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Background Glucocorticoids (GCs) can cause unwanted effects. Both rheumatologists and patients classify osteoporosis, hyperglycemia/diabetes mellitus, cardiovascular diseases, and infections as the most worrisome adverse effects of GCs. Alternatives with less adverse effects but with good efficacy are needed, thus with a better efficacy/safety ratio. Selective GC receptor modulators (SGMRs) are designed to engage the receptor with dissociative characteristics: less transactivation of genes, mainly responsible for unwanted effects, while trans-repression of genes, inducing anti-inflammation, is maintained. Hereby, SGRMs are expected to have a better efficacy/safety ratio. A systematic review providing an overview of the efficacy and safety data of SGRMs is lacking. Objectives To systematically review the current literature on efficacy and safety of SGRMs in arthritis, compared to those of GCs. Methods A search was performed in Medline, Embase and the Cochrane Library, from inception dates of databases to October 5th, 2016. Experimental studies involving animal arthritis models or human material of arthritis patients, as well as clinical studies in patients of arthritis were included, if they reported original data. All types of arthritis were included. Data was extracted on the SGRM studied and on the GC as reference standard, design or setting of the study and whether or not safety and efficacy parameters had been reported. Results A total of 437 articles was retrieved of which 15 articles were eligible for our analysis. The following SGRMs were investigated: Compound A1–6, PF-041713277, LGD-55528–9, Compounds 410, 510, and 1411, (R)-1612, (R)-1813, (R)-2113, (R)-3514, (R)-3712, Ginsenoside Rg115 and Org 214007–016. Results are shown in Table 1. (R)-16 showed better efficacy and safety compared to prednisone. Compound A, Ginsenoside Rg 1, Compounds 14, (R)-18, and (R)-21 had better safety profiles than a GC, but with similar efficacy. (R)-35 and (R)-37 showed better efficacy than a GC, but safety data was lacking. Org 214007–0, LGD-5552, Compounds 4 and 5 and PF-04171327 showed similar efficacy as a GC, but no safety data was provided. Conclusions Studies both assessing efficacy and safety parameters of SGRMs are scarce. Currently, there is insufficient evidence for the presumed superior efficacy/toxicity balance of SGRMs compared to that of GCs. References Dewint P et al. J Immunol. 2008;180:2608–15. Rauch A et al. FASEB J. 2011;25:1323–32. Rauner M et al. Endocrinology. 2013;154:3719–28. Malaise O et al. Rheumatology. 2015;54:1087–92. Gossye V et al. Arthritis Rheum. 2009;60:3241–50. Gossye V et al. Ann Rheum Dis. 2010;69:291–6. Conrado DJ et al. J Pharmacokinet Pharmacodyn. 2016;43:325–41. Miner JN et al. Proc Natl Acad Sci U S A. 2007;104:19244–9. Lόpez et al. Endocrinology. 2008;149:2080–9. Yang MG et al. J Med Chem. 2015;58:4278–90. Razavi H et al. Bioorg Med Chem Lett. 2014;24:1934–40. Riether D et al. J Med Chem. 2010;53:6681–98. Harcken C et al. J ed Chem. 2014;57:1583–98. Weinstein DS et al. J Med Chem. 2011;54:7318–33. Du J et al. J Immunol. 2011;187:942–50. Van Lierop MJ et al. PLoS One.2012;7:e48385. Disclosure of Interest M. Safy Grant/research support from: MS was supported by a research grant from Astra Zeneca. Astra Zeneca was not involved in this study., M. De Hair: None declared, J. Jacobs: None declared, F. Buttgereit: None declared, M. Kraan: None declared, J. van Laar: None declared

Inflammation is the major factor driving the progression of structural damage in rheumatoid arthritis (RA); therefore, it is critical to achieve rapid suppression of inflammation to maximize disease control. The severity of inflammation and progression of joint damage varies from patient to patient. Some patients have the propensity to change slowly over time and then progress in a more rapid and dynamic fashion. In those where inflammation is more severe, extensive damage can occur within only a few years of disease onset. The progress of joint destruction, as assessed radiographically, results in a decline in functional capacity and quality of life. Consequently, the challenge for clinicians is to identify and treat those patients who develop rapid, progressive disease. Several biological markers and clinical indicators have been identified to help predict or establish which of the patients have rapidly progressing disease or who are at most risk for rapid progression. Early diagnosis of patients with rapidly progressing RA enables immediate and intensive intervention (e.g. with biologic therapy) and a greater opportunity to change the course of disease.

Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease characterised by inflammation resulting in structural joint damage and functional disability. Tumour necrosis factor-alpha (TNFalpha) is a pivotal mediator and driver of inflammation in RA. Inflammation is closely related to the production of C-reactive protein (CRP), and a close correlation exists between serum CRP and TNFalpha levels. CRP levels are therefore a convenient, objective biomarker of disease activity. CRP correlates closely with changes in inflammation/disease activity, radiological damage and progression and functional disability. Identification of TNFalpha as a driver of RA progression has led to the introduction of TNFalpha-blocking agents and, subsequently, improvement of disease management. TNFalpha-blocking agents provide rapid, profound and sustained suppression of disease activity in correspondence with a marked reduction in CRP levels. A reduction in CRP level correlates closely with the positive clinical response to TNFalpha-blocking therapy. Thus, CRP levels can be used to predict, assess and monitor response to treatment with TNFalpha-blocking agents, and may be helpful in determining the optimal TNFalpha-blocker dosage. Given the close correlation between inflammation and disease progression and the relation between inflammation and CRP, the latter, if used effectively in clinical practice, may be means to identify patients likely to progress rapidly and who require intensive anti-TNFalpha therapy. The purpose of this review is to identify how CRP levels may be useful for monitoring the effect of therapy on halting disease progression and why monitoring CRP levels at baseline and after treatment should become a routine part of clinical practice.

Background: Tumour necrosis factor alpha (TNFalpha) blockade using infliximab, a chimeric anti-TNFalpha antibody, is an effective treatment for both psoriasis and psoriatic arthritis (PsA). Objective: To analyse the early effects of infliximab treatment on serial skin and synovial tissue biopsy samples. Methods: Twelve patients with both active psoriasis and PsA received a single infusion of either infliximab (3 mg/kg) (n = 6) or placebo (n = 6) intravenously. Synovial tissue and lesional skin biopsy specimens were obtained at baseline and 48 hours after treatment. Immunohistochemical analysis was performed to analyse the inflammatory infiltrate. In situ detection of apoptotic cells was performed by TUNEL assay and by immunohistochemical staining with anti-caspase-3 antibodies. Stained tissue sections were evaluated by digital image analysis. Results: A significant reduction in mean (SEM) T cell numbers was found in both lesional epidermis (baseline 37 (11) cells/mm, 48 hours 26 (11), p = 0.028) and synovial tissue (67 (56) cells/mm(2) v 32 (30), p = 0.043) after infliximab treatment, but not after placebo treatment (epidermis 18 (8) v 43 (20), NS; synovium 110 (62) v 46 (21), NS). Similarly, the number of macrophages in the synovial sublining was significantly reduced after anti-TNFalpha treatment (100 (73) v 10 (8), p = 0.043). The changes in cell numbers could not be explained by induction of apoptosis at the site of inflammation. Conclusions: The effects of anti-TNFalpha therapy in psoriasis and psoriatic arthritis may be explained by decreased cell infiltration in lesional skin and inflamed synovial tissue early after initiation of treatment

In psoriasis, leukocytes that infiltrate skin lesions have been shown to be involved in the pathogenesis of this disease. Previous investigations reporting the presence of CXCR3(+) T lymphocytes in psoriatic lesional skin have suggested a role of this receptor in the recruitment of T cells into the lesion. The purpose of this study was to quantify the mRNA levels of CXCR3 and to perform a systematic analysis of the cell populations that express CXCR3 in human lesional and non-lesional psoriatic biopsies. We showed by real-time reverse transcriptase-polymerase chain reaction that the mRNA levels of CXCR3 and its ligands, CXCL9-11, were significantly elevated in psoriatic lesions, as compared to non-lesional samples. Serial cryostat sections of psoriasis skin biopsies were evaluated by immunohistochemistry. The number of CXCR3(+) cells was low in non-lesional tissues. Quantitative image analysis demonstrated significant increases in the number of both epidermal and dermal CXCR3(+) cells in lesional compared with non-lesional biopsies. The majority of CXCR3(+) cells were located in the dermis of the lesional skin and 74% were demonstrated to be CD3(+) T lymphocytes. A small number of CXCR3(+) cells were CD68(+) myeloid cells. In addition, we found that nearly all BDCA-2(+) plasmacytoid dendritic cells in the psoriatic biopsies were CXCR3(+). These findings support and extend prior reports suggesting the potential role for CXCR3 in the pathophysiology of plaque psoriasis, by mediating the recruitment of plasmacytoid dendritic cells and T cells into the developing lesions.

