PubMed Health⌕ Search

Biomedical subjects

P Barrera

Publications and source records attributed to P Barrera.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of refractory cholestatic pruritus with molecular adsorbent recirculating system (MARS).

UNLABELLED: Pruritus is a common complication of cholestatic liver diseases or liver graft dysfunction. Current medical therapies lack efficacy. The molecular adsorbent recirculating system (MARS) represents an interesting therapeutic option. Our objective was to report our experience in the management of four patients with intractable pruritus with MARS. PATIENTS AND METHODS: The MARS treatment cycle included three consecutive treatments, each of 8 hours duration. The four patients with intractable pruritus who were treated had primary biliary cirrhosis/autoimmune hepatitis overlap syndrome (n = 1), ductopenic allograft rejection (n = 2), or posttransplant cholestatic HCV recurrence (n = 1). Intensity of pruritus was documented 24 hours before as well as 24 hours, 7 and 30 days after MARS therapy, and at the end of follow-up. We measured complete blood cell counts, glucose, BUN, creatinine, sodium, potassium, AST, ALT, GGT, alkaline phosphatase, bilirubin, prothrombin activity, and activated partial thromboplastin time. RESULTS: MARS therapy was well tolerated. Patient 1 experienced temporal relief of pruritus, but needed another MARS cycle because of relapse. Patient 2 experienced partial and temporary relief of pruritus, was listed for retransplantation, and received a liver graft 2 months later. Patient 3 showed a dramatic reduction in the degree of pruritus with MARS. Pruritus in patient 4 decreased promptly with MARS therapy and conversion of immunosuppression to tacrolimus, thereby avoiding retransplantation. CONCLUSION: MARS therapy is a promising, safe therapeutic option to treat refractory pruritus caused by cholestatic liver disorders.

Adult↗
PubMed2006

Adjuvant chemotherapy for prevention of recurrence of invasive hepatocellular carcinoma after orthotopic liver transplantation.

UNLABELLED: Orthotopic liver transplantation (OLT) is the best treatment for nonresectable hepatocellular carcinoma (HCC), but tumor recurrence reduces long-term and medium-term survival. The effectiveness of adjuvant chemotherapy to prevent tumor recurrence has not been fully established. METHODS: Three hundred eighty-seven consecutive patients, including 43 with HCC superimposed on liver cirrhosis, underwent OLT. Twelve patients with one or more prognostic criteria for HCC recurrence were entered into a prospective prophylaxis protocol with monthly cycles of cisplatin (60 mg/m(2)) and adriamycin (30 mg/m(2)), beginning the fourth week post-OLT for a maximum of seven sessions. RESULTS: The 5-year survival of the non-HCC patients was 65.7% and that of the HCC patients was 60.46% (P = NS). Chemotherapy was reasonably well tolerated, but the 9 patients with hepatitis C- or B-associated cirrhosis showed viral and histological recurrence of the primary disease. A high proportion of patients (7 of 12) developed tumor recurrence during the first year after OLT. Six of these patients died, all but one due to HCC relapse. Five patients remain healthy and tumor free at 58 to 130 months. Post-OLT adjuvant chemotherapy does not avoid tumor recurrence and its fatal consequences but may contribute to prolonged tumor-free survival among a significant proportion of patients with high-risk HCC. However, the uncertain implications on viral recurrence and the lack of control groups do not allow post-OLT chemotherapy to be recommended outside controlled clinical trials, which are clearly warranted.

Adult↗
PubMed2005

Methotrexate modulates the kinetics of adenosine in humans in vivo.

BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05). CONCLUSIONS: MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.

Adenosine↗
PubMed2005

Dendritic cells from patients with rheumatoid arthritis lack the interleukin 13 mediated increase of Fc gamma RII expression, which has clear functional consequences.

