Biomedical subjects

L B van de Putte

Publications and source records attributed to L B van de Putte.

At least 19 recordsLinked to original sources

PubMed2001

[Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept].

The current pharmacotherapy of rheumatoid arthritis (RA) consists of non-steroidal anti inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine, leflunomide and methotrexate. DMARDs can be given as monotherapy or in combination. However, not all patients show an adequate response due to toxicity or lack of efficacy. From animal studies and clinical studies in patients with RA, we know that tumour necrosis factor (TNF) is directly involved in the pathogenesis of RA. Two forms of TNF inhibition therapy have been extensively investigated in RA: anti-TNF monoclonal antibodies (infliximab) and TNF receptor-Fc fusion protein (etanercept). Both types of TNF inhibition induce a rapid improvement in multiple clinical measures of disease activity and patient functional status. Furthermore, a beneficial effect was demonstrated on radiographic progression of joint damage. Etanercept and the combination infliximab-methotrexate are generally well tolerated.

Antibodies, Monoclonal↗

PubMed2001

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: results of an open study to assess feasibility, safety, and efficacy.

OBJECTIVE: To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS: Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS: All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION: High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

Adolescent↗

PubMed2001

Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Adult↗

PubMed2001

The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients.

OBJECTIVE: To study the possible relationship between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX treatment because of elevated liver enzyme levels, and the total occurrence of elevated liver enzyme levels during the study. Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677T mutation and toxicity outcomes of MTX treatment. RESULTS: Forty-eight percent of the patients showed the homozygous (T/T) or heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events (relative risk 2.01; 95% confidence interval 1.09, 3.70), mainly due to an increased risk of elevated liver enzyme levels (relative risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy parameters were not significantly different between the patients with and those without the mutation. CONCLUSION: The C677T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA. We postulate that the incidence of clinically important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation.

Alanine Transaminase↗

PubMed2001

Role of activatory Fc gamma RI and Fc gamma RIII and inhibitory Fc gamma RII in inflammation and cartilage destruction during experimental antigen-induced arthritis.

IgG-containing immune complexes, which are found in most RA joints, communicate with hematopoietic cells using three classes of Fc receptors(Fc gamma RI, -II, -III). In a previous study we found that if a chronic T-cell-mediated antigen-induced arthritis (AIA) was elicited in knee joints of FcR gamma-chain-deficient mice that lack functional Fc gamma RI and Fc gamma RIII, joint inflammation was comparable but severe cartilage destruction was absent. We now examined the individual role of the stimulatory Fc gamma RI and Fc gamma RIII and inhibitory Fc gamma RII in inflammation and functional cartilage damage in knee joints with AIA using Fc gamma RI-, Fc gamma RII-, and Fc gamma RIII-deficient mice. Three weeks after immunization with the antigen-methylated bovine serum albumin (BSA), cellular (T-cell responses as measured by lymphocyte proliferation) immunity raised against mBSA was comparable in all groups examined. Humoral (total IgG, IgG1, IgG2a, and IgG2b levels) immunity against mBSA was comparable in Fc gamma RI-/- and Fc gamma RIII-/- but higher in Fc gamma RII-/- if compared to controls. Joint swelling as measured by (99m)Tc uptake at days 1, 3, and 7 was similar in Fc gamma RI-/- and Fc gamma RIII-/- mice and significantly higher in Fc gamma RII-/-. Chronic inflammation and cartilage damage (depletion of proteoglycans, metalloproteinase (MMP)-induced neoepitopes, and matrix erosion) was studied histologically in total knee joint sections stained with hematoxylin or safranin-O. Histologically, at day 7 after AIA induction, exudate and infiltrate in the knee joint was similar in Fc gamma RI-/- and Fc gamma RIII-/- and significantly higher (230% and 340%) in Fc gamma RII-/- mice if compared to controls. Aggrecan breakdown in cartilage caused by MMPs and, which is related to severe irreversible cartilage erosion, was further studied by immunolocalization of MMP-mediated neoepitopes (VDIPEN) and image analysis. MMP-induced neoepitopes determined in various cartilage layers (tibia and femur) were primarily inhibited in Fc gamma RI-/- (79 to 87% and 87 to 88%, respectively) and comparable in Fc gamma RIII-/-. VDIPEN neoepitopes were much higher (82 to 122% and 200 to 250%, respectively) in Fc gamma RII-/- mice. Initial depletion of proteoglycans was similar (60 to 100%) in all groups. In the chronic phase, cartilage matrix erosion in the lateral and medial tibia was significantly elevated in Fc gamma RII-/- (222% and 186%, respectively) but not in Fc gamma RI-/- or Fc gamma RIII-/- mice. These results suggest that during T-cell-mediated AIA, Fc gamma RI and Fc gamma RIII act in concert in acute and chronic inflammation whereas Fc gamma RI is the dominant FcR involved in severe cartilage destruction. Fc gamma RII is a crucial inhibiting factor in acute and chronic inflammation and cartilage erosion.

