Systemic sclerosis: markers and targeted treatments

ARTIGO DE REVISÃO Systemic sclerosis: markers and targeted treatments Cutolo M1, Sulli A1, Pizzorni C1, Paolino S1, Smith V2 ACTA REUMATOL PORT. 2016;41:18-25 abStract IntroductIon Systemic sclerosis (SSc) is characterized by autoantibody production, progressive microvasculopathy, and aberrant extracellular matrix protein (ECM) synthesis in tissues. The disease presents two major clinical hallmarks: Raynaud’s phenomenon (RP) and skin involvement, followed by varying prevalences of internal organ involvement. Despite significant advances in the management of certain organ-specific involvements and symptoms, the research for efficient markers and targets, to be used for an optimized treatment, is still ongoing. Therapies targeting the vasculature (i.e. ET-1 receptor antagonists, phosphodiesterase-5 (PDE-5) inhibitor, angiotensin-converting enzyme inhibition, prostacyclins), the immune system and/or the fibrotic process (i.e. traditional disease modifying anti-rheumatic drugs DMARDs such as methotrexate, cyclosporine or mycophenolate mofetil, biologicals like rituximab, tocilizumab or abatacept) have been or are being evaluated in SSc. Advanced approaches, reserved to unresponsive SSc patients, include autologous haematopoietic stem cell transplantation (HSTC) and intravenous immunoglobulins (IVIG). Interestingly, it is expected that new and future possible diagnostic and therapeutical approaches in SSc will come from epigenetic studies (MicroRNAs). Ideally, combination therapy in SSc seems the best approach, together with the early intervention on the major hallmarks of the disease in “at risk” patients, that consists of the microvascular damage/altered function and the autoimmune reaction, followed by the progressive and systemic fibrotic process. Systemic sclerosis (SSc) is a connective tissue disease (CTD) with autoimmune reactivity, chronic vascular and tissue stromal progressive alterations. These processes lead to autoantibody production, progressive microvasculopathy, and aberrant extracellular matrix protein (ECM) deposition with subsequent severe organ damage in skin, lungs, gastrointestinal tract and several other internal organs. Research is still ongoing to define the initiating cause of the pathophysiological cascade and despite significant advances in the management of certain organ-specific involvements and symptoms, SSc remains the CTD with the higher morbidity and mortality1,2. Systemic sclerosis is an orphan disease with an annual incidence of 19 per million and prevalence of 19-75 per 100,000. The female:male ratio is 3:1, and 8:1 in mid to late childbearing years. Interestigly, juvenile SSc (children < 16 years old) is even more rare and one of the worst rheumatological conditions in children3. Based on the argument that the past SSc classification criteria did not meet current standards for clinimetric properties, recently, new classification criteria based on a collaboration between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have been introduced4. The sensitivity and specificity of the classification criteria have been significantly improved after this revision, and by introducing the analysis of the microvascular damage as detected by the presence of teleangectasia and capillarscopic features. Additionally, to overcome the issue of properly classifying subjects with subclinical disease, Very Early Disease Onset Systemic Sclerosis (VEDOSS) criteria have been proposed5. Keywords: Systemic sclerosis; Capillaroscopy; Raynaud phenomenon; Targeted therapies; Connective tissue diseases; Autoimmune diseases. 1. Research Laboratories and Academic Division of Clinical Rheumatology - Department of Internal Medicine and Specialities – IRCCS San Martino – University of Genova, Italy 2. Department of Rheumatology, Ghent University Hospital; Department of Internal Medicine, Ghent University – Ghent, Belgium SyStemIc ScleroSIS hallmarkS Systemic sclerosis is clinically characterised by two ma- ÓRGÃO OfICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 18 Cutolo M et al jor hallmarks: Raynaud’s phenomenon (RP) and skin involvement, followed by varying prevalences of internal organ involvement. Based on the extension on skin involvement patients with SSc can be classified into limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) involvement. Patients with dcSSc with severe organ involvement may have the worst prognosis. The vast majority of patients with SSc have RP (bi or tri-phasic colour changes of extremities upon exposure to cold or stress)6. It is noteworthy that the RP may occur in a healthy population (without any association with CTD) or in secondary Raynaud's phenomenon (SRP) (mostly due SSc). The key point as a clinical medical doctor or specialist is to be able to make this differential diagnosis. The combination of capillaroscopy and serology allows to do so. Moreover, this combination also allows to pinpoint those patients who only have RP at baseline, without any sign of another CTD, who will progress to a secondary over long time follow up (13.6% of patients with isolated RP at baseline)7. Next to RP and skin involvement, other clinical complications are frequent in SSc. Digital ulcers (DU) and gastrointestinal involvement occur frequently. DU occur in a major part of SSc patients in their disease course. They are associated with an important morbidity (pain, reduced quality of life, disability and disfigurement) and may evolve into tissue necrosis and amputation8. Gastrointestinal involvement is frequent in scleroderma (almost 90%) and in 10% of cases is the presenting feature of the disease9. Of note, several patients are asymptomatic, ranging from 20% for small bowel to half for esophageal involvement. Most frequent gastrointestinal organs affected in SSc are the oesophagus, followed by the anorectum and the small bowel, whereas severe gastrointestinal involvement luckily affects only 8% of the patients, but is associated with a high mortality, with a 9 year survival of only 15%. Also, the risk of malnutrition is high in SSc, with over 28% of patients being at medium or high risk of malnutrition. Other complications are less frequent but linked with high mortality in SSc and should therefore be screened for. Among those pulmonary arterial hypertension (PAH), severe lung fibrosis, myocardial involvement and scleroderma renal crisis are associated with high mortality10. Screening for these afflictions is recommended. In this way screening for PAH is standardly incorporated into daily SSc management and screening according to highly performant the DETECT algorythm which encompasses echocardiography, pulmonary functional tests and optionally BNP or NT-proBNP. Even though, at present, no therapies have attested to be able to stop the natural progression of the disease, still there are organ specific effective treatments. Both for PAH and digital trophic lesions therapies have attested treatme (...truncated)