TNF-{alpha} blockade for herniated intervertebral disc-induced sciatica: a way forward at last?

R. G. Cooper1 and A. J. Freemont2

1University of Manchester Rheumatic Diseases Centre, Hope Hospital, Salford 2Laboratory Medicine Academic Group, University of Manchester, Manchester, UK

Correspondence to: R. G. Cooper, Rheumatic Diseases Centre, Hope Hospital, Salford M6 8HD, UK. E-mail: rcooper{at}fs1.ho.man.ac.uk

Following the recognition that diagnostic triage is fundamental to the delivery and organization of services for low back pain (LBP) patients [1, 2], physiotherapy-led LBP triage and treatment clinics have proliferated. Although such developments have improved the speed and accessibility of such services to LBP patients, they have also meant that many rheumatologists now rarely see LBP patients. This especially applies to those with suspected herniated intervertebral discs (HIDs), who would usually be triaged surgically. Although representing only a small portion of the spectrum of degenerative disc disease problems [3], HIDs are still a common cause of back and radicular pain, and the natural history dictates that symptoms gradually resolve spontaneously, with a good functional outcome in most cases [4]. However, in some patients back and especially sciatic symptoms fail to resolve sufficiently quickly, or at all, so prompting decompressive surgery. Despite radiologically targeted and technically well executed surgery, sciatic symptoms (without radiological evidence of recurrent HID) do not always resolve, and surgical ‘failure’ rates range from 3–14% in some studies [59] to as high as 36% in others [10]. This degree of variation probably reflects between-study differences in outcome assessment methods, but clearly a substantial minority of HID patients do fare badly. In some patients surgery initially cures radicular symptoms, only for these to recur and progress as part of the feared ‘post-surgical back pain syndrome’.

Medical and non-medical treatments remain depressingly ineffective for patients with unresolved or recurrent sciatica, and the level of their resulting pain-related disability is reflected by their disproportionate utilization of healthcare and welfare resources. As surgery has little or no role here, affected patients may instead become time-consuming ‘heart sink’ problems in non-surgical clinics, including those of rheumatologists. While it is generally agreed that surgery affords quicker initial pain relief than conservative management, this early advantage is lost over the subsequent 2–4 yr. After this period the outcome, in terms of pain and function, appears similar whether or not surgery was undertaken [11]. These observations suggest that, although surgery does not appear to increase the risk of poor outcome (through higher postsurgical back pain syndrome rates), it could be deemed unnecessary as it does not alter the ultimate outcome. As these observations [11] also suggest that HID-associated radicular symptom resolution is somehow predetermined, it could alternatively be argued that very early surgery could improve outcome in those destined to do badly, by minimizing HID-associated radicular damage. Such a strategy would, however, require presurgical knowledge of the likely outcome, which is currently not possible. These discussions highlight our ignorance regarding patient selection for surgery and the mechanisms of HID-associated radicular pain, or its resolution. This ignorance is not reflective of lack of scientific curiosity or effort, for many researchers have attempted to elucidate the aetiology of HID-associated radicular pain in the hope of identifying novel therapeutic targets. As many rheumatologists have limited knowledge regarding such research, this article outlines progress to date, and ends with a remarkable discovery capable of altering how rheumatologists may have to view HID problems in the future.