Amino Acid Sequence↗

PubMed2001

Leflunomide and methotrexate.

Methotrexate and leflunomide are both effective drugs in the treatment of patients with rheumatoid arthritis. Methotrexate has been available for many years, whereas leflunomide is a relatively new drug. Several large trials describing its efficacy and safety in comparison with both sulfasalazine and methotrexate and with placebo have been published recently. It appears that leflunomide is approximately equally effective as sulfasalazine and methotrexate. New data are also available on the mechanism of action of leflunomide especially. This drug probably acts as an immunomodulatory agent by interfering with the de novo synthesis of pyrimidines.

Arthritis, Rheumatoid↗

PubMed2001

Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine.

OBJECTIVE: Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period. METHODS: 358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts. RESULTS: The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (-1.46 v -1.11, p=0.03) and patient (-1.61 v -1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Deltamean HAQ -0.65 v -0.36, p=0.0149; DeltaHAQ disability index -0.89 v -0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.

Adult↗

PubMed2001

Prevention of symptomatic thrombosis with short term (low molecular weight) heparin in patients with rheumatoid arthritis after hip or knee replacement.

The need for prevention of venous thromboembolism (VTE) after total hip or knee replacement is obvious. However, the optimal regimen to achieve this remains to be defined. In patients with rheumatoid arthritis (RA) long term coumarins may not be necessary owing to the use of non-steroidal anti-inflammatory drugs (NSAIDs). 103 patients in whom 151 surgical procedures were performed (55 hip and 96 knee prostheses) were treated only with short term subcutaneous heparin. NSAIDs were used daily in 85% of the patients, and they were continued after hospital discharge. Only one patient developed symptomatic deep venous thrombosis during one year follow up. Bleeding complications were seen in 20/151 (13%) of the surgical procedures, all clinically judged as minor, and recovery was not delayed except in one case. Short term (low molecular weight) heparin appears to be an adequate, simple, and safe method for prevention of symptomatic VTE in patients with RA after knee or hip replacement, though further studies are necessary to confirm these preliminary findings.

Aged↗

PubMed2001

Reversibility of histological and immunohistological abnormalities in sublabial salivary gland biopsy specimens following treatment with corticosteroids in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterised by specific lesions in exocrine glands, so sublabial minor salivary gland biopsy (SLGB) plays an important part in its diagnosis. The extent and composition of the lymphocytic infiltrate in SLGB specimens can be considered as target organ specific parameters. They are quantified after histological and immunohistological examination by a focus score (describing the extent of the infiltrate) and IgA% score (describing the composition of the infiltrate), respectively. However, little is known about the factors that contribute to the extent and composition of the infiltrate and whether these features are reversible as repeated SLGBs are rarely performed. A patient with SS is described who underwent SLGBs before and after treatment with high dose corticosteroids. After treatment there was not only clinical improvement, but also improvement in the histological and immunohistological parameters. Although these findings need to be confirmed in further studies, this suggests that histopathological changes may be reversible in SS. Furthermore, it shows that the potential effects of corticosteroid use should be taken into account when interpreting SLGB specimens. When clinical changes do parallel histological changes, repeated SLGBs might offer a marker for disease activity in patients with SS.

Adult↗

PubMed2001

Isolated digital vasculitis in a patient with rheumatoid arthritis: good response to tumour necrosis factor alpha blocking treatment.

