**5. Depression and inflammation**

often misclassified as a "connective tissue disease" (a misnomer), most of which are inflammatory in nature, or that such reference adds a sort of "scientific patina" to the discussion is

This review examines the validity of the concept that cytokine- and chemokine-driven inflam-

At least three observations have been used to provide circumstantial or hypothesis-generating

**1.** The symptoms and signs of "sickness behavior" observed in FMS can be experimentally

**2.** Similar alteration of the hypothalamic–pituitary axis and autonomic nervous system observed in FMS has been etiopathogenically linked to elevated inflammatory cytokines, in-

**3.** Symptoms of disordered sleep, hyperalgesia, and cognitive dysfunction much like FMS were observed when patients with renal cell carcinoma were treated with interleukin-2 lymphokine-activated killer (IL-2 LAK) cell therapy and when chronic hepatitis patients

1. Previous inconsistent reports have demonstrated that C-reactive protein (CRP) can be marginally higher in FMS subjects than in parallel healthy controls [16]. In this analysis,

**2.** Inconsistent elevation of a variety of serum cytokines has, however, been observed in some studies [16–24]. In a meta-analysis of 25 FMS studies, 1255 FMS, and 800 healthy controls (HC), interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), and interleukin-8 (IL-8)

Three integrated reviews, although acknowledging discrepancies in the literature, attempted to associate cytokine abnormalities with core FMS symptoms [26–28]. The first concluded, "There are discrepant findings related to whether pro-inflammatory and anti-inflammatory cytokines are elevated or reduced in persons with FMS and whether they correlate with core symptoms." [26]. The second [27] critiqued one of the more persuasive analysis, "….. may have cytokine driven abnormalities to explain their pain…IL-1ra and IL-6 were significantly higher after stimulating PBMC of FMS patients compared to controls [29]." The results of this

however, serum inflammatory cytokines were not higher than in healthy controls.

cluding interleukin-1 (IL-1), in a variety of clinical settings other than FMS [11–14].

**4. Experimental evidence for cytokine/chemokine pathogenesis**

were the most likely inflammatory cytokines to be elevated [25].

study were not corroborated in a second study [24].

unclear.

**3. Background**

mation is relevant to the pathogenesis of FMS.

2 Discussions of Unusual Topics in Fibromyalgia

induced by inflammatory cytokines [10].

were treated with interferon alpha [15].

evidence to advance a role for inflammatory pathogenesis:

Depression and FMS are very often comorbid and show a bidirectional association [19, 33–38]. The prevalence of depression in FMS has been estimated to range from 20 to 80% in a detailed review [39]. Furthermore, the severity of comorbid depression correlates with FMS severity measures [40–42]. We have reported that depression, with a 73% prevalence, correlated better with core FMS symptoms than did any other variable in a cohort of 305 FMS patients [43].

As in FMS, similar mild elevation of CRP and inflammatory cytokines and chemokines have been demonstrated in depressed individuals in controlled analyses [44–53]. Many primary analyses of FMS inflammation [15, 30, 31, 54–56] and reviews [23, 28], however, failed to control for depression. This is an unfortunate omission.

Maes and colleagues evaluated the serum concentrations of inflammatory cytokines in relationship to depression among 21 FMS patients compared to 33 healthy controls [57].

Serum soluble gp130, an important inflammatory cytokine signal transducer, and a soluble interleukin-6 receptor, Il-1 ra, were significantly higher in FMS patients with a Hamilton Depression Rating Scale score >16 than in FMS patients with scores of 16 or lower or in healthy controls. In the opinion of the Menzies' integrated review, which included the Maes analysis, higher inflammatory cytokines in FMS, including IL6, were related to the degree of depression, although inconsistencies were common [26].

Of interest, higher body mass index partially explained cytokine differences as has been shown in depression [18, 52]. Therefore, inflammation in FMS, measured as higher serum concentrations of cytokines and chemokines, is multifactorial and not necessarily due solely to FMS pathophysiology.

RA treatment [69–71]. In fact, a treatment response resulting in remission in RA comorbid with FMS should not be expected because the higher, poorly responsive PtGA and TJC are not due to RA biological disease activity, but in fact to poorly responsive noninflammatory FMS

Introductory Chapter: A Challenge to the Concept that Inflammation Plays a Prominent…

http://dx.doi.org/10.5772/intechopen.72936

5

Mean CRP values, although reported elevated in some FMS populations compared to control populations, are still within the range of normal CRP [72]. Given this observation, it is both

In RA, serum concentrations of IL-6 measured by enzyme immunoassay (ELISA) [73] in >900 patients demonstrated mean ~ 43 pg/ml, for all, and ~54–84 pg/ml for those with active disease [55]. In another population of 66 RA patients, using a similar assay, IL-6 levels declined

Contrast these serum levels with serum levels in depression and FMS. Using a different more sensitive ELISA assay, Grosse reported mean IL-6 serum concentration of 1.17 ± 2.59 for 214 patients with major depression disorder (MDD) and 0.66 ± 1.94 for healthy controls (HC) [50]. In another analysis of 64 MDD patients and 80 healthy controls, IL-6 levels were reported statistically higher in depression than in controls, 1.39 ± 0.35 versus 0.45 ± 0.28 pg/ml using yet another ELISA [47].

These same comparatively low serum levels were reported in FMS, with IL-6 in the range of 16 pg/ml in FMS and 1 pg/ml in healthy controls using yet another ELISA assay [75]. Although

This discussion apparently shows that inflammatory cytokines, even when relatively elevated in FMS, are much lower than in mildly active RA. If this is true, then the elevations in FMS may not be sufficiently high to initiate clinical signs or symptoms. Unfortunately, as can be seen, diverse assays that produce diverse serum and cellular concentrations and the lack of

Fortunately, two papers do allow comparison. The authors of both studies used very similar ELISA methods. In 16 RA patients with varying disease activity, overnight IL-6 values ranged from a mean of ~40 pg/ml at 11 PM to a peak of ~60 at 8 AM with large individual

In FMS, although the mean values for IL-6 were statistically significantly higher in FMS patients than in healthy controls at night (2.94 versus 2.14 pg/ml), these serum concentrations were at least 10 times lower in FMS than in RA [56]. Are these meager elevations of IL-6, ~0.80 pg/ml in FMS compared to HCs, sufficiently high enough to explain clinical differences?

Let us postulate that mildly elevated cytokines in the CNS such as IL-6 and IL-8 [32] produced by microglial and/or astrocyte cells are sufficient to interfere with processing and produce

higher than HCs, the levels are very low when compared to those in RA.

control for diurnal variation make precise comparisons between diseases difficult.

instructive and necessary to consider whether cytokines follow this same pattern.

**7. Differential magnitude of inflammatory response**

central pain mechanisms [69].

**7.1. Rewrite cytokine section**

variations [76].

to 22.5 pg/ml in low disease activity [74].

Serum inflammatory cytokine concentrations correlate with the degree of depression and fall with effective treatment of depression [58]. Not surprisingly, inflammatory cytokine concentrations have also been shown to correlate with pain symptoms in primary depression alone [59].

This phenomenon even occurs when the treatment is nonpharmacological, suggesting an intrinsic etiopathophysiologic relationship of inflammatory cytokines with depression [46]. This analysis also demonstrated that despite a significant fall of cytokine concentration from baseline, the CRP was not significantly lower.

In summary, these two analyses demonstrate a pain symptom signature integral to depression and that cytokines, while slightly higher in depression than in healthy controls, are in fact trivial with respect to overall inflammation measured as CRP.
