Understanding the totality of systemic sclerosis (SSc) is key to successful diagnosis and management of this rare disease.
Systemic sclerosis is one of the most complex, systemic autoimmune diseases in which inflammation and fibrosis play a crucial role, leading to severe damage and failure of multiple organs.1,2 Its cause is unknown, and it is characterized by immune system activation, vasculopathy, and widespread tissue fibrosis of the skin and certain internal organs. More than 75% of patients with SSc are women.3
The understanding of the pathogenesis of SSc has improved in recent years, though many questions remain. Historically, SSc was considered a fibrotic disease4; however, the paradigm changed after the discovery of the participation of immune response cells and inflammatory mediators, fibroblasts, and other components of extracellular matrix (ECM) and the major role of endothelial damage.2,5 It is now viewed as a complex disease driven by both immune dysregulation and fibrosis.2
The most accepted working hypothesis of the pathogenic process of SSc suggests that a triggering event occurs and causes activation of specific cells of the immune system and ECM. Chronic activation of immune cells and release of proinflammatory and fibrotic mediators can lead to vasculopathy and scarring, also known as fibrosis, organ damage and even loss of organ function.6-9
Early diagnosis can lead to the earlier evaluation of internal organ involvement and treatment. SSc can present with heterogeneous clinical manifestations, making early and accurate diagnosis challenging. Cardinal manifestations like Raynaud phenomenon and gastroesophageal reflux disease often present early in patients, but are also commonly observed among the general population.4 Some patients present with inflammatory skin disease, puffy and swollen fingers, musculoskeletal inflammation, or constitutional manifestations such as fatigue, which may result in a referral to a rheumatologist.1 Other patients present with end organ manifestations, which may include pulmonary arterial hypertension (PAH) and renal failure due to renal crisis.11,12 Pulmonary fibrosis is a common complication of SSc, with up to half of this population developing interstitial lung disease (ILD), the most common cause of mortality in patients.13
Once SSc is suspected, patients are often assessed according to the American College of Rheumatology/European League Against Rheumatism classification criteria. However, not all patients diagnosed with SSc will fulfill this criteria the first time they are assessed, highlighting the importance of follow-up visits. Tests to confirm diagnosis include blood tests (to detect elevated levels of specific antibodies or assess kidney function), pulmonary function tests, electrocardiogram, echocardiogram, and gastrointestinal procedural tests.
Patients diagnosed with SSc should receive pulmonary function tests to evaluate lung restriction and a reduction in diffusion capacity. Additional tests include echocardiogram and brain natriuretic peptide for a pulmonary hypertension (PH) screen, high-resolution computed tomography of the chest for interstitial lung disease, and right heart catheterization for PH.
While gastrointestinal tract involvement is not part of the classification criteria, screening for esophageal dysmotility can be helpful diagnostically.
Research has shown that patients with SSc often need a healthcare team, of which rheumatologists are critical members.14,15 Treating SSc requires a thoughtful approach carefully tailored to patient needs.16 This might be best illustrated by the management of gastrointestinal tract concerns in SSc where the gastroenterologist and rheumatologist work together.17
In addition, ancillary services such as occupational therapy, lymphedema clinic, wound care, dietary services, and pulmonary rehabilitation may be indicated based on specific clinical features such as joint contractures, edema, digital ulcers, malnutrition, and pulmonary disease, respectively. Scleroderma centers can help coordinate these services for patients with SSc, along with providing access to clinical trials.18
Current treatments address the symptoms of SSc, but not the underlying mechanisms that drive inflammation and fibrosis as seen in Table 1.2,19,20
Hematopoietic stem cell transplantation (HSCT) may be considered for patients with rapidly progressive SSc at risk for organ failure19; however, HSCT should only be considered at high-volume centers.
The field is hopeful because there are new potential treatment mechanisms being tested in clinical trials, including those that are designed to modulate inflammation and fibrosis without immunosuppression.
