The cohort 2 patients (n = 16) did not significantly differ from the cohort 1b healthy controls (n = 11) concerning age (56 [46-68] years vs 54 [44-57] years, respectively; P = 0.178) and sex (69% vs 64% women, respectively; P = 1.0). Detailed individual characteristics for cohort 2 are shown in Table 3. Data on 50 inflammation-related proteins were available.
We found a 55% overlap when comparing the top 11 proteins of the 2 OPLS-DA models: LAPTGF-beta-1, CCL11, CXCL10, CCL23, CXCL6, and CCL8 were common to both models. LIF-R, CXCL1, CCL19, CXCL5, and CCL3 were specific for cohort 1a, whereas 4E-BP1, CX3CL1, CD5, CCL25, and CXCL11 were specific for cohort 2. Among the proteins specific for either cohort, the following 5 proteins had VIP 1.0 to 1.3 in the other cohort, that is, were somewhat (albeit not very strongly) associated with NeuP in the other cohort as well: CXCL1, CXCL5, CXCL11, and CX3CL1.
We have determined an extensive CSF inflammatory profile of patients with severe peripheral NeuP who were candidates for (cohort 1a) or had an on-going (cohort 2) treatment with SCS, compared with healthy control subjects (cohort 1b).
A large part of the main findings of cohort 1a could be reproduced in cohort 2, with an overlap of 55% concerning the top 11 proteins. The difference between the top 11 proteins could perhaps be due to the fact that the 2 NeuP cohorts differed concerning the presence or absence of long-term SCS treatment. Even though the 2 cohorts consisted of more or less the same category of patients, it is conceivable that long-term modulatory effects of SCS might have altered the CSF inflammatory profile of cohort 2. Even though the 2 NeuP cohorts were compared with the same control group, which is an obvious limitation, the actual overlap of results between the 2 comparisons is still noteworthy. Also, both patient cohorts were highly refractory to conventional treatment, and our results cannot be generalized to any NeuP.
A description of the chemokine family, and of LAPTGF-beta-1, can be found in supplemental digital content 3 (available online at http://links.lww.com/PAIN/A482). Strikingly, levels of LAPTGF-beta-1 have also been increased in all the other studies that we have hitherto performed with the present panel (including the present study).13,30,55
To the best of our knowledge, among the other major findings of the study, neither CXCL6 nor CCL23 have been implicated in NeuP. In contrast, CCL11 has been investigated in at least 3 models of NeuP43,49,67; see also supplemental digital content 3 (available online at http://links.lww.com/PAIN/A482).
Granted that our results are valid (ie, that they really reflect pain-related pathophysiology and not, eg, a confounding effect of concomitant medicines or of other medical conditions such as the ones listed in Table 1), it is important to consider whether the CSF inflammatory fingerprint that we have described directly relates to the pathophysiology of NeuP (eg, central sensitization due to neuroinflammation) or if it is an inflammatory risk factor that was present prior to the development of NeuP (eg, a genetic susceptibility such as HLA haplotype23,61,66,77). A third possibility could be that the fingerprint is a consequence of NeuP, for example, mirroring pain-related stress, physical inactivity,62 depression,75 or bad sleep.56 Of course, all 3 of these categories may play a role. Disentangling the contribution of these potentially mutually interacting factors will be very difficult. For instance, levels of peripheral IL-6 are known to be influenced by regular exercise, individuals who are inactive having higher baseline levels of this particular cytokine.62
The authors have no conflict of interest to declare.
The study was supported by Uppsala Berzelii Technology Centre for Neurodiagnostics, with financing from the Swedish Governmental Agency for Innovation Systems (Vinnova) and the Swedish Research Council (grant no. P29797-1). The study was also financially supported by the Swedish Research Council (grant no. K2015-99x-21874-05-4), the County Council of Östergötland (LIO-35923, SC-2013-00395-36), and AFA Insurance (140341). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/A482.
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