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Abstract Background A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). Methods DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. Results A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. Conclusions For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. Trial registration Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263, posted on April 19, 2013).

Background: Nailfold capillaroscopy is the only method for morphological assessment of nutritive capillaries. The literature data about capillaroscopic findings in healthy individuals are scarce., Objective: To evaluate and compare the capillaroscopic findings of fingers and toes in healthy subjects., Materials and Methods: 22 healthy individuals were included in the study. Capillaroscopic examination was performed with videocapillaroscope Videocap 3.0 (DS Medica). Exclusion criteria were as follows: history of vasospasm, presence of accompanying diseases, taking any medications, arterial hypertension in first degree relatives, overweight or obesity (body mass index > 25kg/m2) and presence of chronic arterial or venous insufficiency., Results: Poor visibility of nailfold capillaries was found significantly more frequently in the toes (22.7%, 5/22) as compared with fingers (0/22). Slight irregularities in capillary distribution and orientation to their parallel axis were significantly more common in the toes (31.8%, 7/22) as compared with fingers (9%, 2/22), (p<0.05). The mean diameter of the arterial (0.012±0.002mm) and the venous limb (0.017±0.002mm) of the toes did not differ significantly as compared to the respective parameters in the fingers (0.013±0.002mm for the arterial limb, p=0.46 and 0.018±0.002mm for the venous limb, p=0.25). The mean capillary density also did not differ significantly in the fingers and toes. The mean capillary length of the toes (0.165±0.096mm) was shorter as compared with hands (0.220±0.079mm), but the difference was not statistically significant (p=0.37). Presence of tortuous capillaries (>10%) was found significantly more often in the toes (12/22) as compared with fingers (6/22, χ2=6.769, p<0.05). Short capillary loops (length<100µm) were observed significantly more often in the toes (11/22 - toes, 1/22 - fingers, χ2=14.666, p<0.05)., Conclusion: Capillaroscopic examination of the toes shows some differences as compared to those of the fingers such as greater number of cases with poor visibility and slight irregularities of distribution, greater number of shorter capillaries and increased tortuosity, which might be related to the thicker epidermis of the toes and increased capillary pressure due to gravity. The values of the major capillaroscopic parameters such as capillary diameters and capillary density in fingers and toes do not differ significantly., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Although Raynaud's Phenomenon (RP) is observed in a significant proportion of patients with primary fibromyalgia, the available data on capillaroscopic findings in primary fibromyalgia are scarce., Objective: The purpose of the study was to assess the capillaroscopic pattern in patients with primary fibromyalgia., Patients and Methods: 26 patients with primary fibromyalgia (25 women and 1 man) were included in the study. Mean age was 55±10 years. As control groups were examined 31 patients with primary RP and 35 healthy volunteers. Capillaroscopic examination was performed with a videocapillaroscope Videocap 3.0 (DS Medica), magnification 200x with analysis of the main capillaroscopic parameters as follows: capillary distribution, shape, mean capillary diameters and length, mean capillary density, visibility of the subpapillary plexus; presence of avascular areas, microhaemorrhages and neoangiogenic capillaries., Results: Symptoms of RP were observed in 65% (17/26) of the cases with primary fibromyalgia. At capillaroscopic examination, the most frequent finding in patients with primary fibromyalgia was the presence of capillary dilation in 85% (22/26) of the patients - both in cases with and without RP. However, the mean arterial and venous capillary diameters were significantly higher in the subgroup of fibromyalgia patients with clinical symptoms of RP. Of note, microvascular abnormalities characteristic of connective tissue diseases could not be observed in primary fibromyalgia patients. Analogous changes - presence of dilated capillaries - were found in 96.6% (29/30) of patients with primary RP., Conclusion: In our study, the most frequent capillaroscopic finding in patients with primary fibromyalgia was the presence of dilated capillary loops analogous to primary RP. Capillaroscopic signs suggestive of connective tissue disease could not be found in primary fibromyalgia patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Nailfold capillaroscopy is a noninvasive instrumental method for morphological analysis of the nutritive capillaries in the nailfold area. In rheumatology, it is a method of choice among instrumental modalities for differential diagnosis between primary and secondary Raynaud's phenomenon (RP) in systemic rheumatic diseases. RP is a common diagnostic problem in rheumatology. Defining the proper diagnosis is a prerequisite for administration of the appropriate