sE‐selectin for stratifying outcome in rheumatoid arthritis

Objectives

To determine the usefulness of sE‐selectin as a marker for early diagnosis and stratification of rheumatoid arthritis.

Methods

We investigated several markers of disease activity, including circulating adhesion molecules and other standard laboratory tests, in a 2–3 year followup analysis of patients with rheumatoid arthritis.

Results

The mean ± SD levels of sE‐selectin (91.68 ± 31.8 ng/ml versus 49.83 ± 14.76 ng/ml) and rheumatoid factor (375.7 ± 394.4 U versus 44.66 ± 37.63 U) were strongly elevated in severe (n = 15) versus mild (n = 7) courses of disease. Statistical calculation of mean and standard deviation revealed that sE‐selectin represents a highly significant marker for the presence of persistent and aggressive disease over time, regardless of therapeutic intervention and observation time points (P = 0.0004). Notably, regression analysis identified constant values for all parameters analyzed and, therefore, a stable course of the disease could be predicted from the beginning.

Conclusion

sE‐selectin appears to be a powerful marker to predict the severity of rheumatoid arthritis.

     

Interleukin‐20 antibody is a potential therapeutic agent for experimental arthritis

Objective

Interleukin‐20 (IL‐20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti–IL‐20 antibody treatment would modulate the severity of the disease in a collagen‐induced arthritis (CIA) rat model.

Methods

We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti–IL‐20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme‐linked immunosorbent assay. To analyze gene regulation by IL‐20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL‐17, and TNFα. We also used real‐time quantitative polymerase chain reaction analysis and flow cytometry to determine IL‐20–regulated RANKL in mouse osteoblastic MC3T3‐E1 cells and Th17 cells.

Results

In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL‐20, IL‐1β, IL‐6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL‐20 induced TNFα expression in SFs from rats with CIA. IL‐20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells.

Conclusion

Selectively blocking IL‐20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL‐20 is a novel target and that 7E may be a potential therapeutic agent for RA.

     

Amelioration of joint disease in a rat model of collagen‐induced arthritis by M40403, a superoxide dismutase mimetic

Objective

To investigate the effects of M40403, a synthetic mimetic of superoxide dismutase (SOD), on collagen‐induced arthritis (CIA) in rats.

Methods

CIA was elicited in Lewis rats by intradermal injection of 100 μl of an emulsion of bovine type II collagen (CII) in Freund's incomplete adjuvant at the base of the tail. A second injection was given on day 21.

Results

Immunization induced an erosive arthritis of the hind paws. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws by days 24–26 after the first injection, with a 100% incidence by days 27. Severity progressed over a 35‐day period. Radiography revealed soft tissue swelling and focal resorption of bone, together with osteophyte formation in the tibiotarsal joint. Histopathologic features included erosion of the articular cartilage at the joint margins and subchondral bone resorption associated with bone‐derived multinucleated cell–containing granulomatous lesions. Treatment with M40403 (2–10 mg/kg/day) starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26–35 and improved the histologic findings in the joint and paw. Immunohistochemical analysis for nitrotyrosine (a marker of peroxynitrite formation) and poly(ADP‐ribose) polymerase (PARP; a nuclear enzyme activated by DNA single‐strand damage) revealed positive staining in the inflamed joints of CII‐treated rats, suggestive of the formation of peroxynitrite and DNA damage, both of which were markedly reduced by M40403 treatment. Radiographic evidence of protection from bone resorption, osteophyte formation, and soft tissue swelling was apparent in the tibiotarsal joints of M40403‐treated rats. Arthritic rats treated with M40403 gained weight at the same rate and to the same extent as normal, nonarthritic rats.

Conclusion

This study shows that a low molecular weight mimetic of SOD, M40403, attenuates the degree of chronic inflammation, tissue damage, and bone damage associated with CIA in the rat, and supports the possible use of SOD mimetics as therapeutic agents for the management of chronic diseases such as rheumatoid arthritis.

