Spinal Radiographic Progression in Patients with Ankylosing Spondylitis Treated with TNF-α Blocking Therapy: A Prospective Longitudinal Observational Cohort Study

Objectives

To evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in ankylosing spondylitis (AS) patients treated with tumor necrosis factor-alpha (TNF-α) blocking therapy in daily clinical practice.

Methods

Consecutive outpatients from the Groningen Leeuwarden AS (GLAS) cohort were included based on the availability of cervical and lumbar radiographs before start of TNF-α blocking therapy and after 2, 4, and/or 6 years of follow-up. Clinical data were assessed at the same time points. Radiographs were scored by two independent readers using the modified Stoke AS Spine Score (mSASSS). Spinal radiographic progression in relation to clinical assessments was analyzed using generalized estimating equations.

Results

176 AS patients were included, 58% had syndesmophytes at baseline. Median mSASSS increased significantly from 10.7 (IQR: 4.6–24.0) at baseline to 14.8 (IQR: 7.9–32.8) at 6 years. At the group level, spinal radiographic progression was linear with a mean progression rate of 1.3 mSASSS units per 2 years. Both spinal radiographic damage at baseline and radiographic progression were highly variable between AS patients. Male gender, older age, longer disease duration, higher BMI, longer smoking duration, high CRP, and high ASDAS were significantly associated with syndesmophytes at baseline. Significantly more radiographic progression was seen in patients with versus without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years) and in patients >40 versus ≤40 years of age (1.8 vs. 0.7 mSASSS units per 2 years). No longitudinal associations between radiographic progression and clinical assessments were found.

Conclusions

This prospective longitudinal observational cohort study in daily clinical practice shows overall slow and linear spinal radiographic progression in AS patients treated with TNF-α blocking therapy. At the individual level, progression was highly variable. Patients with syndesmophytes at baseline showed a 4-fold higher radiographic progression rate than patients without syndesmophytes.     

Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment

Introduction  

Recent data about radiographic progression during treatment with tumor necrosis factor-alpha (TNF-α) blocker agents in patients with ankylosing spondylitis (AS) have prompted an intensive discussion about the link between inflammation/bone destruction and new bone formation and the order of events. Therefore, we analysed parameters of cartilage degradation, neoangiogenesis, and new bone formation in different cohorts of patients with axial spondyloarthritis with and without treatment with TNF-α blocker agents.     

Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF-κB-dependent pathway

Introduction  

Methotrexate (MTX) induces macrophage apoptosis in vitro, but there is not much evidence for increased synovial macrophage apoptosis in MTX-treated patients. Macrophage apoptosis is reported, however, during clinical response to anti-tumor necrosis factor-alpha (TNF-α) treatments. This implies that TNF-α promotes macrophage survival and suggests that TNF-α may protect against MTX-induced apoptosis. We, therefore, investigated this proposal and the macrophage signaling pathways underlying it.     

Influence of comorbidity with depression on interdisciplinary therapy: outcomes in patients with chronic low back pain

Introduction  

Our previous work showed higher tumour necrosis factor (TNF)-α levels in patients with chronic low back pain (cLBP) compared to healthy controls. However, patients with depression as a comorbidity did not have higher TNF-α levels in comparison to patients without depression. In this study we investigated the influence of depression on therapy outcomes such as TNF-α serum levels, pain intensity and back function in patients with cLBP. Our hypothesis was that patients with both cLBP and depression benefit no less than patients with cLBP alone from the multidisciplinary pain therapy.     

Active immunization to tumor necrosis factor-α is effective in treating chronic established inflammatory disease: a long-term study in a transgenic model of arthritis

Introduction  

Passive blockade of tumor necrosis factor-alpha (TNF-α) has demonstrated high therapeutic efficiency in chronic inflammatory diseases, such as rheumatoid arthritis, although some concerns remain such as occurrence of resistance and high cost. These limitations prompted investigations of an alternative strategy to target TNF-α. This study sought to demonstrate a long-lasting therapeutic effect on established arthritis of an active immunotherapy to human (h) TNF-α and to evaluate the long-term consequences of an endogenous anti-TNF-α response.     

Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors

Introduction  

The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor α (TNF-α) inhibitors.     

The effect of three years of TNF alpha blocking therapy on markers of bone turnover and their predictive value for treatment discontinuation in patients with ankylosing spondylitis: a prospective longitudinal observational cohort study

Introduction

The aim of this study was to investigate the effect of three years of tumor necrosis factor-alpha (TNF-α) blocking therapy on bone turnover as well as to analyze the predictive value of early changes in bone turnover markers (BTM) for treatment discontinuation in patients with ankylosing spondylitis (AS).

