Université de Genève Faculté de Médecine
Hôpitaux Universitaires de Genève
Département des spécialités médicales
TNF-α in the Pathophysiology of Sciatica
Breakthrough or Dead End?
Thèse de privat-docent de
Stéphane Genevay 03/ 02/2011
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Acknowledgments
A ma femme avec tout mon amour. Sa présence à mes côtés est une lumière qui enflamme mon cœur à tous les instants et donne à ma vie toutes les couleurs de l’arc- en-ciel.
A mes enfants, Gabriel et Baptiste dont les rires et les sourires illuminent mon
quotidien.
A mes parents qui m’ont donné leur
confiance et leur soutien quelque soit le tour que prenait ma route et ont su me donner les moyens de réaliser mes rêves.
A tous ceux qui m’ont appris mon métier avec une pensée toute particulière pour les professeurs A. Junod, T.L Vischer et C.
Gabay, mais également aux patients qui en me donnant leur confiance et en partageant avec moi leurs souffrances m’ont offert la possibilité de grandir en tant qu’homme et en tant que médecin.
Enfin, à tout ceux dont j’ai croisé le chemin
et qui d’une manière ou d’une autre on fait
ce que je suis aujourd’hui.
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Sans Dieu l homme ne sait pas où aller et ne parvient même pas à comprendre qui il est.
Benoît XVI
It ain't what you
don't know that gets you into trouble. It's what you know for sure that just ain't so.
Mark Twain
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Table of contents
1. Summary...5
2. Introduction...6
3. Summary of data from animal models of radiculopathy...33
4. The case of human disc herniation...38
5. Trials with TNF inhibitors...54
6. Discussion...68
7. Concluding remarks...70
8. References...7
1
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1. Summary
Over the past 20 years, the hypothesis that inflammation was an important component of the pathophysiology of sciatica has slowly emerged. Numerous studies in a variety of animal models have been published to sustain this hypothesis, but it is only recently that we were able to produce the first evidence that tumor necrosis factor (TNF)-α could be an important mediator in human sciatica. We were able to demonstrate that there was a higher
concentration of TNF-α in the vicinity of the inflamed nerve root in sciatica cases than in controls with other types of back pain. On the other hand, the results from a randomized, double-blind, placebo-controlled trial confirmed the initial impression from a pilot study of the efficacy of TNF-α inhibitors in the treatment of acute severe sciatica. However, the effect was more limited than expected and, both at the bench and at the bedside, clues are
accumulating to suggest that other alternatives to systemically delivered TNF-α inhibitors should now be explored.
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2. Introduction
Sciatica is a radiculopathy involving one of the nerve roots of the sciatic nerve (L4, L5 or S1). For more than 80 years, sciatica has been considered as related to the presence of a disc herniation (DH) in close contact with the symptomatic nerve root [1]. As such, it is one of the few back pain syndromes showing a fairly good association between
symptoms and imagery [2]. Nevertheless, there are some alternative diagnoses to DH, such as radiculopathy due to facet joint cyst [3], to benign tumors [4], or to epidural varices [5]. We described two cases and performed a review of the literature on this latter topic (see manuscript 1: lumboradiculopathy due to epidural varices: two case reports and a review of the literature, Joint Bone Spine 2002 [6]), which showed that there were no clinical clues to help differentiate one cause from the other and careful imaging analysis remained the only tool to clarify the diagnosis before surgery. Despite the clinical analogies between these two different pathophysiological mechanisms, this thesis will focus only on radiculopathy due to DH.
There is no precise definition of sciatica and the term is sometimes used to describe any low back pain radiating into the leg, thus inducing much confusion between patients and clinicians, but also within the research community. In the absence of well defined classification criteria, an important variability in eligibility criteria has been reported in studies on this topic. For example, a recent epidemiology review showed a reported prevalence ranging from 1.2% to 43%![ref?] Although this huge variability may be related to methodological aspects or population selection, the definition of sciatica as reflected by eligibility criteria used in the different studies was an important obvious contributor. In studies reporting higher rates, sciatica was defined as “an episode of leg pain related to
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back pain”, whereas in studies reporting lower figures, specific clinical signs and the confirmation of DH on imaging were among eligibility criteria, suggesting that different diseases were actually addressed in these studies. We have reported the same variation in eligibility criteria between the most recently published, randomized, controlled therapeutic trials (see manuscript 2: Variation in Eligibility Criteria From Studies of Radiculopathy due to a Herniated Disc and of Neurogenic Claudication due to Lumbar Spinal Stenosis, Spine 2010 [7]). The importance of the observed variations between sets of eligibility criteria resulted in a very large variation in the recruited populations, thus making any comparison between studies extremely difficult. It also calls into question the validity of any meta-analysis that would be performed for this syndrome.
