Tumor Necrosis Factor-α Blockade Research Articles

TRAMP study: A phase 2 trial of tumor necrosis factor-α blockade and AR inhibition in men with CRPC.

TRAMP study: A phase 2 trial of tumor necrosis factor-α blockade and AR inhibition in men with CRPC.

Existing and Emerging Targeted Therapies in Juvenile Psoriatic Arthritis: Challenges and Unmet Needs.

Juvenile psoriatic arthritis (JPsA) is a heterogeneous type of non-systemic chronic inflammatory arthritis affecting children and young people. This review focuses on highlighting challenges in harmonising recommendations for the use of available therapies in JPsA, according to its distinct clinical phenotypes, and explores the similarities and differences between the disease classification and management across age. We further explore the emerging therapeutic landscape, summarising the recently completed clinical trials in JPsA, and ongoing studies in both JPsA and adults with psoriatic arthritis, highlighting unmet needs and barriers for translational research in JPsA. The novel therapeutic agents in clinical development in JPsA range from monoclonal antibodies targeting interleukin (IL)-17, IL-12/23 and IL-23 blockades to synthetic small molecules targeting Janus kinase and tyrosine kinase and phosphodiesterase-4 inhibition. In addition, there are head-to-head clinical trials comparing tumour necrosis factor-α blockade with both IL-17 and IL-23 inhibition. Most of these new therapies have been tested in adults with psoriatic arthritis and haveadvanced to the phase III stage of drug development or received license for use, suggesting promising signals for efficacy and potentially acceptable safety and tolerability for JPsA. Further translational research in JPsA is required to improve our understanding of the impact of age at onset on treatment efficacy, as well as to provide opportunities for better management of refractory disease and improved long-term outcomes in JPsA, for ultimate patient benefit.

Diffuse Alveolar Hemorrhage in Hematopoietic Cell Transplantation.

Diffuse alveolar hemorrhage (DAH) is a morbid syndrome that occurs after autologous and allogeneic hematopoietic cell transplantation in children and adults. DAH manifests most often in the first few weeks following transplantation. It presents with pneumonia-like symptoms and acute respiratory failure, often requiring high levels of oxygen supplementation or mechanical ventilatory support. Hemoptysis is variably present. Chest radiographs typically feature widespread alveolar filling, sometimes with peripheral sparing and pleural effusions. The diagnosis is suspected when serial bronchoalveolar lavages return increasingly bloody fluid. DAH is differentiated from infectious causes of alveolar hemorrhage when extensive microbiological testing reveals no pulmonary pathogens. The cause is poorly understood, though preclinical and clinical studies implicate pretransplant conditioning regimens, particularly those using high doses of total-body-irradiation, acute graft-versus-host disease (GVHD), medications used to prevent GVHD, and other factors. Treatment consists of supportive care, systemic corticosteroids, platelet transfusions, and sometimes includes antifibrinolytic drugs and topical procoagulant factors. Therapeutic blockade of tumor necrosis factor-α showed promise in observational studies, but its benefit for DAH remains uncertain after small clinical trials. Even with these treatments, mortality from progression and relapse is high. Future investigational therapies could target the vascular endothelial cell biology theorized to contribute to alveolar bleeding and pathways that contribute to susceptibility, inflammation, cellular resilience, and tissue repair. This review will help clinicians navigate through the limited evidence to diagnose and treat DAH, counsel patients and families, and plan for future research.

POS-353 Beneficial Effects of Tumor Necrosis Factor-α Blockade in a Mouse Model of Diabetic Nephropathy

Recent studies indicate that immune activation may play a role in pathogenesis of diabetic nephropathy (DN). We have previously described a mouse model exhibiting characteristics of human DN including high-grade albuminuria and glomerulosclerosis. In this model, glomerular immune and inflammatory pathways, including networks associated with tumor necrosis factor (TNF)-α signaling are upregulated. In this study, we examine the functional impact of the TNF-α pathway in DN.