Methods

This is a prospective cohort study of 111 consecutive AS outpatients who started TNF-α blocking therapy. Clinical assessments and BTM were assessed at baseline, three and six months, as well as at one, two, and three years. Z-scores of BTM were calculated to correct for age and gender. Bone mineral density (BMD) was assessed yearly.

Results

After three years, 72 patients (65%) were still using their first TNF-α blocking agent. In these patients, TNF-α blocking therapy resulted in significantly increased bone-specific alkaline phosphatase, a marker of bone formation; decreased serum collagen-telopeptide (sCTX), a marker of bone resorption; and increased lumbar spine and hip BMD compared to baseline. Baseline to three months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263 to 0.591), AS disease activity score (ASDAS; HR: 0.488, 95% CI: 0.317 to 0.752), and physician''s global disease activity (HR: 0.739, 95% CI: 0.600 to 0.909) were independent inversely related predictors of time to treatment discontinuation because of inefficacy or intolerance. Early decrease in sCTX Z-score correlated significantly with good long-term response regarding disease activity, physical function and quality of life.

Conclusions

Three years of TNF-α blocking therapy results in a bone turnover balance that favors bone formation, especially mineralization, in combination with continuous improvement of lumbar spine BMD. Early change in sCTX can serve as an objective measure in the evaluation of TNF-α blocking therapy in AS, in addition to the currently used more subjective measures.     

Tumour necrosis factor-α production in fibrosing alveolitis is macrophage subset specific

Background  

Previous studies have revealed that tumour necrosis factor (TNF)-α is upregulated in fibrosing alveolitis (FA) in humans. The aim of this study was to compare the TNF-α secretory profile of alveolar macrophages (AMs) and peripheral blood monocytes (Mos) of patients with cryptogenic FA and systemic sclerosis (SSc), a rheumatological disorder in which lung fibrosis can occur. In particular, we wished to assess whether TNF-α levels differ between SSc patients with FA (FASSc) and a nonfibrotic group.     

Long-term outcome of patients with active ankylosing spondylitis with etanercept-sustained efficacy and safety after seven years

Introduction

Data from clinical studies on the long-term efficacy and safety of anti-tumor necrosis factor (TNF)-α therapy in patients with ankylosing spondylitis (AS) are scarce. This is the first report on continuous treatment with the TNFα fusion protein etanercept over seven years (y).

Methods

Overall, 26 patients with active AS were initially treated with etanercept 2 × 25 mg s.c./week with no concomitant disease modifying anti-rheumatic drugs (DMARDs) or steroids. The clinical response was assessed by standardized parameters. The primary outcome was the proportion of patients in the Spondyloarthritis International Society (ASAS) partial remission at seven years. AS disease activity scores (ASDAS) for status and improvement were compared to conventional outcome measures.

Results

Overall, 21/26 patients (81%) completed two years of treatment and 16/26 patients (62%) completed seven years. In the completer analysis, 31% patients were in ASAS partial remission at seven years, while 44% patients showed an ASDAS inactive disease status. Mean Bath AS activity index (BASDAI) scores, which were elevated at baseline (6.3 ± 0.9), showed constant improvement and remained low: 3.1 ± 2.5 at two years and 2.5 ± 2.2 at seven years, while ASDAS also improved (3.9 ± 0.7 at baseline, 1.8 ± 0.9 at two years, 1.6 ± 0.8 at seven years), all P <0.001. From the 10 dropouts, only 5 patients discontinued treatment due to adverse events. Patients who completed the study had lower baseline Bath AS function index (BASFI) scores vs. patients who discontinued. No other clinical parameter at baseline could predict any long-term outcome.

Conclusions

This study confirms the clinical efficacy and safety of etanercept in patients with active AS over seven years of continuous treatment. After seven years, more than half of the initially treated patients remained on anti-TNF therapy, and one-third were in partial remission.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01289743","term_id":"NCT01289743"}}NCT01289743     

A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells

Background  

Free fatty acids (FFA) and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of many obesity-related metabolic disorders. When human hepatoblastoma cells (HepG2) were exposed to different types of FFA and TNF-α, saturated fatty acid was found to be cytotoxic and its toxicity was exacerbated by TNF-α. In order to identify the processes associated with the toxicity of saturated FFA and TNF-α, the metabolic and gene expression profiles were measured to characterize the cellular states. A computational model was developed to integrate these disparate data to reveal the underlying pathways and mechanisms involved in saturated fatty acid toxicity.     