     

Thrombospondin 1 as an effective gene therapeutic strategy in collagen‐induced arthritis

Objective

Because thrombospondin 1 (TSP‐1) inhibits angiogenesis and activates latent transforming growth factor β (TGFβ), a potent immunosuppressive and antiinflammatory cytokine, we investigated the prophylactic and therapeutic effects of TSP‐1 gene transfer in the collagen‐induced arthritis (CIA) model in rats.

Methods

Adenoviral vectors encoding mouse TSP‐1 (AdTSP‐1) or β‐galactosidase (AdLacZ) as the control were administered by intraarticular injection into CIA rats. The treated ankles were assessed clinically, radiographically, and histologically. Furthermore, expression levels of TSP‐1, TGFβ, vascular endothelial growth factor (VEGF), and interleukin‐1β (IL‐1β) were examined in the synovial tissue.

Results

Intraarticular administration of AdTSP‐1 reduced the severity of CIA as revealed by examination of the clinical, radiographic, and histologic aspects. Rats treated with AdTSP‐1, as compared with AdLacZ‐treated controls, were found to have fewer blood vessels (mean ± SEM 21.0 ± 0.6 versus 45.3 ± 2.3/mm²; P < 0.001) and lower production of VEGF (17 ± 4 versus 45 ± 10 pg/mg of total protein; P < 0.05) and IL‐1β (374 ± 41 versus 526 ± 39 pg/mg of total protein; P < 0.05), as well as higher levels of TSP‐1 and TGFβ in the synovial tissue.

Conclusion

Direct intraarticular administration of adenoviral vectors encoding TSP‐1 significantly ameliorated the clinical course of CIA, accompanied by reduction of synovial hypertrophy and fewer blood vessels. These results suggest that TSP‐1 gene therapy may have therapeutic potential for the management of rheumatoid arthritis.

     

Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats

Objective

To characterize the clinical and histopathologic changes in a rat model of broad‐spectrum matrix metalloproteinase (MMP)–induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.

Methods

Male Lewis rats weighing 150–180 gm were administered 10–30 mg of the broad‐spectrum MMP inhibitor marimastat over a 2‐week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.

Results

Marimastat‐treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high‐stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat‐treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.

Conclusion

This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.

     

Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant‐induced arthritis

Objective

To examine the effect of spinal cord adenosine (Ado) receptor stimulation on rat adjuvant‐induced arthritis (AIA).

Methods

Long‐term intrathecal (IT) catheters were implanted into rats to provide spinal access for drug delivery. Animals were immunized with complete Freund's adjuvant at the tail base. Eight days later and every other day thereafter until day 20, rats were treated IT with the selective Ado A1 receptor agonist cyclohexyladenosine (CHA) or vehicle. In some experiments, animals received an additional daily intraperitoneal injection of the nonselective Ado antagonist theophylline. Paw swelling was measured by water displacement plethysmometry. The effect of IT CHA on the activation of activator protein 1 (AP‐1) was determined by electromobility shift assay. Spinal cord c‐Fos expression was determined by immunohistochemistry.

Results

Spinal CHA significantly inhibited inflammation in AIA, with a mean ± SEM 20.9 ± 16.9% increase in paw swelling in the IT CHA group compared with 81.3 ± 10.6% in the saline group. The antiinflammatory effect of CHA was mediated through Ado receptors since the effect was reversed by coadministration of systemic theophylline. In addition, radiographs showed significantly less bone and cartilage destruction in the CHA‐treated animals. Synovial expression of AP‐1, which is a key regulator of metalloproteinase expression, was lower in IT CHA–treated animals. C‐Fos expression was localized to spinal laminae I–VI, with a modest decrease observed in the superficial laminae in IT CHA–treated rats.

