The pathology of intervertebral disc degeneration and herniation is still not clarified. Many important factors, from physiologic degeneration to mechanical forces or biomechanical changes, may play a role in disc degeneration and herniation. In a recent study in Arthritis & Rheumatism, Shamji et al (1) observed high expression of interleukin-17 (IL-17) in surgically obtained fragments of degenerated and herniated intervertebral discs, suggesting a role of Th17-mediated inflammatory processes in the pathogenesis of intervertebral disc degeneration. The authors concluded that they identified “novel pathways against which local therapy can be targeted to treat both degenerative disc disease and disc herniation radiculopathy.” We would like to discuss this aspect of their study.
First, even in acute pain conditions, there is no close correlation between pain and the degree of disc degeneration as seen on magnetic resonance images. The necessary structural deformations of the lumbar spine that occur as a consequence of adaptation of the spinal components to external forces cannot be seen on radiographs in most cases; however, other potential causes, such as lack of physical activity and fitness, poor job satisfaction, and depression, are often not considered when assessing self-reported chronic low back pain (2). Over the course of many years, we have learned that the relationship between degeneration of the lumbar spine and back pain is poor; for instance, former elite sportsmen with severe back damage reported no or only moderate back pain (3).
Next, chronic back pain is not a problem associated with local disease only. The human mind and the human body form a unit. The high expression of IL-17 in degenerated and herniated lumbar intervertebral discs shows that local immune reactions occur in patients with low back pain. It would be interesting to investigate further whether the systemic immune reaction associated with Th1 cells has changed. Shamji and colleagues stated that pain in patients with degenerative disc disease more frequently had a prominent back component. The question is why the human brain perceives pain when the expression of IL-17 is locally increased in the intervertebral discs.
Our group observed that patients with chronic low back pain showed higher transforming growth factor α (TGFα) levels in blood compared with healthy control subjects (4). We could not demonstrate a correlation between elevated TGFα levels and pain intensity. In other words, systemically delivered anti-TGFα therapy might not be effective for low back pain. In our opinion, local therapy with an anti–IL-17 molecule also will not be effective. Further studies are needed in which the relationship between low back pain and the local immune reaction is analyzed in light of the individual pain experience. Moreover, from an etiologic perspective, the important influence of various factors on the development of pain and mood should be taken into account. Several years ago, a longitudinal study involving volunteers without back pain proved that the existence of a depressive disorder is the largest risk factor for a first episode of low back pain (5). The correlation between low back pain and mood has been corroborated transculturally worldwide and is therefore of central interest.
Last but not least, in recent years, communication between the immune system and the central nervous system has been the focus of investigations into the mechanisms of chronic pain. Chronic pain is a considerable stress factor. Exposure to life events such as bereavement and divorce and to occupational demands is reported to cause stress, depression, and impairment of cellular immune function, which may then affect each other (6). Chronic stress has been shown to impair Th1 responses, including the tumor necrosis factor α response (7). Stressful life events coincide with depressive episodes but can also activate the immune/inflammatory system, leading to excess secretion of cytokines. The release of proinflammatory cytokines by peripheral immune cells during inflammation, infection, or trauma leads to the release of proinflammatory cytokines by glia in the central nervous system; these cytokines are associated with the induction and maintenance of pain (8). Cytokines can enter the brain and cause alterations in the metabolism of serotonin and dopamine. Additionally, cytokines activate corticotropin-releasing factor, which in turn leads to an increase in serum glucocorticoid levels (9). Under physiologic conditions, increased serum glucocorticoid levels induce inhibition of the hypothalamic−pituitary−adrenal (HPA) axis. This negative feedback mechanism is disrupted by prolonged stress (10). Chronic low back pain as a persistent stressor may possibly also interrupt negative glucocorticoid feedback to the HPA axis.
In summary, we applaud the new findings that have emerged from the work by Shamji et al but would like to express the hope that the results from basic research will be in accordance with clinical findings. Before the approach of using local therapy with anti–IL-17 can be advanced, it will be essential to ascertain the interrelationship of local and systemic immune reactions and low back pain in longitudinal studies.