Correlations between changes in cytokines and clinical outcomes for early phase (proof of concept) trials in active diffuse systemic sclerosis using data from an imatinib study

Pope, Janet; Walker, Kevin D.; Leon, Faye de; Vanderhoek, Louise; Seney, Shannon; Summers, Kelly L.

doi:10.1093/rheumatology/keu216

Cited by 7 publications

(5 citation statements)

References 18 publications

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“…Although it is still a controversial issue in the literature, some studies have indirectly suggested the potential usefulness of TGF- β 1 levels as a biomarker. This came to light when they evaluated the reduction of TGF- β 1 after specific treatments [18, 19]. Most of the studies have failed to establish a relationship between TGF- β 1 serum levels and clinical features in SSc patients [7–9] but, in our study, we demonstrated a significant association between higher serum TGF- β 1 levels and diffuse subset, digital ulcers, lung fibrosis, skin involvement, and positive antitopoisomerase I.…”

Section: Discussionsupporting

confidence: 52%

Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Dantas

Gonçalves²,

Almeida³

et al. 2016

Disease Markers

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Objective. To determine active TGF-β1 (aTGF-β1) levels in serum, skin, and peripheral blood mononuclear cell (PBMC) culture supernatants and to understand their associations with clinical parameters in systemic sclerosis (SSc) patients. Methods. We evaluated serum samples from 56 SSc patients and 24 healthy controls (HC). In 20 SSc patients, we quantified spontaneous or anti-CD3/CD28 stimulated production of aTGF-β1 by PBMC. The aTGF-β1 levels were measured by ELISA. Skin biopsies were obtained from 13 SSc patients and six HC, and TGFB1 expression was analyzed by RT-PCR. Results. TGF-β1 serum levels were significantly higher in SSc patients than in HC (p < 0.0001). Patients with increased TGF-β1 serum levels were more likely to have diffuse subset (p = 0.02), digital ulcers (p = 0.02), lung fibrosis (p < 0.0001), positive antitopoisomerase I (p = 0.03), and higher modified Rodnan score (p = 0.046). Most of our culture supernatant samples had undetectable levels of TGF-β1. No significant difference in TGFB1 expression was observed in the SSc skin compared with HC skin. Conclusion. Raised active TGF-β1 serum levels and their association with clinical manifestations in scleroderma patients suggest that this cytokine could be a marker of fibrotic and vascular involvement in SSc.

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Section: Discussionsupporting

confidence: 52%

Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Dantas

Gonçalves²,

Almeida³

et al. 2016

Disease Markers

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show abstract

“…However, also in this situation, the low number of cases does not permit postulating a class-specific immunosuppressant effect. Similar observations have been described for plasma sVCAM-1 concentrations after treatment with imatinib [ 46 ], prostanoids [ 47 ], and nifedipine [ 48 ]. The numerical decline of ANA titers in our study during immunosuppression may additionally indicate a systemic effect on plasma cell activity.…”

Section: Discussionsupporting

confidence: 82%

Serum Soluble Vascular Cell Adhesion Molecule-1 Overexpression Is a Disease Marker in Patients with First-Time Diagnosed Antinuclear Antibodies: A Prospective, Observational Pilot Study

Oleszowsky

Seidel

2018

BioMed Research International

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Objective Antinuclear antibodies (ANA) serve as screening tests for connective tissue diseases but have low specificity. In this pilot study, we aimed to identify patients with first-time positive ANA and musculoskeletal complaints and correlate serum soluble vascular adhesion molecules as biomarkers. Methods Prospective, observational study with 100 ANA-positive patients, comparing them to age- and gender-matched healthy controls (HC, n = 75), was conducted. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), endothelial-leukocyte adhesion molecule-1 (sELAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) were measured. A subgroup of patients with systemic sclerosis (SSc) treated with immunosuppressants was followed over 10 months. Results Patients belonged to three main entities: rheumatoid arthritis (RA, n = 32), collagen diseases (CD, n = 56) also including systemic sclerosis (SSc, n = 11), and other autoimmune diseases (n = 12). sICAM-1 was similar among groups. sELAM-1 was elevated by 1.9-fold in only in SSc. sVCAM-1 was elevated by 3.1-fold in RA and by 3.3-fold in CD and in other autoimmune diseases by 3.4-fold. Seven SSc patients with immunosuppression had a 2.7-fold increased sVCAM-1 at baseline and reached the levels of healthy controls after 5 months, while CRP, ESR, and clinical parameters remained unchanged. Conclusion Our study suggests that sVCAM-1 is a disease marker independent of standard serum parameters in several rheumatic diseases. This study is registered with EU PAS Register number: EUPAS22154.

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“…T cells from mice lacking Abl kinases, a molecular target of imatinib and nilotinib, exhibit defective activation in response to T cell receptor stimulation 38 . In a 6-month clinical trial of imatinib for the treatment of dcSSc, Pope, et al found that the change in plasma levels of soluble CD40L was significantly negatively correlated with change in the physician’s global assessment 39 . This suggests that individuals with increased serum CD40L (and multianalyte signatures) may benefit from imatinib and nilotinib treatment.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment

Haddon

Wand²,

Jarrell³

et al. 2017

J Rheumatol

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Objective Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial. Methods We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc. Results The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib. Conclusion Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139. (First Release March 15 2017; J Rheumatol 2017;44:631–8; doi:10.3899/jrheum.160833)

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Correlations between changes in cytokines and clinical outcomes for early phase (proof of concept) trials in active diffuse systemic sclerosis using data from an imatinib study

Abstract: http://clinicaltrials.gov/show/NCT01545427.

Cited by 7 publications

References 18 publications

Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

Serum Soluble Vascular Cell Adhesion Molecule-1 Overexpression Is a Disease Marker in Patients with First-Time Diagnosed Antinuclear Antibodies: A Prospective, Observational Pilot Study

Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment

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