The earliest authors concluded that mechanical nerve root compression was the major cause of HID-associated radicular pain [12], but later authors postulated that nerve root inflammation was of greater importance [13, 14]. Indeed, in studies in which repeat surgery was undertaken, the authors did describe what they thought was nerve root inflammation and fibrosis [15, 16]. Such changes were thought to explain ongoing radicular symptoms, through increased nerve root mechanosensitivity [13]. Around this time a plasma fibrinolytic defect was also demonstrated in association with various LBP syndromes [17, 18]. This was thought to reflect intraspinal inflammation, and it was hypothesized that, by impairing fibrin clearance from sites of injury, this represented a secondary pathogenic factor contributing to inflammation and thus the chronicity of sciatic pain [18]. Defective fibrinolysis was shown to normalize in HID patients whose symptoms spontaneously resolved, but not in those whose symptoms continued [18]. An abnormal fibrinolytic result prior to decompressive surgery for HID was also predictive of poor outcome [19]. However, prolonged normalization of defective fibrinolysis failed to reduce radicular pain in failed back surgery syndrome patients [20]. Furthermore, while it had been thought that a likely cause of surgically unresolved radicular symptoms was perineural fibrosis [21], radiological studies later confirmed that this was just as likely to be present whether or not patients suffered postsurgical symptoms [22, 23]. Such results appeared to undermine the fibrinolytic hypothesis. Other researchers were simultaneously attempting a characterization of the suspected but previously unconfirmed involvement of inflammation. Thus, many immunohistochemical studies reported ‘inflammatory cells’ in discal and perineural tissues removed at surgery [2426], and for a while it seemed that inflammatory processes may hold the aetiological key. However, intradiscal and perineural tissue inflammatory cells were not seen in all studies [27, 28], and when they were detected they were always very small in number and were limited to the macrophage in type [2426]. More recently, macrophage-like cells have also been found in normal discs [29], and there is a growing opinion that such cells are involved in the autoregulation of the discal extracellular matrix [30] and the resorption of herniated discal material [29], rather than in mediating radicular pathology.

Other factors are potentially at play in this complex arena. Histological examination of cadaveric intervertebral exit foraminae, in which HIDs were present, demonstrated perineural fibrosis in conjunction with marked congestion and thrombosis of local venous structures, with basement membrane thickening and endothelial fibrosis, suggestive of preceding endothelial damage [27]. These vascular changes could have appeared hyperaemic in life, thus potentially explaining the previous mistaken observations of the radicular ‘inflammation’ described during repeat surgeries [15, 16]. Furthermore, despite an absence of direct nerve root compression in these cadaveric exit foraminae, severe intraradicular neural fibrosis and atrophy were frequently seen in association with the perineural venous changes. These fibrotic and atrophic abnormalities occurred without evidence of inflammation, and it was suggested that they had instead resulted from ischaemic damage due to venous outflow obstruction [27]. A subsequent, prospective histological study examined perineural tissues removed from live patients requiring decompressive surgery for radiologically proven HIDs. The results demonstrated perineural tissue vascular and fibrotic abnormalities identical to those seen in cadavers in association with HIDs, again without evidence of inflammation, and which were not present in cadaveric controls without HIDs [28]. In addition, HID patients’ perineural tissues also revealed neovascularization and endothelial abnormalities, including luminal platelet adhesion and reductions in von Willebrand factor levels, and increased expression of the profibrotogenic cytokines IL-1 (interleukin 1), TGF-ß (transforming growth factor ß) and platelet-derived growth factor. None of these abnormalities were found in cadaveric control tissues [28]. These results suggested a pathogenic role for ischaemia in causing radicular scarring, and hence pain. As vascular endothelium is involved in physiological fibrinolysis, these perineural vascular changes may mean that the previously demonstrated HID-associated fibrinolytic abnormalities are explainable as a secondary feature [1719].

While such research was ongoing, other workers were simultaneously searching for HID-related chemical factors capable of irritating and damaging nerve roots, using in vivo animal models of HID. These investigators applied nucleus pulposus material directly onto spinal nerve roots in the epidural space. This resulted in functional, vascular and morphological abnormalities of the nerve root, which were often followed by intraradicular fibrosis and nerve fibre atrophy [3134]. These nerve root changes, and associated vascular changes, were very similar to those previously seen in association with HIDs in the cadaveric and live patient experiments described above [27, 28]. The HID-derived ‘chemical’ agent responsible for these changes was not apparent initially. However, it was subsequently demonstrated not only that discal tissue cells express TNF-{alpha} [35] but also that TNF-{alpha}, applied epidurally onto spinal nerve roots in situ, caused vascular and radicular abnormalities identical to those seen following nucleus pulposus applications [36]. These findings clearly suggested a specific pathological role for TNF-{alpha} in HID-associated nerve root damage in these animal models, especially as the development of such abnormalities was preventable by local TNF-{alpha} blockade [37]. It thus became apparent that TNF-{alpha} blockade might have a therapeutic role in HID [37]. Nucleus pulposus material is known to also produce other proinflammatory cytokines, including IL-1ß and interferon {gamma}, but it was recently demonstrated in a porcine model of HID that these other cytokines play no role in inducing nerve root damage [38].

