TNFMedicine

Nociceptive characteristics of tumor necrosis factor-alpha in naive and tumor-bearing mice

This excellent article, from the group at the University of Minnesota, includes a detailed analysis of the role of local anti-TNF administration in pain secondary to cancer metastasis to bone, as discussed in my 2003 article (Edward Tobinick MD Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. Clinical Therapeutics 2003 Aug; 25(8) :2279-88). My work is both cited and carefully discussed. Highly recommended reading.

Title Nociceptive characteristics of tumor necrosis factor-alpha in naive and tumor-bearing mice.
Author(s) Wacnik PW, Eikmeier LJ, Simone DA, Wilcox GL, Beitz AJ 
Institution Department of Pharmacology, University of Minnesota, School of Medicine, Minneapolis, MN 55455, USA.
Source Neuroscience 2005; 132(2) :479-91.
MeSH Animals
Behavior, Animal
Cell Line, Tumor
Fibrosarcoma
Gene Expression Regulation, Neoplastic
Immunohistochemistry
Male
Mice
Mice, Inbred C3H
Neoplasm Transplantation
Neoplasms, Experimental
Pain
Pain Measurement
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
Abstract A nociceptive role for tumor necrosis factor-alpha (TNF-alpha) in naive mice and in mice with fibrosarcoma tumor-induced primary hyperalgesia was investigated. The presence of TNF-alpha mRNA was confirmed in tumor site homogenates by reverse transcription-polymerase chain reaction (RT-PCR), and examination of TNF-alpha protein levels in tumor-bearing mice indicated a significantly higher concentration of this cytokine in tumor microperfusates and tumor site homogenates compared with that obtained from a similar site on the contralateral limb or in naive mice. Intraplantar injection of TNF-alpha into naive or fibrosarcoma tumor-bearing mice induced mechanical hypersensitivity, as measured by withdrawal responses evoked by von Frey monofilaments. This hypersensitivity suggests that TNF-alpha can excite or sensitize primary afferent fibers to mechanical stimulation in both naive and tumor-bearing mice. In addition, the hyperalgesia produced by TNF-alpha was completely eliminated when the injected TNF-alpha was pre-incubated with the soluble receptor antagonist TNFR:Fc. Importantly, pre-implantation systemic as well as post-implantation intra-tumor injection of TNFR:Fc partially blocked the mechanical hyperalgesia, indicating that local production of TNF-alpha may contribute to tumor-induced nociception.
Language eng
Pub Type(s) Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.
PubMed ID 15802198

Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up

Both this article and a previous publication from this excellent Finnish group cited our earlier work, published in 2003, which was the first peer-reviewed article to present the results of biologic anti-TNF treatment for disc-related pain in humans (Edward Tobinick MD, et. al. Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly 2003 Mar 22; 133(11-12) :170-7). I had the pleasure of speaking at length with Drs. Hurri and Karppinen at the 2003 International Society for the Study of the Lumbar Spine meeting in Vancouver, and found them both to be highly knowledgeable. A subsequent RCT by this Finnish group utilizing systemically delivered (intravenous) infliximab for acute-subacute sciatica failed to show superiority over placebo. This result produced a great deal of discussion in the spinal community. An RCT is only as good as its design; if improperly designed, then an RCT may fail to show a treatment effect even if the therapeutic is, in reality, effective. In the case of this RCT there were multiple potential problems in design. The first confounding factor is that the great majority of patients with acute sciatica experience dramatic pain reduction over time even without treatment. Based on this fact alone it would appear that this might not be the optimal group in which to try and demonstrate a treatment effect. In addition, systemic delivery of anti-TNF biologics may not be the ideal method to reduce localized increased concentrations of TNF at a spinal nerve root. (This, of course, is the rationale behind anatomically localized perispinal administration of etanercept, a concept which I developed and pioneered for the treatment of intractable disc-related pain, as detailed in our 2003 article, which discussed treatment of patients with this method beginning in 2001 or earlier).

