**7. Differential magnitude of inflammatory response**

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

#### **7.1. Rewrite cytokine section**

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

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

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

In rheumatoid arthritis (RA) comorbid FMS is associated with disproportionately higher values for the subjective components, patient global assessment (PtGA), and tender joint count (TJC), which in turn inflate the disease activity score (DAS). This phenomenon is largely mediated by higher patient assessed pain, fatigue, and especially poor mood, and variables that define the criterion, distress, and the etiopathogenesis of FMS [60–64]. As a potential explanation, depression alone can disproportionately increase pain sensitivity, the tender joint count (TJC), and a patient's sense of wellbeing, such as PtGA in RA [19, 65]. Higher subjective signs and symptoms then inflate the DAS. It is important to note that concomitant FMS and depression in RA are not associated with obvious, clinically significant increases of CRP or erythrocyte

Differential response to the treatment of the so-called subjective versus objective variables is a hallmark of comorbid FMS and/or depression in RA. In a prospective analysis of 668 RA patients, 18% with comorbid FMS had higher DAS and Health Assessment Disability Index at baseline compared to patients without FMS [66]. The TJC and PtGA were significantly higher, but the objective factors, ESR, and swollen joint count (SJC) were significantly lower in patients with FMS compared to patients with RA alone. Achievement of low disease activity and remission were significantly less likely in the comorbid FMS cohort. Others have con-

A very instructive, early, placebo-controlled trial showed that the pain of FMS did not respond to the treatment with prednisone 15 mg/day [68]. So too, unlike dose-related reduction of objective signs in RA such as the swollen joint count (SJC) and CRP, FMS-related inflated subjective signs and symptoms are resistant to aggressive anti-immune, anti-inflammatory

to FMS pathophysiology.

4 Discussions of Unusual Topics in Fibromyalgia

**6.1. RA**

sedimentation rate [42, 62, 65].

firmed these observations [67].

baseline, the CRP was not significantly lower.

trivial with respect to overall inflammation measured as CRP.

**6. Different process mechanisms: RA versus FMS/depression**

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

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

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 control for diurnal variation make precise comparisons between diseases difficult.

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 variations [76].

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 centrally mediated pain. We are still left with the lack of clinical response to moderate daily prednisone and even more aggressive antirheumatic, anti-inflammatory treatments which have been shown to reduce inflammation due to cytokines [67, 68, 71, 77].

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There is little question that FMS does associate with mild cytokine change, such as reduced diurnal variation of IL-6 compared to healthy individuals [56]. Forensic objectivity, however, would seem to indicate that the described modest changes in inflammatory mediators, whether primary or secondary, do not seem sufficient to be responsible for clinically relevant FMS symptoms. Furthermore, in some very legitimate contemporary hypotheses of FMS etiopathogenesis, there is no role for chronic cytokine-mediated processes [78, 79].
