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

#### **6.1. RA**

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 sedimentation rate [42, 62, 65].

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 confirmed these observations [67].

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 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 central pain mechanisms [69].