BACKGROUND: Dendritic cell (DC) function is largely tailored by Fc gamma receptors (Fc gamma R) and is critical for every immune response. OBJECTIVE: To compare interleukin (IL) 13 mediated regulation of Fc gamma RII and its related DC function between healthy controls and patients with rheumatoid arthritis (RA). METHODS: DC were derived from peripheral blood mononuclear cells according to standardised protocols. F cgammaRI, II, and III expression and DC phenotype were assessed by FACS analysis. The level of cytokine production and chemokine expression was measured by Luminex and real time quantitative polymerase chain reaction techniques. Antigen uptake capacity was studied by DC fluorescent heat aggregated immunoglobulins and FACS analysis. RESULTS: Replacement of IL4 by IL13 clearly increased the expression of Fc gamma RII on DC from healthy controls (CDC), but had no effect on DC from patients with RA (RADC). The lower production of inflammatory mediators by IL13 CDC upon Fc gamma R mediated triggering suggests that IL13 induces up regulation of specifically Fc gamma RII. RADC co-cultured with IL4 already displayed an inhibitory DC phenotype, but this inhibitory phenotype was not augmented by the addition of IL13. The defective Fc gamma RII regulation was further substantiated by the finding that IL13 CDC increased antigen uptake capacity, whereas IL13 RADC did not. CONCLUSION: IL13 regulates the expression of inhibitory Fc gamma RII in normal subjects but not in RA, potentially resulting in a chronic proinflammatory immune reaction in RA. Unravelling the underlying mechanisms of Fc gamma RII regulation might lead to new therapeutic targets in RA.

Arthritis, Rheumatoid↗
PubMed2005

Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis.

BACKGROUND: Leptin regulates food intake and modulates immunity and inflammation. A positive feedback mechanism has been described between tumour necrosis factor (TNF) and leptin, and it has been suggested that leptin potentiates inflammation in patients with rheumatoid arthritis (RA). OBJECTIVE: To assess whether inflammation correlates with leptin concentrations in patients with RA, and whether anti-TNF treatment modulates leptin concentrations in these patients. METHODS: Leptin, IL6 and CRP were measured (at baseline and after 2 weeks of treatment) in the blood of 31 patients with RA starting either anti-TNF treatment or placebo, and in 18 healthy controls. RESULTS: In patients with RA, plasma leptin concentrations at baseline correlated inversely with the degree of inflammation as assessed by C reactive protein (CRP; r(s)(2) = 0.21, p<0.01) or interleukin (IL) 6 concentrations (r(s)(2) = 0.22, p<0.008). Mean (SD) leptin concentrations did not differ between patients with RA and controls (6.0 (4.6) v 4.2 (2.8) ng/ml in men; 15.1 (7.9) v 13.4 (5.2) ng/ml in women). Short course anti-TNF treatment for 2 weeks did not modify leptin concentrations, despite significant reduction of CRP and IL6. CONCLUSION: A significant inverse correlation between inflammation and leptin concentrations was found in patients with active RA, although plasma leptin concentrations did not significantly differ from those in healthy controls. This suggests that active chronic inflammation may lower plasma leptin concentrations. Two weeks' treatment with anti-TNF did not change plasma leptin concentrations and longer treatment may be needed to see an effect on leptin.

Adalimumab↗
PubMed2005

Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population.

Protein tyrosine phosphatase PTPN22 is involved in the negative regulation of T-cell responsiveness. Recently, the association of a coding variant of the PTPN22 gene-R620W(1858C>T) with a number of autoimmune diseases has been described. Therefore, we tested the association of PTPN22 1858*T allele in Dutch early onset type 1 diabetes (T1D) and rheumatoid arthritis (RA) patients, as well as celiac disease (CD) patients, for which no previous study of PTPN22 has been reported. The PTPN22 variant was strongly associated with T1D in cases vs controls (P=2 x 10(-7), OR=2.3, 95% CI=1.7-3.1) as well as in a transmission disequilibrium test in nuclear trio's (P=9 x 10(-9), OR=3.3, CI=2.1-5.0), RA (case/control: P=0.003, OR=1.8 CI =1.2-2.6), but not CD, in spite of a trend of increased homozygosity (P=0.05) and early age at onset (P=0.01). PTPN22 is not generally associated with T-cell mediated autoimmune diseases, although it might play a role in the CD patients with early clinical manifestation.

