F.P. Lafeber

Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage

OBJECTIVE Adipose tissue is an endocrine tissue releasing adipokines suggested to be involved in the pathogenesis of osteoarthritis (OA). Nevertheless, their relative contribution and exact mechanisms are still ambiguous. The aim of this study is to compare serum adipokine levels between end-stage knee OA patients and controls and to relate these serum levels to local parameters of cartilage damage and synovial inflammation. METHODS Serum was collected from 172 severe knee OA patients, shortly before total knee replacement (TKR) surgery and from 132 controls without radiographic knee OA [Kellgren & Lawrence (K&L) = 0]. Serum adiponectin, leptin, and resistin levels were measured by enzyme-linked immunosorbent assay (ELISA). Cartilage and synovial tissue were collected at TKR surgery and assessed for cartilage degeneration and synovial inflammation by histochemistry and biochemical analyses. RESULTS The adipokine levels were all distinctly higher in OA patients as compared to controls. Especially adiponectin and leptin were associated with female gender (stand beta = 0.239 and 0.467, respectively, P < 0.001) and body mass index (BMI) (stand beta = -0.189 and 0.396, respectively, P < 0.001). No associations between serum levels of adipokines and cartilage damage (histochemistry, proteoglycan content) were found whereas weak but positive associations with synovial inflammation were found [adiponectin and interleukin-1β (IL-1β), stand beta = 0.172, P = 0.02; resistin and histology, stand beta = 0.183, P = 0.034, adjusted for demographics]. CONCLUSION This study suggests an important involvement of adipokines in OA patients considering their high serum levels compared to controls. Associations of systemic adipokines with local synovial tissue inflammation were found, although not represented by similar relations with cartilage damage, suggesting that adipokines are of relevance in the inflammatory component of OA.

The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the dog.

The dog is a common model for study of osteoarthritis (OA). Subjective histologic scoring systems have often served as the reference standard for presence and severity of OA. However, these scoring systems have perceived shortcomings. The system developed for this report attempts to address these shortcomings by providing a standardized methodology for global assessment of the joint, versatility and the potential for relative weighting of pathology, allowing for comparison among time points, studies, and centers, and critical analysis of the systems reliability. The proposed system for assessment of canine tissues appears to provide an effective method for global assessment of articular pathology in OA. The system is versatile, comprehensive, and reliable and appears to have advantages over conventional scoring systems.

Interleukin 7 stimulates tumour necrosis factor α and Th1 cytokine production in joints of patients with rheumatoid arthritis

Background: A large number of activated T cells are found in the joints of patients with rheumatoid arthritis (RA). Interleukin 7 (IL7), a T cell growth factor and a regulator of Th1 and Th2 cytokine production, is produced by synoviocytes from patients with RA. Objective: To investigate the effect on proinflammatory cytokine production of synovial fluid mononuclear cells (SFMC) and the mechanism by which IL7 influences CD4+ T cell activity in patients with RA. Methods: In a cross sectional group of patients with RA, IL7 levels were compared with those of healthy controls and related to disease activity. The effect of IL7 on cytokine production was tested by RA SFMC and on SF CD4+ T cells in the presence of mononuclear cells (MC). Production of tumour necrosis factor α (TNFα), IL1β, interferon γ (IFNγ), and IL4 was measured by enzyme linked immunosorbent assay (ELISA) and by single cell FACS analysis. Expression of the IL7 receptor α chain on CD4+ T cells (essential for IL7 signalling) was assessed. Direct effects of IL7 on isolated synovial fluid (SF) CD4+ T cells were studied by cytokine analysis. By neutralisation of IL12 in MC cultures, indirect effects of IL7 on T cells through accessory cells were studied. Results: IL7 serum levels were higher in patients with RA than in healthy controls and correlated positively with C reactive protein levels. IL7 stimulated TNFα production by SFMC and very potently stimulated IFNγ and TNFα production by SF CD4+ T cells. These effects were probably mediated through the IL7 receptor α chain, which was abundantly expressed on SF CD4+ T cells. Besides the direct stimulation of T cell cytokine production by IL7, its action was partly dependent on IL12, indicating that IL7 also stimulates accessory cell function, leading to T cell activation. Conclusion: IL7 stimulates proinflammatory cytokine production of intra-articular CD4+ T cells and accessory cells from patients with RA. The correlation with measures of disease activity indicates that IL7 might substantially contribute to the perpetuation of Th1 and TNFα mediated proinflammatory responses in patients with RA.