Title Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up.
Author(s) Korhonen T, Karppinen J, Malmivaara A, Autio R, Niinimäki J, Paimela L, Kyllönen E, Lindgren KA, Tervonen O, Seitsalo S, Hurri H 
Institution Department of Physical Medicine and Rehabilitation, Oulu University Hospital, Oulu, Finland.
Source Spine 2004 Oct 1; 29(19) :2115-9.
MeSH Antibodies, Monoclonal
Comparative Study
Drug Administration Schedule
Female
Follow-Up Studies
Humans
Infusions, Intravenous
Intervertebral Disk Displacement
Leg
Male
Pain
Research Support, Non-U.S. Gov't
Sciatica
Time
Treatment Outcome
Tumor Necrosis Factor-alpha
Abstract STUDY DESIGN: An open-label trial.
OBJECTIVES: To test the long-term efficacy of infliximab, a monoclonal antibody against tumor necrosis factor-alpha (TNF-alpha), in disc herniation-induced sciatica.
SUMMARY OF BACKGROUND DATA: Our recent trial indicated that a single infusion of 3 mg/weight-kg of infliximab produced a rapid curative effect in disc herniation-induced sciatica. Here, we describe the 1-year effect of a 3 mg/kg of infliximab in these 10 patients and our experience with a lower dose of 1 mg/kg of infliximab for the same indication in 2 additional patients.
METHODS: Patients with severe sciatica were treated with a single infusion of infliximab, 3 mg/weight-kg in 10 patients and 1 mg/kg in 2 patients, intravenously over 2 hours. The outcomes (leg and back pain on a 100-mm visual scale, Oswestry disability, clinical signs) were assessed at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 1 year after the infusion. The outcomes with 3 mg/kg of infliximab were compared to 62 patients who received periradicular saline for sciatica in a previous trial. The resorption rate of disc herniations from baseline to 1 year was compared between infliximab and control groups.
RESULTS: The response to 1 mg/kg of infliximab for leg pain was good only in 1 of the 2 patients treated, whereas the response to 3 mg/kg of infliximab for leg pain was sustained in most patients over the 1-year follow-up. The 1-year response significantly favored 3 mg/kg of infliximab over periradicular saline in leg pain (P = 0.005) and disability (P = 0.003). Neurologic abnormalities normalized more comprehensively in the infliximab group (P = 0.001). Reduction in disc herniation volume did not differ between the infliximab-treated patients and controls.
CONCLUSIONS: The results showed that the beneficial effect of a single infusion of 3 mg/kg of infliximab for herniation-induced sciatica is sustained in most patients over a 1-year follow-up period. Furthermore, infliximab does not seem to interfere with the spontaneous resorption of disc herniations.
Language eng
Pub Type(s) Clinical Trial
Journal Article
PubMed ID 15454701

Lumbar discography: a comprehensive review of outcome studies, diagnostic accuracy, and principles

Title Lumbar discography: a comprehensive review of outcome studies, diagnostic accuracy, and principles.
Author(s) Cohen SP, Larkin TM, Barna SA, Palmer WE, Hecht AC, Stojanovic MP 
Institution Pain Management Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. scohen40@jhmi.edu
Source Reg Anesth Pain Med 2005 Mar-Apr; 30(2) :163-83.
MeSH Costs and Cost Analysis
False Positive Reactions
Humans
Intervertebral Disk
Intervertebral Disk Displacement
Lumbar Vertebrae
Pain
Physical Stimulation
Spinal Fusion
Vibration
Abstract BACKGROUND AND OBJECTIVES: Since its advent more than 50 years ago, the use of discography has been mired in controversy. The purpose of this review is to provide a clinical overview of lumbar discography and discogenic back pain, with special emphasis on determining the accuracy of discography and whether or not the procedure improves outcomes for surgery.
METHODS: Material for this review was obtained from a MEDLINE search conducted from 1951 thru September 2004, bibliographic references, book chapters, and conference proceedings.
RESULTS: Based on a large number of comparative studies, plain discography is less accurate than magnetic resonance imaging in diagnosing lumbar herniated nucleus pulposus and comparable or slightly more sensitive in detecting degenerative disc disease. For disc degeneration, CT discography remains the gold standard for diagnosis. There are very few studies comparing surgical outcomes between patients who have undergone preoperative provocative discography and those who have not. What little evidence exists is conflicting. Before disc replacement surgery, approximately half the studies have used preoperative discography. A comparison of outcomes did not reveal any significant difference between the 2 groups but none of the studies was controlled, and they used different outcome measures, follow-up periods, and surgical techniques. Because all intradiscal electrothermal therapy (IDET) studies have used discography before surgery, no conclusions can be drawn regarding its effects on outcome.
CONCLUSIONS: Although discography, especially combined with CT scanning, may be more accurate than other radiologic studies in detecting degenerative disc disease, its ability to improve surgical outcomes has yet to be proven. In the United States and Europe, there are inconsistencies in the use of lumbar discography such that it is routinely used before IDET, yet only occasionally used before spinal fusion.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID 15765459