Interleukin-1, tumor necrosis factor-alpha,and transforming growth factor-beta 1 and integrative meniscal repair: influences on meniscal cell proliferation and migration

Introduction  

Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are up-regulated in injured and osteoarthritic knee joints. IL-1 and TNF-α inhibit integrative meniscal repair; however, the mechanisms by which this inhibition occurs are not fully understood. Transforming growth factor-β1 (TGF-β1) increases meniscal cell proliferation and accumulation, and enhances integrative meniscal repair. An improved understanding of the mechanisms modulating meniscal cell proliferation and migration will help to improve approaches for enhancing intrinsic or tissue-engineered repair of the meniscus. The goal of this study was to examine the hypothesis that IL-1 and TNF-α suppress, while TGF-β1 enhances, cellular proliferation and migration in cell and tissue models of meniscal repair.     

Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial

Introduction  

To elucidate in polymyalgia rheumatica (PMR) the role of tumor necrosis factor (TNF) α and the therapeutic potential of blockade with soluble TNF-α receptor, we carried out the first randomized controlled trial with etanercept in PMR.     

Association of TNF-α gene with spontaneous deep intracerebral hemorrhage in the Taiwan population: a case control study

Background  

Genetic factors may play a role in susceptibility to spontaneous deep intracerebral hemorrhage (SDICH). Previous studies have shown that TNF-α gene variation was associated with risks of subarachnoid hemorrhage in multiple ethnicities. The present case-control study tested the hypothesis that genetic variations of the TNF-α gene may affect the risk of Taiwanese SDICH. We examined the association of SDICH risks with four single nucleotide polymorphisms (SNPs) within the TNF-α gene promoter, namely T-1031C, C-863A, C-857T, and G-308A.     

Regulation of catabolic gene expression in normal and degenerate human intervertebral disc cells: implications for the pathogenesis of intervertebral disc degeneration

Introduction  

The aim of this study was to compare the effects of tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) on protease and catabolic cytokine and receptor gene expression in normal and degenerate human nucleus pulposus cells in alginate culture.     

Different effects of antisense RelA p65 and NF-κB1 p50 oligonucleotides on the nuclear factor-κB mediated expression of ICAM-1 in human coronary endothelial and smooth muscle cells

Background  

Activation of nuclear factor-κB (NF-κB) is one of the key events in early atherosclerosis and restenosis. We hypothesized that tumor necrosis factor-α (TNF-α) induced and NF-κB mediated expression of intercellular adhesion molecule-1 (ICAM-1) can be inhibited by antisense RelA p65 and NF-κB1 p50 oligonucleotides (RelA p65 and NF-κB1 p50).     

Engineering inclusion bodies for non denaturing extraction of functional proteins

Background  

For a long time IBs were considered to be inactive deposits of accumulated target proteins. In our previous studies, we discovered IBs containing a high percentage of correctly folded protein that can be extracted under non-denaturing conditions in biologically active form without applying any renaturation steps. In order to widen the concept of correctly folded protein inside IBs, G-CSF (granulocyte colony stimulating factor) and three additional proteins were chosen for this study: GFP (Green fluorescent protein), His7dN6TNF-α (Truncated form of Tumor necrosis factor α with an N-terminal histidine tag) and dN19 LT-α (Truncated form of Lymphotoxin α).     

Maintenance of cytomegalovirus-specific CD4pos T-cell response in rheumatoid arthritis patients receiving anti-tumor necrosis factor treatments

Introduction  

Anti-tumor necrosis factor (TNF)-α biotherapies have considerably changed the treatment of rheumatoid arthritis (RA). However, serious infections are a major concern in patients with rheumatic diseases treated with anti-TNF-α. Little is known about viral, especially latent, infections in anti-TNF-α treatments. Infections by cytomegalovirus (CMV), a β-herpes virus, are frequent and induce a strong CD4^pos T-cell immunity, which participates in the control of infection. We thus have chosen to analyze the CD4^pos T-cell response to CMV antigens as a model of antiviral response in RA patients treated with anti-TNF-α. CD28 expression was evaluated.     

Vasoactive intestinal peptide inhibits TNF-α-induced apoptotic events in acinar cells from nonobese diabetic mice submandibular glands

Introduction  

The role of apoptotic secretory epithelium as a pro-inflammatory triggering factor of exocrine dysfunction is currently explored in Sjogren's syndrome patients and in the nonobese diabetic (NOD) mouse model. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects in various models of chronic inflammation. Our goal was to analyse the effect of TNF-α on apoptotic mediators in isolated acinar cells from NOD submandibular gland and their modulation by VIP.