Conclusion

These data demonstrate that the spinal cord can regulate peripheral inflammation. Therapeutic strategies that target the central nervous system might be useful in arthritis.

     

Enhancement of collagen‐induced arthritis in mice genetically deficient in extracellular superoxide dismutase

Objective

To examine the influence of superoxide on the severity of collagen‐induced arthritis (CIA) in mice.

Methods

CIA was induced in DBA/1J mice lacking the extracellular superoxide dismutase (EC‐SOD) gene (knockout [KO]) and in normal DBA/1J mice (wild‐type [WT]).

Results

The clinical disease activity score was significantly higher in EC‐SOD–KO mice than in WT mice between days 36 and 53, and the histologic scores for joint damage on day 53 increased 2‐fold or more in the EC‐SOD–KO mice. There were no significant differences between the 2 groups of mice in proliferation indices of spleen or lymph node cells in vitro after stimulation with type II collagen. Although both IgG1 and IgG2a anticollagen antibody levels increased in both groups of mice between days 21 and 53, there were no significant differences between the 2 groups. Lipopolysaccharide‐stimulated spleen cells from EC‐SOD–KO mice produced greater levels of tumor necrosis factor α (TNFα) over 48 hours in culture compared with cells from WT mice. Increased steady‐state levels of messenger RNA (mRNA) for interferon‐γ (IFNγ), TNFα, and interleukin‐1β (IL‐1β), and lower levels of IL‐1 receptor antagonist (IL‐1Ra) mRNA were present in the joints of the EC‐SOD–KO mice compared with the WT mice.

Conclusion

The absence of EC‐SOD leads to more severe CIA, which may be accompanied by enhanced production of the proinflammatory cytokines IFNγ, TNFα, and IL‐1β, and decreased production of the antiinflammatory cytokine IL‐1Ra in the joints.

     

Anaerobic exercise capacity in patients with juvenile‐onset idiopathic inflammatory myopathies

Objective

To 1) report the feasibility of an “all‐out” 30‐second cycling exercise test (Wingate Anaerobic Exercise Test [WAnT]) in juvenile‐onset idiopathic inflammatory myopathy (JIIM) patients, 2) describe the anaerobic exercise capacity in juvenile dermatomyositis patients, and 3) determine if the anaerobic exercise capacity could be related to disease duration or disease phase.

Methods

Twenty patients (age 14.13 ± 5.4 years) with JIIM participated in this study. All patients were able to perform the WAnT without adverse events.

Results

Comparison with healthy controls revealed a ?29.3 ± 26.58% (P = 0.001) and ?27.6 ± 25.7% (P = 0.002) impairment in mean power and peak power on the WAnT, respectively. The WAnT correlated with disease phase and with knee extensor muscle strength.

Conclusion

The WAnT might be a valuable adjunct next to other assessment tools in the followup of JIIM patients.

     

Rheumatoid arthritis synovial fluid fibroblasts express TRAIL‐R2 (DR5) that is functionally active

Objective

To examine fibroblasts grown from the synovial fluid of rheumatoid arthritis (RA) patients for TRAIL‐R2 expression, and for susceptibility to apoptosis induced by an agonistic anti–TRAIL‐R2 monoclonal antibody (mAb).

Methods

The expression of TRAIL‐R2 (DR5) was determined by flow cytometry on fibroblasts grown from the synovial fluid of patients with RA, osteoarthritis (OA), seronegative arthritis, and unclassified monarthritis or oligoarthritis, and on fibroblasts from the synovial membrane of RA and OA patients. Susceptibility to apoptosis mediated by an agonistic anti–TRAIL‐R2 mAb was determined by alamar blue bioassay, fluorescence microscopy (annexin V/propidium iodide staining), and caspase activation.

