anti-TNFalpha Treatment Research Articles

Risk of new-onset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFα agents

To determine whether treatment with tumor necrosis factor alpha (TNFalpha)-blocking agents alters the incidence of new-onset uveitis in patients with juvenile idiopathic arthritis (JIA). Cohort study based on retrospective chart review. The charts of all 1109 patients with a diagnosis of JIA seen between January 1, 1996, and June 30, 2003, at our clinic were reviewed for diagnosis of uveitis and treatment with TNFalpha inhibitors. Cox regression analysis was performed with anti-TNFalpha treatment as a time-dependent covariate for risk of development of uveitis. We identified 70 patients treated with anti-TNFalpha without a prior diagnosis of uveitis. Two of these 70 patients (2.9%), both treated with etanercept, had development of new-onset uveitis during anti-TNFalpha therapy. One had juvenile psoriatic arthritis diagnosed 4.1 years before onset of uveitis. The other had extended oligoarticular JIA diagnosed 6.4 years before onset of uveitis. We found no statistically significant difference in the risk for development of uveitis between patients with or without anti-TNFalpha treatment. In our patients with JIA, anti-TNFalpha treatment did not alter the risk for development of new-onset uveitis. However, anti-TNFalpha therapy with etanercept did not prevent the development of uveitis in 2 patients.

Tuberculose lors d'un traitement par agents inhibiteurs du TNF alpha

The clinical forms of tuberculosis that occur during anti-TNFalpha treatment are frequently extrapulmonary or even disseminated and life-threatening. The paradoxical reactions that can occur under appropriate treatment after stopping TNFalpha inhibitors raise the question of an immune restoration phenomenon. Adverse drug reaction reporting and epidemiologic studies, despite their methodological limitations, appear to show an excess risk of tuberculosis. Experimental studies reinforce these data. The French drug agency (Afssaps) has issued guidelines for the prevention and management of tuberculosis occurring under anti-TNFalpha treatment. Analogous guidelines in Spain led to a reduction in the incidence of these cases.

Anti-tumour necrosis factor-alpha therapy over conventional therapy improves endothelial function in adults with rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with cardiovascular morbidity and mortality and inflammation contributes to related endothelial dysfunction. We aimed to investigate the effect of anti-TNFalpha therapy on endothelial function in subjects with rheumatoid arthritis. We measured flow-mediated (FMD) and GTN-mediated dilation of the brachial artery before and following 36 weeks of anti-TNFalpha therapy in nine RA patients and in a group of RA patients on conventional therapy. Thirty-six weeks of anti-TNFalpha therapy improved FMD relative to those on conventional therapy (8.65 +/- 1.50 vs. 1.70 +/- 1.36%, P = 0.02). No significant changes in GTN responses were evident. Significant improvements in tender (P = 0.03) and swollen (P = 0.02) joint counts, patients' global self-assessment (P = 0.01) and DAS-28 scores (P = 0.04) were observed in the anti-TNFalpha treated group. The addition of anti-TNFalpha treatment to conventional therapy, in those with severe RA, reduces inflammatory symptoms and improves endothelial function, potentially lowering future atherosclerotic risk.

The -308 tumour necrosis factor- gene polymorphism predicts therapeutic response to TNF -blockers in rheumatoid arthritis and spondyloarthritis patients

To examine whether the G-to-A polymorphism at position -308 in the promoter of the tumour necrosis factor-alpha (TNFalpha) gene influences the therapeutic response to TNFalpha-blockers in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). A total of 54 patients with RA, 10 with PsA and 22 with AS were genotyped by polymerase chain reaction for the -308 TNFalpha promoter polymorphism. They were treated with infliximab (n = 63), adalimumab (n = 10) or etanercept (n = 13). Clinical response was assessed after 24 weeks by the Disease Activity Score in 28 joints (DAS28) for RA and PsA, and the Bath Ankylosing Spondylitis Activity Index (BASDAI) for AS patients. All patients with the A/A genotype (n = 3, all RA) and two patients with the A/G genotype (AS) failed to respond to anti-TNF treatment. Irrespective of the underlying disease, moderate response (n = 44) was predominantly associated with the A/G genotype (A/G 18/22, G/G 4/22), whereas good response (n = 59) was exclusively seen in patients with the G/G genotype. The average improvement in the DAS28 score was 0.83 in the A/A, 1.50 in the A/G and 2.64 in the G/G group of RA and PsA patients (P < 0.0001). The BASDAI score in AS improved on average by 1.21 in the A/G and by 3.30 in the G/G group (P < 0.005). The data suggest that humans with a TNFalpha -308 G/G genotype are better responders to anti-TNFalpha treatment than those with A/A or A/G genotypes independent of the treated rheumatic disease (RA, PsA or AS).