Distribution and immunocytochemical characterization of dorsal root ganglion neurons innervating the lumbar intervertebral disc in rats: a review

Title Distribution and immunocytochemical characterization of dorsal root ganglion neurons innervating the lumbar intervertebral disc in rats: a review.
Author(s) Aoki Y, Takahashi Y, Ohtori S, Moriya H, Takahashi K 
Institution Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo, Chiba, 260-8670, Japan. yasuaoki@h6.dion.ne.jp
Source Life Sci 2004 Apr 9; 74(21) :2627-42.
MeSH Animals
Calcitonin Gene-Related Peptide
Ganglia, Spinal
Glycoproteins
Immunohistochemistry
Intervertebral Disk
Lectins
Lumbar Vertebrae
Models, Neurological
Neurons, Afferent
Rats
Receptors, Drug
Receptors, Purinergic P2
Substance P
Abstract Previously, it was believed that the lumbar intervertebral disc was innervated segmentally by dorsal root ganglion (DRG) neurons via the sinuvertebral nerves. Recently, it was demonstrated using retrograde tracing methods that the lower disc (L5-L6) is innervated predominantly by upper (L1 and L2) DRG neurons via the sympathetic trunks. Furthermore, we investigated the expression of various pain-related molecules such as calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), P2X(3) receptor and vanniloid receptor 1 (VR1) in DRG neurons innervating the disc using a combination of immunostaining with the retrograde tracing method. This review outlines the distribution and immunocytochemical characterization of DRG neurons innervating the disc. Small nociceptive DRG neurons are classified into nerve growth factor (NGF)-dependent neurons and glial cell line-derived neurotrophic factor (GDNF)-dependent neurons and they can be distinguished by their reactivity for CGRP and IB4, respectively. We found that about half of the neurons innervating the disc were CGRP-immunoreactive (-ir), whilst, only 0.6% of the DRG neurons were IB4-positive, thereby indicating that NGF-dependent neurons are the main subpopulation which transmits and modulates nociceptive information from the disc. In addition, we also demonstrated P2X(3)- and VR1-immunoreactivity in DRG neurons innervating the disc and noted that they were mainly localized in NGF-dependent neurons. It is well known that NGF has sensitizing effects on DRG neurons, with a recent study demonstratng the presence of NGF in the painful intervertebral disc. Therefore, it is suggested that NGF is involved in the generation of discogenic low back pain.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID

Etanercept in chronic severe asthma

Title Etanercept in chronic severe asthma.
Author(s) Oliveri C, Polosa R 
Source Thorax 2006 Jul; 61(7) :640; author reply 640.
MeSH Anti-Asthmatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Asthma
Chronic Disease
Humans
Immunoglobulin G
Receptors, Tumor Necrosis Factor
Respiratory Tract Infections
Language eng
Pub Type(s) Comment
Journal Article
PubMed ID 16807393

Silicone granulomas treated with etanercept

Title Silicone granulomas treated with etanercept.
Author(s) Pasternack FR, Fox LP, Engler DE 
Institution Department of Dermatology, Columbia University Medical Center, New York, NY 10032, USA.
Source Arch Dermatol 2005 Jan; 141(1) :13-5.
MeSH Adult
Buttocks
Cosmetic Techniques
Female
Granuloma
Humans
Immunoglobulin G
Injections
Leg
Middle Aged
Receptors, Tumor Necrosis Factor
Silicones
Skin Diseases
Treatment Outcome
Language eng
Pub Type(s) Case Reports
Journal Article
PubMed ID 15655137

Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer

Title Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer.
Author(s) Anderson GM, Nakada MT, DeWitte M 
Institution Centocor, 200 Great Valley Parkway, Malvern, PA 19355, USA. MAnders4@cntus.jnj.com
Source Curr Opin Pharmacol 2004 Aug; 4(4) :314-20.
MeSH Animals
Humans
Neoplasms
Signal Transduction
Tumor Necrosis Factor-alpha
Abstract The critical pathogenic role of tumor necrosis factor (TNF)alpha in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease is well established. The role played by TNFalpha in both the treatment and pathogenesis of cancer remains less understood. Recent advances help to create a framework for understanding seemingly paradoxical effects of TNFalpha as both an anti-tumour agent and a mediator of tumour growth. High pharmacological doses of TNFalpha combined with chemotherapy can regress otherwise intractable tumours, and efforts continue to optimize delivery to avoid severe toxicities. Mounting evidence demonstrates that pathophysiological concentrations of endogenous TNFalpha act to promote tumour genesis and growth. The cellular and molecular pathways mediating these phenomena are starting to be clarified. Current data support the continued development of both TNFalpha and anti-TNFalpha therapy for clinical treatment of cancers in distinct settings.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID 15251122

The soluble tumor necrosis factor receptor etanercept: a new strategy for the treatment of autoimmune rheumatic disease

Title The soluble tumor necrosis factor receptor etanercept: a new strategy for the treatment of autoimmune rheumatic disease.
Author(s) Cole P, Rabasseda X 
Institution Medical Information Department, Prous Science, Provença 388, 08025 Barcelona, Spain.
Source Drugs Today (Barc) 2004 Apr; 40(4) :281-324.
MeSH Animals
Antirheumatic Agents
Arthritis, Rheumatoid
Clinical Trials
Cost-Benefit Analysis
Dose-Response Relationship, Drug
Drug Therapy, Combination
Humans
Immunoglobulin G
Methotrexate
Quality of Life
Receptors, Tumor Necrosis Factor
Recombinant Fusion Proteins
Severity of Illness Index
Treatment Outcome
Tumor Necrosis Factor-alpha
Abstract Rheumatoid arthritis is a severe, debilitating condition for which existing therapies are of limited efficacy. In addition, the most common structure of treatment for patients with rheumatoid arthritis has recently been called into question, and many believe it should be reversed so that stronger treatments are administered earlier in the progression of the disease. Pivotal to the changes in rheumatoid arthritis treatment is the introduction of the pro-inflammatory tumor necrosis factor (TNF) antagonists. Overexpression of cytokines in inflamed joints plays an important role in joint inflammation and tissue damage, and the place of cytokines in the pathology of rheumatoid arthritis has offered hope that their antagonism will reduce symptoms and slow the advancement of the condition. With this in mind, etanercept, a fully human soluble TNF receptor fusion protein, was developed. The potency of this novel drug in blocking TNF activity has been shown in animal models and in clinical trials. The latter have demonstrated a positive safety profile and efficacy in reducing pain and the number of tender and swollen joints in rheumatoid arthritis patients. The effects of etanercept have also been observed soon after administration and have been sustained over several years. Etanercept has offered encouragement for those seeking new, more efficacious and less toxic methods of treating rheumatoid arthritis in children, adults and the elderly. In addition to the treatment of adult and juvenile rheumatoid arthritis, etanercept has also demonstrated utility in treating ankylosing spondylitis and psoriatic arthritis.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID 15190385

Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica

Title Tumor necrosis factor-alpha monoclonal antibody, infliximab, used to manage severe sciatica.
Author(s) Karppinen J, Korhonen T, Malmivaara A, Paimela L, Kyllönen E, Lindgren KA, Rantanen P, Tervonen O, Niinimäki J, Seitsalo S, Hurri H 
Institution Department of Physical Medicine and Rehabilitation, Oulu University Hospital, Finland. jaro.karppinen@occuphealth.fi
Source Spine 2003 Apr 15; 28(8) :750-3; discussion 753-4.
MeSH Adult
Antibodies, Monoclonal
Antirheumatic Agents
Female
Follow-Up Studies
Humans
Infusions, Intravenous
Intervertebral Disk Displacement
Male
Middle Aged
Research Support, Non-U.S. Gov't
Sciatica
Treatment Outcome
Tumor Necrosis Factor-alpha
Abstract STUDY DESIGN: An open-label study was conducted.
OBJECTIVE: To evaluate the efficacy and safety of infliximab, a monoclonal chimeric antibody, against tumor necrosis factor-alpha (TNFalpha) for the treatment of severe sciatica.
SUMMARY OF BACKGROUND DATA: Evidence from animal studies indicates that TNFalpha plays a role in the pathophysiology of sciatica. Anti-TNFalpha therapy has not been previously evaluated in sciatic patients.
METHODS: In this study, 10 patients with disc herniation-induced severe sciatica received infliximab (Remicade 3 mg/kg) intravenously over 2 hours. The outcome was assessed at 1 hour, 1 week, 2 weeks, 1 month, and 3 months after the infusion and compared to historical control subjects consisting of 62 patients who received saline in a trial of periradicular infiltration for sciatica. Leg pain was the primary outcome, with more than a 75% decrease from the baseline score constituting a painless state. Fisher's exact test and repeated measures analysis of variance were used for statistical analysis.
RESULTS: At 1 hour after the infusion, leg pain had decreased by 50%. At 2 weeks, 60% of the patients in the infliximab group were painless, as compared with 16% of the control patients (P = 0.006). The difference was sustained at 3 months (90% vs 46%; P = 0.014). Infliximab was superior over the whole follow-up period in terms of leg pain (P = 0.003) and back-related disability (P = 0.004). At 1 month, every patient in the infliximab group had returned to work, whereas 38% of the control subjects still were on sick leave (P = 0.02). None of the patients treated with infliximab underwent surgery during the follow-up period. No immediate or delayed adverse drug reactions and no adverse effects related to medication were observed.
CONCLUSIONS: Anti-TNFalpha therapy is a promising treatment option for sciatica. There is an urgent need for a randomized controlled trial to evaluate whether thesepromising early results can be confirmed.
Language eng
Pub Type(s) Clinical Trial
Controlled Clinical Trial
Journal Article
PubMed ID 12698115

Treatment of severe acute respiratory syndrome.

Title Treatment of severe acute respiratory syndrome.
Author(s) Lai ST 
Institution Division of Infectious Disease, Department of Medicine, Princess Margaret Hospital, 2-10, Princess Margaret Hospital Road, Lai Chi Kok, Kowloon, Hong Kong Special Administrative Region, China. laist@ha.org.hk
Source Eur J Clin Microbiol Infect Dis 2005 Sep; 24(9) :583-91.
MeSH Adrenal Cortex Hormones
Antiviral Agents
Clinical Protocols
Humans
Immunoglobulins, Intravenous
Medicine, Chinese Traditional
Plasma Exchange
Positive-Pressure Respiration
Respiration, Artificial
Severe Acute Respiratory Syndrome
Abstract The best treatment strategy for severe acute respiratory syndrome (SARS) is still unknown. Ribavirin and corticosteroids were used extensively during the SARS outbreak. Ribavirin has been criticized for its lack of efficacy. Corticosteroids are effective in lowering the fever and reversing changes in the chest radiograph but have the caveat of encouraging viral replication. The effectiveness of corticosteroids has only been suggested by uncontrolled observations, and the role of these agents in therapy remains to be established by randomized controlled studies. Both ribavirin and corticosteroids have very significant side effects. The lopinavir/ritonavir combination has been shown to reduce the intubation rate and the incidence of adverse clinical outcomes when used with ribavirin. When patients deteriorate clinically despite treatment with ribavirin and corticosteroids, rescue treatment with convalescent plasma and immunoglobulin may be beneficial. Noninvasive positive pressure ventilation is a sound treatment for SARS patients with respiratory failure if administered with due precaution in the correct environment. Interferons and other novel agents may hold promise as useful anti-SARS therapies in the future. The experience with traditional Chinese medicine is encouraging, and its use as an adjuvant should be further investigated.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID 16172857