Results

Fibroblasts grew from 35 of 50 RA synovial fluid samples, of which 26 were DR5+ (mean [±SD] fluorescence intensity [MFI] 18.74 ± 2.5). Fibroblasts also grew from 15 of 30 seronegative arthritis synovial fluid samples, 28 of 40 OA synovial fluid samples, and 8 of 20 unclassified monarthritis or oligoarthritis synovial fluid samples; all of these were DR5− (MFI 0.32 ± 0.02). All 10 of the fibroblast lines from joint replacement surgery or synovectomy specimens of RA patients were DR5+ (MFI 20.3 ± 3.2). All fibroblast lines from the synovium of 10 OA patients were DR5−, as were fibroblasts from the skin of 5 healthy subjects. DR5+ fibroblast cultures underwent apoptosis when treated in vitro with an agonistic anti‐DR5 antibody.

Conclusion

Fibroblasts grown from the synovial fluid and synovial membrane of RA patients express TRAIL‐R2 that is functionally active. An agonistic anti–TRAIL‐R2 antibody that does not induce hepatocyte toxicity may be an alternative strategy for treatment of RA.

     

Synovial fluid levels of anti–cyclic citrullinated peptide antibodies and IgA rheumatoid factor in rheumatoid arthritis,psoriatic arthritis,and osteoarthritis

Objective

To assess the levels of anti–cyclic citrullinated peptide (anti‐CCP) and IgA rheumatoid factor (IgA‐RF) in synovial fluids of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA).

Methods

Knee effusions of 29 patients with RA (23 women, 6 men; mean ± SD age 60 ± 15 years), 20 with PsA (6 women, 14 men; mean age 51 ± 12 years), and 19 with OA (9 women, 10 men; mean age 73 ± 11.8 years) were aspirated, tested for white blood cell (WBC) counts, centrifuged, and stored at ?20°. Sera of 22, 11, and 12 of these patients with RA, PsA, and OA, respectively, were similarly stored. IgG anti‐CCP and IgA‐RF were detected by enzyme‐linked immunosorbent assay. Erythrocyte sedimentation rate and C‐reactive protein levels were used as measures of disease activity.

Results

Mean levels of synovial fluid anti‐CCP and IgA‐RF were significantly increased in RA joint effusions compared with PsA and OA (anti‐CCP: 150 ± 134, 34 ± 29, and 24 ± 26 units, respectively [P < 0.003]; IgA‐RF: 76 ± 77, 15.7 ± 10, and 18 ± 20 units, respectively). No significant difference was noted between OA and PsA. A significant correlation was found between synovial fluid anti‐CCP and serum anti‐CCP and IgA‐RF. In patients with RA, a significant correlation was found between synovial fluid WBC counts and IgA‐RF (P = 0.03) and serum IgA‐RF (P = 0.008), but not between synovial fluid and serum anti‐CCP levels. In RA patients, C‐reactive protein correlated with serum IgA‐RF.

Conclusion

Anti‐CCP and IgA‐RF were significantly increased in synovial fluid of RA in comparison with PsA and OA patients.

     

Expression of hypoxia‐inducible factor 1α by macrophages in the rheumatoid synovium: Implications for targeting of therapeutic genes to the inflamed joint

Objective

To determine if the rheumatoid synovium is a suitable target for hypoxia‐regulated gene therapy.

Methods

Sequential sections of wax‐embedded synovial membrane samples were obtained from 10 patients with rheumatoid arthritis (RA), 10 with primary osteoarthritis (OA), and from 6 healthy controls. Membrane sections from each patient were immunostained for hypoxia‐inducible factor 1α (HIF‐1α) and CD68 (a pan–macrophage marker).

Results

HIF‐1α was expressed abundantly by macrophages in most rheumatoid synovia, predominantly close to the intimal layer but also in the subintimal zone. There was markedly lower expression of HIF‐1α in OA synovia, and it was absent from all of the healthy synovia.

Conclusion

These observations indicate that macrophages transduced with a therapeutic gene under the control of a hypoxia‐inducible promoter could be administered to RA patients systemically. Migration of these cells to synovial tissue would result in the transgene being switched on in diseased joints but not in healthy tissues.

