Inflammatory Profile and Response to Anti-Tumor Necrosis Factor Therapy in Patients with Chronic Pulmonary Sarcoidosis

Abstract

Sarcoidosis is an inflammatory, granulomatous disease of unknown etiology that most commonly afflicts the lungs. Despite aggressive immunosuppressive therapies, many sarcoidosis patients still chronically present significant symptoms. Infliximab, a therapeutic tumor necrosis factor alpha (TNF-␣) monoclonal antibody (MAb), produced a small but significant improvement in forced vital capacity (FVC) in sarcoidosis patients in a double-blind, placebo-controlled, phase II clinical trial. In the current study, serum samples from this clinical trial were assessed to evaluate the underlying hypothesis that treatment with infliximab would reduce systemic inflammation associated with sarcoidosis, correlating with the extent of clinical response. A 92-analyte multiplex panel was used to assess the expression of serum proteins in 134 sarcoidosis patients compared with sera from 50 healthy controls. A strong systemic inflammatory profile was associated with sarcoidosis, with 29 analytes significantly elevated in sarcoidosis (false-discovery rate, <0.05 and >50% higher than controls). The associated analytes included chemokines, neutrophil-associated proteins, acute-phase proteins, and metabolism-associated proteins. This profile was evident despite patients receiving corticosteroids and immunosuppressive therapies. Following infliximab treatment, sarcoidosis patients expressing the highest levels of TNF-␣, who had more severe disease, had the greatest improvement in FVC and reduction in serum levels of the inflammatory proteins MIP-1␤ and TNF-RII. This study supports the need for further exploration of anti-TNF therapy for chronic sarcoidosis patients, particularly for those expressing the highest serum levels of TNF-␣.

Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis

“…Thirdly, only a subset of sarcoidosis patients may have TNF-a driven disease. A subset analysis of the prior infliximab trial in pulmonary sarcoidosis showed better improvement in FVC in patients with measurable serum TNF-a levels at baseline (.lower limit of detection of 4 pg?mL -1 ) [10]. The median serum TNF-a level in patients at baseline in the current study was ,5 pg?mL -1 , and those with higher levels at baseline had slightly greater improvement in FVC, but this was not consistent across all inflammatory biomarkers (table S1).…”

“…In a phase II, multicentre, randomised, double-blind, placebo-controlled study of 138 patients with chronic sarcoidosis, treatment with infliximab (a chimeric monoclonal antibody that inhibits TNF-a) resulted in a statistically significant improvement in the percentage predicted forced vital capacity (FVC) compared with placebo [1]. Improvement was also observed in other disease activity measures, such as chest radiograph reticulation (R) scores [13], MIP-1b levels [10], and serum angiotensin-converting enzyme (ACE) levels [1]. In a case series of 54 patients with lupus pernio, near or complete resolution was achieved in 77% of patients who received infliximab treatment compared with only 19% of patients receiving systemic corticosteroids [14].…”

“…Macrophage inflammatory protein (MIP)-1b, an immune cell chemoattractant (CCL4), is regulated by TNF-a [10] and higher levels of this inflammatory chemokine in some but not all sarcoidosis patients may indicate heightened activation of the TNF pathway in the subset of patients with the highest levels. TNF-a inhibition in patients with sarcoidosis has been shown to reduce disease signs and symptoms [11,12].…”

Sarcoidosis: treatments beyond prednisone and methotrexate

“…This would create opportunities for the development of biomarkers, allowing clinicians to identify who would most benefit from such therapy. A step toward that direction was taken by Loza and colleagues, who analyzed the serum of patients participating in the main infliximab trial [23,27]. The authors were able to demonstrate that patients with more severe disease expressed higher levels of tumor necrosis factor alpha (TNFα), and also had a greater response to infliximab [27].…”

“…A step toward that direction was taken by Loza and colleagues, who analyzed the serum of patients participating in the main infliximab trial [23,27]. The authors were able to demonstrate that patients with more severe disease expressed higher levels of tumor necrosis factor alpha (TNFα), and also had a greater response to infliximab [27]. Novel biomarkers, such as CXCL9, are likely to provide additional avenues for precision medicine in sarcoidosis treatment [28].…”