reports on serum ghrelin level in chronic inflammatory states revealed contradictory results. The study was undertaken to determine ghrelin in patients with rheumatoid arthritis receiving infliximab, a TNF-α blocking agent. Serum ghrelin was determined in 18 female rheumatoid patients before the treatment with infliximab, 1 week after the first infusion and after 53 weeks of medication and compared with 15 age-matched healthy women. Serum ghrelin level was shown to be increased in the patients. A decrease in serum ghrelin level was found after the first infusion of infliximab and similarly decreased ghrelin level but still higher than in the control was shown in the 53rd week of medication. The obtained results suggest that ghrelin level is related to inflammation, and its serum level in patients with severe rheumatoid arthritis behaves similarly to acute-phase reactants.

Plasma leptin and neuropeptide Y concentrations in patients with rheumatoid arthritis treated with infliximab, a TNF-α antagonist.

TNF-α is one of the key proinflammatory cytokines in pathogenesis of rheumatoid arthritis (RA). TNF-α was also found to enhance synthesis of leptin. Leptin is mainly adipocyte-derived hormone controlling appetite and energy expenditure. It acts through inhibition of neuropeptide Y secretion. It is possible that TNF-α-induced leptin secretion contributes to body mass reduction in patients with RA. The study was designed to determine the influence of inactivation of the TNF-α with infliximab on plasma leptin and neuropeptide Y concentrations in patients with RA. Sixteen female patients with RA treated with infliximab and 16 healthy women were investigated. Plasma leptin and neuropeptide Y concentrations were determined before, during and after 1 year management of the patients with infliximab and were compared with body mass index and body fatty and lean mass. There was no difference in plasma leptin concentration between the rheumatoid patients before therapy and the controls (15.6 ± 1.85 and 14.5 ± 2.15 ng/ml, respectively). Neuropeptide Y concentration was higher in the patients than in the controls (54.5 ± 3.96 and 24.8 ± 2.80 pmol/l, respectively). Treatment with infliximab resulted in enhancement in leptin concentration (18.5 ± 2.34 ng/ml) and a slight increase in neuropeptide Y concentration (58.7 ± 4.66 pmol/l). Physiological relationship between leptin and body mass was shown in the patients and was not altered during the treatment. There was no significant correlation between the disease activity and plasma leptin or neuropeptide Y concentrations.

Is there a role for TNFα antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique.

OBJECTIVES: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. METHODS: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. RESULTS: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-α inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNF-α antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-α antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-α antagonists for arthritis associated with SSc. CONCLUSIONS: Most of the experts do not recommend the routine use of TNF-α antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-α antagonists are needed before general recommendations can be given.

Changes of poststimulatory plasma renin activity in women with hyperthyroidism or hypothyroidism in relation to therapy.

OBJECTIVE: The influence of thyroid hormones upon renin-angiotensin-aldosterone system is poorly understood. Under basal conditions, individuals belong to normal, low or high plasma renin activity (PRA) subjects. The study was designed to evaluate basal and poststimulatory PRA and serum aldosterone (Aldo) level in patients with hyperthyroidism or hypothyroidism during therapy. MATERIAL AND METHODS: We examined 73 women with hyperthyroidism, 27 women with hypothyroidism and 36 healthy controls. The patients were investigated before initiation of therapy and after attainment of euthyroid state. All subjects were investigated under basal conditions (normal-sodium diet) and after application of a low-sodium diet for three days and upright position for 3 hr. PRA, serum Aldo level, blood pressure, serum sodium, potassium and thyroid hormone levels were determined in all subjects. The subjects were classified as low PRA (<1.0 ng/ml/h), normal PRA (1.0-4.0 ng/ml/h) and high PRA (>4.0 ng/ml/h) individuals according to results obtained under basal conditions. RESULTS: Relatively higher poststimulatory enhancement in PRA was found in patients with hyperthyroidism, especially those with low basal PRA, than in those with hypothyroidism. In women with thyroid dysfunctions poststimulatory increase in Aldo were relative lower than poststimulatory enhancement of PRA. After therapy these difference disappeared. The poststimulatory changes in PRA depended on the basal PRA. CONCLUSIONS: Poststimulatory PRA is higher in hyperthyroid women, especially those with low basal PRA. In women with hypothyroidism, basal and poststimulatory PRA is low. Blood pressure and severity of thyroid dysfunction was found to be similar in the patients with low, normal or high basic PRA. In women with thyroid dysfunctions, serum Aldo level and its relative poststimulatory increments are inadequate to changes of PRA; it is suggested that the dissociation in the renin-angiotensin-aldosterone system occurs in hyperthyroid and hypothyroid women.

