Introduction: The efficacy and the optimal type and volume of aerobic exercise (AE) in fibromyalgia syndrome (FMS) are not established. We therefore assessed the efficacy of different types and volumes of AE in FMS. Methods: The Cochrane Library, EMBASE, MEDLINE, PsychInfo and SPORTDISCUS (through April 2009) and the reference sections of original studies and systematic reviews on AE in FMS were systematically reviewed. Randomised controlled trials (RCTs) of AE compared with controls (treatment as usual, attention placebo, active therapy) and head-to-head comparisons of different types of AE were included. Two authors independently extracted articles using predefined data fields, including study quality indicators. Results: Twenty-eight RCTs comparing AE with controls and seven RCTs comparing different types of AE with a total of 2,494 patients were reviewed. Effects were summarised using standardised mean differences (95% confidence intervals) by random effect models. AE reduced pain (-0.31 (-0.46, -0.17); P < 0.001), fatigue (-0.22 (-0.38, -0.05); P = 0.009), depressed mood (-0.32 (-0.53, -0.12); P = 0.002) and limitations of health-related quality of life (HRQOL) (-0.40 (-0.60, -0.20); P < 0.001), and improved physical fitness (0.65 (0.38, 0.95); P < 0.001), post treatment. Pain was significantly reduced post treatment by land-based and water-based AE, exercises with slight to moderate intensity and frequency of two or three times per week. Positive effects on depressed mood, HRQOL and physical fitness could be maintained at follow-up. Continuing exercise was associated with positive outcomes at follow-up. Risks of bias analyses did not change the robustness of the results. Few studies reported a detailed exercise protocol, thus limiting subgroup analyses of different types of exercise. Conclusions: An aerobic exercise programme for FMS patients should consist of land-based or water-based exercises with slight to moderate intensity two or three times per week for at least 4 weeks. The patient should be motivated to continue exercise after participating in an exercise programme.

Background: Autologous chondrocyte implantation (ACI) is frequently used to treat symptomatic defects of the articular cartilage. Purpose: To test whether matrix-associated autologous chondrocyte implantation or the original periosteal flap technique provides superior outcomes in terms of clinical efficacy and safety. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Twenty-one patients (mean age, 29.3 ± 9.1 years) with symptomatic isolated full-thickness cartilage defects (mean 4.1 ± 09 cm2) at the femoral condyle were randomized to matrix-associated autologous chondrocyte implantation or the original periosteal flap technique. The primary outcome parameter was the postoperative change in knee function as assessed by the International Knee Documentation Committee (IKDC) score at 12 months after ACI. In addition, the IKDC score was assessed at 3, 6, 12, and 24 months after surgery. Secondary outcome parameters were postoperative changes in health related quality of life (Short Form-36 Health Survey), knee functionality (Lysholm and Gillquist score), and physical activity (Tegner Activity Score) at 3, 6, 12, and 24 months after ACI. Magnetic resonance imaging was performed to evaluate the cartilage 6, 12, and 24 months after ACI and rated using the Magnetic Resonance Observation of Cartilage Repair Tissue score. Adverse events were recorded to assess safety. Results: The primary outcome parameter showed improvement of patients 1 year after autologous chondrocyte implantation, but there was no difference between the periosteal flap technique and matrix-associated ACI (P = .5573); 2 years after ACI, a similar result was found (P = .4994). The study groups did not show differences in the Short Form-36 categories and in knee functionality as assessed by Tegner Activity Score 12 months (P = .4063) and 24 months (P = .1043) after ACI. There was a significant difference in the Lysholm and Gillquist score at 12 months (P = .0449) and 24 months (P = .0487) favoring the periosteal flap technique group. At 6 months after surgery, a significantly lower Magnetic Resonance Observation of Cartilage Repair score was obtained in the matrix-associated ACI group (P = .0123), corresponding to more normal magnetic resonance imaging diagnostic findings. Twelve and 24 months after ACI, the differences between the 2 groups were not significant (12 months, P = .2065; 24 months, P = .6926). Adverse events were related to knee problems such as transplant delamination, development of an osseous spur, osteochondral dissection, and transplant hypertrophy. Systemic (allergic, toxic, or autoimmune) reactions did not occur. Conclusion: There was no difference in the efficacy between the original and the advanced ACI technique 12 and 24 months after surgery regarding International Knee Documentation Committee, Tegner Activity Score, and Short Form-36; however, with respect to the Lysholm and Gillquist score, better efficacy was observed in the periosteal flap technique group.

The aim of this study was to identify inflammatory mediators of potential clinical relevance in synovial fluid (SF) samples of patients with knee osteoarthritis (OA). Therefore, radiographic OA severity, knee pain and function of 34 OA patients undergoing unicompartmental (UC) and bicompartmental (BC) knee arthroplasty were assessed prior to surgery and SF samples were analyzed for a broad variety of inflammatory mediators, including interleukins (ILs), interferons (IFNs), C-X-C motif ligand chemokines (CXCLs), and growth factors (nerve growth factor; NGF, vascular endothelial growth factor; VEGF, and stem cell growth factor β; SCGF-β) using multiplex assay. Significant differences were observed between the SF levels of different inflammatory markers. When compared to UC OA, significantly higher concentrations of IL-7, IL-8, IL-10, IL-12, IL-13, IFN-γ, VEGF and CXCL1 were detected in BC OA. Correlation analyses revealed significant associations between OA severity and IL-6, IL-8, IFN-γ, SCGF-β, VEGF, CXCL1. Interestingly, increases in both anti- (IL-10, IL-13) and pro-inflammatory (IL-7, IL-12, IFN-γ) cytokines, as well as growth factors (SCGF-β, VEGF), correlated significantly with the level of knee pain. Poorer knee function was associated with higher IL-6, IL-10, IL-12, IL-13, IL-18, βNGF, SCGF-β, VEGF and CXCL9 levels. In conclusion, this study provides an extensive profile of synovial inflammatory mediators in knee OA and identifies cytokines of potential clinical relevance. In fact, five of the mediators examined (IL-10, IL-12, IL-13, SCGF-β, VEGF) significantly correlate with both knee pain and function.

