Treatment of ankylosing spondylitis and extra-articular manifestations in everyday rheumatology practice

The SpAs are a group of overlapping, chronic, inflammatory rheumatic diseases including AS, a chronic inflammatory disease primarily affecting the SI joints. In addition to inflammatory back pain, AS patients are also more likely to experience extra-articular manifestations belonging to the SpA concept which can affect the eyes, the gastrointestinal tract and the skin and other related inflammatory conditions. This review focuses on current progress in treatment options in SpA with special emphasis on extra-articular features. TNF inhibition has demonstrated effectiveness in the treatment of AS symptoms and all currently available anti-TNF agents appear to have similar efficacy. However, the efficacy of anti-TNF agents varies in the treatment of extra-articular manifestations and comorbidities. Analyses of trials of anti-TNF agents in patients with AS have revealed significant reductions in the incidence of flares of uveitis and IBD with infliximab and adalimumab (uveitis only) treatment but not with etanercept. All three anti-TNF agents (infliximab, adalimumab, etanercept) have demonstrated efficacy in psoriasis (not associated with AS). When evaluating as to which agent to use in the treatment of AS, an important consideration is the overall well-being of the patient. This should include any additional inflammatory burden that manifests in other parts of the body, which may currently be subclinical. Based on current evidence, among TNF inhibitors, the monoclonal antibodies (infliximab and adalimumab) are more appropriate than etanercept if extra-articular manifestations or comorbid conditions are present or suspected. To date, infliximab appears to be the best studied agent with a wide spectrum of proven efficacy

Registry Evaluation of Digital Ulcers in Systemic Sclerosis

Digital ulcers are a very frequent complication of systemic sclerosis affecting about half of the SSc patients, and about 75% of the affected patients have their first DU episode within 5 years from their first non-Raynaud symptom. The lack of adequate classification criteria as well as the lack of knowledge of the development of DU have contributed to the opening of specific registries to better understand the natural history of these lesions. For these reason, specific disease registries play a fundamental role in this field of research. Thanks to the systematic collection of data and their subsequent analysis and comparison between different cohorts, it is possible to improve understanding of the underlying trigger mechanisms of DU development and to determine temporal trends. In the future, the development of recommendations for the management of DU remains of pivotal importance to prevent DU development and obtain rapid healing as well as reduction of pain and disability

Pathophysiology of Hemophilic Arthropathy

Spontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy—a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the synovial tissue, articular cartilage, and subchondral bone, with early damages and molecular changes determining the perpetuation of a chronic inflammatory condition. Synovitis is one of the earliest complications of hemarthrosis, and is characterized by synovial hypertrophy, migration of inflammatory cells, and a high degree of neo-angiogenesis with subsequent bleeding. The pathogenic mechanisms and molecular pathways by which blood in the joint cavity causes articular cartilage and subchondral bone destruction have yet to be fully elucidated. Both cytokines and matrix metalloproteinases and hydroxyl radicals may induce chondrocyte apoptosis. Members of the tumor necrosis factor receptor superfamily (such as the molecular triad: osteoprotegerin—OPG; receptor activator of nuclear factor κB—RANK; RANK ligand—RANKL) seem instead to play a major role in the inflammatory process. These pathogenic processes interact with each other and ultimately lead to a fibrotic joint and the disabling condition characteristic of hemophilic arthropathy

Cyclophosphamide in systemic sclerosis: still in search of a 'real life' scenario

In systemic sclerosis (SSc), there is no proven treatment to prevent disease progression. In a recent meta-analysis of three randomised controlled trials (RCTs) and six open prospective studies on cyclophosphamide (CYC), no significant changes in lung function were observed. However, CYC is associated with an improvement of Mahler's dyspnea index, short form-36 (physical and mental domains), and health-related quality of life, contributing to the amelioration of patients' functional status. Further RCTs on early SSc are needed to assess the real efficacy of CYC in inducing remission and increasing survival

The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem?

In systemic sclerosis (SSc), peripheral vasculopathy is characterized by a progressive and irreversible loss of capillaries following endothelial cell injury, due to defects in both vascular repair and expected increase in new vessel growth (angiogenesis). The discovery of key molecular targets may help to develop the most effective therapeutic strategy for the SSc-related vasculopathy. A pathway worth targeting in SSc may include vascular endothelial growth factor, 165b isoform, an endogenous angiogenesis inhibitor abnormally expressed and released by different cell types, including activated endothelial cells and platelets

Circulating autoantibodies to endothelial progenitor cells: binding characteristics and association with risk factors for atherosclerosis.

