Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis.

OBJECTIVE: To study the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with RA participated in 3 groups: recent onset active RA (n = 20), longstanding active RA (n = 20) and long-standing RA in remission (n = 10), and were compared with 20 healthy controls. The activity of the HPA-axis was assessed under basal conditions and in response to stress (insulin tolerance test, ITT). In addition, patients with recent onset RA underwent a corticotropin releasing hormone (CRH) test and a dexamethasone suppression test. Plasma levels of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6 were also measured. RESULTS: Basal plasma, salivary and urinary cortisol levels and plasma adrenocorticotropic hormone (ACTH) levels were not different between patients with RA and healthy controls. During the ITT, cortisol levels were consistently lower in RA patients than in healthy controls. ACTH levels during the ITT were not different between patients with RA and healthy controls. ACTH and cortisol responses to CRH were assessed only in patients with recent onset RA and were found to be within normal limits. Basal circulating plasma IL-6 levels were significantly higher in patients with active RA than in the other groups. CONCLUSION: Under the standardized conditions of the ITT, patients with RA have decreased plasma cortisol levels compared to healthy controls, despite elevated levels of IL-6. The defect is probably located at the adrenal level and may be of pathogenetic significance for the development of chronic arthritis.

Decreased prolactin response to hypoglycaemia in patients with rheumatoid arthritis: correlation with disease activity.

OBJECTIVE: To compare basal and stimulated prolactin levels between patients with rheumatoid arthritis and healthy controls, and to assess the effects of antirheumatic treatment on prolactin concentrations. METHODS: Serum prolactin was assessed under basal conditions and during an insulin tolerance test (ITT) in 20 patients with recently diagnosed active rheumatoid arthritis and 20 age and sex matched controls. The patients were reassessed after two weeks' treatment with naproxen and after six months' additional treatment with either sulfasalazine or methotrexate. Disease activity was assessed by the disease activity score (DAS). RESULTS: Basal levels of prolactin were not significantly different between patients with rheumatoid arthritis and controls. Prolactin responses to hypoglycaemia were less in untreated rheumatoid patients than in controls. DAS scores correlated negatively with the area under the curve (AUC) for prolactin concentrations during the ITT. Treatment with naproxen for two weeks did not influence either basal or stimulated prolactin levels. After six months of antirheumatic treatment, prolactin responses to hypoglycaemia increased significantly to levels observed in controls. At the same time point, DAS had improved considerably. The improvement correlated with the increase in AUC of prolactin during the ITT (r = 0.48; p = 0.05). CONCLUSIONS: Patients with active rheumatoid arthritis have a decreased prolactin response to hypoglycaemia induced stress. The response recovers following treatment with antirheumatic drugs.

Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system.

OBJECTIVE: To develop and validate an extensive radiographic scoring system for ankylosing spondylitis (AS). METHODS: The Stoke Ankylosing Spondylitis Spinal Score (SASSS) was modified by adding a score for the cervical spine and defining squaring. This modified SASSS (mSASSS) is the sum of the lumbar and cervical spine score (range 0-72). 370 lateral views of the lumbar and cervical spine were used for development of the mSASSS, standardisation of observers, and for studying reliability. In a 48 week NSAID study of 57 patients, change over time and construct validity were studied. RESULTS: Interobserver correlations of the lumbar and cervical spine scores were good (r>0.95). The interobserver duplicate error was 0.55 in a range from 0 to 36. The mean change in the cervical and lumbar spine scores between weeks 0 and 48 of all patients was 1.45 (range 0-6.0) and 1.06 (0-5.0), respectively (paired t testing, p<0.001). Change in radiological score was seen in 36/57 (63%) patients (lumbar and cervical spine 11, cervical spine 12, lumbar spine 13 patients). CONCLUSION: The mSASSS is useful for assessing extensive radiographic damage in AS. It is reliable, detects changes over 48 weeks, and shows a satisfactory face and construct validity.

Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate.