treatment. Thus, nailfold capillaroscopic examination is of crucial importance for the every-day practice of the rheumatologists and is currently gaining increasing attention. The most specific capillaroscopic changes are observed in Systemic Sclerosis (SSc). Due to the high prevalence of the capillaroscopic changes in this clinical entity and their early appearance, they could be used for early and very early diagnosis of the disease. More recently, "scleroderma" type capillaroscopic changes have been defined as diagnostic criterion in the new EULAR/ACR classification criteria for SSc together with the presence of scleroderma-related autoantibodies, RP, telangiectasia and other clinical signs. Capillaroscopic changes in other connective tissue diseases and in different rheumatic-like conditions like those in diabetes mellitus (e.g., diabetic stiff-hand syndrome) and paraneoplastic syndromes associated with microvascular pathology should be interpreted properly in order to obtain precise diagnosis in the shortest possible differential diagnostic process., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Osteoarthritis (OA) is the most common joint disease and a leading cause for impaired function and disability with significant treatment costs and socio-economic burden. Despite recent achievements in the knowledge on disease pathogenesis, the treatment is still a challenge and contrary to the inflammatory joint diseases, no disease-modifying drugs are currently available for OA. Different response in different localizations of the disease further complicates the therapeutic choice. The standard pharmacological treatment includes agents for control of pain and inflammation (non-steroidal anti-inflammatory drugs, analgesics including opioids, intraarticular corticosteroids) and the group of the symptomatic slow acting drugs for OA such as glucosamine sulfate, chondroitin sulfate, diacerein, unsaponifiables extract of soybean and avocado administered orally and intrarticular hyaluronic acid. In addition, a number of studies investigate the efficacy of classic disease-modifying drugs used in inflammatory arthritides and antiresoptive agents as potential future therapies that could prevent structural progression of the disease. In a number of small studies, therapeutic efficacy of hydroxychloroquine (HCT) in OA has been suggested, but the results are contradictory. The first results from a multicenter, randomized, double-blind, placebo-controlled trial focused on symptomatic hand OA were recently reported (British HERO study). It has been concluded that HCQ was not superior than placebo as analgesic treatment or for reduction of the radiographic progression in hand OA. Placebo-controlled trial evaluating the efficacy of HCT in inflammatory and erosive hand OA is under way (OA TREAT study). Another field of recent research is the efficacy of TNF-alpha blockers based on the knowledge of their high efficacy in the inflammatory joint diseases and the significant role of TNF-alpha in the pathogenesis of OA. However, current evidence from the available studies does not support the use of TNF-alpha blockers in OA. The benefit of TNF-alpha blockers in specific sub-groups of patients with higher level of inflammation, objective criteria for the expected responders as well as cost-effectiveness of such treatment is a matter of further research and discussion. New biologic agents that target the nerve growth factor-β are other currently investigated drugs as a potential symptomatic therapeutic option in OA. Significant research has been also focused on revealing potential symptomatic or eventually disease-modifying efficacy of drugs that target bone metabolism due to contemporary notion for the crucial role of the subchondral bone in OA pathology and the positive association between the increased subchondral bone turnover and the progressive cartilage loss. A significant delay of joint width narrowing vs. placebo has been observed in patients with symptomatic knee OA after treatment with strontium renelate. The intraarticular administration of platelet-rich plasma is evaluated as potential future therapy and has been tried in knee and hip OA with beneficial effect. Based on the current knowledge about the OA pathogenesis and the undergoing studies, new therapies for OA are awaited both as a safe symptomatic treatment - alternative to the conventional treatment options and as a disease-modifying therapy that would revolutionize the contemporary approach to OA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: In view of the already existing and the expected growing costs due to the pathological osteoarthritic joint alterations and the related consequences, preventive and conservative strategies which can avoid or delay osteoarthritic joint alterations are welcomed from a socioeconomical perspective. Here, it should be mentioned that corresponding primary prevention measures should take place early by already educating children about a healthy diet and motivating them to regular physical exercise. In overt or symptomatic osteoarthritis, a good joint function and reduction of disease-related pain as well as a delay in the progression of osteoarthritis should be the primary goals of non-surgical therapeutic approaches., Objective: The current body of