In all recent reviews on the topic [8-10], including ours (see manuscript 3: Sciatica, Best Practice & Research Clinical Rheumatology 2010 [11]), there is a consensus that clinical symptoms and signs are the most important determinants of the diagnosis. A synthesis of these symptoms and signs is provided in Table 1.
Table 1. Symptoms and signs suggesting lumbar radiculopathy due to disc herniation 1. Pain radiating to the lower limb following a dermatomal pattern
2. Positive straight leg raise test
3. Increased pain with Valsalva maneuvers 4. Hypoesthesia in a dermatomal pattern 5. Asymmetric deep tendon reflex 6. Motor weakness
3 to 5 should relate to the same dermatome as the pain distribution
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Imaging studies come only second in the list of diagnostic requirements. The role of computerized tomography (CT) scan or magnetic resonance imaging (MRI) is to confirm the presence of DH in the vicinity of the clinically symptomatic nerve root. Of note, in an asymptomatic population, DH was found in up to 60% of volunteers [12] and its presence is not considered to be a predictor for the development of radiculopathy [13]. The
observation of a poor relationship between the presence of DH on imaging and the development of radiculopathy was one of the most important arguments against the theory that radiculopathy is the pure result of the mechanical compression of the nerve root by the DH - the theory in practice since the first description of the syndrome and the role of DH in 1934 by Mixter & Barr [1]. This, along with other arguments summarized in Table 2, led to the development of a new paradigm in which local inflammation is also an important component of sciatica.
Table 2. Arguments against mechanical compression as the main pathophysiological mechanism for sciatica
Presence of DH in asymptomatic subjects
Pressure on normal nerve roots does not cause pain
Pressure on adjacent level nerve roots does not cause pain
Severe symptoms without evidence of nerve root compression
Symptom severity not in correlation with the size of the DH
Outcome might be favorable with conservative treatment
Outcome might be favorable despite persistence of the DH
Discectomy has only moderate long term success
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3. Summary of data from animal models of radiculopathy
From the time of recognition that mechanical compression was not the only component in the physiopathology of radiculopathy due to DH, two hypotheses emerged from the literature. The first was based on the observation that the intervertebral disc is normally excluded from the development of immunological tolerance and, in the process of DH, an auto-immune reaction could take place [14]. However, very little evidence is available to sustain this hypothesis. The second hypothesis states that radiculopathy results from the presence of chemical factors leaking from the nucleus pulposus (NP), the core part of the intervertebral disc, through the annulus fibrosus. Several pro-inflammatory mediators have been suggested as potential candidates, such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, prostaglandin E2, thromboxane A2, or nitric oxides. As summarized in our editorial in 2005 (see manuscript 4: Is disk-related sciatica a TNFα-dependent inflammatory disease? Joint Bone Spine 2005), evidence from animal models developed during the 1990s suggested that TNF-α was a key molecule for the development of radiculopathy due to an intervertebral disc. First, it was shown that NP, the main component of DH, presents
inflammatory properties [15, 16]. Indeed, in vivo gentle deposition of NP on a rat nerve root induces pain, electrical dysfunction of the nerve, and histological modifications [17-19].