Clinical Manifestation Therapy Skin (scleroderma) Immunosuppressive therapies (IST) eg, methotrexate Musculoskeletal (inflammatory arthritis) IST eg, methotrexate Renal (scleroderma renal crisis) Angiotensin-converting enzyme inhibitors Gastrointestinal (GERD) Lifestyle modifications, proton-pump inhibitors Peripheral vascular (Raynaud phenomenon, digital ulcers, critical ischemias) Calcium channel blockers, phosphodiesterase 5 inhibitors, angiotensin II receptor blockers, endothelin receptor antagonists Pulmonary (ILD, PAH) Tyrosine kinase inhibitors, immunosuppressive treatment (eg, mycophenolate mofetil, cyclophosphamide), endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogs, soluble guanylate cyclase agonists Cardiovascular (heart failure, inflammatory cardiac disease) Drug therapies (eg, angiotensin-converting enzyme inhibitors and diuretics) and IST (eg, corticosteroids and/or cyclophosphamide)
Editor’s Note: Visit www.totalssc.com, a physician resource for a comprehensive look at totality in SSc.
- Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:272.
- Sierra-Sepulveda A, Esquinca-Gonzalez A, Benavides-Suarez SA, Sordo-Lima DE, Caballero-Islas AE, Cabral-Castaneda AR, et al. Systemic sclerosis pathogenesis and emerging therapies, beyond the fibroblast [published January 23, 2019]. Biomed Res Int. doi:10.1155/2019/4569826
- Peoples C, Medsger TA, Jr., Lucas M, Rosario BL, Feghali-Bostwick CA. Gender differences in systemic sclerosis: Relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord. 2016;1(2):177-240.
- Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699.
- van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747-1755.
- Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Ann Rev Pathol. 2011;6:509-537.
- Asano Y. Systemic sclerosis. J Dermatol. 2018;45(2):128-138.
- Jimenez SA. Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis [published September 23, 2013]. ISRN Rheumatol. doi:10.1155/2013/835948
- Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557-567.
- Bellando-Randone S, Guiducci S, Marco Matucci-Cerinic M. Very early diagnosis of systemic sclerosis. Pol Arch Intern Med. 2012;122:18-23.
- Domsic RT, Nihtyanova SI, Wisniewski SR, Fine MJ, Lucas M, Kwoh CK, et al. Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis. Arthr Rheumatol. 2014;66(6):1616-1624.
- Cavagna L, Codullo V, Ghio S, Scire CA, Guzzafame E, Scelsi L, et al. Undiagnosed connective tissue diseases: High prevalence in pulmonary arterial hypertension patients. Medicine (Baltimore). 2016;95(39):e4827.
- Tackling systemic sclerosis from all angles. Editorial. Lancet Rheumatol. 2020;2(3):e121.
- Thombs BD, Jewett LR, Assassi S, Baron M, Bartlett SJ, Maia AC, et al. New directions for patient-centred care in scleroderma: the Scleroderma Patient-centred Intervention Network (SPIN). Clin Exp Rheumatol. 2012;30(2 Suppl 71):S23-29.
- Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016;55(10):1906-1910.
- Shah AA, Wigley FM. My approach to the treatment of scleroderma. Mayo Clin Proc. 2013;88(4):377-393.
- Sakkas LI, Simopoulou T, Daoussis D, Liossis SN, Potamianos S. Intestinal involvement in systemic sclerosis: A clinical review. Dig Dis Sci. 2018;63(4):834-844.
- Allred D, Frech TM, McComber C, Peterson K, Ortiz G, McNeill C, et al. Chronic multiorgan rare disease: The role of the nurse practitioner as a leader of the healthcare team. J Med Pract Manage. 2017;32(6):413-416.
- Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-1339.
- Smith V, Scire CA, Talarico R, Airo P, Alexander T, Allanore Y, et al. Systemic sclerosis: state of the art on clinical practice guidelines. RMD Open. 2018;4(Suppl 1):e000782.
- Eldoma M, Pope J. The contemporary management of systemic sclerosis. Expert Rev Clin Immunol. 2018;14(7):573-582.