Tumour necrosis factor alpha (TNFalpha) blocking agents are among the most promising new treatments for rheumatoid arthritis (RA). However, no data exist about the effect of these agents on extra-articular manifestations of RA. A patient is described with small vessel vasculitis that repeatedly responded well to treatment with the soluble p55 TNFalpha receptor fusion protein Ro 45-2081 (lenercept).

Arthritis, Rheumatoid↗

PubMed2001

Effects of treatment with a fully human anti-tumour necrosis factor alpha monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNFalpha in patients with rheumatoid arthritis.

OBJECTIVES: To study the short term effects of a single dose of D2E7, a fully human anti-tumour necrosis factor (TNFalpha) monoclonal antibody (mAb), on the local and systemic homeostasis of interleukin 1beta (IL1beta) and TNFalpha in patients with rheumatoid arthritis (RA). METHODS: All patients with RA enrolled in a phase I, single dose, placebo controlled study with D2E7 in our centre were studied. Systemic cytokine levels, acute phase reactants, and leucocyte counts were studied at days 0, 1, and 14 after the first administration of anti-TNF mAb (n=39) or placebo (n=11). The cellularity and the expression of IL1 and TNFalpha in synovial tissue were studied in knee biopsy specimens obtained at baseline and at day 14 in 25 consenting patients. RESULTS: A single dose of anti-TNF mAb induced a rapid clinical improvement, a decrease in acute phase reaction, and increased lymphocyte counts in patients with active RA. The protein levels of IL1beta in the circulation were low and remained unchanged, but the systemic levels of IL1beta mRNA (p=0.002) and the concentrations of IL1 receptor antagonist (IL1ra) and IL6 (p=0.0001) had already dropped within 24 hours and this persisted up to day 14. Systemic levels of TNFalpha mRNA were low and remained unchanged, though total TNFalpha (free and bound) in the circulation increased after D2E7, probably reflecting the presence of TNF-antiTNF mAb complexes (p<0.005, at days 1 and 14). Both TNF receptors dropped below baseline levels at day 14 (p<0.005). Despite clinical improvement of arthritis, no consistent immunohistological changes were seen two weeks after anti-TNF administration. Endothelial staining for IL1beta tended to decrease in treated patients (p=0.06) but not in responders. The staining for IL1beta and TNFalpha in sublining layers and vessels was mutually correlated (r(s)=0.47 and 0.58 respectively, p<0.0005) and the microscopic scores for inflammation correlated with sublining TNFalpha and IL1beta scores (r(s)=0.65 and 0.54 respectively, p<0.0001), though none of these showed significant changes during the study. CONCLUSIONS: Blocking TNFalpha in RA results in down regulation of IL1beta mRNA at the systemic level and in reduction of the endogenous antagonists for IL1 and TNF and of other cytokines related to the acute phase response, such as IL6, within days. At the synovial level, anti-TNF treatment does not modulate IL1beta and TNFalpha in the short term. The synovial expression of these cytokines does not reflect clinical response to TNF neutralisation.

Aged↗

PubMed2001

Genetic anticipation in rheumatoid arthritis in Europe. European Consortium on Rheumatoid Arthritis Families.

OBJECTIVE: To investigate whether there is evidence for genetic anticipation in rheumatoid arthritis (RA) in Europe. METHODS: Cross sectional comparison of data from all affected parent-offspring pairs identified among (1) the RA population attending our department and (2) a large cohort of families from RA probands with both parents alive recruited by the European Consortium on RA families (ECRAF) for association studies. Longitudinal comparison between probands with and without parental RA. We used prospectively collected data on disease activity, therapies, and radiological outcomes from our Dutch inception cohort of patients with early RA during the first 6 years of followup. RESULTS: From a total of 683 Dutch and 170 European patients we identified 28 Dutch and 21 European parent-offspring pairs with RA. Probands with parental RA had an earlier disease onset compared with affected parents (Dutch p < 0.002, European p < 0.0001). In Dutch patients, the prevalence of HLA-DR4, DR4 double dose, and shared epitope (SE) double dose was slightly higher in probands with parental RA than in those without [odds ratios (95% CI) 2.0 (0.7-5.8), 2.79 (0.8-9.4), and 2.12 (0.6-8.7), respectively]. The same was true for European probands concerning SE double dose [OR (95% CI) 1.76 (0.6-8.7)]. No other relevant differences in demographic or clinical indices were found between probands with affected parents and those without. Disease course (Disease Activity Score) and therapies used during the first 6 years of followup were similar in Dutch patients with and without parental RA. Radiological damage at baseline was lower in the former group and this difference persisted after 3 and 6 years. CONCLUSION: Our data suggest that genetic anticipation in RA does occur in terms of an earlier disease onset in the offspring. Despite a slightly higher prevalence of HLA alleles encoding for the SE, probands with confirmed parental RA had no worse outcome than those without.

