Current Rheumatology Reviews - Volume 9, Issue 4, 2013

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis, autoimmunity and vascular damage. Although fibrosis is often considered the main feature of the disease, there is evidence that the underlying vasculopathy plays an important role in the initiation and perpetuation of SSc. Vascular manifestations such as Raynaud’s phenomenon and digital ulcers are prominent in early disease stages and might substantially contribute to the SSc related mortality in later disease stages when pulmonary arterial hypertension becomes clinically evident. Vascular damage is thought to start with endothelial cell injury and apoptosis resulting in tissue hypoxia. Hypoxia is considered a main stimulus for vascular regenerative processes. However, despite the significant deterioration in number and quality of microvessels, there is a lack of appropriate compensatory repair processes by angiogenesis and vasculogenesis. In this review, we will discuss recent data about the pathophysiology of peripheral (acral) microvascular damage in SSc, highlight novel aspects behind the defective repair mechanisms in the vascular system in SSc and focus on SSc animal models with peripheral vascular changes.

Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that is very difficult to diagnose in the early phase, because of the low sensitivity of the classification criteria currently used to identify patients without skin involvement, with an important delay on the therapy that is often started when internal organ involvement has already irreversible. The biggest challenge in the fight against SSc is to detect valid predictors of disease so as to treat patients since the earliest stages of disease. Raynaud’s phenomenon (RP), antinuclear antibodies (ANA) positivity, and puffy fingers have been recently indicated as the“red flags”, the main elements to suspect SSc and then to perform further tests to confirm the diagnosis in particular nailfold video capillaroscopy and evaluation of specific disease antibodies (anticentromere and anti-topoisomerase I). Particularly, RP is the earliest, even if aspecific sign of SSc, and more and more attention should be paid to its early identification in order to reduce the diagnostic delay. Besides, the time gap between the onset of RP and the diagnosis should be considered as a “window of opportunity” for SSc patients, through which the physician can act with effective drugs able to block or at least slow the progression of the disease.

Nailfold microvascular impairment represents an early feature of systemic sclerosis (SSc) and its progression through different patterns of capillary damage and their validated scoring, is evaluable by nailfold videocapillaroscopy (NVC) in a safe and reliable manner. The presence of specific morphological microvascular alterations at the NVC (i.e., presence of giant capillaries) is fundamental and mandatory for the early diagnosis of SSc, together with the presence of the Raynaud's phenomenon. Furthermore, a recent longitudinal study showed a dynamic transition of microvascular damage through different NVC patterns of microangiopathy in almost 50% of SSc patients and clinical symptoms progressed in accordance with the NVC morphologic changes in 60% of the SSc patients. A pilot study was the first demonstrating an association between baseline NVC patterns and future severe, peripheral vascular and lung involvement with stronger odds according to worsening scleroderma patterns. Prognostic indexes for digital trophic lesions, especially for daily use in SSc clinics and simply limited to the mean score of capillary loss are now validated. Very recently, it has been described that efficacious potentially disease modifying therapies in SSc may interfere with progression of nailfold microvascular damage, as assessed by NVC, over long term at least in presence of digital ulcers. NVC is a safe and reliable tool for the early diagnosis of SSc and the different NVC scleroderma patterns have a predictive value for the clinical complications of the disease.

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.

Introduction: Diagnosis of systemic sclerosis (SSc) at very early stage could allow starting an appropriate therapy and improving the patient outcome. Skin involvement is often the first non-Raynaud’s phenomenon (RP) symptom. Its uncovering may play an important role for the initial diagnosis. Objective: To introduce a simplified method for non-invasive evaluation of skin mechanical properties in patients with clinically evident or suspected SSc. Material and Methods: A total of 94 patients and 162 healthy subjects were studied. According to clinical and nailfold videocapillaroscopy findings the patients were divided into four groups: 20 with edematous phase of SSc (group 1), 28 with indurative phase of SSc (group 2), 26 with suspected secondary RP (group 3), and 20 with primary RP (group 4). Mechanical properties of the volar forearm skin were evaluated using a non-invasive suction device (Cutometer) equipped with 2-mm diameter probe. The skin mechanical parameters analyzed were distensibility (Uf), elasticity (Ua/Uf) and viscoelasticity (Uv/Ue). Results: Skin distensibility was reduced and skin viscoelasticity increased in group 1-3 compared to age matched healthy controls. There were no significant changes in skin elasticity. Mechanical parameters in group 4 were normal. Comparison of individual patient’s values with population 95% confidence intervals of the mean showed increased skin viscoelasticity in group 1 (100%), group 2 (93%), and group 3 (81%), whereas the incidence in group 4 was 10%. Conclusions: Noninvasive method applied is appropriate for objective and quantitative evaluation of sclerodermatous skin. In combination with nailfold videocapillaroscopy it could be predictive in pre-scleroderma patients. The increased skin viscoelasticity parameter could be proposed as the possible new fifth sign for the very early diagnosis of SSc.