The innate immune system in human kidney inflammaging.

Elderly individuals with chronic disorders tend to develop inflammaging, a condition associated with elevated levels of blood inflammatory markers, and increased susceptibility to chronic disease progression. Native and adaptive immunity are both involved in immune system senescence, kidney fibrosis and aging. The innate immune system is characterized by a limited number of receptors, constantly challenged by self and non-self stimuli. Circulating and kidney resident myeloid and lymphoid cells are all equipped with pattern recognition receptors (PRRs). Recent reports on PRRs show kidney overexpression of toll-like receptors (TLRs) in inflammaging autoimmune renal diseases, vasculitis, acute kidney injury and kidney transplant rejection. TLR upregulation leads to proinflammatory cytokine induction, fibrosis, and chronic kidney disease progression. TLR2 blockade in a murine model of renal ischemia reperfusion injury prevented the escape of natural killer cells and neutrophils by inflammaging kidney injury. Tumor necrosis factor-α blockade in endothelial cells with senescence-associated secretory phenotype significantly reduced interleukin-6 release. These findings should encourage experimental and translational clinical trials aimed at modulating renal inflammaging by native immunity blockade.

Absence of TNF Leads to Alternative Activation in Peritoneal Macrophages in Experimental Listeria Monocytogenes Infection

ABSTRACT Macrophages are crucial effectors of innate immunity against the pathogenic bacterium Listeria monocytogenes. The pro-inflammatory cytokine tumour necrosis factor-α (TNF) has been shown to be crucial for resistance to L. monocytogenes and mice deficient in TNF signalling succumb quickly after infection. However, the mechanisms underlying TNF-mediated defence against L. monocytogenes infection have not been completely elucidated. Here, we demonstrate that TNF concurrently functions to support a pro-inflammatory M1 phenotype while actively blocking macrophage polarization to the M2 phenotype. Compared to WT mice, peritoneal macrophages in TNF-deficient mice inoculated with L. monocytogenes respond with M2 polarization by upregulating Arg1. Consistently, TNF blockade in vitro resulted in M2 polarization in peritoneal macrophages during L. monocytogenes infection. Additionally, TNF promotes the transition from M2 to M1 polarization in peritoneal macrophages. Further investigation of peritoneal macrophage polarization suggested the NF-κB pathway is involved in the TNF-dependent M2 to M1 shift. Conversely, treatment of peritoneal macrophage with a PPARγ agonist blunted the expression of M1 genes induced by TNF and reduced NF-κB signalling pathway activation. Competing signalling mechanisms therefore play an essential role in the ability of peritoneal macrophage to resolve L. monocytogenes infections with TNF playing an essential role in driving M1 polarization. Abbreviations: LPM: large peritoneal macrophage; SPM: small peritoneal macrophage; LLO: listeriolysin O; iNOS: inducible nitric oxide synthase; DCs: dendritic cells

Mending Broken Hearts

Mending Broken Hearts

Blockade of angiotensin-converting enzyme or tumor necrosis factor-α reverses maternal high-fat diet-induced sensitization of angiotensin II hypertension in male rat offspring.

Maternal high-fat diet (HFD) is associated with metabolic syndrome and cardiovascular diseases in adult offspring. Our previous study demonstrated that maternal HFD enhances pressor responses to ANG II or a proinflammatory cytokine (PIC), which is associated with increased expression of brain renin-angiotensin system (RAS) components and PICs in adult offspring. The present study further investigated whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor-α (TNF-α) blocks sensitization of ANG II hypertension in offspring of HFD dams. All offspring were bred from dams with normal fat diet (NFD) or HFD starting two weeks before mating and maintained until weaning of the offspring. Then the weaned offspring were treated with an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water through the end of testing with a slow-pressor dose of ANG II. RT-PCR analyses of the lamina terminalis and paraventricular nucleus revealed upregulation of mRNA expression of several RAS components and PICs in male offspring of HFD dams when compared with age-matched offspring of NFD dams. The enhanced gene expression was attenuated by blockade of either RAS or PICs. Likewise, ANG II administration produced an augmented pressor response in offspring of HFD dams. This was abolished by either ACE or TNF-α inhibitor. Taken together, this study provides mechanistic evidence and a therapeutic strategy that systemic inhibition of the RAS and PICs can block maternal HFD-induced sensitization of ANG II hypertension, which is associated with attenuation of brain RAS and PIC expression in offspring.