CHECK (Cohort Hip and Cohort Knee): similarities and differences with the Osteoarthritis Initiative

Objective: To describe the osteoarthritis study population of CHECK (Cohort Hip and Cohort Knee) in comparison with relevant selections of the study population of the Osteoarthritis Initiative (OAI) based on clinical status and radiographic parameters. Methods: In The Netherlands a prospective 10-year follow-up study was initiated by the Dutch Arthritis Association on participants with early osteoarthritis-related complaints of hip and/or knee: CHECK. In parallel in the USA an observational 4-year follow-up study, the OAI, was started by the National Institutes of Health, on patients with or at risk of symptomatic knee osteoarthritis. For comparison with CHECK, the entire cohort and a subgroup of individuals excluding those with exclusively hip pain were compared with relevant subpopulations of the OAI. Results: At baseline, CHECK included 1002 participants with in general similar characteristics as described for the OAI. However, significantly fewer individuals in CHECK had radiographic knee osteoarthritis at baseline when compared with the OAI (p<0.001). In contrast, at baseline, the CHECK cohort reported higher scores on pain, stiffness and functional disability (Western Ontario and McMaster osteoarthritis index) when compared with the OAI (all p<0.001). These differences were supported by physical health status in contrast to mental health (Short Form 36/12) was at baseline significantly worse for the CHECK participants (p<0.001). Conclusion: Although both cohorts focus on the early phase of osteoarthritis, they differ significantly with respect to structural (radiographic) and clinical (health status) characteristics, CHECK expectedly representing participants in an even earlier phase of disease.

In early OA, thinning of the subchondral plate is directly related to cartilage damage: results from a canine ACLT-meniscectomy model

OBJECTIVE The pathogenesis of osteoarthritis (OA) includes cartilage degeneration, synovial inflammation, and bone changes. Slowly, the sequence and inter-relationship of these features is becoming clearer. Early models of OA suggest thinning of the subchondral plate in addition to trabecular bone changes. In the present study subchondral bone changes were studied in the canine anterior cruciate ligament transection (ACLT)-meniscectomy model. This model is characterized by intra-joint variability with respect to cartilage damage (predominantly medial) and loading (lateral unloading due to a shifted axis). METHODS In 13 Labrador dogs, OA was induced by transection of the anterior cruciate ligament and removal of the medial meniscus. Twelve weeks later, cartilage integrity was evaluated histologically using the modified Mankin score (0-11), and proteoglycan content was determined by Alcian Blue assay. Bone architecture of the tibia was quantified by micro-CT. RESULTS Cartilage damage was severe in the medial compartment (Mankin score +3.5, glycosaminoglycan (GAG) content -28%) and mild in the lateral compartment (Mankin score +1.6, GAG content -15%). Thinning and porosity of the subchondral plate were only present on the medial side (-21%, +87%, respectively). Interestingly, changes in trabecular bone structure did almost not occur in the medial compartment (volume fraction -7%) but were clear in the lateral compartment (-20%). CONCLUSION Thinning of the subchondral plate is a localized phenomenon related to cartilage degeneration while trabecular bone changes are related to mechanical (un)loading. The different mechanisms responsible for bone changes in OA should be taken in account when designing and interpreting studies interfering with bone turnover in the treatment of OA.

Proinflammatory cytokine production and cartilage damage due to rheumatoid synovial T helper-1 activation is inhibited by interleukin-4.

OBJECTIVES--To investigate the role of T helper-1 cell (Th1) activation in the induction of proinflammatory cytokine production and cartilage damage by rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMNC) and the subsequent possible beneficial role of the T helper-2 cell (Th2) cytokine interleukin-4 (IL-4) in the inhibition of this process. METHODS--SFMNC were stimulated with bacterial antigen (hsp60) to activate Th1 cells. Th1 and Th2 specific cytokine profiles (interferon gamma (IFN gamma) and IL-4) and proinflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha) in the conditioned media were analysed. In addition, the conditioned media were tested for their ability to induce cartilage damage. The same parameters were measured in the presence of IL-4. RESULTS--Stimulation of SFMNC with bacterial antigen resulted in an increase in IFN gamma, IL-1, and TNF alpha production which was accompanied by the induction of cartilage damage. Th1 activation could be inhibited by IL-4 as shown by a reduction of IFN gamma. This was accompanied by a decrease in IL-1 and TNF alpha production and inhibition of cartilage damage. CONCLUSIONS--Th1 activation is a possible mechanism by which inflammation in RA joints is enhanced. The Th2 cytokine IL-4 inhibits this Th1 activity and may diminish inflammation and induction of cartilage damage in RA joints.