The relapsing polychondritis damage index (RPDAM): Development of a disease-specific damage score for relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis is a rare, multi-systemic and inflammatory condition of unknown origin. We currently lack a core set of measures to assess and follow damage in patients suffering from this condition. Our primary aim was to derive a disease-specific damage measuring tool for relapsing polychondritis, the Relapsing Polychondritis Damage Index (RPDAM). METHODS: We performed an international 4-round multicenter Delphi study during which experts were asked to rate the relevance of potential damage items for relapsing polychondritis (141 items were obtained from a literature review and 12 from expert suggestion), using a Likert Scale. The selection of items for each subsequent round was based on the median rating of each item. RESULTS: Twenty-four experts from 11 nationalities participated in round 1 and 22 in rounds 2, 3 and 4. From the initial 153 potential damage items, 44 items were selected during round 1, 30 items during round 2 and 16 during round 3. During round 4, we refined the index to a total of 17 items referring to ear nose and throat, eye, respiratory, cardiovascular and hematological systems as well as to treatment-related specific damage items. CONCLUSION: We have developed by international consensus a scoring system to assess damage in patients with relapsing polychondritis. Following its validation, the RPDAM may contribute to improve the care of patients suffering from this rare condition as well as to standardize data collection for future clinical trials.

Fibulin-3 and other cartilage metabolism biomarkers in relationship to calprotectin (MRP8/14) and disease activity in rheumatoid arthritis patients treated with anti-TNF therapy.

BACKGROUND: Fibulin-3 (Fib-3) is a new potential biomarker of articular cartilage metabolism. OBJECTIVES: The aim of the study was to evaluate the effect of anti-TNF therapy on serum fibulin-3, cartilage oligomeric matrix protein (COMP), procollagen II C-propeptide (PIICP), and urinary C-terminal telopeptide of type II collagen (CTX-II) levels in relation to calprotectin (MRP8/14) and disease activity in rheumatoid arthritis patients. MATERIAL AND METHODS: In the study, 35 female patients with rheumatoid arthritis (RA) were investigated. The concentration of fibulin-3, COMP, PIICP, MRP8/14, and urinary CTX-II in serum was measured before and after anti-TNF therapy. Ten healthy women were investigated as the controls. RESULTS: The concentration of fibulin-3 in RA patients before treatment did not differ significantly from the concentration of fibulin-3 in the control group. A significantly higher concentration of fibulin-3 was noted prior to treatment in the group of women with a worse response to the therapy (non-responders) compared to the concentration of fibulin-3 in the healthy women. During the anti-TNF therapy, the serum fibulin-3 level decreased in patients. The fibulin-3 level correlated with CRP and ESR after anti-TNF treatment. Significant lowering of MRP8/14 was noted in the patients after anti-TNF therapy. No correlation between fibulin-3 and MRP8/14 was observed in the study group or in the control group. CONCLUSIONS: During the anti-TNF therapy, the serum fibulin-3 level decreased in RA patients. Serum MRP8/14 concentration also decreased. No correlation between fibulin-3 and MRP8/14 was observed in the study group before and after the treatment. We found a poor correlation between serum fibulin-3 and other cartilage metabolism biomarkers after anti-TNF therapy.

Statins Therapy for Connective Tissue Diseases: New Therapeutic Opportunities.

BACKGROUND AND OBJECTIVE: Statins, 3-hydroxyl-3-methyl-glutharyl Coenzyme A reductase inhibitors showed their therapeutic potential in the treatment of atherosclerosis-related diseases. Recently, the properties of statins, separate from their lipid lowering activity have attracted much attention. These properties that cover a wide area of physiopathological activities including cell maturation, immune response regulation, tissue fibrosis, endothelial activity and are called pleiotropic activity. Many in vitro studies demonstrated significant, statins-dependent regulation of immune system reactivity, reduction of pro-inflammatory and pro-fibrotic cytokines as well as suppression of endothelial activity and damage. METHODS: The present study reviewed the potential utility of statins as a concomitant regimen in the treatment of various connective tissue diseases. To address this we performed a methodical search though Pubmed database searching for term statins and pleiotropic effects and connective tissue disease or rheumatology. RESULTS: One hundred and thirty one prominent research and review papers were identified and analyzed. Majority of research papers focused on laboratory models of statins activity, only a few of them analyzed data from human studies. CONCLUSION: Statins may have a therapeutic potential as a concomitant treatment for connective tissue diseases, that has been elegantly proven in many animal and laboratory studies. They deep interfere with immunological mechanism of autoantigen presentation, expressions of adhesion molecules. These phenomena may be recognized as the most important mode of action. Less is known about the potential of statins in clinical practice. Many small trials examined therapeutic potentials in various autoimmune diseases with contradictory results, disabling making the final conclusions. The future human studies should answer what patients population may benefit with concomitant statins' treatment.