Adolescent↗
PubMed2004

Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors.

BACKGROUND: Dendritic cells (DC) have a role in the regulation of immunity and tolerance, attracting inflammatory cells by the production of various chemokines (CK). Fc gamma receptors (Fc gamma R) may be involved in regulation of the DC function. OBJECTIVE: To assess the expression of CK by immature (iDC) and mature DC (mDC) and its regulation by Fc gamma R in patients with RA and healthy donors (HC). METHODS: Expression of CK by DC from patients with RA and from HC was determined by real time quantitative PCR and ELISA. DC were derived from monocytes following standardised protocols. To study the potential regulation by Fc gamma R, iDC were stimulated with immune complexes (IC) during lipopolysaccharide (LPS) induced maturation. The presence of CK was studied in synovial tissue from patients with RA, osteoarthritis, and healthy subjects by RT-PCR and immunohistochemistry. RESULTS: iDC from patients with RA had markedly increased mRNA levels of the CK CCL18 and CXCL8. Upon maturation with LPS, expression of CCL18, CCL19, CXCL8, CCL3, and CCL17 increased dramatically, reaching significantly higher levels in patients with RA. Monocytes failed to express these CK, except for CXCL8 and CCL3. IC-mediated triggering of the Fc gamma R on DC from patients with highly active RA down regulated all CK, whereas the reverse was seen when DC from patients with low disease activity and healthy donors were stimulated. CCL18 was significantly increased in RA synovial tissue. CONCLUSION: Increased CK expression by DC was found in patients with RA. This expression is partly regulated by Fc gamma R triggering and results in an inhibitory DC subtype in RA upon Fc gamma R-mediated triggering.

Arthritis, Rheumatoid↗
PubMed2004

Inhibition of TNF alpha during maturation of dendritic cells results in the development of semi-mature cells: a potential mechanism for the beneficial effects of TNF alpha blockade in rheumatoid arthritis.

BACKGROUND: Dendritic cells orchestrate pivotal immunological processes mediated by the production of cytokines and chemokines. OBJECTIVE: To assess whether neutralisation of tumour necrosis factor alpha (TNF alpha) during maturation of dendritic cells affects their phenotype and behaviour, which might explain the beneficial effects of TNF alpha neutralisation in rheumatoid arthritis. METHODS: Immature and fully matured dendritic cells were cultured from blood monocytes from patients with rheumatoid arthritis and healthy controls following standardised protocols. TNF alpha was neutralised by addition of the p55 soluble TNF alpha receptor, PEGsTNFRI. The effect of TNF alpha neutralisation on the phenotype (CD14, CD16, CD32, CD64, CD80, CD83, CD86, and MHC) of dendritic cells was investigated by flow cytometry. Expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8) and production of IL1 beta and IL6 during dendritic cell differentiation and maturation were examined. RESULTS: Neutralisation of TNF alpha during the differentiation and maturation of dendritic cells did not result in an altered dendritic cell phenotype in the rheumatoid patients or the healthy controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8 by dendritic cells was significantly reduced when TNF alpha activity was inhibited during lipopolysaccharide triggered dendritic cell maturation. The production of IL1 beta and IL6 by mature dendritic cells was inhibited by PEGsTNFRI. CONCLUSIONS: Inhibition of TNF alpha activity during dendritic cell maturation leads to the development of semi-mature cells. These data suggest a novel pathway by which the neutralisation of TNF alpha might exert its therapeutic effects.

Arthritis, Rheumatoid↗
PubMed2004

High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon FcgammaR triggering.