Objective: To analyse the effects of leflunomide and methotrexate treatment on matrix metalloproteinase (MMP) activity levels in a2 macroglobulin/MMP (α2M/MMP) complexes in the systemic circulation of rheumatoid arthritis (RA) patients. Methods: A total of 102 RA patients from a prospective, double-blind, randomised clinical trial comparing leflunomide and methotrexate were selected; clinical data and blood samples were collected at baseline, at 4 months and at 1 year. Serum MMP activity levels in α2M were quantified using low molecular weight fluorogenic substrates, indicating the proportion of activated MMPs that were not inhibited by specific tissue inhibitors of MMP (TIMP). Results: Patients had active disease as shown by high disease activity score (DAS, mean of 6.9 and 7.0 for methotrexate and leflunomide patients respectively), which was reduced over the study period (4.2 and 5.2 respectively, p

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis.

Objective: To explore whether pretreatment features of synovial tissue in patients with gonarthritis could predict the clinical effect of radiation synovectomy with yttrium-90 ( 90 Y) and glucocorticoids or with intra-articular glucocorticoids alone. Methods: A synovial biopsy was carried out blindly 2 weeks before treatment in 66 patients with persistent gonarthritis, who were randomised to treatment either with 90 Y and triamcinolone or with placebo and triamcinolone. Immunohistochemistry was used to detect T cells, macrophages, B cells, plasma cells, fibroblast-like synoviocytes, adhesion molecules and pro-inflammatory cytokines. Stained sections were evaluated by digital image analysis. Individual patient improvement was expressed using a composite change index (CCI; range 0–12). Successful treatment was defined as CCI ⩾6 after 6 months. Results: Patients with rheumatoid arthritis, psoriatic arthritis, undifferentiated arthritis and other causes of gonarthritis were included. The overall response rate was 47%. Clinical efficacy in both therapeutic groups was similar and not dependent on diagnosis. No significant differences were noted between baseline microscopic features of synovial tissue inflammation in patients with rheumatoid arthritis and in those with non-rheumatoid arthritis (ie, all diagnoses other than rheumatoid arthritis). The number of macrophages in the synovial sublining was significantly higher in responders than in non-responders (p = 0.002), independent of treatment group and diagnosis. The clinical effect was positively correlated with pretreatment total macrophage numbers (r = 0.28; p = 0.03), sublining macrophage numbers (r = 0.34; p = 0.005) and vascular cell adhesion molecule 1 expression (r = 0.25; p = 0.04). Conclusion: The observations support the view that intra-articular treatment either with 90 Y and glucocorticoids or with glucocorticoids alone is especially successful in patients with marked synovial inflammation.

Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue.In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1).Paired synovial tissue sections were available in 35 patients (16 taking leflunomide, 19 taking methotrexate). Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial tissue. In the subset of patients fulfilling the 20% response criteria of the American College of Rheumatology, a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders.Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity.

Leflunomide is a novel immunomodulating drug that has recently been approved as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). The aim of this study was to determine the relationship between the clinical effects of leflunomide and neutrophil migration.The effects of leflunomide and methotrexate on neutrophil chemotaxis were studied in 15 RA patients who participated in a prospective, randomized, double-blind clinical trial. When possible, neutrophil numbers were counted in synovial fluid (SF) samples at baseline and after 14 days, 4 months, and 1 year of treatment. The chemotactic properties of peripheral blood neutrophils from RA patients treated with either leflunomide or methotrexate were studied by the Boyden chamber technique, using the activators formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neutrophils from 7 healthy control subjects were also investigated.Both therapy groups exhibited clinical improvement, including rapid reductions in SF neutrophil counts and reduced joint swelling and tenderness. On day 14, 3 of 7 patients who received leflunomide showed no detectable effusions. There was a significant effect on neutrophil chemotaxis (P0.001), which was similar for leflunomide and methotrexate. The direct effects on the neutrophils diminished over time. Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis.Leflunomide treatment is beneficial in RA patients. Different mechanisms are operative in various phases of treatment, leading to decreased recruitment of inflammatory cells in the joints.