Adult↗

PubMed2001

Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF).

OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger influence than in patients with sporadic RA. We investigated the NIMA hypothesis in a large cohort of European patients with familial RA. METHODS: The distribution of NIMA, noninherited paternal antigens (NIPA), and inherited HLA-DR antigens was assessed in patients with familial RA from all family sets collected from 1996 onwards by the ECRAF. HLA-DRB1 oligotyping from patients and all available nonaffected siblings and parents was carried out. Familial RA was defined by the presence of at least 2 affected first-degree relatives in the same family. The frequencies of HLA-DR NIMA and NIPA were compared using odds ratios after stratification for HLA-DR*04, *0401, and/or *0404 and shared epitope (SE) status. NIMA/NIPA that coincided with inherited parental HLA-DR antigens were considered redundant and were excluded from analysis. RESULTS: NIMA and NIPA could be analyzed in 165 RA patients with familial RA and 84 nonaffected siblings. Patients were predominantly female, rheumatoid factor positive, and had erosive disease (81, 75, and 84%, respectively). Possession of HLA-DR*04 and *0401/*0404 alleles tended be more frequent in patients than in nonaffected siblings but this did not reach statistical significance. SE possession was similar in patients and healthy siblings, although the former had a double dose SE more often (37.6 vs 17.8%; p = 0.002). Transmission of SE encoding alleles from parents to offspring was skewed only in patients [OR (95% CI) 3.56 (2.55-4.95) vs 1.16 (0.75-1.79) in nonaffected siblings]. Using the NIPA as control, the frequencies of HLA-DRB1*04, *0401/*0404, and SE positive NIMA were not increased in patients lacking these susceptibility alleles. The frequencies of NIMA encoding susceptibility alleles in DR*04 and *0401/*0404 negative patients were lower than in nonaffected siblings. CONCLUSION: Our results corroborate the association between RA and inherited SE alleles and do not support a role for noninherited HLA-DR maternal antigens in the susceptibility for familial RA.

Adult↗

PubMed2001

Chronic comorbidity in patients with early rheumatoid arthritis: a descriptive study.

OBJECTIVE: To study the presence of chronic coexisting diseases in patients with rheumatoid arthritis (RA) and its effect on RA treatment, disease course, and outcome during the first years of the disease. METHODS: From January 1985 to December 1990, 186 patients with recent onset RA were enrolled in a prospective longitudinal study. Between January 1991 and November 1992 patients were interviewed on the basis of a comorbidity questionnaire. For analysis the diseases were coded according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) medical diagnoses. Disease activity during the period of followup was measured by the Disease Activity Score. Outcome in terms of physical disability (Health Assessment Questionnaire) and radiological damage (Sharp's modified version) over 3 and 6 year periods was determined. RESULTS: In the group of 186 patients, with mean disease duration of 4.3 years at January 1991, 50 patients (27%) reported at least one chronic coexisting disease. The most frequently reported coexisting diseases were of cardiovascular (29%), respiratory (18%), or dermatological (11%) origin. For the major part (66%) chronic coexisting diseases were already present before onset of RA. No statistically significant differences in use of disease modifying antirheumatic drugs or corticosteroids were observed between RA patients with and without chronic coexisting diseases. No statistically significant differences were found in disease activity or in outcome in terms of physical disability and radiological damage over 3 and 6 year periods between the 2 groups with RA. CONCLUSION: The results showed that about 27% of patients with RA in this inception cohort had at least one chronic coexisting disease. Treatment, disease course, and outcome did not differ between patients with and without chronic coexisting diseases during the first years of the disease.

Adult↗

PubMed2000

Fc gamma R expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA).