Later, similarities between the effect of NP deposition on the nerve root and the local deposition of TNF-α were soon observed. Endoneural TNF-α injection induces axonal changes, such as characteristic myelin injury, increased vascular permeability and
intravascular coagulation, that are strikingly similar to those observed in the model of NP deposition [20 25]. The role of TNF-α was further confirmed in a study in which the effects of NP were reproduced by similarly adding a small quantity of TNF-α extracted from the NP
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directly on the nerve root [21]. In addition, the effect of specific TNF-α blocking agents commonly used for the treatment of patients with inflammatory diseases (e.g., rheumatoid arthritis, ankylosing spondylarthritis, psoriasis, etc.), was reported in several animal models of radiculopathy[15, 22-25]. After almost 15 years of development, the hypothesis that TNF- α plays an important role in the different animal models of radiculopathy is well supported.
Nevertheless, at the same time, the role of mechanical compression has not been totally discarded. First, it has been shown that mechanical compression potentiates the effect of inflammation [20] and second, the local production of inflammatory cytokines, such as TNF-α and IL-1, was induced in a model of light compression applied on the nerve root over a long period of time [26]. Recently, the exact importance of TNF-α in these animal models has been called into question in a study reporting the development of a radiculopathy
accompanied by histological modifications and clinical symptoms in TNF knock-out mice after gentle deposition of NP on the nerve root [27]. Although radiculopathy developed to a lesser degree than in wild-type mice, this observation raises the question of other inflammatory mediators that have been overshadowed by TNF-α during all these years.
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4. The case of human disc herniation
In parallel to the development of animal models for radiculopathy, histological and immunohistological studies on DH have been available in the literature for more than 20 years. DH is most often composed of a mixture of degenerated NP and annulus fibrosus and, occasionally, cartilaginous endplate [28]. Inflammatory cells are found only in about 60% of specimens and are mainly macrophages [29]. Their quantity depends on the type of DH classified according to its position in relation to the posterior longitudinal ligament; a lower number of inflammatory cells are found in a minority of subligamentous herniation or protrusion, a frequently high number in transligamentous herniation, and almost always a high number in sequestered herniation [29-32]. There is no correlation between the type of HD and the clinical presentation [29, 33, 34] or evolution [33]. However, involution of DH depends on its type. In a study by Takada et al, the volume of nearly all sequestered
herniation decreased at least 50% within 6 months, whereas it was observed for only 25% of subligamentous protrusion at 12 months [35]. The shrinking of DH correlates even better with the presence of inflammation on MRI [33]. There is also a good relationship between the involution of the DH tissue and the clinical evolution [33, 35], although the clinical evolution seems to precede the radiological involution [35]. Involution of DH in a co-culture system with mice cells was shown to be dependent on chondrocytes producing matrix metalloproteinases (MMP)-3 [36] with TNF-α required for the induction of high levels of MMP-3 by the chondrocytes [37]. In an in vitro experiment on human DH and in contrast to previous experiments on intervertebral discs [38, 39], we showed that MMP-3 was indeed expressed at a much higher level than MMP-1 (see manuscript 5: Influence of cytokine inhibitors on concentration and activity of MMP-1 and MMP-3 in disc herniation, Arthritis
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Research & Therapy 2009 [40]). More importantly, we were able to demonstrate that the incubation of DH with either dexamethasone or TNF-α decreased the level of active MMP-3, thus confirming the results observed by Haro et al in their mouse model [36]. However, the precise impact and the clinical consequences of these observations require further
investigation.
Numerous studies have been published on the role of inflammatory cytokines in human DH. At the end of 2010, eight studies, including our report (see manuscript # 6:
Elevated Levels of Tumor Necrosis Factor-Alpha in Periradicular Fat Tissue in Patients With Radiculopathy from Herniated Disc, Spine 2008[41]), sought to determine the presence of TNF-α [34, 41-47] . Among these, three were negative and five were positive. The negative studies used tools such as the enzyme-linked immunosorbent assay (ELISA) to determine the presence of cytokines, while almost all positive studies used more sensitive methods, such as immunohistochemisty, real-time polymerase chain reaction (PCR), reverse-transcriptase PCR, or Western blot analysis. Among the positive studies, only the more recent studies [41, 45, 46]included control material (degenerative intervertebral disc from patients without
radicular pain) to determine if an increased level of TNF-α could be demonstrated in patients with radicular pain compared to low back pain patients without radicular pain. In all three studies, the level of TNF-α was identical in both the DH and the degenerative intervertebral disc. To the best of our knowledge, our study is the only one to have analyzed the
periradicular fat tissue in addition to DH and degenerative intervertebral disc. We
hypothesized that as periradicular fat tissue envelops nerve roots in the epidural canal, it could be used as a good representation of the environment in which the nerve root lies. In patients with sciatica, we were able to demonstrate that TNF-α, but not IL-1, IL-6 or IL-8, was expressed in a higher concentration in periradicular fat tissue samples than in DH samples
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and, more importantly, at a higher concentration in patients with sciatica compared to those without. We did not directly investigate the source of production of TNF-α in these tissue samples. However, the level of TNF-α in periradicular fat tissue samples was drastically reduced after 48 hours of incubation with dexamethasone. This result is in contrast to the theory that TNF-α is produced by the DH and rather suggests that producing cells were included in the periradicular tissue samples, being either the adipocytes themselves[48] or invading macrophages.