     

Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long‐term treatment with anti–tumor necrosis factor α antibody

Objective

Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of tumor necrosis factor α (TNFα). Anti‐TNFα antibody improved endothelial function in RA patients after a 12‐week treatment. The aim of the present study was to assess whether improvement of endothelial function is still effective in long‐term infliximab‐treated RA patients.

Methods

Seven RA patients (5 women; age range 25–73 years) were studied. They had been treated with infliximab for at least 1 year and were currently being treated with this drug every 8 weeks. Endothelial‐dependent and independent vasodilatation were measured by brachial ultrasonography.

Results

Following infliximab infusion, a rapid increase in the percentage of endothelial‐dependent vasodilatation was found in all patients (mean ± SD 9.4 ± 5.5% 2 days postinfusion compared with 2.8 ± 2.5% 2 days before infusion). However, values returned to baseline by 4 weeks after infusion. There were no differences in the percentage of endothelial‐independent vasodilatation prior to and after infusion. A decrease in the individual disease activity score for each patient was observed at day 7 postinfusion (P = 0.02).

Conclusion

Our study confirms an active but transient effect of infliximab on endothelial function in RA patients treated periodically with this drug. It may support long‐term use of drugs that block TNFα function to reduce the high incidence of cardiovascular complications in RA.

     

Noncardiac vascular disease in rheumatoid arthritis: Increase in venous thromboembolic events?

Objective

To investigate the incidence of noncardiac vascular disease in a community‐based incidence cohort of patients with rheumatoid arthritis (RA) and compare it to that in the general population and to investigate trends in the incidence of noncardiac vascular disease in patients with RA.

Methods

A population‐based inception cohort of patients with incident RA between January 1, 1980 and December 31, 2007 in Olmsted County, Minnesota and a cohort of non‐RA subjects from the same population base was assembled and followed up until December 31, 2008. Venous thromboembolic, cerebrovascular, and peripheral arterial events were ascertained by medical record review.

Results

The study population included 813 patients with RA with a mean ± SD age of 55.9 ± 15.7 years (68% women) and an average length of followup of 9.6 ± 6.9 years. Compared to non‐RA subjects of similar age and sex, patients diagnosed as having RA between 1995 and 2007 had a higher incidence (%) of venous thromboembolism (cumulative incidence ± SE 6.7 ± 1.7 versus 2.8 ± 1.1, respectively; P = 0.005) but similar rates of cerebrovascular and peripheral arterial events. Among patients with RA, the incidence of venous thromboembolic, cerebrovascular, and peripheral arterial events was similar in the 1995–2007 time period compared to the 1980–1994 time period.

Conclusion

Our findings indicate that the incidence of venous thromboembolism is increased in patients with RA compared to non‐RA subjects. The incidence of cerebrovascular events and peripheral vascular disease events is similar in patients with RA compared to non‐RA subjects. Among patients with RA, the incidence of noncardiac vascular disease has remained stable in recent decades.

     

Spirituality,well‐being,and quality of life in people with rheumatoid arthritis

Objective

To evaluate spirituality, well‐being, and quality of life (QOL) among people with rheumatoid arthritis (RA).

Methods

Questionnaires assessing positive and negative affect, depression, QOL and spirituality were completed. Disease activity was assessed by rheumatologic examination.

Results

Women (n = 62) had a mean (± SD) age of 53.0 (± 13.0) years with 12 (± 13) swollen and tender joints (STJ). Men (n = 15) were 61.9 (± 13.0) years with 7 (± 11) STJ. Disease activity was associated (P < 0.05) positively with depression (r = 0.23), pain (r = 0.26), poorer self‐ratings of health (r = 0.29) and physical role limitations (r = 0.26). Spirituality was associated directly with positive affect (r = 0.26) and higher health perceptions (r = 0.29). In multiple regression, spirituality was an independent predictor of happiness and positive health perceptions, even after controlling disease activity and physical functioning, for age and mood.