studies is already able to prove the effectiveness of differential indicative physiotherapeutic and physical measures and should be further developed in the future. Nevertheless, the implementation of the available knowledge from the studies under evidencebased medicine criteria proves difficult during the daily routine in clinics. On one hand, an assessment of the effectiveness of physical therapy within the framework of a multimodal treatment approach (e.g. thermotherapy in combination with manual therapy) is difficult to define., Result and Conclusion: On the other hand, an objective assessment of treatment success, owing to the heterogeneity among the patients (above all varied disease activity, functional limitations, accompanying diseases and therapy) will also remain complicated., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Rheumatoid arthritis (RA) is the most common autoimmune articular disorder. It is characterized by chronic inflammation and progressive joint destruction. As research traditionally focused on immune cells and cytokines, the role of stromal cells was addressed only to a limited extent. However, cell-cell interactions within the rheumatoid synovium alter the phenotype of synovial fibroblasts (SFs), which are nowadays considered as active and aggressive drivers in the destructive process of RA. SFs actively attach to and invade articular cartilage, thereby expressing increased amounts of adhesion molecules and proinflammatory and matrix-degrading mediators. Furthermore, RASFs stimulate synovial vascularization through the release of proangiogenic factors. As a result, angiogenesis supports the influx of immune cells into affected joints, thereby perpetuating inflammatory processes, and facilitates access of RASFs to the bloodstream, thus boosting dissemination of RA. Despite intensive research, early pathophysiological processes still remain largely unknown. In this respect, a prearthritic phase of RA is discussed. Early and intensive therapy is considered to be very effective and beneficial for long-term outcome. However, although innovative therapy and improved treatment strategies are applied to achieve clinical remission, failure of or only partial response to therapy remains common. Given that none of the currently approved therapies target RASFs, intensive research into new strategies is warranted. In this review, novel findings leading to the altered fibroblast phenotype in RA are discussed in terms of progressive inflammation and destruction. Potential novel therapeutic concepts are also addressed.

In the nailfold area, specific diagnostic microvascular abnormalities are easily recognized via capillaroscopic examination in systemic sclerosis (SSc). They are termed "scleroderma" type capillaroscopic pattern, which includes presence of dilated, giant capillaries, haemorrhages, avascular areas, and neoangiogenic capillaries and are observed in the majority of SSc patients (in more than 90%). LeRoy and Medsger (2001) proposed criteria for early diagnosis of SSc with inclusion of the abnormal capillaroscopic changes and suggested to prediagnose SSc prior to the development of other manifestations of the disease. It is a new era in the diagnosis of SSc. At present, an international multicenter project is performed. It aims validation of criteria for very early diagnosis of SSc (project VEDOSS (Very Early Diagnosis of Systemic Sclerosis) and is organized by European League Against Rheumatism (EULAR) Scleroderma Trials and Reasearch. Very recently the first results of the VEDOSS project were processed and new EULAR/ACR (American College of Rheumatology) classification criteria have been validated and published (2013), in which the characteristic capillaroscopic changes have been included. Our observations confirm the high frequency of the specific capillaroscopic changes of the fingers in SSc, which have been found in 97.2% of the cases from the studied patient population. We have performed for the first time capillaroscopic examinations of the toes in SSc. Interestingly,"scleroderma type" capillaroscopic pattern was also found at the toes in a high proportion of patients - 66.7%, but it is significantly less frequent as compared with fingers (97.2%, p<0.05). In our opinion, the examination of the toes of SSc patients should be considered as it suggests an additional opportunity for evaluation of the microvascular changes in these patients although the observed changes are in a lower proportion of cases. Thus, capillaroscopic examination is a cornerstone for the very early diagnosis of SSc. Patients with clinical symptoms of peripheral vasospasm (Raynaud's phenomenon (RP)) in association with puffy fingers and/or sclerodactyly should be carefully examined. Hence, appearance of "scleroderma" type capillaroscopic changes in RP patients should be interpreted in the clinical context, because some of the components of this pattern may be observed in several other connective tissue diseases such as mixed connective tissue disease, undifferentiated connective tissue disease that are termed "scleroderma-like" capillaroscopic changes. Capillaroscopic examination is an obligatory screening method in these cases, but the pathologic capillaroscopic changes are not specific and their interpretation is in clinical context.

Objective: To examine the expression of the thioredoxin (TRX)-thioredoxin reductase (TR) system in patients with rheumatoid arthritis (RA) and patients with other rheumatic diseases., Methods: Levels of TRX in plasma and synovial fluid (SF) were measured using enzyme-linked immunosorbent assay. Cellular distribution of TRX was determined by flow cytometry and histochemistry. Cellular expression of TR was studied by in situ messenger RNA (mRNA) hybridization. The effect of oxidative stress and tumor necrosis factor alpha (TNF alpha) on TRX expression by cultured rheumatoid fibroblast-like synoviocytes was studied., Results: Significantly increased TRX levels were found in the SF from 22 patients with RA, when compared with plasma levels in the same patients (P < 0.001) and compared with SF TRX levels in 15 patients with osteoarthritis (P < 0.001), 13 patients with gout (P < 0.05), and 9 patients with reactive arthritis (P < 0.0001). The presence of TRX could be demonstrated within the SF-derived mononuclear cells and synovial tissue (ST) of RA patients. Concordantly, expression of TR mRNA was observed in the ST of these patients. Stimulation of synovial fibroblast-like synoviocytes with either H2O2 or TNF alpha induced an increase in the production of TRX., Conclusion: The data demonstrate significantly increased concentrations of TRX in the SF and ST of RA patients when compared with the levels in patients with other joint diseases. Evidence is presented that the local environment in the rheumatic joint contributes to increased TRX production. Based on its growth-promoting and cytokine-like properties, it is proposed that increased expression of TRX contributes to the disease activity in RA.

The synovium in rheumatoid arthritis (RA) is characterized by an increase in lining layer thickness and infiltration of inflammatory cells into the sublining area. Fibroblasts in the lining layer develop the appearance of "transformed cells", under the influence of proto-oncogenes involved in the regulation of the cell cycle. Fibroblast and macrophage-derived cytokines such as IL-1 and TNF-alpha are present abundantly in the rheumatoid synovium and stimulate these cells to produce destructive enzymes. Other cytokines such as IL-4 and IL-10 represent a physiological attempt to reverse the inflammatory process. Adhesion molecules facilitate both the migration of cells to the joint as well as the attachment of synovium to bone and cartilage. Joint destruction is mediated by enzymes such as serine proteases, matrix metalloproteinases (MMPs) and the cathepsins. Treatments directed against various components of the inflammatory cascade have shown promise. Inhibition of MMPs or adhesion molecules, blockade of IL-1 or TNF-alpha and the use of anti-Fas antibodies to induce apoptosis offer new possibilities for the treatment of RA. More recently, the employment of genes with antiarthritic properties has shown therapeutic potential.

Objective: To examine the relationship among the expression of protooncogenes such as c-fos and c-myc, Fas antigen, Fas ligand, and apoptosis in the synovial tissue of patients with rheumatoid arthritis (RA)., Methods: The expression of c-fos, c-myc, Fas antigen, and Fas ligand was examined in synovial tissues of 6 patients with RA and 4 with osteoarthritis (OA) using in situ reverse transcriptase (RT) assay and immunohistochemical staining. Apoptosis was detected by TUNEL method in situ., Results: Expression of protooncogenes, c-fos, and c-myc was detected in all samples from patients with RA, but in only a few cells of OA synovium. 30 to 90% of cells in RA synovium positive for these protooncogenes also coexpressed Fas antigen. Fas positive cells in RA synovium underwent apoptosis to a significant degree. Fas ligand mRNA was detected only in mononuclear cells in RA synovium., Conclusion: The expression of protooncogenes is closely related to Fas mediated apoptosis in RA synoviocytes.