Paired synovial tissue samples were obtained from both clinically uninvolved (CU) and clinically involved (CI) knee joints of eight rheumatoid arthritis (RA) patients. In addition, biopsies were taken from five control subjects. We observed the expression of the chemokines CXCL8, CXCL9, CXCL10, CCL2 and CCL4 in CI and CU joints of RA patients. In particular, CXCL8 protein levels were specifically increased in CI joints compared with CU joints, which was confirmed by immunohistochemistry and in situ hybridization.

Interferon-beta (IFNbeta) treatment is emerging as a potentially effective form of therapy in various immune-mediated conditions. This study evaluated the effects of IFNbeta therapy on the cell infiltrate, cytokine profile, and expression of metalloproteinase 1 (MMP-1) in synovial tissue from patients with rheumatoid arthritis (RA). To further assess the mechanism of action, in vitro experiments were conducted to determine the effects of IFNbeta on the production of MMP-1, MMP-3, tissue inhibitor of metalloproteinases 1 (TIMP-1), and prostaglandin E2 (PGE2) by human fibroblast-like synoviocytes (FLS).Eleven patients were treated for 12 weeks with purified natural fibroblast IFNbeta (Frone; Ares-Serono, Geneva, Switzerland) subcutaneously 3 times weekly with the following dosages: 6 million IU (n = 4), 12 million IU (n = 3), and 18 million IU (n = 4). Synovial biopsy specimens were obtained by needle arthroscopy at 3 time points: directly before and at 1 month and 3 months after initiation of treatment. Immunohistologic analysis was performed using monoclonal antibodies specific for the following phenotypic markers and mediators of joint inflammation and destruction: CD3, CD38, CD68, CD55, tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), IL-6, MMP-1, and TIMP-1. In addition, we measured the production of MMP-1, MMP-3, TIMP-1, and PGE2 by RA FLS and dermal fibroblasts in the presence and absence of IFNbeta.A statistically significant reduction in the mean immunohistologic scores for CD3+ T cells and the expression of MMP-1 and TIMP-1 at 1 month, CD38+ plasma cells and the expression of IL-6 at 3 months, and the expression of IL-1beta at both 1 and 3 months was observed in synovial tissue after IFNbeta treatment. The scores for CD68+ macrophages and TNFalpha expression also tended to decrease, but the differences did not reach statistical significance. The in vitro experiments revealed inhibition of MMP-1, MMP-3, and PGE2 production by RA FLS, whereas TIMP-1 production was only slightly decreased. These effects were more consistent in RA FLS than in dermal fibroblasts.The changes in synovial tissue after IFNbeta treatment and the in vitro data support the view that IFNbeta therapy has immunomodulating effects on rheumatoid synovium and might help to diminish both joint inflammation and destruction. Larger well-controlled studies are warranted to show the efficacy of IFNbeta treatment for RA.

Analysis of serial synovial biopsy specimens is increasingly used as an outcome measure for the evaluation of therapeutic interventions. However, observations in placebo treated groups are scarce. We describe the immunohistologic features of the synovium in placebo treated patients with RA and in those who received interleukin 10 (IL-10).Ten patients with active RA received dosages of either placebo (n = 7) or 5 microg/kg (n = 1) or 10 microg/kg (n = 2) of recombinant human IL-10 (rhIL-10; SCH 52000, Schering-Plough, Kenilworth, NJ, USA) daily for 28 consecutive days. Synovial biopsy specimens from the knee joint were obtained by needle arthroscopy before and 4 weeks after initiation of treatment. Immunohistochemistry was performed using monoclonal antibodies specific for the following surface markers and cytokines: CD3, CD4, CD8, CD38, CD68, CD55, IL-1beta, IL-6, and tumor necrosis factor-alpha.No patient exhibited clinical improvement after treatment with placebo or any rhIL-10 dosage. Microscopic analysis of synovial tissue revealed no significant change in the scores for infiltration by inflammatory cells or in the scores for the expression of cytokines after treatment.Studies of serial synovial biopsies from patients treated with placebo or IL-10 revealed no changes in immunohistologic scores. This suggests that the biopsy procedure itself has no effect on the features of the synovium.

