"Scleroderma" and "Scleroderma-like" Capillaroscopic Pattern-Differences and Similarities.

INTRODUCTION: The "scleroderma" type capillaroscopic pattern is a reference pattern in rheumatology that is a diagnostic sign for systemic sclerosis (SSc) in an appropriate clinical context and is observed in more than 90% of scleroderma patients. Similar microvascular changes, the so-called "scleroderma-like", have been described albeit in a lower proportion of patients with other rheumatic diseases, such as dermatomyositis (DM), undifferentiated connective tissue diseases (UCTD), systemic lupus erythematosus (SLE), etc. Three distinct stages of "scleroderma" pattern have been suggested by Cutolo et al., i.e., "early", "active", and "late". However, disease duration is just one of the factors that contributes to the progression of microvascular changes, and in this regard, "active" or even "late" pattern could be observed in patients with shorter disease duration. In addition, stable microvascular changes could be found for long periods in other cases. OBJECTIVE: The aim of the study was to assess the presence of differentiating features between "scleroderma" pattern in SSc and "scleroderma-like" pattern in other rheumatic diseases. METHODS: 684 capillaroscopic images demonstrating a "scleroderma" and "scleroderma-like" pattern have been analysed in the current retrospective cross-sectional study. 479 capillaroscopic pictures were obtained from 50 SSc patients, 105 from 7 DM patients, 38 from 10 rheumatoid arthritis (RA) patients, 36 images from 5 patients with SLE, and 26 images from 9 patients with UCTD. All capillaroscopic images used in the current analysis have fulfilled the criteria for "sclerderma/scleroderma-like" pattern, as the pathological changes in the capillaroscopic parameters have also been confirmed by quantitative measurement of capillary diameters, capillary density, and intercapillary distance. All the images have been categorized into one of the following groups, i.e., "early", "active" and "late" phases (according to the definition of Cutolo et al.), or "other" findings, the latter being specifically described as they could not be attributed to one of the other three categories. RESULTS: 479 capillaroscopic pictures were obtained from 50 scleroderma patients. 31 of them showed an "early", 391 an "active" phase, and 57 a "late" phase "scleroderma" type microangiopathy. In 69 images assessed as an "active" pattern, neoangiogenesis was found. In 43 out of 105 capillaroscopic pictures from DM patients, an "active" phase was detected; in 2 of the images, a "late" pattern was found, and in 60 capillaroscopic pictures, neoangiogenesis in combination with giant capillary loops was observed. Early microangiopathy was not found in this group. Among capillaroscopic images from SLE patients, "late" phase microangiopathy was not found. "Early" phase was present in 3 images, "active" phase in 29, neoangiogenesis in "active" phase in 4 pictures. Early microangiopathy was detected in 11 capillaroscopic pictures from RA patients (8 out of 9 patients), an "active" phase in 4 images (3 patients), and in 23 capillaroscopic images, neoangiogenesis with mild capillary derangement and capillary loss and single giant capillaries ("rheumatoid neoangiogenic pattern") were observed. Classic "late" type microangiopathy was not found in RA patients as well as among patients with UCTD. The predominant capillaroscopic pattern in UCTD patients was early microangiopathy (n = 23). The rest images from UCTD exhibited features of the "active" phase. CONCLUSION: In conclusion, early microangiopathy was observed in RA, SLE, and UCTD patients, but not in patients with DM. An "active" phase "scleroderma" type capillaroscopic pattern was detected in all patient groups other than SSc, i.e., DM, SLE, RA, and UCTD. "Late" phase "scleroderma" type microangiopathy was present in patients with scleroderma and DM and was not observed in SLE, RA, and UCTD. Despite the fact that in some cases, microangiopathy in scleroderma and other rheumatic diseases may be indistinguishable, the results of the current research have shown the presence of some differentiating features between "scleroderma" and "scleroderma-like" microangiopathy that might be a morphological phenomenon associated with differences in the pathogenesis and the degree of microvascular pathology in various rheumatic diseases.

