Decrease in neuroimmune activation by HSV-mediated gene transfer of TNFα soluble receptor alleviates pain in rats with diabetic neuropathy.

The mechanisms of diabetic painful neuropathy are complicated and comprise of peripheral and central pathophysiological phenomena. A number of proinflammatory cytokines are involved in this process. Tumor necrosis factor α (TNF-α) is considered to be one of the major contributors of neuropathic pain. In order to explore the potential role of inflammation in the peripheral nervous system of Type 1 diabetic animals with painful neuropathy, we investigated whether TNF-α is a key inflammatory mediator to the diabetic neuropathic pain and whether continuous delivery of TNFα soluble receptor from damaged axons achieved by HSV vector mediated transduction of DRG would block or alter the pain perception in animals with diabetic neuropathy. Diabetic animals exhibited changes in threshold of mechanical and thermal pain perception compared to control rats and also demonstrated increases in TNFα in the DRG, spinal cord dorsal horn, sciatic nerve and in the foot skin, 6 weeks after the onset of diabetes. Therapeutic approaches by HSV mediated expression of p55 TNF soluble receptor significantly attenuated the diabetes-induced hyperalgesia and decreased the expression of TNFα with reduction in the phosphorylation of p38MAPK in the spinal cord dorsal horn and DRG. The overall outcome of this study suggests that neuroinflammatory activation in the peripheral nervous system may be involved in the pathogenesis of painful neuropathy in Type 1 diabetes which can be alleviated by local expression of HSV vector expressing p55 TNF soluble receptor.

Clinical development of onercept, a tumor necrosis factor binding protein, in psoriasis.

BACKGROUND: Tumor necrosis factor (TNF)-α plays a critical role in psoriasis pathogenesis, and several anti-TNF agents have been developed as therapeutic drugs in this indication. SCOPE: To present the preclinical rationale and clinical data for onercept, a novel anti-TNF agent developed for the treatment of moderate-to-severe psoriasis, and to critically evaluate the onercept clinical development program. FINDINGS: Onercept was shown in preclinical studies to inhibit TNF-α and suppress clinical signs in several inflammatory conditions. In phase II studies onercept demonstrated a therapeutic benefit in psoriasis and psoriatic arthritis and no safety issues were identified. Based on these results, a phase III program comprising three multicenter, randomized, double-blind, placebo-controlled studies examining onercept in moderate-to-severe plaque psoriasis was initiated. Following the occurrence of two cases of systemic inflammatory response syndrome (SIRS) and lower than expected efficacy results, an independent Data Safety Monitoring Board (DSMB) determined that the risk-benefit ratio was not sufficiently favorable to justify continued development, and all clinical studies were promptly terminated. Although not initially diagnosed as such by the investigators, two further SIRS events were reported, one after study discontinuation. Although an increased incidence of infection and sepsis-like events has been associated with other anti-TNF therapies, an increased risk of infection was not observed with onercept treatment. Moreover, no infectious etiology was determined in the SIRS cases. The data suggest that the SIRS reactions were due to a systemic inflammatory response. CONCLUSIONS: Despite promising early clinical results, onercept showed many of the expected risks associated with other anti-TNF agents and proved not to have an exceptional efficacy and safety profile. The clinical development of onercept highlights the critical importance of DSMBs and closely monitoring patient safety and evaluating risk-benefit profiles in large clinical programs.

Endometriosis: in search of optimal treatment.

Endometriosis is an enigmatic, debilitating disease which affects as many as 15% of all women of reproductive age and is characterized by pelvic pain and infertility. Current treatment regimes used to manage the disease do so by inducing a hypoestrogenic state. While the absence of circulating estrogen levels lead to a regression of the disease, this hypoestrogenism also induces many unpleasant and unwanted side-effects. As such, these and other shortcomings of current drug therapies emphasize their limitations and the necessity for the development of novel endometriosis treatments. In this review, current therapies for medical management of endometriosis are discussed as are their shortcomings. Potential target areas which may be attractive alternatives to current therapies are also reviewed and include aromatase inhibitors, angiogenesis disruptors and anti-tumor necrosis factor-alpha inhibitors.

Lack of effect of TNFalpha blockade therapy on circulating adiponectin levels in patients with autoimmune disease: results from two independent prospective studies.

BACKGROUND: Adiponectin is an anti-inflammatory and potentially antiatherogenic molecule. Some recent reports suggest that tumour necrosis factor alpha (TNFalpha) blockade therapy increases circulating adiponectin levels, but data are sparse and inconsistent. METHODS: Data from a double-blind placebo controlled study of onercept in 126 patients with psoriatic arthritis (PsA) and from pre- and post-adalimumab treatment in 171 patients with rheumatoid arthritis (RA) were used to examine the effect of TNFalpha blockade therapy on adiponectin. RESULTS: Despite expected associations of adiponectin with gender and baseline high-density lipoprotein cholesterol and triglyceride, adiponectin levels did not change over time with TNFalpha blockade therapy in either group. The mean+/-SD absolute change in adiponectin levels was -0.23+/-4.6 microg/ml in patients with PsA treated with combined onercept 50 mg and onercept 100 mg (vs placebo, p=0.60) and 0.28+/-3.23 microg/ml in patients with RA treated with adalimumab (vs baseline, p=0.66). CONCLUSION: These results do not support a significant effect of TNFalpha blockade therapy on circulating adiponectin levels in patients with autoimmune disease.