In summary, although there are only few data available on TNF-α in humans, we were able to provide evidence that this cytokine was indeed elevated in patients suffering from sciatica and thus could be involved in the pathophysiology of the disease. Although our results strongly support the role of TNF-α in human sciatica, a definite confirmation would require replication of these results and further investigation to locate the producing cells.
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5. Trials with TNF inhibitors
Although approximately 90% of patients are treated without using a surgical approach, there is a paucity of evidence in the literature regarding conservative therapies for the treatment of sciatica [9, 10, 49] and clinicians have to rely on their knowledge of the treatment of back pain. Even the epidural injection of steroids is highly controversial [10, 49] and, if any, the benefit is relatively short-lived with no incidence on the rate of surgery [9].
In this context, results from animal models and the recent availability of TNF-α inhibitors led us to conduct a pilot study to investigate the effect of a short course of
etanercept (subcutaneous administration of 25 mg on days 1, 4, and 7) (see manuscript# 7:
Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study, Annals of Rheumatic Diseases 2004). Etanercept is a protein fusion complex between the soluble TNF receptor 2 and the Fc component of human immunoglobulin G1, which acts as a decoy receptor. In addition to the usual analgesic treatment, 10 patients treated with etanercept were compared to an historic group of 10 patients with the same clinical characteristics and who received three iv injections of solumedrol 250 mg in a single administration every 3 days, a protocol specifically designed to be as similar as possible to the administration of etanercept. At week 6, but not at day 10, the group of patients treated with etanercept had much improved both in terms of pain and function compared to those treated with
solumedrol. Our study was published soon after a similar trial [50] explored the effect of one injection of infliximab (a chimeric antibody agaist TNF-α) in 10 patients and reported similar beneficial effects.
These positive results encouraged us to conduct a multicenter, randomized control trial (see manuscript# 8: Adalimumab in the Treatment of Acute Severe Sciatica, a
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Randomized Double Blind Placebo Controlled Study, Arthritis & Rheumatism 2010 [51]).
For this study, two subcutaneous injections of either adalimumab, a fully humanized
monoclonal antibody against TNF-α, or placebo were administered 7 days apart, in addition to the standard pain treatment, in 61 patients recruited in five rheumatology centers in Switzerland. A statistically significant effect was observed on leg pain, the primary outcome.
This effect was small and its clinical significance remains to be proven. However, beneficial effects, which were both statistically significant and clinically relevant, were noted for many of the secondary endpoints, thus supporting a positive effect of the treatment. In particular, a decrease in the number of patients who had surgery was observed at the last follow-up at 6 months in the adalimumab group compared to the placebo group; the number needed to treat to avoid one surgery was four.
Two other placebo-controlled studies using systemic delivery of a TNF inhibitor have been published [52, 53]. A first study with infliximab randomized 40 patients and found no difference between the group who received one injection of 5 mg/kg of infliximab and the placebo group [52]. The second study intended to randomize 80 patients, but stopped the recruitment after four years and 15 patients [53]. One dose of 25 mg of etanercept or placebo was administered subcutaneously in the perispinal area. The same evolution in terms of pain and functional impairment was observed for the two groups up to 3 months after the injection. Recently, a randomized dose-finding study on etanercept administered epiduraly was published [54]. More than two-thirds of patients receiving etanercept (any dose between 2, 6 or 8 mg) reported at least 50% improvement in leg pain compared to only 17% in the placebo group. However, a dose-effect could not be demonstrated as 100% of patients in the 2 mg group reported this endpoint.