Vasculite avec ulcérations cutanées au cours de la polyarthrite rhumatoïde : traitement par anti TNFδ

Anti-TNFalpha has occasionally been used in the treatment of recalcitrant forms of systemic vasculitis such as Behçet's disease, Wegener's granulomatosis and Churg-Strauss syndrome. We report on the outcome of treatment in rheumatoid arthritis patients with cutaneous vasculitis lesions on anti-TNFalpha. Two patients with rheumatoid arthritis present for several years had necrotic ulcers of the lower limbs due to cutaneous vasculitis. After the failure of various immunosuppressive drugs (cyclophosphamide, azathioprine, methotrexate), the two patients were treated with anti-TNFalpha: infliximab in the first case and adalimumab in the second. Cutaneous ulcers healed within two to four months of the start of anti-TNFalpha treatment. Despite ongoing anti-TNFalpha treatment, these cutaneous ulcers relapsed four to six months after complete healing. Initially spectacular healing of cutaneous vasculitis ulcers under anti-TNF alpha treatment followed by relapse after several months of treatment is suggestive of an escape mechanism.

Neurological symptoms suggestive of demyelination in Crohn??s disease after infliximab therapy

Anti-TNFalpha drugs are currently used in the treatment of patients with Crohn's disease. Studies have reported neurological side effects occurring after anti-TNFalpha treatment, including infliximab-induced complications.

Contribution de l’IRM des sacro-iliaques dans l’évaluation des spondylarthropathies sous infliximab (étude prospective sur 34 patients)

Thirty-four patients who met ESSG criteria for spondylarthropathy and were eligible for anti-TNFalpha treatment (infliximab) were enrolled in this open-label study lasting 14 weeks. The aims were to evaluate the progression of sacroiliitis by means of MRI, and to determine the positive predictive value of this exam for the treatment response. Patients underwent MRI of the sacroiliac region at baseline (W0), and also at 14 weeks if the baseline MRI showed sacroiliitis. Two blinded readers reviewed all imaging studies. The patients also had a physical examination and ESR and CRP assays at W0 and W14. Sacroiliitis was found in 22 patients (65%) at W0, but only 18 of these patients had a second MRI at W14, for technical reasons. After 14 weeks of therapy, MRI signs of sacroiliac inflammation diminished by 77.7% on average. Clinical and biological parameters also improved. However, MRI was not predictive of the treatment response. Sacroiliac MRI seems to be interesting for objective therapeutic evaluation and monitoring of patients with spondyloarthropathy.