Cartilage Oligomeric Matrix Protein in Osteoarthritis and Obesity-Do New Considerations Emerge?

The diagnosis of osteoarthritis (OA) is based on radiological changes that are delayed, along with clinical symptoms. Early and very early diagnosis at the stage of molecular pathology may eventually offer an opportunity for early therapeutic intervention that may retard and prevent future damage. Cartilage oligomeric matrix protein (COMP) is a non-collagenous extracellular matrix protein that promotes the secretion and aggregation of collagen and contributes to the stability of the extracellular matrix. There are contradictory literature data and currently, the parameter is used only for scientific purposes and its significance is not well-determined. The serum level of COMP in patients with metabolic type OA of the knee has not been evaluated. The aim of the study was to analyze serum COMP levels in metabolic knee OA and controls with different BMI. Our results showed that the mean COMP values were significantly higher in the control group (1518.69 ± 232.76 ng/mL) compared to the knee OA patients (1294.58 ± 360.77 ng/mL) (p = 0.0012). This may be related to the smaller cartilage volume in OA patients. Additionally, COMP levels negatively correlated with disease duration (p = 0.04). The COMP level in knee OA with BMI below 30 kg/m2 (n = 61, 1304.50 ± 350.60 ng/mL) was higher compared to cases with BMI ≥ 30 kg/m2 (n = 76, 1286.63 ± 370.86 ng/mL), but the difference was not significant (p = 0.68). Whether this finding is related to specific features in the evolution of the metabolic type of knee OA remains to be determined. Interestingly, comparison of COMP levels in the controls with different BMI revealed significantly higher values in overweight and obese individuals (1618.36 ± 203.76 ng/mL in controls with BMI ≥ 25 kg/m2, n = 18, 1406.61 ± 216.41 ng/mL, n = 16; p = 0.0092). Whether this finding is associated with increased expression of COMP in the adipose tissue or with more intensive cartilage metabolism in relation to higher biomechanical overload in obese patients, considering the earlier development of metabolic type knee OA as an isolated finding, remains to be determined.

The Value of Nailfold Capillaroscopy in the Classification and Differential Diagnosis of Raynaud's Phenomenon in Rheumatology.

Among instrumental techniques, nailfold capillaroscopy plays a leading role in the assessment of Raynaud's phenomenon (RP) patients because it is the only method that provides opportunities for morphological assessment of capillaroscopic findings in the nailfold area, with proven diagnostic and prognostic significance in rheumatology. The discussion about updating the classification of RP in rheumatology is interesting given the current understanding of capillaroscopic findings in rheumatic diseases and improvements in immunological diagnostics. The presence of dilation of the "true" capillary diameters in primary RP could be observed. There are some cases of primary RP where the capillaroscopic pattern is completely normal and there are no dilated capillaries present, which could be related to the duration and severity of the symptoms. It is possible that longer duration and greater severity are associated with the appearance of capillary dilations, but more research is needed to confirm it. Rarely, pathological capillaroscpic features of microangiopathy could be observed in RP patients in whom clinical, laboratory and immunological findings are compatible with the diagnosis "primary RP". These cases should be defined as "suspected secondary RP" and require closer follow-up for the assessment of symptom evolution. Abnormal "scleroderma" type capillaroscopic pattern has been established as a new classification criterion for systemic sclerosis (SSc) in 2013. Similar changes ("scleroderma-like" pattern) could be observed in other rheumatic diseases, i.e., undifferentiated connective tissue disease (UCTD), systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, including without evidence of overlap with scleroderma. The appearance of such microvascular abnormalities at disease presentation is less well studied in diseases different from SSc. However, "scleroderma-like" microangiopathy has also been reported as an initial sign in some systemic rheumatic diseases, such as UCTD and systemic lupus erythematosus. Thus, interpretation of capillaroscopic findings is performed in overall context, including clinical findings and laboratory and immunological test results.

Changes in the Subchondral Bone, Visfatin, and Cartilage Biomarkers after Pharmacological Treatment of Experimental Osteoarthritis with Metformin and Alendronate.

