Current and Future Outlook on Disease Modification and Defining Low Disease Activity in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is an autoimmune rheumatic disease with heterogeneous clinical manifestations and a variable course in which the severity of the pathology dictates the disease prognosis and course. Among autoimmune rheumatic diseases, SSc has the highest mortality rate among all rheumatic diseases, though there are exciting new therapeutic targets that appear to halt the progression of SSc manifestations such as skin or lung fibrosis. In selected patients, high-intensity regimens with autologous stem cell transplantation can favorably modify the course. In what was once thought to be an untreatable disease, targeted therapies have now changed the outlook of SSc to a treatable disorder. Herein, we discuss the targeted therapies modifying the outlook on selected organ involvement and creating opportunities for future treatment. We also present a framework for defining low disease activity in SSc.

Figure 1:. The usual timing of organ-specific manifestations in systemic sclerosis

ILD Interstitial Lung Disease, GIT gastrointestinal tract, PBC Primary Biliary Cirrhosis (Adapted from Steen V, Medsger TA. Systemic Sclerosis: Lippincott Williams & Wilkins; 1996)

Figure 2:. The long-term impact of ideal disease-modifying therapy in predominately fibrotic phenotype on SSc outcomes (in comparison to HSCT)

DMT Disease Modifying Therapy, HSCT Hematopetic Stem Cell Therapy, DLCO diffusion capacity for carbon monoxide, FVC forced vital capacity, MRSS Modified Rodnan Skin Score, HAQ Health Assessment Questionnaire

Figure 3:. Low disease activity state in systemic sclerosis

These are author-driven preliminary proposals, influenced by the data from RCTs and observational studies. These proposals will need rigorous testing and validation using a consensus methodology in future studies. LDA = low disease activity, SSc = systemic sclerosis, mRSS = modified Rodnan skin score, HAQ-DI Health Assessment Questionnaire Disability Index, PGA = patient global assessment, ILD = interstitial lung disease, FVC% pred = forced vital capacity percentage predicted, TLC% pred = total lung capacity percentage predicted, RP = Raynaud’s phenomenon, RCS = Raynaud’s Condition Score, DU = digital ulcers, VAS = visual analog scale, SHAQ = Scleroderma Health Assessment Questionnaire PAH = pulmonary arterial hypertension, PAP = pulmonary arterial pressure, PVR = pulmonary vascular resistance, BNP = brain natriuretic peptide, NT-Pro-BNP = N-terminal pro brain natriuretic peptide, RV = right ventricle, NYHA = New York Heart Association, REVEAL = Registry to Evaluate Early and Long-Term PAH Disease Management, SRC = scleroderma renal crisis *Chosen arbitrarily as mid-point between P Khanna et al’s estimate of the PASS and Pauling et al’s seasonal data