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6. Discussion
Over the past two decades, sufficient data have been gathered to suggest that inflammation is an important component of sciatica and that the mere mechanical compression of a nerve root by a DH could not account for all the clinical and radiological observations. Experimental data in animals suggest that this inflammation could be induced by the NP breaking out of the center of the disc and entering the spinal canal through the annulus fibers. Additional experiments pointed out that TNF-α was a key molecule in almost all animal models of radiculopathy, in particular when radiculopathy was induced by the addition of NP in contact with the nerve root. Similar to others, we were unable to demonstrate a greater
concentration of TNF-α in DH of patients with radiculopathy, but we were able to show that the periradicular fat tissue in these patients contained a higher amount of TNF-α compared to back pain patients without radicular pain.
Taken together, all these observations provided sufficient evidence to conduct clinical trials in order to study the effect of TNF inhibitors in patients with sciatica. Pilot trials with different TNF inhibitors were largely positive, whereas data from placebo-controlled trials are more controversial. Excluding two very small, underpowered trials (one negative with low- dose subcutaneous etanercept and the other rather positive with the same drug
administered epiduraly), there is only one study with negative results that can be compared to our trial. The main differences between the two studies do not lie solely in terms of drug and dosage used (one iv infusion of infliximab 3 mg/kg versus two subcutaneous injections of adalimumab 40 mg, respectively), but also in terms of eligibility criteria and thus the studied populations. In the infliximab study, the straight leg raise test was the only mandatory sign and severity was loosely defined as “patients who were addressed to the clinic for surgery”.
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In our study, patients could present with either a positive straight leg raise test or any neurological abnormalities related to the involved dermatomal distribution of pain. Severity was precisely defined as patients with a high level of functional impairment (Oswestry disability index (ODI) greater than 50). As a consequence, our population had a much higher level of impairment at inclusion (mean ODI, 70 versus 40, respectively) and thus an increased chance of improvement. Both studies included patients having leg pain for less than 12 weeks, but patients in our study revealed to have a much shorter mean duration of leg pain (3.5 weeks versus 8 weeks, respectively). These differences, together with a possible lack of power in the infliximab study (no power calculation is provided) may well explain the difference in outcomes. Of note, the percentage of patients who required surgery in the infliximab study was similar in both treatment groups and was close to that observed in our placebo group. This reinforced the impression that the observed difference in the rate of surgery was due to a lower rate in the adalimumab group and not to a high rate in the placebo group. In conclusion, the main factor differentiating these two studies is the duration of leg pain before treatment. In an animal model of radiculopathy induced by NP deposition, allodynia was significantly reduced by TNF inhibitors when given 6 days after the injury, but not when given 20 days later [55]. This suggests that time between the onset of pain and the beginning of treatment could be of great importance.
The study by Cohen et al.[54]associating animal experiments to demonstrate the safety of epiduraly-administered etanercept and a placebo-controlled, dose-ranging study of foraminal injection of etanercept in patients with sciatica opened a new avenue for the treatment of this condition. Despite an overall favorable effect and a possible gain in terms of surgery, our trial failed to demonstrate a clinically significant decrease in leg pain in the treated group. Together with the fact that the long-lasting delivery of locally applied
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etanercept was more effective than a 10-fold increase of systemically administered drugs to reduce allodynia in an animal model of radiculopathy [56], this suggests that future
developments in the treatment of human sciatica should also be directed towards the epidural delivery of drugs with long-lasting effects.
7. Concluding Remarks
At the present time, a review of all available evidence on the possible role of TNF-α in sciatica do not allow for a definite and unilateral conclusion. Clearly, TNF-α inhibitors are not the Holy Grail expected by the spine community after the first pilot trials were published. On the other hand, the deep deception following the publication of the first placebo- controlled study should now be balanced by the favorable results from the adalimumab study and Cohen’s preliminary work. Further research in the field of sciatica should now be conducted with locally-delivered, long-acting drugs with a focus on patients with acute and severe disease. As already observed in the field of rheumatology, although animal models provide important steps to an improved understanding of causative mechanisms, there may be fundamental differences in the way pro-inflammatory cytokines are related to each other.