Tumor necrosis factor-α blockade ameliorates diabetic nephropathy in rats.

BackgroundTubular injury plays a critical role in the development of diabetic nephropathy (DN), but current DN therapies do not combat tubular injury. This study was conducted to investigate if tumor necrosis factor (TNF)-α inhibition protects against tubular injury in diabetic rats and to examine the associated mechanisms. MethodsKidney biopsy tissues were collected and analyzed from 12 patients with DN and 5 control subjects. Streptozotocin (STZ)-induced diabetic rats were treated with a TNF-α inhibitor for 12 weeks. Renal function, albuminuria, histological injury, renal TNF-α messenger RNA (mRNA) and the NOD- (nucleotide-binding), LRR- (domain-like receptor) and pyrin domain-containing protein 3 (NLRP3) inflammasome were assessed.ResultsDiabetic patients with tubulointerstitial injury (TIN) presented with higher renal tubular expression of TNF-α mRNA and the NLRP3 inflammasome (P < 0.05). TNF-α inhibition reduced albuminuria, glomerular injury and tubular injury in STZ-induced diabetic rats (P < 0.05). Importantly, TNF-α inhibition significantly reduced the NLRP3 inflammasome in tubules (P < 0.05). Moreover, TNF-α inhibition decreased expression of tubular interleukin (IL)-6 and IL-17A mRNA.ConclusionsTNF-α inhibition protects against TIN by suppressing the NLRP3 inflammasome in DN rats. Future studies may focus on the clinical protective effects of TNF-α inhibition using prospective observation.

Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens.

The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.

Stress-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Blockade of Angiotensin-Converting Enzyme or Tumor Necrosis Factor-α.

Post-traumatic stress disorder (PTSD) is characterized by a disordered stress response and associated with increased cardiovascular disease risk. The present study investigated whether angiotensin (Ang) II-elicited hypertensive response is sensitized in a model of PTSD and whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor (TNF)-α prior to PTSD blocks this sensitization of Ang II hypertension. The resident-intruder paradigm was used to model PTSD. Each intruder rat (male Sprague-Dawley) was given normal drinking water or was pretreated with either an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water for 2 weeks. Subsequently, they were exposed to a different resident (male Long-Evans) for 2 hours on 3 days with each session separated by 1 day and then received a subcutaneous infusion of Ang II for 2 weeks. The stressed rats had a significantly enhanced hypertensive response to the Ang II infusion (stressed Δ40.2 ± 3.9 mm Hg vs. unstressed Δ20.5 ± 4.5 mm Hg) and an upregulation of mRNA or protein expression of renin-angiotensin system (RAS) and proinflammatory cytokine (PIC) components and of a microglial marker in the lamina terminalis and hypothalamic paraventricular nucleus when compared with unstressed control rats. Both the sensitized hypertensive response and enhanced gene and protein expression were blocked by pretreatment with either ACE (Δ21.3 ± 3.9 mm Hg) or TNF-α inhibitor (Δ21.4 ± 2.6 mm Hg). The results indicate that upregulation of the brain RAS and PICs produced by severe stress contributes to traumatic-induced sensitization of hypertensive response to Ang II, and disorders such as PTSD may predispose individuals to development of hypertension.

Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2

AbstractDeficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1. DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency and bone marrow failure. Tumor necrosis factor-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9) and reduced intensity (5). Donors were HLA-matched sibling (n = 1), HLA-matched unrelated (n = 9), HLA-mismatched unrelated (n = 3), and HLA haploidentical sibling (n = 1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18 months (range, 5 months to 13 years). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as day +14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft-versus-host disease grade 1 in 2, grade 2 in 3, and grade 3-4 in 1, and moderate chronic graft-versus-host disease in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment of DADA2.

Ozone-induced eosinophil recruitment to airways is altered by antigen sensitization and tumor necrosis factor-α blockade.

Ozone is an atmospheric pollutant that causes lung inflammation and airway hyperresponsiveness. Ozone's effects occur in two distinct phases that are mediated by different populations of eosinophils. In the acute phase 1 day after exposure, mature airway‐resident eosinophils alter parasympathetic nerve function that results in airway hyperresponsiveness. At this time point, the severity of hyperresponsiveness correlates with the number of eosinophils in close proximity to airway nerves, but not with eosinophils in bronchoalveolar lavage. Three days later, newly divided eosinophils are recruited to airways by a tumor necrosis factor‐α‐dependent mechanism. These new eosinophils paradoxically attenuate ozone‐induced airway hyperresponsiveness. Ozone's effects on airway tissue eosinophils and nerve‐associated eosinophils 3 days after exposure are unknown. Thus, we tested ozone's effects on eosinophils in airway subepithelium and around airway nerves 1 and 3 days after ozone in nonsensitized and ovalbumin‐sensitized guinea pigs with or without the tumor necrosis factor‐α antagonist, etanercept, and compared changes in eosinophils with ozone‐induced airway hyperresponsiveness. More eosinophils were present in small, noncartilaginous airways and along small airway nerves compared to large cartilaginous airways in all treatment groups. The number of airway and nerve‐associated eosinophils were unaffected 1 day after ozone exposure, whereas significantly fewer airway eosinophils were present 3 days later. Airway and nerve‐associated eosinophils were also decreased in small airways 3 days after ozone in sensitized animals. These changes were blocked by etanercept. Airway eosinophils, but not nerve‐associated or bronchoalveolar lavage eosinophils correlated with airway hyperresponsiveness 3 days after ozone. Our findings indicate ozone causes persistent alterations in airway eosinophils and reinforce the importance of characterizing eosinophils’ effects within distinct airway compartments.

Tumor necrosis factor-α blockade treatment decreased CD154 (CD40-ligand) expression in rheumatoid arthritis.

ContextsCD154 (commonly referred to as CD40-ligand) is a critical T cell factor that participates in the pathogenesis of autoimmune and is over-expressed in rheumatoid arthritis (RA). TNF-α blockade treatment had dramatic efficacy in RA.ObjectiveTo investigate whether TNF-α blockade treatment can inhibit CD154 expression in RA.MethodsBlood samples were collected from 33 patients with rheumatoid arthritis before and 3 months after TNF-α blockade treatment. Clinical serological data determined by standard assays and T cell CD154 expression levels determined by flow cytometry were statistically analyzed for these two time points.ResultsThe percentage of CD154 expression on gated CD4+ T cells of PBMCs from RA patients after 3 months TNF-α blockade treatment was significantly lower than before treatment (2.94 ± 3.21% vs. 7.21 ± 5.64%; p = 0.0001). The disease activity and anti-CCP antibody levels were also significantly reduced after TNF-α blockade treatment. The CD154 expression levels were positively correlated with disease activity index DAS28, and CRP. The post-stimulated CD154 expression percentage of purified CD4+ T cells between baseline and after TNF-α blockade treatment was not significantly different (p = 0.221). Baseline CD154 levels were positively correlated with treatment-induced changes in DAS28 (p = 0.014; r2 = 0.187).ConclusionsTNF-α blockade treatment significantly decreased the CD154 expression on CD4+ T cells, disease activity and anti-CCP antibody simultaneously in RA patients. However TNF-α blockade did not impair T cell capacity to express CD154 after stimulation. These results suggest that decreased CD154 expression after TNF-α blockade may be due to decreased RA disease activity but not direct inhibition of CD154 responsiveness of T cells.