CNS demyelination during anti–tumor necrosis factor alpha therapy

Sirs: Tumor Necrosis Factor alpha (TNFalpha) is a cytokine released by activated monocytes, macrophages, and T-lymphocytes. It is involved in several processes, but plays an important role particularly in inflammation [1]. Its overproduction is implicated in a wide range of pathological conditions, including rheumatoid arthritis (RA) [2] and multiple sclerosis (MS) [3]. High concentrations of TNFalpha are present in synovial fluid of RA patients [4] and in cerebro-spinal fluid (CSF) of MS patients [5]. Considering its role in inflammatory disease, numerous drugs have been developed to modulate its action on inflammation in recent years [6, 7]. Some are characterized by monoclonal antibodies against TNFalpha (Infliximab, Adalimumab), while others are soluble TNF-receptor fusionproteins (Etanercept, Lenercept), but all inhibit the TNFalpha effect [6, 7]. In the literature the effectiveness of TNFalpha therapy in experimental models and in studies of RA in humans is well known [8]. In addition several studies have shown its preventive role in experimental autoimmune encephalomyelitis (EAE), a well established experimental model of MS [9]. Despite these findings, antiTNFalpha treatment for MS worsens the disease. In a trial of antiTNFalpha-targeted therapy using Lenercept, treated patients had significantly more exacerbations than placebo-treated patients [7]. Moreover, other studies have demonstrated that Etanercept and Infliximab may also worsen preexisting MS and trigger de-novo CNS demyelination [10, 11]. The patient we report experienced CNS demyelination using Adalimumab, a new TNFalpha-blocker. A 40-year old woman with RA on methotrexate (10 mg i. m. once a week) treatment for several months started a therapy with Adalimumab (40 mg s. c. once 15 days), a TNFalpha-blocker. After two months she experienced diplopia, headache, nausea and dizziness with subacute onset. She had no family history of neurological disturbances and there was no evidence of a previous febrile episode or other previous neurological dysfunction. Neurological examination showed VI and VII right cranial nerve palsy, a tetrapyramidal syndrome, bladder voiding disorder, mild leg extremity sensory deficit. Immunological and infection investigations were normal, whereas CSF analysis showed barrier damage and several oligoclonal bands. VEPs, SEPs and BAEPs were abnormal. Brain and spinal cord MRI revealed several T2-hyperintensities in the hemispheric white matter, in the brainstem and in the spinal cord. Following gadolinium-DTPA (Gd) administration, some areas of enhancement were present in both hemispheres and in cervical spinal cord (Fig. 1A, B). Anti-TNFalpha therapy was stopped and methylprednisolone 1 g/day i. v. for five days was administered with a progressive improvement of the clinical picture. After six months brain and spinal MRI showed the persistence of T2-weighted hyperintensities (Fig. 1C), but there was no evidence of enhancement after Gd administration (Fig. 1D). After 6 and 14 months the clinical picture was normal except for mild hyperreflexia in all four limbs. Exacerbation of previously quiescent MS and new-onset demyelinating disease have been reported during Infliximab and Etenarcept therapy for RA. Moreover it has been well documented that another TNF-antagonist, Lenercept, increased the number of attacks of pre-existing MS [7, 10, 11]. The present data – in particular the temporal correlation of neurological symptoms onset with TNFalpha-blocker administration and the monophasic course – suggest that even Adalimumab, like other TNFalpha blockers, may trigger denovo CNS demyelination. Therefore, although a causal relationship between anti-TNFalpha therapy and CNS demyelination has not been well established, all reports make this association more plausible, indicating a possible protective role of TNFalpha in demyelinating diseases. Until further long-term safety data are available, we suggest that anti-TNFalpha therapy should not be administered to patients with MS or to patients with neurological signs or symptoms possibly arising from previous demyelinating episodes. Moreover it would be useful to look for MRI signs of leukoencephalopathy, possibly due to silent CNS demyelination, before starting a therapy with TNF-blockers.

Neuropathy resembling CIDP in patients receiving tumor necrosis factor-α blockers

Tumor necrosis factor-alpha (TauNuFalpha) blockers are effective in the treatment of inflammatory arthritis but can induce autoimmune disorders including multiple sclerosis. Described are two patients who developed chronic inflammatory demyelinating polyneuropathy after initiation of anti-TNFalpha treatment.

Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey

The development of drug-induced lupus remains a matter of concern in patients treated with anti-tumour necrosis factor (TNF) alpha. The incidence of such adverse effects is unknown. We undertook a retrospective national study to analyse such patients.Between June and October 2003, 866 rheumatology and internal medicine practitioners from all French hospital centres prescribing anti-TNF in rheumatic diseases registered on the website of the 'Club Rhumatismes et Inflammation' were contacted by email to obtain the files of patients with TNF-induced systemic lupus erythematosus. Twenty-two cases were collected, revealing two aspects of these manifestations. Ten patients (six patients receiving infliximab, four patients receiving etanercept) only had anti-DNA antibodies and skin manifestations one could classify as 'limited skin lupus' or 'toxidermia' in a context of autoimmunity, whereas 12 patients (nine patients receiving infliximab, three patients receiving etanercept) had more complete drug-induced lupus with systemic manifestations and at least four American Congress of Rheumatology criteria. One patient had central nervous system manifestations. No patients had lupus nephritis. The signs of lupus occurred within a mean of 9 months (range 3–16 months) in patients treated with infliximab and within a mean of 4 months (range 2–5 months) in patients treated with etanercept. In all cases after diagnosis was determined, anti-TNF was stopped and specific treatment introduced in eight patients: two patients received intravenous methylprednisolone, four patients received oral steroids (15–35 mg/day), and two patients received topical steroids. Lupus manifestations abated within a few weeks (median 8 weeks, standard deviation 3–16) in all patients except one with longer-lasting evolution (6 months). At that time, cautious estimations (unpublished data from Schering Plough Inc. and Wyeth Inc.) indicated that about 7700 patients had been exposed to infliximab and 3000 to etanercept for inflammatory arthritides in France. It thus appears that no drug was more implicated than the other in lupus syndromes, whose incidence was 15/7700 = 0.19% with infliximab and 7/3800 = 0.18% with etanercept.Clinicians should be aware that lupus syndromes with systemic manifestations may occur in patients under anti-TNF alpha treatment.

NF-κB: a signal for cancer

NF-κB functions as a tumour promoter in inflammation-associated cancer. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galum E, Ben-Neriah Y. The causes of sporadic human cancer are seldom recognized, but it is estimated that carcinogen exposure and chronic inflammation are two important underlying conditions for tumor development, the latter accounting for approximately 20% of human cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that activation of the nuclear factor kappaB (NF-kB), a hallmark of inflammatory responses that is frequently detected in tumours, might constitute a missing link between inflammation and cancer. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-kB through upregulation of tumour-necrosis factor-alpha (TNFalpha) in adjacent endothelial and inflammatory cells. Switching off NF-kB in mice from birth to seven months of age, using a hepatocyte-specific inducible IkB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kB inhibition through anti-TNFalpha treatment or induction of IkB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Our studies thus indicate that NF-kB is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases. [Abstract reproduced by permission of Nature 2004;431:461–6]

Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol

It has been recently hypothesized that both TNFalpha and anti TNFalpha treatment have a stimulating effect on nitric oxide synthesis and release. Moreover, an in vitro experiment has demonstrated that HDL-cholesterol binds TNFalpha. Aims of our study were to investigate wall shear stress of peripheral arteries and endothelial function of brachial artery in subjects with Rheumatoid Arthritis (RA) at baseline and after infliximab. Moreover, we evaluated the effect of anti TNFalpha therapy on lipid profile. Ten patients with RA received infliximab therapy at weeks 0, 2 and 6. Lipids and vascular parameters were measured before and the day after each infusion. After the first treatment, FMD increased (3.7 ± 1.9% versus 17.5 ± 2.9%, P < 0.01) and common carotid and brachial artery diameters decreased (5.9 ± 0.2 mm versus 5.5 ± 0.2 mm; 3.5 ± 0.4 mm versus 3.1 ± 0.4 mm, respectively, P < 0.005). Common carotid and brachial artery wall shear stress increased (21.1 ± 1.1 dynes/cm 2 versus 23.9 ± 1.4 dynes/cm 2; 42.0 ± 4.7 dynes/cm 2 versus 51.6 ± 5.7 dynes/cm 2, P < 0.01). Similar results were observed after the second and third infusion. All these parameters returned to pre-treatment level at the following infusion. HDL-cholesterol and apolipoprotein AI significantly decreased after each treatment (1st treatment: 1.4 ± 0.05 mmol/L versus 1.2 ± 0.06 mmol/L, P < 0.01; 1.73 ± 0.05 g/L versus 1.57 ± 0.02 g/L, P < 0.03). The present data show vasoconstriction and an increase of wall shear stress in studied arteries after infliximab. HDL cholesterol is reduced by treatment and does not seem to influence FMD.