Subchondral bone that has intense communication with the articular cartilage might be a potential target for pharmacological treatment in the early stages of osteoarthritis (OA). Considering the emerging data about the role of adipokines in the pathogenesis of OA, the administration of drugs that influence their level is also intriguing. Metformin and alendronate were administered in mice with collagenase-induced OA (CIOA) as a monotherapy and in combination. Safranin O staining was used for the assessment of changes in subchondral bone and articular cartilage. Before and after treatment, serum levels of visfatin and biomarkers of cartilage turnover (CTX-II, MMP-13, and COMP) were assessed. In the current study, the combined administration of alendronate and metformin in mice with CIOA led to the protection against cartilage and subchondral bone damage. In mice with CIOA, metformin led to a decrease in visfatin level. In addition, treatment with metformin, alendronate, or their combination lowered the level of cartilage biomarkers (CTX-II and COMP), while the level of MMP-13 was not influenced. In conclusion, personalized combination treatment in OA according to clinical phenotype, especially in the early stages of the disease, might lead to the identification of a successful disease-modifying therapeutic protocol in OA.

Pleiotropic Effects of Metformin in Osteoarthritis.

The involvement of the knee joint is the most common localization of the pathological process in osteoarthritis (OA), which is associated with obesity in over 50% of the patients and is mediated by mechanical, inflammatory, and metabolic mechanisms. Obesity and the associated conditions (hyperglycemia, dyslipidemia, and hypertension) have been found to be risk factors for the development of knee OA, which has led to the emerging concept of the existence of a distinct phenotype, i.e., metabolic knee OA. Combined assessment of markers derived from dysfunctional adipose tissue, markers of bone and cartilage metabolism, as well as high-sensitivity inflammatory markers and imaging, might reveal prognostic signs for metabolic knee OA. Interestingly, it has been suggested that drugs used for the treatment of other components of the metabolic syndrome may also affect the clinical course and retard the progression of metabolic-associated knee OA. In this regard, significant amounts of new data are accumulating about the role of metformin-a drug, commonly used in clinical practice with suggested multiple pleiotropic effects. The aim of the current review is to analyze the current views about the potential pleiotropic effects of metformin in OA. Upon the analysis of the different effects of metformin, major mechanisms that might be involved in OA are the influence of inflammation, oxidative stress, autophagy, adipokine levels, and microbiome modulation. There is an increasing amount of evidence from in vitro studies, animal models, and clinical trials that metformin can slow OA progression by modulating inflammatory and metabolic factors that are summarized in the current up-to-date review. Considering the contemporary concept about the existence of metabolic type knee OA, in which the accompanying obesity and systemic low-grade inflammation are suggested to influence disease course, metformin could be considered as a useful and safe component of the personalized therapeutic approach in knee OA patients with accompanying type II diabetes or obesity.

Microangiopathy in Rheumatic Diseases.

Capillaries are part of the microcirculation, which consists of arterioles, capillaries, and venules and are the connecting link between the arterial and venous blood circulation [...].

Knee Osteoarthritis-How Close Are We to Disease-Modifying Treatment: Emphasis on Metabolic Type Knee Osteoarthritis.

Osteoarthritis (OA) is a whole-joint disease that affects cartilage, bone, and synovium as well as ligaments, menisci, and muscles [...].

Capillaroscopy and Immunological Profile in Systemic Sclerosis.