Serum concentration of surfactant protein D in patients with systemic sclerosis: The potential marker of the interstitial lung disease severity.

Pulmonary involvement is a severe manifestation of systemic sclerosis (SSc). The study was designed to determine the serum level of surfactant protein D (SP-D) in patients with SSc in relation to clinical and laboratory parameters as well as to analyze dynamics of changes of these indices within one year of observation. SP-D was assayed in 41 patients with SSc and 15 healthy controls. Additionally, pulmonary function tests, chest high-resolution computed tomography (HRCT), and inflammatory markers were assessed. All tests were performed twice: at entry and repeated after one year of observation. The serum level of SP-D was significantly higher in patients with SSc than in healthy controls. Serum concentration of SP-D was significantly higher in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) than in those without SSc-ILD. SP-D was found to correlate with lung involvement evaluated with the Medsger score (diffusing capacity of the lung for carbon monoxide (DLCO), forced vital capacity, radiological changes, and estimated pressure in the pulmonary artery in echocardiography). SP-D correlated with the honeycombing and/or reticular pattern in HRCT and ground glass opacification pattern. Serum concentration of SP-D was elevated in patients with a decreased DLCO. Furthermore, SP-D was higher in patients with diffuse cutaneous type (dcSSc) of the disease than in those with SSc limited type (lcSSc). Because of the small size of the group, it was not possible to perform a statistical analysis for patients who had different results in HRCT, VC, and Medsger score between the first and the second evaluation. SP-D seems to be an index for assessing lung involvement. It reflects the state of pulmonary fibrosis but not the dynamics of the pulmonary fibrosis progression. Further studies are needed to evaluate clinical application of the index, and currently, there is no evidence for the recommendation of the application of SP-D in routine evaluation of patients with SSc.

Seronegative arthritis in patient with solitary bone plasmacytoma.

We report a patient with localized focus of the bone destruction due to a rare disease, solitary bone plasmacytoma (SBP). The patient suffered from arthritis, mimicking seronegative rheumatoid arthritis. To our knowledge, it is the first description of coexistence of arthritis and SBP.

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

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.

Serum level of the circulating angiogenesis inhibitor endostatin in patients with hyperthyroidism or hypothyroidism.

Serum level of endostatin, a natural angiogenesis inhibitor, was measured in 12 patients with hyperthyroidism and 9 patients with hypothyroidism. Control values were obtained from 12 healthy individuals. Hyperthyroidism was shown to be associated with an increased level of endostatin and hypothyroidism with a decreased endostatin level. There was no correlation of serum endostatin with thyroid hormone levels. Endostatin is a fragment of type XVIII collagen, and it is possible that reported changes are related to the effect of thyroid hormones on connective tissue metabolism.

Chikungunya fever.

Chikungunya fever (CF) is an acute illness caused by Chikungunya virus (CHIKV) belonging to the alphavirus genus of the Alphaviruses (Togaviridae) family. The virus is transmitted by Aedes mosquitoes. CF is primarily tropical disease occurring in Africa, Asia and Indian Ocean islands but in the last decade an outbreak of CHIKV autochthonous infections were reported in Italy and France. It is associated with viral genome mutations facilitating transmission of the disease by Aedes albopictus, a mosquito occurring in several European countries. The CF is highly symptomatic, characterized by fever, cutaneuos rash and severe athralgia and arthritis. In some patients severe neurological or hemorrhagic manifestations occur. The disease is self-limiting but a part of the patients suffers from a long-lasting arthritis akin to rheumatoid arthritis. Treatment is only symptomatic. Prevention includes reduction of mosquito bite (mosquito net, repellent) or application of measures against mosquito larvae. Vaccination is not currently available but investigations are in progress. CF presents a significant worldwide health problem affecting in the last decade millions of person, and currently dangerous also for European countries.