OBJECTIVE: Endothelial progenitor cells (EPC) are committed to transform into EC promoting vasculogenic ischemic repair. Anti-endothelial cells (AECA) have been described in various disorders with an associated vascular damage. Herein, we explored a novel circulating population of IgG reactive with EPC, in patients with differential risk profile for atherosclerotic vascular disease. APPROACH AND RESULTS: A novel cyto-ELISA system was established where the coated cells were late outgrowth EPC. Levels of anti-EPC antibodies were determined in 100 subjects and differential risk score for atherosclerosis, as well as to circulating EPC levels and the inflammatory markers IL-6 and C-reactive protein. To study endothelial cell (EC) activating properties, sera were tested for their ability to induce VCAM-1 expression in a cell ELISA system. Detectable levels of anti-EPC antibodies, that correlated with age, Framingham risk score and CRP concentrations but did not associate with levels of LDL, HDL, hypertension or diabetes, were detected. Anti-EPC antibodies were distinct from EC binding antibodies as shown by competitive inhibition studies, and have been positively correlated with the extent of EC activation manifested by in vitro VCAM-1 expression. CONCLUSION: This is the first study showing a newly defined subgroup of self-antibodies binding EPC and associating positively with the Framingham risk score. Further studies are required to characterize and test this interesting subset of EPC binding autoantibodies and their potential significance

EARLY SCLERODERMA

Sustavna skleroza (SSc) kronična je autoimuna bolest obilježena visokim stupnjem heterogenosti i povezana s visokim morbiditetom, kao i s najvišim mortalitetom specifičnim za samu bolest, u odnosu na sve druge autoimune bolesti vezivnog tkiva. SSc moguće je jednostavno dijagnosticirati u uznapredovaloj fazi, dakle kad se već razvila obliterativna vaskulopatija te fibroza kože i unutrašnjih organa, ali teško je postaviti dijagnozu u ranoj fazi bolesti. Ta činjenica ograničuje mogućnost ranog liječenja i potencijalnog preveniranja razvoja bolesti i oštećenja tkiva. Raynaudov fenomen (engl. skr. RP) predložen je kao jedno od definirajućih kliničkih obilježja za dijagnozu „rane“ SSc te stoga pozornost valja poglavito usmjeriti na taj simptom, čak i u slučaju odsustva drugih znakova bolesti. Na temelju prethodnih dijagnostičkih kriterija dijagnoza SSc može biti postavljena nakon više godina od početka RP, pa i nakon pojave prvih simptoma nevezanih za RP. Ovaj je vremenski raskorak između pojave simptoma i postavljanja dijagnoze, ponajprije temeljen na fibrozi kože i unutrašnjih organa, „prozor mogućnosti“ koji bi mogao biti vrijeme za intervenciju u ranoj fazi bolesti te time potencijalno prevenirati oštećenje organa. Prijedlog definicije vrlo rane SSc jest stanje obilježeno RP-om, difuznom oteklinom prstiju, pozitivnim protutijelima specifičnima za bolest i patognomoničnim mirkovaskularnim promjenama vidljivima na kapilaroskopiji, a bez zahvaćenosti kože i unutrašnjih organa. U bolesnika s navedenim simptomima, radi otkrivanja pretkliničkih promjena na unutarašnjim organima u SSc, mogu se provesti i pretrage kao što su ezofagealna manometrija, ehokardiografija u B-modu i funkcijski testovi pluća. Nedavno su predloženi novi klasifikacijski kriteriji radi identificiranja bolesnika u najranijoj fazi bolesti. Međutim, prediktori tijeka bolesti i dalje su nepoznati te je stoga potrebno redovito praćenje, iako idealna učestalost kontrolnih pregleda nije utvrđena.Systemic sclerosis (SSc) is a chronic autoimmune disease, characterized by a high level of clinical heterogeneity and associated with a high morbidity along with the highest disease-specific mortality of all autoimmune connective tissue diseases. SSc is quite easy to diagnose in the advanced phase, i.e., when it has already evolved to obliterative vasculopathy and skin and internal organ fibrosis, but it is difficult to establish a diagnosis in the early phase. This limits the possibility to start early treatment, as well as the potential for prevention of disease evolution and tissue damage. Raynaud’s phenomenon (RP) has been proposed as one of the defining clinical features for the diagnosis of “early” SSc, so that particular attention should be paid to this symptom, even in the absence of other signs of the disease. Based on previous diagnostic criteria, the diagnosis of SSc can be delayed for several years after the onset of RP, and even after the onset of the first non-RP symptom. This time gap between symptoms and diagnosis, mainly based on dermal or internal organ fibrosis, is a ‘‘window of opportunity’’ that could represent a chance to intervene earlier in the disease course, thus potentially preventing organ damage. The definition of Very early SSc has been proposed as a state characterized by RP, puffy fingers, disease-specific autoantibodies, and pathognomonic microvascular alterations at capillaroscopy, without skin and internal organ involvement. In patients with the above symptoms further investigations such as esophageal manometry, B-mode echocardiography, and lung function tests are recommended to detect preclinical alterations of internal organs in SSc. Recently, new classification criteria have been proposed with the goal to identify patients in the earliest phase of the disease. However, as predictors of the future course of the disease are still unknown, patients must be followed up regularly, even though the ideal frequency of visits has not yet been established