Introduction: Data on the associations between capillaroscopic changes and diagnostic systemic-sclerosis (SSc)-related antibodies are scarce. Presence of such correlation would improve current knowledge about the disease's pathogenesis by revealing the mechanisms of microangiopathy. The microvascular pathology of SSc is a hallmark of the disease, and immunological abnormalities probably contribute to its development. Patients and methods: 19 patients with definite diagnosis of SSc were included in the current pilot study; 16 had limited and 3 had diffuse cutaneous involvement; their mean age was 51.56 ± 15.07 years. All patients exhibited symptoms of Raynaud's phenomenon of the fingers. A "scleroderma" type capillaroscopic pattern was classified according to the staging suggested by Cutolo et al. (2000): "early", "active" or "late" phase. In the presence of different degrees of capillaroscopic changes in different fingers, the most-advanced microvascular pathology was chosen for classification. In cases without capillaroscopic features of microangiopathy, the findings were categorized as normal or nonspecific (dilated, tortuous capillaries, and/or hemorrhages). Indirect immunofluorescence on HEp-2 cells was performed as the gold-standard screening method for the detection of antinuclear autoantibodies (ANA), and determination of the immunofluorescent staining pattern (anti-cell pattern) was in accordance with the International Consensus on ANA Patterns. Scleroderma-associated autoantibodies in the patients' serum were assessed using line immunoblot assay for detection of autoantibodies to 13 scleroderma-associated autoantigens: Scl-70, CENP A, CENP B, RP11/RNAP-III, RP155/RNAP-III, fibrillarin, NOR-90, Th/To, PM-Scl100, PM-Scl75, Ku, PDGFR, and Ro-52. Results: In 73.7% (n = 14) of the examined patients, "scleroderma" type capillaroscopic changes were found, and in 26.3% (n = 5), capillaroscopic features of microangiopathy were absent (nonspecific changes, n = 3; normal findings, n = 2). In SSc patients with positive anti-Scl-70 (n = 7) antibodies, significantly lower mean capillary density was observed along with a higher frequency of "active" and "late" phase capillaroscopic changes as compared to the anti-Scl-70-negative patients (p < 0.05). Anti-RNAP III−155 positive patients (n = 4) had significantly higher mean capillary density than anti-RNAP III−155 negative patients (n = 15). In three of the anti-RNAP III−155-positive cases, capillaroscopic features of microangiopathy were not detected, and in one case there was an "early" phase "scleroderma" pattern. Conclusion: In the current pilot study, the association between more advanced capillaroscopic changes and the presence of anti-Scl-70 autoantibodies was confirmed. As a novel observation, positive anti-RNAP III−155 antibodies were found in SSc patients with or without early microangiopathy. The question of associations between microvascular changes in SSc and other SSc-related autoantibodies requires further research.

Disease-Modifying Potential of Metformin and Alendronate in an Experimental Mouse Model of Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease causing progressive damages of the cartilage and subchondral bone, synovial inflammation, and severe pain. Despite the complex pathomorphological changes that occur in OA, the approach to different forms of OA is standardized. The global results from pharmacological treatment are not satisfactory. Hence, this study aimed to explore the effects of metformin, alendronate, and their combination on OA development and progression in mice with collagenase-induced osteoarthritis (CIOA). Female ICR (CD-2) mice were randomized to five groups: control group, CIOA untreated, CIOA + metformin, CIOA + alendronate, and CIOA + metformin + alendronate. OA was induced by the intra-articular (i.a.) injection of collagenase. OA phenotype was analyzed by flow cytometry (bone marrow cell differentiation), ELISA (serum levels of the adipokines leptin and resistin), and histology (pathological changes of the knee joint). Treatment with metformin, alendronate, or their combination inhibited the expression of RANK and RANKL on osteoblasts and osteoclasts obtained by ex vivo cultivation of bone marrow cells in mineralization or osteoclastogenic media. In addition, metformin treatment was effective for the attenuation of fibroblast differentiation, but not of mesenchymal stem cells (MSCs), while alendronate had an opposite effect. The combination of metformin and alendronate had a suppressive effect on both MSCs and fibroblasts differentiation. Treatment with metformin, alendronate, and their combination decreased serum concentrations of leptin and resistin in the chronic phase of arthritis. The histopathological examination showed that compared with the untreated CIOA group (OA score 9), the groups treated with metformin (OA score 4) or alendronate (OA score 6) had lower scores for cartilage changes. Metformin combined with alendronate significantly decreased the degree of cartilage degeneration (OA score 2), suggesting that this combination might be a useful approach for the treatment of OA patients.

Serum Leptin and Resistin Levels in Knee Osteoarthritis-Clinical and Radiologic Links: Towards Precise Definition of Metabolic Type Knee Osteoarthritis.