Biological therapy of inflammatory bowel disease.

Ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis are defined as inflammatory bowel diseases (IBD). Those diseases involve disorders of numerous immunological mechanisms associated with cellular and humoral immune response. In CD cellular response is considered to be of crucial importance, and dominant cytokines include: tumor necrosis factor alpha (TNF-alpha), interferon gamma (INF-gamma) and interleukins 1beta (IL-1beta), IL-2, IL-6, IL-8, IL-12. In UC, increased expression of Th2 (responsible for humoral response) is observed. It is connected with increased production of interleukins: 4 (IL-4), IL-5, IL-6, IL-10 and TNF-alpha. Lack of balance between pro-inflammatory and anti-inflammatory cytokines is of vital importance in pathogenesis of IBD. Conventional therapy of CD and UC quite commonly fails to bring satisfactory results, therefore an interest in new therapeutic options, that is, biological therapy, gene therapy, hematopoietic stem cell transplantation, and leucapheresis, has aroused recently. Biological therapy is focused on different stages of the inflammatory process. The fundamentals of biological strategy involve neutralization of pro-inflammatory cytokines, use of anti-inflammatory cytokines and inhibition of neutrophil adhesion. Biological therapy is a promising option because it enables to withdraw corticosteroids and immunosuppressive agents or to reduce their dose. Moreover, it shortens the hospital stay, allows to avoid surgical procedures, extends the remission period and improves patients' quality of life. Currently, 2 agents, infliximab and adalimumab, are registered for the biological therapy of CD in Poland.

Recombinant human TNF-binding protein-1 (rhTBP-1) treatment delays both symptoms progression and motor neuron loss in the wobbler mouse.

TNF-alpha overexpression may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). We investigated the intracellular pathway associated with TNF-alpha in the wobbler mouse, a murine model of ALS, at the onset of symptoms. TNF-alpha and TNFR1 overexpression and JNK/p38MAPK phosphorylation occurred in neurons and microglia in early symptomatic mice, suggesting that this activation may contribute to motor neuron damage. The involvement of TNF-alpha was further confirmed by the protective effect of treatment with rhTNF-alpha binding protein (rhTBP-1) from 4 to 9 weeks of age. rhTBP-1 reduced the progression of symptoms, motor neuron loss, gliosis and JNK/p38MAPK phosphorylation in wobbler mice, but did not reduce TNF-alpha and TNFR1 levels. rhTBP-1 might possibly bind TNF-alpha and reduce the downstream phosphorylation of two main effectors of the neuroinflammatory response, p38MAPK and JNK.

Effects of tumor necrosis factor blockade on cardiovascular risk factors in psoriatic arthritis: a double-blind, placebo-controlled study.

OBJECTIVE: To conduct a robust, double-blind, placebo-controlled study examining the effects of tumor necrosis factor (TNF) modulation on concentrations of traditional and novel cardiovascular disease risk factors in patients with an inflammatory condition. METHODS: In this double-blind study, 127 patients with psoriatic arthritis (PsA) and active psoriasis were randomized to 1 of 3 treatment arms (placebo, onercept 50 mg, or onercept 100 mg for 12 weeks). Traditional and novel biochemical risk factors were evaluated at baseline and at the end of the treatment period. RESULTS: At baseline, an elevated C-reactive protein (CRP) level correlated positively with lipoprotein(a) (Lp[a]), intercellular adhesion molecule 1, interleukin-6, and homocysteine levels but was inversely correlated with concentrations of all other lipid moieties and sex hormone binding globulin (SHBG). Onercept at a dose of 100 mg induced significant (P < or = 0.002) reductions in the levels of CRP (-14.0 versus 6.5 mg/liter with placebo), Lp(a) (-3.11 versus 1.52 mg/dl with placebo), and homocysteine (-1.72 versus 0.34 mumoles/liter with placebo) and an increase in the SHBG concentration (4.3 versus -1.3 mmoles/liter with placebo). The 100-mg dose of onercept was also associated with significant (P < 0.05) increases in the level of circulating apolipoprotein AI (Apo A-I) (4.0 versus -5.6 mg/dl with placebo); however, levels of Apo B (6.3 versus -0.4 mg/dl with placebo) and triglycerides (0.09 versus 0.04 mmoles/liter) were also increased. CONCLUSION: This study is the first to demonstrate that targeting the TNF pathway can significantly decrease Lp(a) and homocysteine levels and elevate Apo A-I and SHBG concentrations. These data support an important precursor role for high-grade inflammation in modulating these putative risk parameters. However, TNF blockade-induced increases in triglyceride and Apo B levels were unexpected and suggest that it is not possible, on the basis of biochemical changes in isolation, to suggest that cardioprotection would necessarily follow; rather, direct measures of atherosclerotic progression with TNF blockade (e.g., using carotid ultrasound) would be better.