For this reason, the inhibition of alterative cytokines potentially involved in the pathophysiology of sciatica needs also to be investigated.
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8. References
1. Mixter WJ, Barr JS (1934) Rupture of the intervertebral disc with involvement of the spinal canal. New Engl J Med 211:210-215
2. Jarvik JG, Deyo RA (2002) Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med 137:586-597.
3. Chevalier X, Martigny J, Jacquet M, Larget-Piet B (1992) Nerve root pain secondary to posterior articular cysts: a report of 6 cases and review of the literature. Clin Exp Rheumatol 10:51-56
4. Loke TK, Ma HT, Ward SC, Chan CS, Metreweli C (1995) MRI of intraspinal nerve sheath tumours presenting with sciatica. Australas Radiol 39:228-232
5. Benny BVB, Nagpal ASA, Singh PP, Smuck MM (2011) Vascular causes of radiculopathy: a literature review. The spine journal 11:73-85
6. Genevay SS, Palazzo EE, Huten DD, Fossati PP, Meyer OO (2002) Lumboradiculopathy due to epidural varices: two case reports and a review of the literature. Joint bone spine 69:214- 217
7. Genevay SS, Atlas SJS, Katz JNJ (2010) Variation in eligibility criteria from studies of radiculopathy due to a herniated disc and of neurogenic claudication due to lumbar spinal stenosis: a structured literature review. Spine (Philadelphia, Pa 1976) 35:803-811
8. Van Boxem K, Cheng J, Patijn J, van Kleef M, Lataster A, Mekhail N, Van Zundert J (2010) 11. Lumbosacral radicular pain. Pain Pract 10:339-358.
9. Stafford MA, Peng P, Hill DA (2007) Sciatica: a review of history, epidemiology,
pathogenesis, and the role of epidural steroid injection in management. Br J Anaesth 99:461- 473.
10. van Tulder M, Peul W, Koes B (2010) Sciatica: what the rheumatologist needs to know.
Nat Rev Rheumatol 6:139-145.
10.1038/nrrheum.2010.3
11. Valat JP, Genevay S, Marty M, Rozenberg S, Koes B Sciatica. Best Pract Res Clin Rheumatol 24:241-252.
12. Weishaupt D, Zanetti M, Hodler J, Boos N (1998) MR imaging of the lumbar spine:
prevalence of intervertebral disk extrusion and sequestration, nerve root compression, end plate abnormalities, and osteoarthritis of the facet joints in asymptomatic volunteers.
Radiology 209:661-666
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13. Borenstein DG, O'Mara JW, Jr., Boden SD, Lauerman WC, Jacobson A, Platenberg C, Schellinger D, Wiesel SW (2001) The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects : a seven-year follow-up study. J Bone Joint Surg Am 83-A:1306-1311
14. Geiss AA, Larsson KK, Junevik KK, Rydevik BB, Olmarker KK (2009) Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: an
experimental study on the autoimmune properties of nucleus pulposus. Journal of Orthopaedic Research 27:97-103
15. Olmarker K, Blomquist J, Stromberg J, Nannmark U, Thomsen P, Rydevik B (1995) Inflammatogenic properties of nucleus pulposus. Spine 20:665-669
16. McCarron RF, Wimpee MW, Hudkins PG, Laros GS (1987) The inflammatory effect of nucleus pulposus. A possible element in the pathogenesis of low-back pain. Spine 12:760- 764
17. Olmarker K, Rydevik B, Nordborg C (1993) Autologous nucleus pulposus induces
neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine 18:1425- 1432
18. Byrod G, Rydevik B, Nordborg C, Olmarker K (1998) Early effects of nucleus pulposus application on spinal nerve root morphology and function. Eur Spine J 7:445-449
19. Olmarker K, Nordborg C, Larsson K, Rydevik B (1996) Ultrastructural changes in spinal nerve roots induced by autologous nucleus pulposus. Spine 21:411-414
20. Olmarker K, Larsson K (1998) Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine 23:2538-2544
21. Igarashi T, Kikuchi S, Shubayev V, Myers RR (2000) 2000 Volvo Award winner in basic science studies: Exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats. Spine 25:2975- 2980
22. Sasaki N, Kikuchi S, Konno S, Sekiguchi M, Watanabe K (2007) Anti-TNF-alpha antibody reduces pain-behavioral changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine 32:413-416.
