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-α) 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-α, who had more severe disease, had the greatest improvement in FVC and reduction in serum levels of the inflammatory proteins MIP-1β 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-α.

Fig. 1.

Association between baseline analyte concentrations and sarcoidosis. The baseline concentrations for the indicated analytes (y axes) are shown for male and female subpopulations in the healthy control and sarcoidosis cohorts. Each symbol represents an individual patient. Median and interquartile range are shown for each population. The dashed lines indicate the LDDs for the analyte. (A to F) Top 6 of 29 analytes with increased concentrations associated with sarcoidosis. (G and H) Top 2 of 6 analytes with decreased concentrations associated with sarcoidosis. (I) TNF-α concentrations were increased in sarcoidosis but below the LDD in nearly half of patients.

Fig. 2.

Change in serum analyte concentrations after 24-week infliximab treatment. Results are shown for analytes demonstrating FDRs of <0.05 (†) for differences between the infliximab treatment group (3 or 5 mg/kg) and the placebo group or P < 0.05 (*) for both the 3- and 5-mg/kg treatment groups versus placebo. The ratio of the analyte concentration after 24-week treatment to the baseline concentration per patient is expressed as the signed fold (y axis) for each treatment condition. Box (median and interquartile range) and whiskers (range) plots are presented.

Fig. 3.

Correlation between changes in analyte concentrations and clinical measures after infliximab treatment. Changes in the concentrations of MIP-1β as correlated with ppFVC (A) and 6MWD (B) and changes in the concentrations of TNF-RII as correlated with ppFVC (C) and 6MWD (D), expressed as log₂ of the week 24/baseline level (x axis), for 24-week treatment of sarcoidosis patients with placebo, 3 mg/kg infliximab, or 5 mg/kg infliximab are plotted for each patient analyzed.

Fig. 4.

Stratification by TNF-α expression. Sarcoidosis patients were stratified into subsets based on having TNF-α levels below (<) or above (>) the LDD. (A to C) The baseline ppFVC (A) and 6MWD (B) in the total study population and the baseline ePOST score (C) in sarcoidosis patients presenting with extrapulmonary involvement are shown for each patient. Medians (bars) and P values for differences between the TNF-α-defined subsets are reported. (D) Adjusted least squares means (plus 95% confidence intervals) for the change in ppFVC from baseline to week 24 after infliximab (3- and 5-mg/kg) treatment or placebo. The means were adjusted for gender, age, baseline ppFVC, and baseline therapy (OCS versus OCS plus immunomodulator), and P values for infliximab versus placebo treatment were calculated in General Linear Model analyses. (E) Changes in MIP-1β serum levels after 24-week treatment with placebo or infliximab at the indicated dose are expressed as signed fold over baseline for the TNF-α-defined subsets for each patient. Medians (bars) and P values for infliximab versus placebo treatment are shown.