OBJECTIVE: This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite previous MTX therapy. METHODS: Fifty-four patients were randomized to two injections of i.v. or s.c. adalimumab (1 mg/kg) or placebo while continuing on MTX (mean dose, 15.7 mg/week). Dosing intervals were determined by the European League Against Rheumatism (EULAR) response criteria, and were allowed to range from 1 to 3 months. Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology (ACR) response criteria. RESULTS: Moderate EULAR response was achieved at least once within 29 days after the first injection in 83% and 61% of patients receiving i.v. and s.c. adalimumab respectively, compared with 44% for placebo [probability (p) < or = 0.05 for i.v. adalimumab versus placebo]. A 20% improvement in disease activity according to the ACR criteria (ACR20 response) was achieved by 72% and 67% of patients receiving i.v. and s.c. adalimumab respectively, compared with 28% for placebo (p < or = 0.01 and p < or = 0.05, respectively, versus placebo). By Day 15 after the first and second injections, statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v. or s.c. adalimumab compared with placebo (p < or = 0.05). The mean times to second injection for i.v. adalimumab, s.c. adalimumab, and placebo were 42.2 days (range: 27-84 days), 38.3 days (range: 26-85 days), and 28.4 days (range: 26-32 days), respectively (minimum time allowed by the protocol between the first and second injections was 4 weeks). Adalimumab in combination with MTX was well tolerated, with no patients being withdrawn because of adverse events. CONCLUSION: Either i.v. or s.c. adalimumab added to MTX significantly improved the signs and symptoms of RA compared with MTX alone. Subcutaneously administered adalimumab appeared to provide a response that was as great, as rapid, and as enduring as that with i.v. adalimumab.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.

OBJECTIVE: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. METHODS: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). RESULTS: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). CONCLUSION: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.

Efficacy and safety of the fully human anti-tumour necrosis factor alpha monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study.

OBJECTIVES: To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). METHODS: During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. RESULTS: Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p

Successful treatment of dermatomyositis and polymyositis with anti-tumor-necrosis-factor-alpha: preliminary observations.

Tumor necrosis factor alpha neutralization seems a rational therapy for myositis because this proinflammatory cytokine has been implicated in the pathogenesis of this disorder. Until now, we have treated 2 patients with a chimeric anti-TNF-alpha monoclonal antibody (infliximab). Both patients demonstrated a marked and sustained subjective and objective improvement without the occurrence of any side effects. These preliminary results suggest that anti-TNF-alpha treatment with infliximab is a safe and rapidly effective therapy for myositis.

[Early diagnosis of rheumatoid arthritis with a test based upon a specific antigen: cyclic citrullinated peptide]. / Vroegdiagnostiek van reumatoïde artritis met een test op basis van een specifiek antigeen: cyclisch gecitrullineerd peptide.

In patients with rheumatoid arthritis (RA), joint erosions occur at a very early stage of the disease before clinical symptoms can be detected. Early treatment with currently available antirheumatic drugs may stop or delay the development of such erosions. A simple and specific diagnostic test is needed for treatment to be initiated at an early stage. The specificity of the routinely used rheumatoid factor (RF) test is too low for that purpose. A novel autoantibody, directed to citrullinated antigens in the synovium, seems to provide a new starting point. These citrullinated autoantigens (e.g. fibrin) are specifically present in inflamed synovia and the antibodies for these are locally produced. The autoantibodies can be detected in the blood of the patients with RA years before the first clinical signs are manifest, and high titres appear to correlate strongly with erosive disease. The test for cyclic citrullinated peptide, which has recently become available, has a specificity of 98-99% and a sensitivity of 75-80%.

Purine enzymes in patients with rheumatoid arthritis treated with methotrexate.

OBJECTIVES: To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment. METHODS: One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment. RESULTS: Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity. CONCLUSION: MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.

The synergistic value of focus score and IgA% score of sublabial salivary gland biopsy for the accuracy of the diagnosis of Sjögren's syndrome: a 10-year comparison.

OBJECTIVE: Increasing the accuracy of the diagnosis of Sjögren's syndrome (SS) by placing emphasis on objective findings such as the presence of anti-Ro and anti-La autoantibodies and abnormal salivary gland tissue (SGT) histology is a current issue. In order to obtain optimal disease sensitivity and specificity of SGT findings, histological and immunohistological SGT examinations were compared. The first describes the extent of the lymphocytic infiltrate as a focus score (LFS), whereas the latter describes the composition of the infiltrate as a percentage of IgA-containing plasma cells (IgA%). METHODS: Both the LFS and IgA% score were assessed in 279 SGT biopsies taken from patients with symptoms suggestive of SS. In case histological conclusions did not match immunohistological conclusions patients were assigned to so-called mismatch groups. Patients in the mismatch groups were further classified using objective, serological parameters [rheumatoid factor (RF), anti-Ro, anti-La, anti-nuclear antibodies, gammaglobulin level]. RESULTS: In 249 samples (89%), LFS and IgA% resulted in the same conclusion. Within this group a total of 63 SGT samples (25%) were characteristic for SS showing LFS >1.0 and IgA% <70. In the mismatch groups after serological classification, both false positive as well as false negative scores were observed less frequently for IgA% as compared with LFS (50 vs 75% and 25 vs 50%, respectively). CONCLUSIONS: Additional immunohistological SGT examination provides greater disease sensitivity and specificity than histological SGT examination alone, thereby increasing accuracy of SS diagnosis.

Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis.

OBJECTIVE: To study (i) the influence of methotrexate (MTX) therapy on homocysteine and folate metabolism in patients with rheumatoid arthritis (RA), (ii) the influence of the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) on the change in plasma homocysteine levels during MTX treatment, and (iii) the interference of folate and homocysteine metabolism with the efficacy and toxicity of treatment with MTX. METHODS: The 113 patients enrolled in this study were participating in a 48-week, multicentre, double-blind, placebo-controlled study comparing the efficacy and toxicity of MTX treatment with and without folic or folinic acid supplementation. The MTX dose was 7.5 mg/week initially and increased to a maximum of 25 mg/week if necessary. Concentrations of total folate, 5-methyl tetrahydrofolate (in serum and in erythrocytes) and of homocysteine, cysteine and cysteine-glycine and the MTHFR genotype were determined before the start of the study, after 6 weeks, and after 48 weeks or on withdrawal from the study. Blood was drawn from fasting patients at a standardized time in the morning, 16 h after intake of MTX. The laboratory results were related to parameters of efficacy and toxicity of MTX treatment. RESULTS: Baseline values were distributed equally in the three treatment groups. The mean plasma homocysteine level (normal range 6-15 micromol/l) before the start of MTX was relatively high in all groups: 15.4 micromol/l [95% confidence interval (CI) 13.5 to 17.2] in the MTX plus placebo group (n=39), 14.3 micromol/l (95% CI 12.2 to 16.4) in the MTX plus folic acid group (n=35) and 15.9 micromol/l (95% CI 13.7 to 18.1) in the MTX plus folinic acid group (n=39). After 48 weeks of MTX therapy, the mean homocysteine level showed an increase in the placebo group (+3.6 micromol/l, 95% CI 1.7 to 5.6). In contrast, a decrease was observed in the groups supplemented with folic or folinic acid (folic acid, -2.7 micromol/l, 95% CI -1.4 to -4.0; folinic acid, -1.6 micromol/l, 95% CI -0.1 to -3.0). The differences in the change in plasma homocysteine level between the placebo group and each of the two folate-supplemented groups were statistically significant (P<0.0001), contrary to the difference between the folic and folinic acid groups (P=0.26). Linear regression analysis showed that the change in plasma homocysteine level was statistically significantly associated with folic or folinic acid supplementation (P=0.0001) but not with the presence or absence of the C677T mutation in the MTHFR gene. Homozygous mutants had a higher plasma homocysteine concentration at baseline. No relationship was found between the change in disease activity and the change in homocysteine concentration or the mean homocysteine concentration after 48 weeks of MTX therapy. Toxicity-related discontinuation of MTX treatment was not associated with the change in homocysteine concentration. CONCLUSIONS: Low-dose MTX treatment in RA patients leads to an increased plasma homocysteine level. Concomitant folate supplementation with either folic or folinic acid decreases the plasma homocysteine level and consequently protects against potential cardiovascular risks. No relationship was found between the change in homocysteine concentration and the presence or absence of the C677T mutation in the MTHFR gene. Homocysteine metabolism was not associated with efficacy or toxicity of MTX treatment.

Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha antibody compared with methotrexate in long-standing rheumatoid arthritis.