Conclusion

Spirituality may facilitate emotional adjustment and resilience in people with RA by experiencing more positive feelings and attending to positive elements of their lives.

     

A20 suppresses inflammatory responses and bone destruction in human fibroblast‐like synoviocytes and in mice with collagen‐induced arthritis

Objective

Nuclear factor‐κB (NF‐κB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis (RA). The purpose of this study was to determine whether A20, a universal inhibitor of NF‐κB, might have antiarthritic effects.

Methods

An adenovirus containing A20 complementary DNA (AdA20) was used to deliver A20 to human rheumatoid fibroblast‐like synoviocytes (FLS) in vitro as well as to mice with collagen‐induced arthritis (CIA) in vivo via intraarticular injection into the ankle joints bilaterally.

Results

In vitro experiments demonstrated that AdA20 suppressed NF‐κB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor α in FLS. Mice with CIA that were treated with AdA20 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels, than did control virus–injected mice. The protective effects of AdA20 were mediated by the inhibition of the NF‐κB signaling pathway. The severity of arthritis was also significantly decreased in the untreated front paws, indicating a beneficial systemic effect of local suppression of NF‐κB. Surprisingly, mice treated with AdA20 after the onset of CIA had significantly decreased arthritis severity from the onset of clinical signs to the end of the study.

Conclusion

These results suggest that using A20 to block the NF‐κB pathway in rheumatoid joints reduces both the inflammatory response and the tissue destruction. The development of an immunoregulatory strategy based on A20 may therefore have therapeutic potential in the treatment of RA.

     

The good initial response to therapy with a combination of traditional disease‐modifying antirheumatic drugs is sustained over time: The eleven‐year results of the Finnish rheumatoid arthritis combination therapy trial

Objective

To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease‐modifying antirheumatic drugs (DMARDs) or with a single DMARD.

Methods

A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission.

Results

At 11 years, 138 patients were assessed (68 in the combination‐DMARD group and 70 in the single‐DMARD group). The mean ± SD HAQ scores were 0.34 ± 0.54 in the combination‐DMARD group and 0.38 ± 0.58 in the single‐DMARD group (P = 0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P = 0.016) of the combination‐DMARD group and the single‐DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P = 0.017), respectively.

Conclusion

Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single‐DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

     

Inhibition of interleukin‐1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

Objective

To assess the capacities of the cytokine inhibitors interleukin‐1 receptor antagonist (IL‐1Ra; anakinra) and PEGylated soluble tumor necrosis factor receptor I (PEG sTNFRI; pegsunercept) to suppress neovascularization.

Methods

A corneal angiogenesis assay was performed by implanting nylon discs impregnated with an angiogenic stimulator (basic fibroblast growth factor or vascular endothelial growth factor) into one cornea of female Sprague‐Dawley rats. Animals were treated with IL‐1Ra or PEG sTNFRI for 7 days, after which new vessels were quantified. In a parallel study, male Lewis rats with mycobacteria‐induced adjuvant‐induced arthritis were treated with IL‐1Ra or PEG sTNFRI for 7 days beginning at disease onset, after which scores for inflammation and bone erosion as well as capillary counts were acquired from sections of arthritic hind paws.

Results

Treatment with IL‐1Ra yielded a dose‐dependent reduction in growth factor–induced corneal angiogenesis, while PEG sTNFRI did not. IL‐1Ra, but not PEG sTNFRI, significantly reduced the number of capillaries in arthritic paws, even though both anticytokines reduced inflammation and bone erosion to a similar degree.

Conclusion

These data support a major role for IL‐1, but not TNFα, in angiogenesis and suggest that an additional antiarthritic mechanism afforded by IL‐1 inhibitors, but not anti‐TNF agents, is the suppression of the angiogenic component of pannus.