23. Homma Y, Brull SJ, Zhang JM (2002) A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat. Pain 95:239-246.
24. Schafers M, Lee DH, Brors D, Yaksh TL, Sorkin LS (2003) Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor- alpha after spinal nerve ligation. J Neurosci 23:3028-3038.
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25. Murata Y, Onda A, Rydevik B, Takahashi K, Olmarker K (2004) Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced histologic changes in the dorsal root ganglion. Spine 29:2477-2484.
26. Kobayashi S, Baba H, Uchida K, Kokubo Y, Kubota C, Yamada S, Suzuki Y, Yoshizawa H (2005) Effect of mechanical compression on the lumbar nerve root: localization and changes of intraradicular inflammatory cytokines, nitric oxide, and cyclooxygenase. Spine 30:1699- 1705.
27. Yamashita M, Ohtori S, Koshi T, Inoue G, Yamauchi K, Suzuki M, Takahashi K (2008) Tumor necrosis factor-alpha in the nucleus pulposus mediates radicular pain, but not increase of inflammatory peptide, associated with nerve damage in mice. Spine 33:1836-1842.
00007632-200808010-00005 [pii]
28. Willburger RER, Ehiosun UKU, Kuhnen CC, Krmer JJ, Schmid GG (2004) Clinical symptoms in lumbar disc herniations and their correlation to the histological composition of the
extruded disc material. Spine (Philadelphia, Pa 1976) 29:1655-1661
29. Virri J, Grnblad M, Seitsalo S, Habtemariam A, Kp E, Karaharju E (2001) Comparison of the prevalence of inflammatory cells in subtypes of disc herniations and associations with straight leg raising. Spine (Philadelphia, Pa 1976) 26:2311-2315
30. Arai Y, Yasuma T, Shitoto K, Yamauchi Y, Suzuki F (2000) Immunohistological study of intervertebral disc herniation of lumbar spine. Journal of orthopaedic science 5:229-231 31. Haro H, Shinomiya K, Komori H, Okawa A, Saito I, Miyasaka N, Furuya K (1996) Upregulated expression of chemokines in herniated nucleus pulposus resorption. Spine (Philadelphia, Pa 1976) 21:1647-1652
32. Ikeda T, Nakamura T, Kikuchi T, Umeda S, Senda H, Takagi K (1996) Pathomechanism of spontaneous regression of the herniated lumbar disc: histologic and immunohistochemical study. Journal of spinal disorders 9:136-140
33. Ahn SH, Ahn MW, Byun WM (2000) Effect of the transligamentous extension of lumbar disc herniations on their regression and the clinical outcome of sciatica. Spine (Philadelphia, Pa 1976) 25:475-480
34. Nygaard OP, Mellgren SI, Osterud B (1997) The inflammatory properties of contained and noncontained lumbar disc herniation. Spine (Philadelphia, Pa 1976) 22:2484-2488
35. Takada EE, Takahashi MM, Shimada KK (2001) Natural history of lumbar disc hernia with radicular leg pain: Spontaneous MRI changes of the herniated mass and correlation with clinical outcome. Journal of orthopaedic surgery 9:1-7
36. Haro H, Crawford HC, Fingleton B, MacDougall JR, Shinomiya K, Spengler DM, Matrisian LM (2000) Matrix metalloproteinase-3-dependent generation of a macrophage
chemoattractant in a model of herniated disc resorption. The Journal of clinical investigation 105:133-141
2 03.02.11
37. Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM, Matrisian LM (2000) Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of
herniated disc resorption. The Journal of clinical investigation 105:143-150
38. Weiler C, Nerlich AG, Zipperer J, Bachmeier BE, Boos N (2002) 2002 SSE Award
Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption. Eur Spine J 11:308-320.
