The importance of inflammatory biomarkers in non-specific acute and chronic low back pain: a systematic review

The recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [27] were followed to perform this systematic review, and its protocol was registered on the International prospective register of systematic reviews (PROSPERO—ID CRD42022375174).

A systematic search was conducted on July 2022 in Cochrane Library, MEDLINE and Web of Science for all the available literature, based on the following query: (“low back pain” OR “lower back pain” OR “back pain” OR “backache” OR "back ache" or “lumbago” OR “lumbar pain” OR “sciatica” OR “back disorder”) AND (“inflammation mediators” OR “inflammatory markers” OR “cytokines” OR “interleukins” OR “monokines” OR “chemokines” OR “tumor necrosis factor” OR “C-Reactive Protein” OR "CRP" OR “C-reactive protein” OR “hs-CRP” OR "hsCRP" OR “biological markers” OR “biomarkers”). Studies were retrieved and duplicates removed electronically and manually. References were transferred to the reference management software Rayyan (https://​rayyan.​qcri.​org). This software was developed specifically to expedite the initial screening of abstracts and titles for systematic reviews and to allow for blinded screening, in this case, between two authors.

Cross-sectional, longitudinal cohort or case–control studies that evaluated the relationship between inflammatory biomarkers and low back pain in humans were considered eligible for inclusion, as well as prospective and retrospective studies.

Each full-text article was searched for reports studying a correlation between inflammatory biomarkers and the prevalence and intensity of chronic LBP. Observational cohort studies (with and without control group), cross-sectional studies and randomized clinical trials (RCT) were included. Studies that comprised patients older than 18 years old, in which one or more inflammatory biomarkers were measured in blood plasma, were included. We excluded publications in a population with previous lumbar pathology, with underlying systemic pathology (e.g. autoimmune diseases or osteoarthritis) that could influence the systemic inflammatory biomarkers measurement and studies with fewer than 20 subjects. The duration of LBP was retrieved to distinguish between acute (< 6 weeks) and chronic (≥ 6 weeks) NsLBP, and studies in a population with different sources of pain besides LBP were excluded, as well as studies with evaluation of areas other than the lumbar spine (e.g. cervical and thoracic spine) or evaluating inflammatory biomarkers in the intervertebral discs. Studies specifically evaluating the effectiveness of pharmaceutical intervention on pain or anti-cytokine therapy, biomechanical and cadaver studies, duplicate publications and studies that did not meet the inclusion criteria were also excluded (Fig. 1).

The following items were recorded from all eligible studies: study design and study purpose, patient demographics and related characteristics (number, age, gender, body mass index), inclusion and exclusion criteria, patient outcomes associated with biomarker concentrations and included biomarkers. Data concerning the measuring instrument or scale used to evaluate the severity of LBP, quality of life and return to work were also extracted. The type, number and concentration of the assessed inflammatory biomarkers were extracted, and no particular biomarker associated with changes in inflammatory processes was excluded. Data of titles and abstracts were analysed independently by two reviewers, and any discrepancies were resolved by consensus. After the primary selection, full-text eligibility was done by two reviewers using screening tools developed a priori. The most common limitations amongst the studies were a low number of patients included, lack of ascertainment of exposure or definition of controls, lack of blinding for outcome assessments and adequacy of follow-up of cohorts. We present the results of the cross-sectional studies and the longitudinal studies separately. When odds ratios (ORs) were presented, the p-value and the 95% confidence interval (CI) were extracted. For other measures of association, the p-value was used to assess whether the association was statistically significant.

The methodological quality of included studies was evaluated using two versions (for case–control and cohort studies) of the Newcastle–Ottawa Assessment scale (NOS) [28] (Table 2). As described in Table 2, amongst all studies, the minimum score was 4 out of 9 and maximum score was 7 out of 9, with a median score of 6.

The systematic database search resulted in a total of 4016 records (Web of Science (n = 1962), MEDLINE (n = 2051), Cochrane Library (n = 3)). Following deduplication, a total of 3022 potentially relevant studies were identified and screened for retrieval, of which 2831 articles were excluded as they did not fulfil the eligibility criteria. Regarding the selection of articles for full-text screening, there was 95% consensus between the two reviewers, and 191 studies were included, of which 176 were excluded. The reasons for exclusion were as follows: review articles (n = 10), articles with non-serum biomarkers evaluation (i.e. inflammatory biomarkers evaluated by intervertebral disc, ligamentum flavum or muscle biopsy) (n = 33), evaluation of patients with specific spinal disorders (n = 28) and articles that did not meet the inclusion criteria (n = 105). Hence, 15 articles were included for synthesis in this systematic review. The entire selection process is presented in the flowchart of Fig. 1.

