Activation of the complement cascade is thought to play a role in scleroderma vasculopathy. We previously showed that complement factor D was elevated in patients with limited cutaneous SSc and pulmonary arterial hypertension (PAH). In this study, we sought to assess multiple relevant components of the complement cascade to determine if they are altered in SSc-PAH, as well as their potential utility as biomarkers of disease severity and progression.
Complement components (n = 14) were measured using multiplex assays in 156 patients with SSc-PAH from a multi-site repository and were compared to 33 patients with SSc without PAH, and 40 healthy controls. Data were evaluated for correlations between complement levels, right heart catheterization measures, and clinical endpoints including 6-minute walk distance. To assess complement longitudinally, serum complement levels were assayed at 0, 4, 12, 24, 36 and 48 weeks in 52 SSc-PAH patients who participated in a prior clinical trial.
We found that factor D was significantly elevated in SSc-PAH compared to SSc without PAH (p < 0.0001) and was highly sensitive and specific for SSc-PAH (AUC=0.82, p < 0.001). In SSc-PAH patients, alterations in factor H, C4, and factor D were associated with measures of PAH disease severity including right heart catheterization measurements (cardiac output, right atrial pressure, and VO2 max), survival, and 6-minute walk distance. No significant changes in complement levels or clinical associations were seen over time or associated with treatment in the longitudinal clinical trial study.
Our work confirms prior studies demonstrating a role for complement activation in SSc vascular disease and elevations of factor D in a large SSc-PAH population. Further, factor H and other complement factors are associated with severity of PAH including mortality. Taken together, these findings suggest that the alternative complement pathway plays a role in SSc-PAH pathogenesis and may serve as a biomarker to inform diagnosis and prognosis.
To review the evidence on barriers and facilitators to application of treat-to-target (T2T) in axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) in daily practice.
A systematic search was conducted in MEDLINE/Embase up to December 2023, focusing on axSpA/PsA. Any type of quantitative/qualitative original research was eligible for inclusion if barriers or facilitators to application of T2T were explored. In a qualitative synthesis, barriers/facilitators were classified by the level to which they apply (healthcare provider [HCP], patient, organisation).
Of 28 included studies, most focused on PsA (n = 21/28). Studies included patients (n = 23/28), HCP (n = 4/28) or both (n = 1/28). In total, over 25 barriers and 15 facilitators to application of T2T were identified. At the HCP level, most studies focused on the measurement of the target, especially in PsA, highlighting that agreement among instruments was suboptimal. At the patient level, the role of patient-reported outcomes (PROs), while deemed relevant, was shown to act as a barrier to achieve targets that included PRO components. At the organisational level, the increased time and resources needed for T2T were considered a barrier, although it was noted that T2T could also reduce healthcare use and sick leave. Notably, for several components, no facilitators were identified at all.
Various barriers and facilitators were identified, acting on several levels. Data in axSpA were scarce, as was evidence on certain components of T2T. Future research should address these knowledge gaps and explore how these barriers and facilitators could be targeted to improve application of T2T in practice.