Synovial cell metabolism and chronic inflammation in rheumatoid arthritis

Metabolomic studies of body fluids show that immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are associated with metabolic disruption. This is likely to reflect the increased bioenergetic and biosynthetic demands of sustained inflammation and changes to nutrient and oxygen availability in damaged tissue. The synovial membrane lining layer is the principle site of inflammation in RA. Here the resident cells are the fibroblast-like synoviocytes (FLS) and the synovial tissue macrophages (STM), which are transformed toward overproduction of enzymes which degrade cartilage and bone, and cytokines which promote immune cell infiltration. Recent studies have shown metabolic changes in both FLS and macrophages from RA patients and these may be therapeutically targetable. However, as the origins and subset specific functions of synoviocytes are poorly understood and the signaling modules which control metabolic deviation in RA synovial cells are yet to be explored, significant additional research is needed to translate these findings toward clinical application. Furthermore, in many inflamed tissues, different cell types can forge metabolic collaborations through solute carriers (SLC) in their membranes, to meet a high demand for energy or biomolecules. Such relationships are likely to exist in the synovium and are yet to be explored. Finally, it is not yet known whether metabolic change is a consequence of disease or if primary changes to cellular metabolism might underlie or contribute to early stage disease pathogenesis. This article collates what is known about metabolism in synovial tissue cells and highlights future research directions in this area

A qualitative exploration of physical, mental and ocular fatigue in patients with primary Sjögren's Syndrome

Introduction Primary Sjögren's Syndrome (pSS) affects exocrine glands such as those producing the tear film, leading to dry and painful eyes, but is also associated with fatigue. The experience of fatigue in pSS, and its relationship with sicca symptoms, is poorly understood. Methods Twenty people diagnosed with pSS were recruited to participate in a semi-structured qualitative interview about their symptoms experience. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. Results People with pSS described physical tiredness, mental fatigue and ocular fatigue. Mental fatigue was characterised by difficulties in attention, particularly, the ability to follow conversations and short-term memory problems. Participants linked their experience of fatigue to feeling of depression, frustration, irritation and anxiety, and therefore, fatigue was suggested to have had a large impact on their psychological well-being. People with pSS also described a range of ocular symptoms including pain, dryness, and itching, which were compounded by fatigue. For some, eye fatigue was pervasive, and daily activities involving the eyes such as reading, using the computer and driving were impaired. In some cases, the level of ocular discomfort was so severe it prevented sleep, which in turn impacted on general fatigue levels. Conclusions People with pSS experience fatigue in a range of ways; physical, mental and ocular fatigue were described. Fatigue was suggested to exacerbate other ocular symptoms, posed serious physical limitations and caused psychological distress. Further research into the nature of fatigue and ocular symptoms in pSS is required

Tissue inflammation signatures point towards resolution in adhesive capsulitis

Proresolving receptors, macrophage and fibroblast activation point towards a resolving inflammatory milieu in adhesive capsulitis

Targeting platelet inhibition receptors for novel therapies: PECAM-1 and G6b-B

While current oral antiplatelet therapies benefit many patients, they deregulate the haemostatic balance leaving patients at risk of systemic side-effects such as haemorrhage. Dual antiplatelet treatment is the standard approach, combining aspirin with P2Y12 blockers. These therapies mainly target autocrine activation mechanisms (TxA2, ADP) and, more recently, the use of thrombin or thrombin receptor antagonists have been added to the available approaches. Recent efforts to develop new classes of anti-platelet drugs have begun to focus on primary platelet activation pathways such as through the immunoreceptor tyrosine-based activation motif (ITAM)-containing collagen receptor GPVI/FcR-chain complex. There are already encouraging results from targeting GPVI, with reduced aggregation and smaller arterial thrombi, without major bleeding complications, likely due to overlapping activation signalling pathways with other receptors such as the GPIb–V–IX complex. An alternative approach to reduce platelet activation could be to inhibit this signalling pathway by targeting the inhibitory pathways intrinsic to platelets. Stimulation of endogenous negative modulators could provide more specific inhibition of platelet function, but is this feasible? In this review, we explore the potential of the two major platelet immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing inhibitory receptors, G6b-B and PECAM-1, as antithrombotic targets

Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

Pathological processes involved in the initiation of rheumatoid synovitis remain unclear. We undertook the present study to identify immune and stromal processes that are present soon after the clinical onset of rheumatoid arthritis ( RA) by assessing a panel of T cell, macrophage, and stromal cell related cytokines and chemokines in the synovial fluid of patients with early synovitis. Synovial fluid was aspirated from inflamed joints of patients with inflammatory arthritis of duration 3 months or less, whose outcomes were subsequently determined by follow up. For comparison, synovial fluid was aspirated from patients with acute crystal arthritis, established RA and osteoarthritis. Rheumatoid factor activity was blocked in the synovial fluid samples, and a panel of 23 cytokines and chemokines measured using a multiplex based system. Patients with early inflammatory arthritis who subsequently developed RA had a distinct but transient synovial fluid cytokine profile. The levels of a range of T cell, macrophage and stromal cell related cytokines ( e. g. IL-2, IL-4, IL-13, IL-17, IL-15, basic fibroblast growth factor and epidermal growth factor) were significantly elevated in these patients within 3 months after symptom onset, as compared with early arthritis patients who did not develop RA. In addition, this profile was no longer present in established RA. In contrast, patients with non-rheumatoid persistent synovitis exhibited elevated levels of interferon-gamma at initiation. Early synovitis destined to develop into RA is thus characterized by a distinct and transient synovial fluid cytokine profile. The cytokines present in the early rheumatoid lesion suggest that this response is likely to influence the microenvironment required for persistent RA