STATEMENT OF FINDINGS: We investigated the role of Fc gamma receptors (Fc gamma Rs) on synovial macrophages in immune-complex-mediated arthritis (ICA). ICA elicited in knee joints of C57BL/6 mice caused a short-lasting, florid inflammation and reversible loss of proteoglycans (PGs), moderate chondrocyte death, and minor erosion of the cartilage. In contrast, when ICA was induced in knee joints of Fc receptor (FcR) gamma-chain(-/-) C57BL/6 mice, which lack functional Fc gamma RI and RIII, inflammation and cartilage destruction were prevented. When ICA was elicited in DBA/1 mice, a very severe, chronic inflammation was observed, and significantly more chondrocyte death and cartilage erosion than in arthritic C57BL/6 mice. The synovial lining and peritoneal macrophages of naïve DBA/1 mice expressed a significantly higher level of Fc gamma Rs than was seen in C57BL/6 mice. Moreover, elevated and prolonged expression of IL-1 was found after stimulation of these cells with immune complexes. Zymosan or streptococcal cell walls caused comparable inflammation and only mild cartilage destruction in all strains. We conclude that Fc gamma R expression on synovial macrophages may be related to the severity of synovial inflammation and cartilage destruction during ICA.

Animals↗

PubMed2000

Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease.

Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.

Animals↗

PubMed2000

Basic biology and clinical application of specific cyclooxygenase-2 inhibitors.

In summary, COX-2 is a highly regulated gene product that catalyzes the local production of PGs in pathologic and physiologic situations (Figure 1). It is clear that COX-2 is the isoform responsible for production of the PGs that mediate inflammation, pain, and fever. However, the role for COX-2 in normal physiology is still being defined. Specific COX-2 inhibitors represent a significant conceptual advance in therapy for patients with arthritis. Although there is no expectation of superior efficacy, clinical trials suggest that efficacy will be comparable with that of nonselective NSAIDs. Clinical trials demonstrate the potential for clinically meaningful reductions in the incidence of the most serious GI complications found with nonselective NSAIDs, i.e., ulcer, perforation, and GI bleeding. Over the next several years, treatment of large numbers of patients with specific COX-2 inhibitors will help to define the biology of COX-2. The magnitude of this advance in the therapy of rheumatic diseases is yet to be accurately determined, but the development of specific COX-2 inhibitors may afford significant new treatment options for many patients.

Cyclooxygenase 2↗

PubMed2000

Role of Fc receptor gamma chain in inflammation and cartilage damage during experimental antigen-induced arthritis.

OBJECTIVE: To study the role of Fc receptor (FcR) gamma chain in inflammation and cartilage destruction during antigen-induced arthritis (AIA). METHODS: FcR gamma-/- mice and controls were immunized with methylated bovine serum albumin (mBSA) in Freund's complete adjuvant, followed by induction of arthritis by local injection of mBSA into the right knee joint. Joint inflammation was studied by 99mTc uptake and by histology. Breakdown of proteoglycans from the cartilage matrix was determined by loss of red staining in Safranin O-stained knee joint sections, and matrix metalloproteinase (MMP)-mediated aggrecan degradation was determined by immunolocalization using anti-VDIPEN antibodies. Chondrocyte death was measured by determining empty lacunae in hematoxylin-stained sections and with the TUNEL assay in cryostat sections. Erosion was detected as ruffling of the cartilage surface. RESULTS: Joint swelling, as measured by 99mTc uptake on days 1, 3, and 7, was significantly decreased in FcR gamma-/- mice compared with controls. On day 7 after AIA induction, sustained joint inflammation, as seen histologically, was not significantly lower in FcR gamma-/- deficient mice. In various cartilage layers (femur, tibia, patella) of central arthritic knee joints, marked depletion of proteoglycans (40-70%), chondrocyte death (25-50%), and mild surface erosion were found. In FcR gamma-/- knee joints, depletion of proteoglycans was comparable (40-70%). Strikingly, chondrocyte death and matrix erosion were absent. Furthermore, MMP-induced aggrecan neoepitopes, which were abundantly found in controls, were also absent in FcR gamma-/-. Nevertheless, latent MMPs were present in the cartilage matrix as seen in APMA-activated patellae. CONCLUSION: FcR gamma chain is involved in the severity of acute and sustained inflammation and is a crucial factor in cartilage erosion during AIA, probably by regulating activation of latent MMPs present in the cartilage matrix.

Animals↗