OBJECTIVES: To compare the 48-week drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody (moAb) and methotrexate (MTX) in patients with active long-standing rheumatoid arthritis (RA). Secondary aims were to identify potential predictors for clinical response. METHODS: Patients with RA, enrolled in phase I trials with a human anti-TNF-alpha moAb and followed for at least 48 weeks at our centre, were compared with patients receiving MTX monotherapy without folate supplementation. The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study. Patients treated with MTX participated in a 48-week, double-blind, phase III study of MTX alone vs MTX with folate supplementation, which was co-ordinated by our department. The studies with anti-TNF-alpha and MTX were performed in the same period and had very similar inclusion, exclusion, response and stop criteria. RESULTS: Sixty-one patients treated with anti-TNF-alpha moAb were compared with 137 receiving MTX monotherapy. At baseline, patients in the anti-TNF-alpha group had a longer disease duration (median 108 vs 50 months, P=0.0001) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX (median 4 vs 1, P=0.0001). The 48-week dropout rate was lower among patients treated with anti-TNF (23 vs 45% in the MTX group, P<0.005). Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [relative risk (95% confidence interval): 0.28 (0.12-0.6) uncorrected and 0.17 (0.06-0.45) corrected for confounders). The 48-week area under the curve for the disease activity score (DAS) was smaller in the anti-TNF-alpha group than in the MTX group (P=0.005). The percentage of responders was higher in the anti-TNF-alpha group over the whole study period. The median percentage of visits in which a patient fulfilled the European League Against Rheumatism (EULAR) response criteria was 83% in the anti-TNF-alpha group vs 40% in the MTX group (P=0.0001). Clinical and demographic characteristics were, in general, poor predictors for response to therapy at week 48. The clinical response after the first anti-TNF-alpha dose tended to increase the chance of prolonged efficacy of this approach [relative risk (95% confidence interval): 2 (0.75-6.0)]. The previous number of second-line drugs was the only predictive variable for response to MTX to which it was inversely related [relative risk (95% confidence interval): -0.71 (-0.57 to -0.88)]. CONCLUSIONS: In patients with active, long-standing RA, blocking TNF-alpha is more effective and better tolerated than MTX monotherapy. An early response increases the chance of a sustained effect of anti-TNF-alpha. In contrast to MTX, the response to anti-TNF-alpha is not affected by previous disease-modifying anti-rheumatic drug history.

Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation.

OBJECTIVES: To investigate the effect of prolonged neutralisation of tumour necrosis factor alpha (TNFalpha) on the radiological course in rheumatoid arthritis (RA). To assess whether the radiological course can be predicted by clinical variables or biological markers of cartilage and synovium turnover and of endothelial activation. PATIENTS AND METHODS: Forty seven patients with active RA enrolled at our centre in monotherapy trials with adalimumab (D2E7), a fully human anti-TNFalpha monoclonal antibody, were studied for two years. Radiographs of hands and feet obtained at baseline and after one and two years were scored in chronological order by a single, blinded observer using the modified Sharp method. Radiological course was classified as stable or progressive using the smallest detectable difference as cut off point. The relation between radiological course and serum markers of cartilage and synovium turnover (metalloproteinases (MMP-1 and MMP-3), cartilage oligomeric matrix protein (COMP), human cartilage glycoprotein-39 (HC gp-39)), endothelial activation (soluble E-selectin and intercellular adhesion molecule (ICAM-1)), and integrated measures of disease activity were assessed using univariate and multivariate analysis. RESULTS: Radiological evaluation was performed in 36 patients with paired sets of radiographs at baseline and two years. After two years a total of 15/36 (42%) presented no radiological progression. More patients with stable radiological course were still receiving anti-TNFalpha treatment after two years (13/15 (87%) v 11/21 (52%); p=0.03) and had lower baseline COMP and sICAM-1 levels (p=0.01 and 0.04, respectively) than those in the group with progressive disease. In a logistic regression model the combination of sustained TNF neutralisation and baseline COMP and sICAM-1 levels was predictive for radiological outcome (p=0.03). C reactive protein and disease activity score area under the curve were significantly correlated with changes in radiological scores after two years (r=0.40 and 0.37, p<0.05). Long term TNFalpha neutralisation decreased the levels of COMP, sICAM, MMPs, and HC gp-39, but not sE-selectin. CONCLUSION: The results suggest that long term monotherapy with anti-TNFalpha has a positive effect on radiological outcome and modulates cartilage and synovium turnover as measured by biological markers. Baseline serum sICAM-1 levels and COMP levels may be helpful to identify patients with progressive or non-progressive radiological outcome.

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.

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.

[Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept]. / Behandeling van reumatoïde artritis door blokkade van tumornecrosisfactor met infliximab of 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.

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.

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.