39. Le Maitre CL, Hoyland JA, Freemont AJ (2004) Studies of human intervertebral disc cell function in a constrained in vitro tissue culture system. Spine (Phila Pa 1976) 29:1187-1195.
40. Genevay SS, Finckh AA, Mezin FF, Tessitore EE, Guerne PP-A (2009) Influence of cytokine inhibitors on concentration and activity of MMP-1 and MMP-3 in disc herniation. Arthritis research & therapy 11:R169
41. Genevay S, Finckh A, Payer M, Mezin F, Tessitore E, Gabay C, Guerne PA (2008) Elevated levels of tumor necrosis factor-alpha in periradicular fat tissue in patients with radiculopathy from herniated disc. Spine (Philadelphia, Pa 1976) 33:2041-2046
42. Ahn SS-H, Cho YY-W, Ahn MM-W, Jang SS-H, Sohn YY-K, Kim HH-S (2002) mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Philadelphia, Pa 1976) 27:911-917
43. Burke JG, Watson RWRWG, McCormack DRWG, Dowling FERWG, Walsh MGRWG, Fitzpatrick JMRWG (2002) Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. Journal of bone and joint surgery British volume 84:196-201 44. Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Donaldson WF, Evans CH (1996) Herniated lumbar intervertebral discs spontaneously produce matrix
metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine (Philadelphia, Pa 1976) 21:271-277
45. Le Maitre CLC, Hoyland JAJ, Freemont AJA (2007) Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1beta and TNFalpha expression profile. Arthritis research & therapy 9:R77
46. Lee SS, Moon CSC, Sul DD, Lee JJ, Bae MM, Hong YY, Lee MM, Choi SS, Derby RR, Kim BB- J, Kim JJ, Yoon JJ-S, Wolfer LL, Kim JJ, Wang JJ, Hwang SS-W, Lee SS-H (2009) Comparison of growth factor and cytokine expression in patients with degenerated disc disease and herniated nucleus pulposus. Clinical biochemistry 42:1504-1511
47. Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y, Kakiuchi T (1996) Inflammatory cytokines in the herniated disc of the lumbar spine. Spine (Philadelphia, Pa 1976) 21:218-224 48. Rosen ED, Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847-853.
49. Valat JJ-P, Genevay SS, Marty MM, Rozenberg SS, Koes BB (2010) Sciatica. Baillière's best practice & research Clinical rheumatology 24:241-252
2 03.02.11
50. Karppinen JJ, Korhonen TT, Malmivaara AA, Paimela LL, Kyllnen EE, Lindgren KK-A, Rantanen PP, Tervonen OO, Niinimki JJ, Seitsalo SS, Hurri HH (2003) Tumor necrosis factor- alpha monoclonal antibody, infliximab, used to manage severe sciatica. Spine (Philadelphia, Pa 1976) 28:750-753; discussion 753
51. Genevay SS, Viatte SS, Finckh AA, Zufferey PP, Balagu FF, Gabay CC (2010) Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial.
Arthritis & rheumatism 62:2339-2346
52. Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren KA, Jarvinen S, Niinimaki J, Veeger N, Seitsalo S, Hurri H (2005) The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study. Spine 30:2724- 2728.
53. Okoro TT, Tafazal SIS, Longworth SS, Sell PJP (2010) Tumor necrosis alpha-blocking agent (etanercept): a triple blind randomized controlled trial of its use in treatment of sciatica.
Journal of spinal disorders & techniques 23:74-77
54. Cohen SPS, Bogduk NN, Dragovich AA, Buckenmaier CC, Griffith SS, Kurihara CC, Raymond JJ, Richter PJP, Williams NN, Yaksh TLT (2009) Randomized, double-blind, placebo-controlled, dose-response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology 110:1116-1126
55. Sasaki N, Kikuchi S, Konno S, Sekiguchi M, Watanabe K (2007) Anti-TNF-alpha antibody reduces pain-behavioral changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine (Phila Pa 1976) 32:413-416.
56. Zanella JMJ, Burright ENE, Hildebrand KK, Hobot CC, Cox MM, Christoferson LL, McKay WFW (2008) Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Philadelphia, Pa 1976) 33:227-234