NF-kappaB functions as a tumour promoter in inflammation-associated cancer.

The causes of sporadic human cancer are seldom recognized, but it is estimated that carcinogen exposure and chronic inflammation are two important underlying conditions for tumour development, the latter accounting for approximately 20% of human cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that activation of the nuclear factor kappaB (NF-kappaB), a hallmark of inflammatory responses that is frequently detected in tumours, may constitute a missing link between inflammation and cancer. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-kappaB through upregulation of tumour-necrosis factor-alpha (TNFalpha) in adjacent endothelial and inflammatory cells. Switching off NF-kappaB in mice from birth to seven months of age, using a hepatocyte-specific inducible IkappaB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kappaB inhibition through anti-TNFalpha treatment or induction of IkappaB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Our studies thus indicate that NF-kappaB is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.

The histopathology of spondyloarthropathy.

An extensive histopathological analysis of diseased tissues and organs is a crucial step in our understanding of how specific molecular and cellular events described in vitro or in animal models might by relevant to the clinical presentation of a specific disease in humans. Although in spondyloarthropathy (SpA) such an approach is hampered by the fact that some target tissues are not readily accessible for biopsy sampling (the sacroiliac joint, the axial skeleton, the enthesis, and the eye), numerous histological studies of the synovial membrane of the peripheral joint, the gut, and the skin have contributed to new insights into the cellular and molecular base of SpA. Firstly, the peripheral synovitis is characterized by an extensive hypervascularity and the presence of specific macrophage and T cell subsets. Secondly, the fact that the same subsets of macrophages and T cells can be identified in the gut mucosa, even before histological inflammation is present, point to a role for early immune alterations of the gut in the development of the disease. Thirdly, macrophages and macrophage-derived cytokines such as the pro-inflammatory TNFalpha and the anti-inflammatory IL-10 appear to be crucial mediators of the tissue inflammation. Therefore, neovascularization, recirculation of inflammatory cells between gut and synovium, and macrophage-derived cytokines are all potential targets for immunotherapy. As a proof of concept, anti-TNFalpha treatment has been demonstrated to have an impressive clinical effect as well as a major impact on the histological tissue inflammation. Further research should benefit from the combination of classical histopathology with newer molecular techniques (genomics, proteomics) to unravel the molecular and cellular base of the different disease presentations and should aim to translate these basic findings into clinical applications such as histopathological differential diagnosis and follow-up of targeted therapies.

Effects of neutralizing antibodies to tumor necrosis factor-alpha on nucleus pulposus-induced abnormal nociresponses in rat dorsal horn neurons.

The effect of an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody on abnormal discharges caused by application of nucleus pulposus to the nerve root was investigated in an electrophysiologic study. To assess whether inhibition of TNFalpha can reduce nucleus pulposus-induced abnormal discharges. It has been shown that TNFalpha, a proinflammatory cytokine, is a key pathogenic factor in the development of nucleus pulposus-induced abnormal discharges as a pain sensation. However, the electrophysiologic mechanisms involved in sciatica after disc herniation still have not been elucidated. Extracellular activities of wide-dynamic-range neurons were assessed in 21 rats. Autologous nucleus pulposus harvested from the tail was applied to the L5 nerve root. The animals were simultaneously treated with antibodies to TNFalpha (anti-TNF + nucleus pulposus group) and with phosphate-buffered saline (nucleus pulposus group). As a control (control group), a similar volume of muscle was applied to the nerve root with phosphate-buffered saline. Responses of wide-dynamic-range neurons to noxious and innocuous stimuli were examined for 2 hours. Discharges evoked during noxious stimulation and discharges after withdrawal of stimulation in the nucleus pulposus group were significantly higher than those in the control group (P < 0.05). In the anti-TNF + nucleus pulposus group, discharges after withdrawal of stimulation were remarkably inhibited, as compared with those of the nucleus pulposus group (P < 0.05). However, evoked discharges during stimulation apparently were not inhibited. Responses to innocuous stimulation did not change throughout the measurements. These data indicate that application of TNFalpha antibodies to the nerve root partially prevents the nucleus pulposus-induced abnormal nociresponses. Therefore, anti-TNFalpha treatment may have a therapeutic effect on sciatica after lumbar disc herniation.