Introduction: CD4⁺CD25^+/highCD127^low/- regulatory T cells (Tregs) play a crucial role in maintaining peripheral tolerance. Data about the frequency of Tregs in rheumatoid arthritis (RA) are contradictory and based on the analysis of peripheral blood (PB) and synovial fluid (SF). Because Tregs exert their anti-inflammatory activity in a contact-dependent manner, the analysis of synovial membrane (SM) is crucial. Published reports regarding this matter are lacking, so we investigated the distribution and phenotype of Tregs in concurrent samples of SM, SF and PB of RA patients in comparison to those of osteoarthritis (OA) patients. Methods: Treg frequency in a total of 40 patients (18 RA and 22 OA) matched for age and sex was assessed by flow cytometry. Functional status was assessed by analysis of cell surface markers representative of activation, memory and regulation. Results: CD4⁺ T cells infiltrate the SM to higher frequencies in RA joints than in OA joints (P = 0.0336). In both groups, Tregs accumulate more within the SF and SM than concurrently in PB (P < 0.0001). Relative Treg frequencies were comparable in all compartments of RA and OA, but Treg concentration was significantly higher in the SM of RA patients (P = 0.025). Both PB and SM Tregs displayed a memory phenotype (CD45RO⁺RA^-), but significantly differed in activation status (CD69 and CD62L) and markers associated with Treg function (CD152, CD154, CD274, CD279 and GITR) with only minor differences between RA and OA. Conclusions: Treg enrichment into the joint compartment is not specific to inflammatory arthritis, as we found that it was similarly enriched in OA. RA pathophysiology might not be due to a Treg deficiency, because Treg concentration in SM was significantly higher in RA. Synovial Tregs represent a distinct phenotype and are activated effector memory cells (CD62L^-CD69⁺), whereas peripheral Tregs are resting central memory cells (CD62L⁺CD69^-).

Objective: To explore the involvement of protease‐activated receptor 1 (PAR‐1) and PAR‐2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR‐1 or PAR‐2 in mice.Methods: OA was induced in the joints of wild‐type (WT), PAR‐1^+/+, PAR‐1^−/−, and PAR‐2^−/− mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks post‐DMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/activity were studied in cultures of mouse femoral head tissue with or without interleukin‐1α (IL‐1α). At 1 week post‐DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription–polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry.Results: Deletion of PAR‐2, but not that of PAR‐1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR‐1 or PAR‐2 ablation on IL‐1α–induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post‐DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4+ T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR‐2^−/− mice compared to PAR‐1^−/− and WT mice.Conclusion: Deletion of PAR‐2, but not that of PAR‐1, results in a significant decrease in DMM‐induced cartilage damage. The chondroprotection in PAR‐2^−/− mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.

Background: Investigating the pathophysiological mechanisms of early osteoarthritis (OA) is of utmost interest since this stage holds the strongest promise for therapeutic interventions. The aims of this study were to analyze if synovial inflammation is already present in early OA and to characterize the involved cell populations, by investigating synovial fluid (SF) and synovial membrane (SM) of early OA patients for the presence and polarization status of CD4 T cells.Methods: A quantitative analysis of CD4⁺T cell infiltration in SF and SM compared to peripheral blood (PB) was performed in patients with early stages of OA. We further investigated intracellular staining (ICS), surface marker, and chemokine receptor expression profiles of CD4⁺T cells in SF, SM, and PB, as well as cytokine expression in native SF and PB. Matched samples of SF, SM, and PB were harvested from 40 patients with early OA at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Samples were analyzed by flow cytometry for surface markers and cytokines, which are preferentially expressed by distinct T cell subsets (Th1, Th2, Th17, regulatory T cells). Furthermore, we analyzed native SF and PB supernatants using MACSPlex for multiple cytokine expression profiles.Results: SF and SM showed a distinct infiltration of CD4⁺T lymphocytes, with significantly increased expression of chemokine receptors CXCR3/CCR5, cytokine IFN-γ (preferentially expressed by Th1 cells), and CD161 (preferentially expressed by IL-17 producing Th17 cells) compared to PB. Furthermore, the percentage of CD4⁺T cells polarized to Treg was significantly increased in SM compared to SF and PB. No significant differences were observed for CCR3 and CCR4 (preferentially expressed by Th2 cells), although IL-4 values were significantly higher in SM and SF compared to PB. Cytokine analysis showed comparable results between PB and SF, with only IL-6 being significantly increased in SF.Conclusions: Early OA joints show already significant inflammation through CD4⁺T cell infiltration, with predominant Th1 cell polarization. Inflammation seems to be driven by direct proinflammatory cell interaction. Cytokine signaling seems to be negligible at the site of inflammation in early OA, with only IL-6 being significantly increased in SF compared to PB.