Studies characteristics and demographics are presented in Table 1. All the papers were published between 2006 and 2022, with 12 of the 15 included studies published from 2016 to 2022. Eleven studies [19, 29‐39] were cross-sectional and four were longitudinal [40‐43]. Regarding the characteristics of the population included, seven studies [34, 35, 37, 39‐43] assessed non-specific acute low back pain (NsALBP) and ten studies [19, 29, 32‐34, 36‐41] included persons with NsCLBP. The differentiation cut-off between acute low back pain (ALBP) and CLBP was 6 weeks. Ten studies [19, 29, 32‐34, 37‐41] presented a control group. Regarding the restrictions in patient inclusion, two studies included only female patients [32, 44] and one studied a multi-generation cohort with evaluations at 14, 17, 20 and 22 years [42]. Sample size comprised a total of 14,555 patients with LBP (ALBP (n = 2073); CLBP (n = 12,482)) and 494 controls. Excluding the multi-generation cohort study [42], the mean age ranged from 29 to 71 years. Regarding the most common inflammatory biomarkers evaluated (Table 3), nine studies included C-reactive protein (CRP) or Hs-CRP (high-sensitive C-reactive protein) [30, 34, 36, 38, 40‐43], eight studies included IL-1 and IL-1β [32‐34, 37‐39, 41, 43], ten studies included IL-6 [19, 29, 32, 34, 35, 37‐39, 41, 43], two studies included IL-10 [19, 34] and eight studies included TNF-α [32, 34, 35, 37‐39, 41, 43]. Other inflammatory biomarkers that were not analysed in more than one study are described in Table 1, but an exhaustive analysis of these was not carried out. Pain severity was evaluated most commonly using the visual analogue scale (VAS) in five studies [32, 34, 37, 39, 40], Roland–Morris Disability Questionnaire (RMDQ) in four studies [32, 34, 41, 43], numerical rating scale (NRS) in three studies [35, 41, 43], McGill Pain Questionnaire (MPQ) in three studies [29, 35, 38] and Oswestry Disability Index (ODI) in two studies [37, 38].

LBP assessment, duration of symptoms, biomarkers studied, source and technique of collection, analysis of inflammatory biomarkers and the type of association (positive, negative, or non-existent) between clinical parameters and inflammatory biomarkers are presented in Tables 2 and 3. A positive association means that the presence of LBP is associated with higher levels of the pro-inflammatory biomarkers measured in the blood serum. Regarding Hs-CRP, only one study [40] demonstrated a positive association with the presence of LBP and two studies [40, 42] did not find any relation between these variables. In studies that evaluated only C-reactive protein (CRP) [30, 34, 36, 39, 41, 43], all showed a positive association with the presence of LBP. Within the eight studies evaluating interleukin 1 (IL-1) and IL-1β, in seven studies [33‐35, 37, 39, 41, 43] no association was found with the presence of LBP. On the contrary, in a cross-sectional study including 148 patients with CLBP and 150 controls, Dadkhah et al. [38] found a positive correlation between these variables. The pro-inflammatory biomarker interleukin 6 (IL-6) was assessed in ten studies, and a positive association was found between IL-6 and CLBP in six studies [19, 34, 35, 38, 39, 43]. Klyne et al. [34], in a study comparing a group of 99 patients with ALBP (acute low back pain) (divided into a high and low pain intensity subgroups) with 55 controls, found a positive correlation between IL-6 and patients with high low back pain intensity (p = 0.045), but there were no significant differences between low pain intensity subgroup and control group (p = 0.141). The rest of the studies found no association between these variables [29, 32, 41]. The evaluation of the interleukin 10 (IL-10) biomarker was only assessed in two studies, with a negative association with the presence of LBP. These studies presented a low [19] and moderate [37] risk of bias. The association between changes in serum TNF-α and presence of LBP was achieved in eight studies [32, 34, 35, 37‐39, 41, 43], with five studies [32, 35, 37, 38, 43] demonstrating a positive association between these variables. Four studies [37, 39‐41] have made direct comparisons between ALBP and CLBP groups regarding their inflammatory biomarkers profile. Gebhardt et al. [40] found no association between Hs-CRP and acute or chronic LBP. On the other hand, Injeyan et al. [37] demonstrated that IL-1, IL-1β and IL-6 values were significantly higher in the ALBP group (p = 0.0001), but not in the CLBP group, and that TNF-α values were significantly higher in the ALBP group (p = 0.0001) and CLBP group (p = 0.003).