This article highlights the efforts, failures and achievements of various spinal researchers in trying to better understand the aetiological mechanisms underlying chronic post-HID related radicular pain. The exciting experimental results described for TNF-{alpha} suggest that a basic science approach may at last have succeeded in identifying a therapeutic target capable of potentially altering the natural history of HID-related sciatica, and thus outcome. If the promise of TNF-{alpha} blockade is substantiated, it could revolutionize how difficult and unresolving HID-related sciatica is treated in the future. To date, only one small pilot study has examined whether TNF-{alpha} blockade is effective in HID-related pain in humans. This study was of only 10 human subjects with radiologically proven acute or subacute (i.e. 2–12 weeks duration) HID-related sciatica. The results demonstrated that a single infusion of infliximab was highly effective in reducing sciatic pain, by a mean of 49% within 1 h of the infusion. This benefit was maintained at 1 week, and indeed sciatic symptoms improved further at 1, 3 and 6 months following the infusion, with the result that none of the subjects underwent surgery and all returned to work within 1 month of the infusion [39]. This result, and those of the TNF-{alpha} animal studies already discussed, suggest that a large randomized and placebo-controlled trial of TNF-{alpha} blockade for patients with acute or subacute (<12 weeks) HID-associated sciatica is now urgently required. However, it is also apparent from the many previous studies that the results have produced a number of false dawns in terms of elucidating the mechanisms of HID-associated nerve root pain. It would thus appear unwise to conduct any human TNF-{alpha} trial without designing in the ability to examine the role of yet unexplored potential causes of pain persistence. Even if TNF-{alpha}-induced damage is the major cause of radicular pain, this fails to explain why only certain individuals get persistent pain. If it is the degree of TNF-{alpha} induced nerve root damage which is the most important factor dictating pain persistence, then understanding damage control mechanisms will be crucial. Alternatively, if the main factor dictating pain persistence were the degree of nerve-root scarring following TNF-{alpha}-induced damage, then understanding scar control mechanisms would be more important. As the production of TNF-{alpha} and profibrotic cytokines, such as TGF-ß, is genetically controlled, inter-individual variations in the expression of the genes for these cytokines may explain why only certain subjects seem predestined to develop chronic radicular pain following HID. The contribution of such genetic factors to the chronicity of HID-associated sciatica has not been examined to date. Acting over and above any genetic considerations are psychological factors, whose role in LBP persistence is well recognized [4042]. These genetic and psychological factors could clearly confound the results of any TNF-{alpha} blocker trial in HID, and would thus have to be taken into account during such trials.

If TNF-{alpha} blocking therapies are eventually confirmed as effective in reducing the severity and persistence of HID-associated radicular pain, this should translate into reductions in HID-related disability, thus reducing the associated health and welfare costs. Consequent changes in the delivery of services for HID could also result. Thus, if TNF-{alpha} blockade renders decompressive surgery mostly redundant in HID except when mandatory, as in acute cauda equina syndrome, spinal surgeons may understandably consider HID a non-surgical problem. Thus, HID patients might in the future be triaged non-surgically—probably by rheumatologists, given their growing expertise with TNF-{alpha} blockade. Moreover, if proven effective in HID-related sciatica, TNF-{alpha} blockade could be tried in other LBP syndromes where sciatica represents a significant cause of disability, e.g. exit foraminal stenosis, with or without signs of radicular compression. If TNF-{alpha} blockade is effective in these disabling conditions, the implications for rheumatology services appear obvious.

The authors have declared no conflicts of interest.

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