Interleukin‐7 induced immunopathology in arthritis

Interleukin (IL)-7 is a potent immunoregulatory cytokine that is detected in joints of patients with rheumatoid and juvenile idiopathic arthritis and which correlates with parameters of disease. Several synovial cell types that play an important role in inflammation and immunopathology, such as macrophages, dendritic cells, and fibroblasts, produce IL-7. IL-7 induces cytokines produced by arthritogenic T cells (for example, interferon γ (IFNγ), IL-17), T cell differentiating factors (for example, IL-12), chemokines capable of attracting inflammatory cells (for example, macrophage induced gene (MIG), macrophage inflammatory protein (MIP)-1α) as well as molecules involved in cell adhesion, migration, and costimulation (for example, lymphocyte function associated antigen (LFA)-1, CD40, CD80). In addition, IL-7 can induce bone loss by stimulating osteoclastogenesis that is dependent on receptor activator of nuclear factor κB ligand (RANKL). IL-7 induces tumour necrosis factor α (TNFα) secretion by T cells and by monocytes after T cell dependent monocyte/macrophage activation. Importantly, induction of both IL-7 and IL-7 induced effects seems to be able to operate independent of TNFα. Together this suggests that IL-7 is an important cytokine in several rheumatic conditions, capable of inducing inflammation and immunopathology. Thus it may be an important target for immunotherapy.

The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production.

OBJECTIVES The influence of dexamethasone on interleukin 10 (IL10) production and the type 1 (T1)/type 2 (T2) T cell balance found in rheumatoid arthritis (RA) was studied. METHODS Peripheral blood mononuclear cells (PB MNC) were isolated from 14 RA patients both before and 7 and 42 days after high dose dexamethasone pulse therapy. The ex vivo production of IL10, interferon γ (IFNγ) (T1 cell), and IL4 (T2 cell) by PB MNCs was assessed, along with parameters of disease activity (erythrocyte sedimentation rate, C reactive protein, Visual Analogue Scale, Thompson joint score). In addition, the in vitro effect of dexamethasone (0.02, 0.2, and 2 μM) on PB MNC IL10, IFNγ, and IL4 production was studied. RESULTS Dexamethasone pulse therapy resulted in a rapid and sustained decrease in RA disease activity. IL10 production increased after dexamethasone treatment and this was sustained for at least six weeks. A transient strong decrease in IFNγ was seen shortly after corticosteroid treatment, while IL4 only decreased slightly. This led to an increased IL-4/IFNγ ratio. In vitro, IL10 production was not detectable, IFNγ and IL4 decreased, but the effect was more pronounced for IFNγ than for IL4, which again resulted in an increased IL4/IFNγ ratio. CONCLUSION Dexamethasone therapy in RA patients leads to a rapid, clinically beneficial effect. The upregulation of IL10 production may be involved in the prolonged clinical benefit. The strong immunosuppressive effect is most evident in the decrease in IFNγ, and is therefore accompanied by a relative shift towards T2 cell activity. In vitro evaluation showed that this shift in T cell balance was a direct effect of dexamethasone and thus independent of the hypothalamic-pituitary-adrenal axis.

Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell balance.

OBJECTIVES The balance between interferon γ(IFNγ) and interleukin 4 (IL4) producing T cells (T1 and T2 cells) seems to be of importance in many (auto)immune disorders. In general, T1 cell activity is important in cellular immunity whereas T2 cell activity plays a part in humoral responses. T1 cell activity predominates in joints of patients with rheumatoid arthritis (RA) whereas T2 cell activity is characteristic of atopic syndromes. This study investigated whether the prevalence of hay fever in RA is low and if severity of RA (T1 cell activity) can be influenced by the concomitant occurrence of a T2 cell mediated disease (hay fever). METHODS The prevalence of hay fever was assessed in 643 consecutive (RA and non-RA) patients seen in our outpatient clinic and confirmed by skin test and specific IgE. Of this group the 12 RA patients with hay fever were compared with RA patients without hay fever (matched for age, sex, and disease duration). RESULTS The prevalence of hay fever in RA patients is lower than in non-RA patients (4% versus 8%), and yields a relative risk for RA patients to develop hay fever of 0.48. RA patients with hay fever showed a lower disease activity (erythrocyte sedimentation rate, C reactive proten, Thompson joint score, and radiographic joint damage (Sharp) score) than RA patients without hay fever. The clinical data were related to peripheral blood T1/T2 cell balance: a lower IFNγ/IL4 ratio was observed for RA patients with hay fever, indicating a comparatively increased T2 cell activity in RA patients with hay fever. CONCLUSION These results argue in favour of the exploration of treatments aimed at regulation of a possible imbalance in T1/T2 cell activity in RA.

Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammation

OBJECTIVE To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögrens syndrome. METHODS Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögrens syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects. RESULTS The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell-attracting and T cell-differentiating cytokines (monokine induced by interferon-gamma [IFNgamma], IFNgamma-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFNgamma), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor alpha and IL-1alpha), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7-induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects. CONCLUSION The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7-mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS.