Systemic sclerosis (scleroderma)

What changes during this transition

Systemic sclerosis is the most editorially constrained autoimmune substrate Juno carries, and it should be. The disease is multisystem, life-shortening when poorly controlled, and managed at the leading edge of rheumatology with a stack of validated therapies that no peptide adjunct should disturb. The autoimmunity-plus-vasculopathy-plus-fibrosis triad means three different pathogenic processes need to be addressed simultaneously, and the antibodies define the risk profile. Anti-centromere antibodies (ACA) cluster with limited cutaneous SSc and predict late pulmonary arterial hypertension. Anti-topoisomerase I (Scl-70) antibodies cluster with diffuse cutaneous SSc and predict interstitial lung disease. Anti-RNA polymerase III antibodies cluster with diffuse skin disease, scleroderma renal crisis, and a documented cancer association that changes surveillance. Three safety threads are load-bearing across this batch and across any SSc conversation. First, STEROID AVOIDANCE in dcSSc. High-dose glucocorticoids increase scleroderma renal crisis risk. This is one of the recognized iatrogenic disasters in rheumatology and the reason modern SSc protocols use steroid-sparing immunosuppression (mycophenolate, cyclophosphamide, tocilizumab, rituximab) rather than the steroid-heavy approach common in other rheumatic diseases. Second, PAH ANNUAL SCREENING. Pulmonary arterial hypertension carries the highest mortality of any SSc complication after ILD, and it's silent until late. The standard is annual transthoracic echocardiography with TAPSE measurement plus NT-proBNP, with right heart catheterization confirmatory. Patients with anti-centromere antibodies are at particular risk. Third, ILD HRCT SURVEILLANCE. Interstitial lung disease is the leading cause of SSc mortality. The diagnostic workup pairs HRCT (NSIP pattern more common than UIP) with PFTs and DLCO; surveillance PFTs every 3-6 months on active treatment catch progression before symptoms. The paradigm shifts in the past five years matter for the editorial honesty of this entry. Tocilizumab (Actemra) — anti-IL-6 receptor monoclonal antibody — gained FDA approval September 2021 for SSc-ILD via the focuSSced trial. This was the first IL-6 receptor antagonist approved in the indication and reframed SSc as a disease where cytokine-targeted therapy works, not just broad immunosuppression. Nintedanib (Ofev) — multi-kinase inhibitor targeting PDGFR, FGFR, and VEGFR — gained FDA approval September 2019 for SSc-ILD via the SENSCIS trial. This was the first anti-fibrotic in the SSc indication and provided a non-immunosuppressive lever for fibrotic progression. Mycophenolate remains first-line for skin plus ILD based on the Scleroderma Lung Study II head-to-head against cyclophosphamide. Cyclophosphamide retains a role for severe ILD. Autologous hematopoietic stem cell transplantation (AHSCT), validated in the ASTIS and SCOT trials, demonstrated mortality benefit for severe rapidly progressive dcSSc with cardiopulmonary involvement and is offered at specialized centers. Rituximab (anti-CD20 B-cell depletion, RECITAL trial), abatacept (CTLA4-Ig T-cell costimulation blockade, ASSET trial), JAK inhibitors, and early CAR-T (anti-CD19) trials in refractory SSc round out the emerging landscape. None of these are peptide therapies. The PAH treatment landscape is its own discipline — endothelin receptor antagonists (bosentan, ambrisentan, macitentan), PDE5 inhibitors (sildenafil, tadalafil), soluble guanylate cyclase stimulators (riociguat), prostacyclin receptor agonists (selexipag), with upfront combination therapy now standard for higher-risk patients. SSc patients with PAH belong in PAH-specialized care. The substrate entries for the five peptides in this batch (BPC-157, TB-500, thymosin alpha-1, LL-37, NMN) all return some version of the same answer: the rheumatologist is the right partner, the validated therapies have transformed prognosis, and peptide adjuncts have no SSc trial anchor and several disease-specific reasons to be cautious. This is the 37th deliberate non-elevation in the substrate program.