The p53 tumor suppressor gene is overexpressed in synovial tissue (ST) from patients with longstanding rheumatoid arthritis (RA), and may contain somatic mutations. The aim of this study was to determine p53 expression in ST from RA patients in different stages of the disease, compared with disease controls.ST biopsy specimens were obtained from the knee joints of 31 RA patients in varying disease phases, 8 patients with reactive arthritis (ReA), 10 patients with inflammatory osteoarthritis (OA), and 6 control patients (4 with meniscus pathology, 2 with vascular insufficiency). ST was also obtained from the clinically uninvolved knee joints of 9 RA patients. Expression of p53 was determined by immunohistology with DO1 monoclonal antibody (mAb) in all patients and by Western blot analysis with DO7 mAb in a subgroup of the patients.The p53 protein was detected by immunohistology in 10 of the 13 patients with early RA (duration6 months) and in 12 of the 14 patients with longstanding RA (duration5 years). The p53 protein was also demonstrated in clinically uninvolved knee joints. Western blots revealed immunoreactive p53 in ST extracts from all RA patients. Expression of p53 was about twice as high in ST from patients with longstanding RA as in early RA samples, but the difference did not reach statistical significance. Small amounts of p53 were also detected in ST from ReA and OA patients, although the expression in RA synovium was significantly higher. Immunohistologic analysis of normal ST gave negative results for p53.This study shows that p53 overexpression is specific for RA, compared with OA and ReA. This phenomenon is probably secondary to increased production of wild-type p53 protein in response to DNA damage and secondary to somatic mutations caused by the genotoxic local environment in inflamed ST. Of interest, p53 overexpression can also be found in the earliest stages of RA and in clinically uninvolved joints.

It has been hypothesized that asymptomatic synovitis may precede clinical manifestations of arthritis in the earliest phase of rheumatoid arthritis (RA). To obtain more insight into this disease phase, we investigated the immunohistologic features of synovial tissue (ST) from the knee joints of rhesus monkeys with induced arthritis and from RA patients with both clinically involved and clinically uninvolved knee joints.Serial ST biopsy specimens from the knee joints of 4 rhesus monkeys that had been immunized with type II collagen and ST from 10 RA patients were investigated. Eight patients without inflammatory joint disease served as controls.In ST from immunized monkeys, an influx of macrophages was observed well before the occurrence of arthritis. Signs of inflammation were also demonstrated in ST from clinically uninvolved knee joints of all RA patients evaluated. The ST was characterized in particular by infiltration with macrophages and by the expression of macrophage-derived cytokines.The findings support the view that asymptomatic synovitis precedes clinically manifest arthritis in both early and established RA. This implies that the debut of RA already represents a chronic phase of the disease.

Backgroundand objectives Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept, a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T cell activation, has been shown to result in improvement in psoriasis and has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key pro-inflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown. Material and methods Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open study. Skin biopsies were taken before and after 1 and 6 weeks while synovial biopsies were obtained before and after 4 and 12 weeks of treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n=10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated by digital image analysis. Double staining with IL-20 and CD68 (macrophages) and CD55 (fibroblast-like synoviocytes, FLS) was performed to determine the phenotype of IL-20 positive cells in PsA synovium. IL-20 expression in skin sections (n=6) was analysed semi-quantitatively. Results IL-20 was abundantly expressed in both RA and PsA synovial tissues. In inflamed PsA synovium CD68 + macrophages and CD55 + FLS co-expressed IL-20 and its expression correlated with the numbers of FLS. IL-20 expression in lesional skin of PsA patients correlated positively with the Psoriasis Area and Severity Index (PASI). While IL-20 expression in PsA synovium was not affected by alefacept treatment, IL-20 expression in lesional skin decreased significantly (p=0.04) after 6 weeks of treatment. Conclusions Conceivably, the relatively limited effectiveness of alefacept in PsA patients might be explained in part by persistent FLS-derived IL-20 expression.