Does Treatment of Psoriasis Reduce Cardiovascular Comorbidities?

Psoriasis has been associated with an increase in myocardial infarctions. Several registries have shown reductions in major adverse cardiovascular events in psoriasis patients and rheumatoid arthritis patients treated with tumor necrosis factor-α antagonists. Many assume that the reduction in cardiovascular events can be attributed to the anti-inflammatory effect of tumor necrosis factor blockers, but a 52-week study conducted by Bissonnette and coworkers failed to show a reduction in cardiovascular inflammation in psoriasis patients treated with adalimumab. Longer and larger studies are needed to explain why tumor necrosis factor-α blockade appears to reduce cardiovascular events in patients with severe psoriasis.

Antibodies to paraoxonase 1 are associated with oxidant status and endothelial activation in rheumatoid arthritis.

Traditional and non-traditional cardiovascular (CV) risk factors underlie CV disease occurrence in rheumatoid arthritis (RA). Recently, a functional impairment of high-density lipoprotein (HDL) has been observed. Although the actual players are unknown, anti-HDLs were associated with altered lipid profile, decreased paraoxonase 1 (PON1) activity and CV disease in RA. Therefore, we aimed to evaluate whether the presence of antibodies against PON1 may be involved in this scenario. IgG anti-PON1 antibodies were quantified by ELISA in serum samples from 212 RA patients, 175 healthy controls (HC) and 54 subjects with traditional CV risk factors (CVR). A subgroup of 13 RA patients was prospectively followed upon tumour necrosis factor-α (TNFα) blockade. Serum PON1 activity, nitric oxide (NO) and total antioxidant capacity (TAC) were measured. Interferon-γ (IFNγ), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule (sICAM) and TNFα serum levels were assessed by immunoassays. PON1 rs662 (Q > R) status was studied by reverse transcription (RT)-PCR. IgG anti-PON1 antibodies are increased in RA patients compared with HC (P<0.0001) and CVR subjects (P<0.001), even after correcting for total IgG levels. Although no associations with lipid profile were found, a positive correlation with Health Assessment Questionnaire (HAQ) was observed (r=0.215, P=0.004). Anti-PON1 antibodies were associated with PON1 activity, NO and TAC, a rs662-mediated gene-dosage effect being found. Similarly, anti-PON1 antibodies were associated with sICAM serum levels in univariate and multivariate models. Finally, these antibodies were not affected by TNFα blockade. Anti-PON1 antibodies can be responsible for PON1 impairment in RA patients, with a potential impact on biomarkers of oxidative status and endothelial activation. A gene-environment interaction of rs662 variants is supported.

Disseminated Histoplasmosis in Patients Receiving Tumor Necrosis Factor-α Inhibitors

Abstract Since their introduction in the late 1990s, tumor necrosis factor (TNF)-α inhibitors have proven effective in the treatment of several inflammatory disorders, and their use has become increasingly common. Tumor necrosis factor-α blockade is nonetheless associated with an increase in the risk of infection by intracellular, granuloma-forming pathogens, such as Histoplasma capsulatum. We performed a query of our medical records for all cases of disseminated histoplasmosis in patients receiving TNF-α inhibitors between the years 1999 and 2014 at University Hospitals Case Medical Center in Cleveland, Ohio, an area of moderate histoplasmosis endemicity. A total of 357 cases of disseminated histoplasmosis were identified, 8 (2.2%) of whom were receiving TNF-α inhibitor therapy at the time of diagnosis. Five patients were receiving infliximab, and 3 were receiving adalimumab. All patients had generalized, nonspecific presenting symptoms, and all but one had a complete response to antifungal treatment and the cessation of the inciting TNF-α inhibitor. Five of the patients eventually resumed TNF-α inhibitor therapy a year after their initial diagnosis with disseminated histoplasmosis. The only patient who succumbed to the infection had a delayed diagnosis. The increasing use of TNF-α inhibitors should come with an increased awareness of its association with opportunistic infections including disseminated histoplasmosis and by other endemic fungi. This case series highlights the importance of early diagnosis of such infections to achieve a favorable outcome. Further research will need to focus on determining the best long-term treatment strategies in managing these patients after the resolution of the acute infection.

Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.

Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages. Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression. Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.

Tumor necrosis factor-α blockade in recurrent and disabling chronic sciatica associated with post-operative peridural lumbar fibrosis: results of a double-blind, placebo randomized controlled study

IntroductionThe aim of this study was to assess the efficacy and safety of tumor necrosis factor (TNF)-α inhibition with infliximab (IFX) in treating recurrent and disabling chronic sciatica pain associated with post-operative peridural lumbar fibrosis.MethodA double-blind, placebo-controlled study randomized 35 patients presenting with sciatica pain associated with post-operative peridural lumbar fibrosis to two groups: IFX (n = 18), a single intravenous injection of 3 mg/kg IFX; and placebo (n = 17), a single saline serum injection. The primary outcome was a 50 % reduction in sciatica pain on a visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar VAS pain at day 0 and radicular and lumbar VAS pain, Québec disability score, drug-sparing effect and tolerance at days 10, 30, 90, and 180.ResultsAt day 10, the placebo and IFX groups did not differ in the primary outcome (50 % reduction in sciatica pain observed in three (17.6 %) versus five (27.8 %) patients; p = 0.69). The number of patients reaching the patient acceptable symptom state for radicular pain was significantly higher in the placebo than IFX group after injection (12 (70.6 %) versus five (27.8 %) patients; p = 0.01). The two groups were comparable for all other secondary outcomes.ConclusionTreatment with a single 3 mg/kg IFX injection for post-operative peridural lumbar fibrosis-associated sciatica pain does not significantly reduce radicular symptoms at day 10 after injection.Trial registrationClinicalTrials.gov NCT00385086; registered 4 October 2006 (last updated 15 October 2015).

Protective effects of tumor necrosis factor-α blockade by adalimumab on articular cartilage and subchondral bone in a rat model of osteoarthritis.

We aimed to investigate the effects of an anti-tumor necrosis factor-α antibody (ATNF) on cartilage and subchondral bone in a rat model of osteoarthritis. Twenty-four rats were randomly divided into three groups: sham-operated group (n=8); anterior cruciate ligament transection (ACLT)+normal saline (NS) group (n=8); and ACLT+ATNF group (n=8). The rats in the ACLT+ATNF group received subcutaneous injections of ATNF (20 μg/kg) for 12 weeks, while those in the ACLT+NS group received NS at the same dose for 12 weeks. All rats were euthanized at 12 weeks after surgery and specimens from the affected knees were harvested. Hematoxylin and eosin staining, Masson's trichrome staining, and Mankin score assessment were carried out to evaluate the cartilage status and cartilage matrix degradation. Matrix metalloproteinase (MMP)-13 immunohistochemistry was performed to assess the cartilage molecular metabolism. Bone histomorphometry was used to observe the subchondral trabecular microstructure. Compared with the rats in the ACLT+NS group, histological and Mankin score analyses showed that ATNF treatment reduced the severity of the cartilage lesions and led to a lower Mankin score. Immunohistochemical and histomorphometric analyses revealed that ATNF treatment reduced the ACLT-induced destruction of the subchondral trabecular microstructure, and decreased MMP-13 expression. ATNF treatment may delay degradation of the extracellular matrix via a decrease in MMP-13 expression. ATNF treatment probably protects articular cartilage by improving the structure of the subchondral bone and reducing the degradation of the cartilage matrix.