Down-regulation of the nonspecific and antigen-specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab.

Treatment of active ankylosing spondylitis (AS) with the monoclonal tumor necrosis factor alpha (TNF alpha) antibody infliximab is highly clinically effective. This study was undertaken to investigate the precise mechanism of action of anti-TNF alpha treatment in AS. Cytokine expression of CD4+ and CD8+ T cells was investigated before and 6 and 12 weeks after the start of treatment in 10 patients treated with infliximab, and before and after 6 weeks of treatment and 6 weeks after placebo was switched to infliximab in 10 patients treated initially with placebo. Peripheral blood mononuclear cells (PBMCs) were stimulated for 6 hours either nonspecifically with phorbol myristate acetate (PMA)/ionomycin or antigen specifically with a pool of 46 overlapping 18-mer peptides derived from the G1 domain of aggrecan. Cells were stained for T cell surface markers CD4 and CD8 and for the intracellular cytokines interferon-gamma (IFN gamma), TNF alpha, interleukin-4 (IL-4), and IL-10. Positive cells were quantified by flow cytometry. For monocyte-derived cytokines, PBMCs were stimulated with lipopolysaccharide (LPS) for 18 hours and TNF alpha and IL-10 in the supernatant were measured by enzyme-linked immunosorbent assay. Compared with baseline, infliximab treatment induced a significant decrease at 12 weeks in the number of CD4+ and CD8+ T cells that were positive for IFN gamma and TNF alpha upon PMA/ionomycin stimulation (P = 0.005). A significant reduction had already begun to occur at 6 weeks. No change in the percent IFN gamma or TNF alpha positivity among CD4+ and CD8+ subpopulations was observed after 6 weeks in patients treated with placebo. However, when these patients began infliximab treatment after 6 weeks of receiving placebo, there was a similar significant decrease in IFN gamma and TNF alpha production by CD4+ and CD8+ T cells (P < 0.05). Furthermore, infliximab treatment induced a significant reduction in the number of IFN gamma+ and TNF alpha+ CD8+ T cells (P = 0.005 at week 6 and week 12) after antigen-specific in vitro stimulation with G1-derived peptides. Between-group analysis showed that the change in the expression of IFN gamma and TNF alpha in both CD4+ and CD8+ T cells was significantly different between the infliximab and placebo groups (P = 0.001 for all variables). There was no change in the number of IL-10+ or IL-4+ T cells during treatment. No significant change in the production of TNFalpha and IL-10 upon in vitro stimulation of PBMCs with LPS was detectable during infliximab treatment. Infliximab down-regulates both IFN gamma and TNF alpha secreted by T cells but does not induce a change in cytokines produced by monocytes during 3 months of treatment. This is likely to be a relevant mechanism for the clinical efficacy of this therapy.

High levels of osteoprotegerin and soluble receptor activator of nuclear factor kappa B ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor alpha treatment.

To test the hypotheses that 1) proinflammatory cytokines affect osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappa B ligand (sRANKL) production and therefore the OPG and sRANKL levels differ in rheumatoid arthritis (RA) patients in comparison with healthy individuals; and 2) anti-tumor necrosis factor alpha (anti-TNF alpha) therapy influences OPG and sRANKL levels. Sera were obtained from healthy individuals or RA patients receiving the combination of infliximab and methotrexate. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were isolated from RA patients. Fibroblast-like synoviocytes (FLS) were isolated from synovial tissue obtained at total knee replacement in RA patients. Supernatants from cells stimulated with cytokines were collected after culture in vitro. Concentrations of OPG and sRANKL were determined by enzyme-linked immunosorbent assays. A strong positive correlation between OPG concentration and age was observed in healthy individuals but not in RA patients. The OPG and sRANKL levels were higher in RA patients than in healthy controls. Cultured FLS spontaneously secreted much higher amounts of OPG than PBMCs or SFMCs. Proinflammatory cytokines enhanced OPG production. Anti-TNF alpha treatment resulted in the normalization of serum OPG and sRANKL levels in RA patients without influencing the OPG:sRANKL ratio. Although higher serum levels of OPG and sRANKL are present in RA patients than in healthy individuals, the ratio of OPG:sRANKL is similar. There is an age-dependent increase of OPG but not sRANKL levels in healthy subjects. Anti-TNF alpha treatment results in the normalization of elevated levels of OPG and sRANKL in RA patients.

Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha–mediated effect

Based on previous reports for impaired hematopoiesis in rheumatoid arthritis (RA), and in view of the current interest in exploring the role of autologous stem cell transplantation (ASCT) as an alternative treatment in patients with resistant disease, we have evaluated bone marrow (BM) progenitor cell reserve and function and stromal cell function in 26 patients with active RA. BM progenitor cells were assessed using flow cytometry and clonogenic assays in short-term and long-term BM cultures (LTBMCs). BM stroma function was assessed by evaluating the capacity of preformed irradiated LTBMC stromal layers to support the growth of normal CD34(+) cells. We found that RA patients exhibited low number and increased apoptosis of CD34(+) cells, defective clonogenic potential of BM mononuclear and purified CD34(+) cells, and low progenitor cell recovery in LTBMCs, compared with healthy controls (n = 37). Patient LTBMC stromal layers failed to support normal hematopoiesis and produced abnormally high amounts of tumor necrosis factor alpha (TNF alpha). TNF alpha levels in LTBMC supernatants inversely correlated with the proportion of CD34(+) cells and the number of colony-forming cells, and positively with the percentage of apoptotic CD34(+) cells. Significant restoration of the disturbed hematopoiesis was obtained following anti-TNF alpha treatment in 12 patients studied. We concluded that BM progenitor cell reserve and function and BM stromal cell function are defective in RA probably due, at least in part, to a TNF alpha-mediated effect. The role of these abnormalities on stem cell harvesting and engraftment in RA patients undergoing ASCT remains to be clarified.

New treatment options in ankylosing spondylitis: a role for anti-TNFα therapy

Anti-TNFalpha treatment seems to be highly effective in AS. The results available indicate that this treatment is at least as effective as in RA. Furthermore, because no other treatments are...

The role of CD40 ligand and tumor necrosis factor alpha signaling in the transgenic K/BxN mouse model of rheumatoid arthritis.

Spontaneous arthritis in the KRN transgenic mouse (K/BxN) model is due to the autoreactivity of the transgenic T cell receptor and subsequent induction of autoantibodies directed against glucose-6-phosphate isomerase (G6PI). This study sought to analyze the potential of anti-CD40 ligand (anti-CD40L) and anti-tumor necrosis factor alpha (anti-TNFalpha) antibodies in preventing and treating arthritis in this murine model. Groups of K/BxN mice were injected with anti-CD40L and anti-TNFalpha antibodies during various stages of arthritis. Disease was assessed by clinical scoring, measurements of paw swelling, and histology. The results were correlated with the levels of autoantibodies in the serum, as assessed by enzyme-linked immunosorbent assay. Anti-CD40L antibody treatment was able to diminish significantly the arthritis development in K/BxN mice when given a week before the onset of clinically apparent disease. However, no effect on disease was seen when the antibodies were administered after clinical onset. Surprisingly, neutralizing anti-TNFalpha antibodies were unable to prevent arthritis in K/BxN mice. The success of antibody treatment in preventing disease correlated with low levels of anti-G6PI antibodies in the serum. These results suggest that anti-CD40L treatment can prevent arthritis development in a model of immunoglobulin-mediated arthritis, but anti-TNFalpha treatment cannot. The unsuccessful treatment of established disease was possibly due to the continued presence of autoreactive antibodies in the arthritic mice.