Molecular and Structural Effects of Percutaneous Interventions in Chronic Achilles Tendinopathy.

Achilles tendinopathy (AT) is a common problem, especially in people of working age, as well as in the elderly. Although the pathogenesis of tendinopathy is better known, therapeutic management of AT remains challenging. Various percutaneous treatments have been applied to tendon lesions: e.g., injectable treatments, platelet-rich plasma (PRP), corticosteroids, stem cells, MMP inhibitors, and anti-angiogenic agents), as well as percutaneous procedures without any injection (percutaneous soft tissue release and dry needling). In this review, we will describe and comment on data about the molecular and structural effects of these treatments obtained in vitro and in vivo and report their efficacy in clinical trials. Local treatments have some impact on neovascularization, inflammation or tissue remodeling in animal models, but evidence from clinical trials remains too weak to establish an accurate management plan, and further studies will be necessary to evaluate their value.

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis.

Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1-phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF-α and IL-17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro-inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR-induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P1/3 , but their contribution to S1P-impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.

Wnt5a is expressed in spondyloarthritis and exerts opposite effects on enthesis and bone in murine organ and cell cultures.

Spondyloarthritis (SpA) is a chronic inflammatory joint disorder that initiates at the enthesis, where tendons attach to bone through a fibrocartilage zone. At late stages, excessive bone apposition appears within the diseased enthesis. Because Wnt5a participates to normal bone formation and appears related to inflammatory processes, we investigated the role of this Wnt growth factor in inflammation-associated ossification in SpA. The concentration of Wnt5a assessed by enzyme-linked immunosorbent assay in synovial fluids of patients with SpA (2.58 ± 0.98 ng/mL) was higher than in osteoarthritic patients (1.33 ± 0.71 ng/mL). In murine primary cultures of tendon cells, chondrocytes, and osteoblasts and in an organotypic model of mouse ankle, we showed that tumor necrosis factor α reversibly diminished Wnt5a expression and secretion, respectively. Wnt5a decreased gene expression of differentiation markers and mineralization in cultured chondrocytes and reduced alkaline phosphatase activity in Achilles tendon enthesis (-14%) and osteocalcin protein levels released by ankle explants (-36%). On the contrary, Wnt5a stimulated ossification markers' expression in cultured osteoblasts and increased the bone volume of the tibial plateau of the cultured explants (+19%). In conclusion, our results suggest that Wnt5a is expressed locally in the joints of patients with SpA. Wnt5a appears more associated with ossification than with inflammation and tends to inhibit mineralization in chondrocytes and enthesis, whereas it seems to favor the ossification process in osteoblasts and bone. Further studies are needed to decipher the opposing effects observed locally in enthesis and systemically in bone in SpA.

High pain catastrophizing scores in one-fourth of patients on biotherapy for spondylarthritis or rheumatoid arthritis.

OBJECTIVES: To measure catastrophizing scores in patients on biotherapy for spondyloarthritis (SpA) or rheumatoid arthritis (RA). METHODS: The first 140 outpatients or day-hospital patients seen at a teaching hospital rheumatology department for biotherapy administration completed the validated French version of the Pain Catastrophizing Scale (PCS, total score ranging from 0 to 52); a questionnaire on perceived support and past, current, and future disease activity; and a questionnaire on perceived understanding of their disease by family and co-workers. RESULTS: PCS scores were significantly higher in the 54 SpA patients than in the 86 RA patients (20.8 ± 12.1 versus 17.0 ± 13.6; P = 0.08), as a result of a higher helplessness subscore (10.0 ± 6.2 versus 7.8 ± 6.2; P = 0.046). The PCS score was ≥30 in 14/54 (26%) SpA patients and in 19/86 (22%) RA patients; physicians identified catastrophizing in only 17 of these 33 patients. PCS scores showed moderate correlations with the AS-DAS and DAS-28 and slightly stronger correlations with the overall pain score (Pearson, +0.431; P = 0.0001). SpA patients reported significantly worse understanding by their co-workers than did RA patients (33.9 ± 33.4 versus 53.9 ± 36.3; P = 0.007). CONCLUSION: One-fourth of patients with SpA or RA had very high pain catastrophizing scores despite biotherapy. Pain catastrophizing was missed by the physicians in half the cases and was relatively independent from other follow-up parameters. Pain catastrophizing can jeopardize treatment outcomes and deserves specific management.

Information on glucocorticoid therapy in the main studies of biological agents.

OBJECTIVE: To evaluate reported information on prednisone therapy in the main studies of biological agents used to treat rheumatoid arthritis (RA). METHODS: We reviewed 66 publications (including four abstracts), including 11 studies of infliximab, 19 of etanercept, eight of adalimumab, five of golimumab, four of certolizumab, four of rituximab, eight of abatacept, and seven of tocilizumab. RESULTS: Whether concomitant prednisone therapy was used, it was specified in only 56 (85%) of the 66 publications. Only 42 (64%) publications indicated that the prednisone dosage remained unchanged throughout the study. The maximum prednisone dosage allowed was specified in only 39 (59%) reports and was lower than 8 mg/day in only four (6%) studies. Data enabling determination of the mean daily prednisone dosage in prednisone-treated patients was available for only eight (12%) studies; the mean dosage ranged from 5.0 to 9 mg/day (mean, 7.1 ± 1.5). The percentage of patients receiving prednisone therapy was reported for only 41 (62%) studies. All the above-mentioned information was available in only two (3%) study reports. The percentage of patients on prednisone therapy ranged from 34% to 93% (mean, 58 ± 13%) overall and varied across biological agents as follows: abatacept, 74.4%; golimumab, 67.9%; infliximab, 60.6%; certolizumab, 57.5%; rituximab, 57.5%; etanercept, 54.4%; tocilizumab, 52.8%; and adalimumab, 50.4%. These percentages did not decline between 1997 and 2010. CONCLUSION: Study reports provide inadequate information on prednisone therapy during biological treatment for RA.