Obesity is considered a major risk factor for the development and progression of knee osteoarthritis (OA). Apart from the mechanical effect of obesity via increase in mechanical overload of weight-bearing joints, an association with hand OA has been observed. There has been increasing interest in the role of adipokines in the pathogenesis of OA in the recent years. It has been suggested that their systemic effects link obesity and OA. In this regard, the aim of the current study was measurement and analysis of serum levels of leptin and resistin in patients with knee OA with different body mass index (BMI). Seventy-three patients with primary symptomatic knee OA at the age between 35 and 87 years (mean age 66 years) were included in the study (67 women and 6 men). The patients were from 2nd to 4th radiographic stage according to Kellgren-Lawrence scale. 43 patients were with concomitant obesity (BMI ≥ 30 kg/m2, mean values 38.34 ± 8.20) and 30 patients with BMI < 30 kg/m2 (mean values 25.07 ± 2.95). Eleven individuals with different BMIs, including cases with obesity but without radiographic knee OA, were examined as a control group. Serum levels of leptin and resistin were measured via ELISA method. In patients with knee OA and BMI ≥ 30 kg/m2, serum levels of leptin (39.546 ± 12.918 ng/mL) were significantly higher as compared with healthy individuals (15.832 ± 16.531 ng/mL, p < 0.05) and the patients with low BMI (p < 0.05). In patients with BMI < 30 kg/m2 the levels of leptin (13.010 ± 10.94 ng/mL) did not differ significantly from the respective values in the control group (p = 0.48). Serum levels of resistin were also higher in knee OA patients in comparison with healthy controls, but the difference was statistically significant only for patients with high BMI (2.452 ± 1.002 ng/mL in the group with BMI ≥ 30 kg/m2; 2.401 ± 1.441 ng/mL in patients with BMI < 30 kg/m2; 1.610 ± 1.001 ng/mL in the control group, p < 0.05). A correlation was found between the serum levels of leptin and radiographic stage of OA, i.e., higher leptin levels were present in the more advanced 3rd and 4th radiographic stage, while for resistin a correlation was observed in the patient subgroup with BMI < 30 kg/m2. Serum leptin and resistin levels and clinical characteristics were analyzed in patients with different clinical forms of OA. Novel clinical correlations have been found in the current study in patients with isolated knee OA vs. cases with presence of other disease localizations. It has been observed that patients with isolated knee OA were significantly younger and had higher BMI as compared with cases in whom OA is combined with other localizations i.e., spondyloarthritis ± presence of hip OA and with generalized OA. This supports the hypothesis that presence of obesity promotes earlier development of knee OA as an isolated localization of the disease in younger patients before appearance of osteoarthritic changes at other sites. The levels of leptin and resistin in isolated knee OA were also higher. Serum levels of leptin and resistin in combination with patients' clinical characteristics suggest existence of different clinical and laboratory profile through which more precise definition of metabolic phenotype of knee OA would be possible. Considering the fact that obesity is a modifiable risk factor that has an impact on progression of knee OA, different approaches to influence obesity may offer potential for future disease-modifying therapeutic interventions.

Inhomogeneity of capillaroscopic findings in systemic sclerosis.

BACKGROUND: Despite the great interest in capillaroscopy in systemic sclerosis (SSc), research on the possible combinations of different microvascular phenomena at different fingers in SSc patients have not been performed until now. OBJECTIVE: To assess the diversity of capillaroscopic findings in SSc. METHODS: The study includes analysis of the capillaroscopic findings in 40 SSc patients who were divided into the following categories: "scleroderma", type pattern - "early", "active", "late" phase, normal and/or nonspecific findings. The data were analyzed using descriptive statistics and t test. RESULTS: In 77% of the patients, inhomogeneity of the capillaroscopic findings of the fingers was detected. The most frequent combinations of capillaroscopic patterns were "early + active" (n = 7), "active + late" phase (n = 7), "active" phase + normal and/or nonspecific findings (n = 6), "early + active" phase + normal and/or nonspecific findings (n = 4). Concomitant presence of normal and/or nonspecific findings and "late" phase was detected in only 3 cases. CONCLUSION: Inhomogeneity of the capillaroscopic findings in SSc is a frequent phenomenon. The results indicate that combinations of "scleroderma" type capillaroscopic findings from different phases could be observed as well as concomitant appearance of pathological and normal/or nonspecific findings of different digits. This phenomenon could be a result of the complex action of different factors eg, disease duration, severity of Raynaud's phenomenon, presence of digital ulcers, local action of different angiogenic and angiostatic factors, gradual transition from one phase to another due to the extensive capillary area, therapeutic interventions.