Digital ulcers (DUs) are frequent and recurrent complication in systemic sclerosis (SSc) and are the main cause of pain, impaired function of the hand and disability in SSc. The current study is a retrospective analysis of 60 SSc patients (47 patients with limited cutaneous SSc, 8 patients with diffuse cutaneous SSc and 5 patients with overlap syndrome, mean age 54.5±14.2 years, 52 women and 8 men). The frequency and evolution of DUs as well as the applied therapeutic strategies were analyzed. During the follow-up for a period between 6 months and 6 years, DUs at the fingers were registered in 35% of patients (21/60), more often in patients with diffuse cutaneous SSc (75%, 6/8) as compared with patients with limited cutaneous SSc (29%, 14/47, p<0.05) and overlap syndrome (20%, 1/5). The most frequently observed DUs were ischemic lesions at the fingerpads (85.7%, 18/21) and ulcerations over bony prominences of the fingers (23%, 5/21), which may be found simultaneously. More rare types of DUs were necrotic lesions (14%, 3/21). Thirty-eight percents (8/21) of the patients with DUs showed signs of inflammation. In one patient (4.76%, 1/21) an osteomyelitis developed and an amputation of a finger’s distal phalanx was performed. DUs at the toes were significantly less frequent as compared with DUs at the fingers (10%, 6/60, p<0.05). The period of healing of the DUs is prolonged and in the studied group was 3.39±2.39 months. The treatment regimen in SSc patients with DUs included vasodilators, local antiseptic treatment, antiplatelet drug; anticoagulant in cases with development of necrotic lesions, antibiotics in cases of infection or necrotic lesions, and other symptomatic therapies. In conclusion, DUs are a common complication in SSc and require complex therapeutic measures for achievement of a positive outcome.

Digital ulcers (DUs) are among the most frequent and disabling vascular complications in patients with systemic sclerosis (SSc). The etiology and pathogenesis of DUs differs depending on the lesion localization. For this reason the underlying etiologic and pathogenetic factors will guide the therapeutic decision. The main pathogenic mechanism that contributes to the development of fingertip DUs is ischemia owing to SSc-related vasculopathy. DUs over bony prominences are mainly a result of skin fibrosis, epidermal thinning and mechanical friction. At the areas of subcutaneous calcinosis DUs can develop as a result of mechanical friction and inflammation. Thus, in cases of DUs over bony prominences and calcinosis, avoidance of trauma and skin care are main measures of primary prophylaxis. In pure ischemic DUs, a combination of vasodilators (calcium channel blockers (CCBs), intravenous prostanoid, phosphodiesterase inhibitors) and antiplatelet drugs should be applied. Despite the lack of controlled trials addressing the administration of antiplatelet agents and anticoagulants in DUs in the context of SSc, the current knowledge about the platelet and coagulation dysfunction leads to their frequent administration from the leading experts in the field of SSc. In our opinion, as more powerful agents, anticoagulants should be considered in severe cases of development of digital gangrenes. Analgetics and antibiotics may be indicated and local treatment is a mandatory care. Currently, the EUSTAR recommendations for the treatment of RP and DUs in SSc include CCBs, intravenous prostanoids and endothelin receptor antagonists. Although for the inclusion of other options in the official recommendations, their efficacy should be confirmed by controlled clinical trials, they are routinely used in the leading scleroderma-centers based on the current knowledge about the pathogenesis of development of DUs in SSc.

Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science®, PubMed® and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science® or PubMed® or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics.

Introduction: Cervical intraepithelial neoplasia (CIN) is increased in women with systemic lupus erythematosus (SLE). Cervical neoplasia is caused by human papilloma virus (HPV) infection which persists and causes malignant transformation of infected cervical cells. Women with lupus have impaired immune systems which can facilitate HPV persistence. We hypothesized that women with SLE who developed CIN would be younger, have more severe disease and received more immunosuppressive treatment. To test this hypothesis, a case-control study was conducted focusing on two key variables, SLE disease severity and immunosuppressive treatment, which we believed would be the major determinants of CIN development in SLE. Methods: A case control analysis was performed to compare the clinical characteristics of SLE women with cervical neoplasia (cases) to SLE women without cervical neoplasia (controls). Formalin fixed blocks of neoplastic cervical tissue were obtained from 113 women with SLE and tissue histology confirmed by 2 pathologists. Clinical data was obtained by retrospective chart reviews. Logistic regression was used to evaluate for any significant differences in clinical variables between the cases and the controls. Two sets of controls were used for comparison with a 2:1 match for each control group to cases group. Results: Using matched controls adjusting for age and race, logistic regression analysis showed no significant difference between cases and controls for any of the clinical variables. In particular, there were no significant differences between cases vs. matched and vs. unmatched controls for factors related to SLE (disease severity, use of immunosuppressive drugs), chronic metabolic diseases (hypertension, diabetes) and HPV risk factors (marital status, smoking, gravidity parity). Conclusion: The key finding of this study is that SLE patients who develop CIN are not clinically different from SLE patients who do not develop CIN. Thus, lupus disease severity and immunosuppressive treatment were not susceptibility factors for CIN in our female lupus cohort.