Nailfold capillaroscopy in systemic sclerosis - state of the art: The evolving knowledge about capillaroscopic abnormalities in systemic sclerosis.

Capillaroscopy is a unique method for morphological evaluation of the nailfold capillaries that plays a crucial role for early diagnosis of systemic sclerosis. The first description of the pathological capillaroscopic changes in systemic sclerosis was made by Brown and O'Leary in 1925. Several decades later they have been validated and accepted as a diagnostic criterion in the current 2013 EULAR/ACR classification criteria. This article summarizes the evolving knowledge about the use of nailfold capillaroscopy in systemic sclerosis. Initially, Maricq et al. suggested two major categories of capillaroscopic findings in systemic sclerosis - an 'active'and 'slow' capillaroscopic pattern. Their description and terminology suggested a correlation between capillaroscopic changes and disease activity and progression. In the later classification of Cutolo et al., three phases were defined, i.e. 'early', 'active' and 'late' that reflect the time-related evolution of the capillaroscopic changes suggesting their association with disease duration. Current knowledge about the microvascular changes in systemic sclerosis supports both associations with disease activity and disease duration. The general opinion about the association of capillaroscopic findings with clinical involvement and disease activity in systemic sclerosis is not uniform. This is supposedly because the phase changes of systemic sclerosis-related microangiopathy are almost a universal feature in scleroderma and are not specific for a certain type of an accompaning clinical manifestation. Thus, the speed of progression of microvascular alterations might be a decisive criterion, and in cases of rapid dynamics of capillaroscopic findings, it could be considered as an indicator of disease activity. Interestingly, vascular 'recovery' has been observed after treatment with immunosuppressive drugs, haematopoietic stem cell transplantation, and the endothelin receptor antagonist - bosentan. The evolving knowledge about nailfold capillaroscopy in systemic sclerosis will further spread its application from a mainly diagnostic tool to an established, reliable method for evaluation of disease activity, prognosis and therapeutic response.

Mosaic capillaroscopic findings in systemic sclerosis.

A 67-year-old woman with triphasic Raynaud's phenomenon since 2 years was diagnosed as having limited cutaneous systemic sclerosis (SSc) 1 year ago based on puffy fingers, positive antinuclear and anti-Scl-70 autoantibodies, and initial pulmonary fibrosis. Capillaroscopic examination revealed "mosaic" capillaroscopic findings that included normal pattern; "scleroderma"-type capillaroscopic pattern "early" phase, with single giant capillaries and haemorrhages, preserved capillary distribution; and "scleroderma"-type capillaroscopic pattern "active" phase, with high number of giant capillary loops and haemorrhages, moderately disturbed distribution. Nailfold capillaroscopy is an established non-invasive imaging technique for morphologic evaluation of the capillaries in the nail-fold area that reveals diagnostic changes in the majority of SSc patients. It has been included in the recently published EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria for SSc (2013). The generalized microangiopathy is a cardinal feature of SSc, but the underlying endothelial damage of the capillaries varies in the different compartments of the body, sometimes even within the same organ. As typical capillaroscopic findings are diagnostic in clinical context, this case of a "mosaic" pattern should remind the clinicians that the capillaroscopic examination should be performed for the eight fingers bilaterally (excluding the thumbs because of poor visibility), in order to detect the presence of all types and grades of pathological microvascular changes to facilitate the highest diagnostic accuracy.