OBJECTIVE: To assess whether DC from RA produce altered cytokine levels and whether this is regulated by triggering of Fc gamma receptors (FcgammaR). METHODS: The production of proinflammatory (TNFalpha, IL1, IL6), Th1 (IL12, IFNgamma), and Th2 (IL10) cytokine profiles of immature DC (iDC) from patients with RA and healthy subjects upon triggering of FcgammaR dependent and independent pathways was investigated. iDC, derived from blood monocytes by standardised protocols, were stimulated with immune complexes (IC) at day 6 for 48 hours and, subsequently, for 2 days with LPS in the presence or absence of IC or IFNgamma, resulting in fully matured DC (mDC). IL1, IL6, TNFalpha, IFNgamma, IL12, and IL10 levels in supernatants were measured by ELISA and RIA. RESULTS: mDC from patients with RA showed a markedly increased production of IL1, IL6, TNFalpha, and IL10 compared with DC from healthy donors. Triggering of FcgammaR decreased the production of proinflammatory cytokines IL1, IL12, and IFNgamma by iDC and mDC in RA and controls. The production of IL6 and TNFalpha decreased in patients with RA, whereas it was increased in controls. Triggering of FcgammaR independent mechanisms using IFNgamma increased the production of proinflammatory and Th1 cytokines, which was more pronounced in RA. CONCLUSION: FcgammaR dependent pathways influence cytokine production by DC. A skewed balance towards proinflammatory and Th1 cytokines in RA can, at least partly, be restored by triggering FcgammaR on DC in RA. Insight into the mechanism which determines the FcgammaR balance might lead to new strategies to abrogate Th1 driven inflammatory processes in RA.

Arthritis, Rheumatoid↗
PubMed2004

Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages.

BACKGROUND: Antibodies directed to proteins containing the non-standard amino acid citrulline, are extremely specific for rheumatoid arthritis (RA). Peptidylcitrulline can be generated by post-translational conversion of arginine residues. This process, citrullination, is catalysed by a group of calcium dependent peptidylarginine deiminase (PAD) enzymes. OBJECTIVE: To investigate the expression and activity of four isotypes of PAD in peripheral blood and synovial fluid cells of patients with RA. RESULTS: The data presented here show that citrullination of proteins by PAD enzymes is a process regulated at three levels: transcription-in peripheral blood PAD2 and PAD4 mRNAs are expressed predominantly in monocytes; PAD4 mRNA is not detectable in macrophages, translation-translation of PAD2 mRNA is subject to differentiation stage-specific regulation by its 3' UTR, and activation-the PAD proteins are only activated when sufficient Ca(2+) is available. Such high Ca(2+) concentrations are normally not present in living cells. In macrophages, which are abundant in the inflamed RA synovium, vimentin is specifically citrullinated after Ca(2+) influx. CONCLUSION: PAD2 and PAD4 are the most likely candidate PAD isotypes for the citrullination of synovial proteins in RA. Our results indicate that citrullinated vimentin is a candidate autoantigen in RA.

Arthritis, Rheumatoid↗
PubMed2004

Increased FcgammaRII expression and aberrant tumour necrosis factor alpha production by mature dendritic cells from patients with active rheumatoid arthritis.

OBJECTIVES: To investigate potential differences in phenotype and behaviour of immature (iDC) and mature dendritic cells (mDC) from patients with RA and healthy subjects. METHODS: iDC and mDC were derived from blood monocytes of patients with RA and healthy controls following standardised protocols. FACS was used to analyse expression of FcgammaRI, II, and III and molecules to characterise DC. Discrimination between FcgammaRIIa and FcgammaRIIb was achieved by RT-PCR. Immunohistochemistry was performed on synovial biopsy specimens of three patients with RA and three healthy controls. TNFalpha production by iDC and mDC upon FcgammaR dependent stimulation was compared between patients with RA and controls by ELISA. RESULTS: iDC from patients with active RA but not from patients with inactive RA or healthy controls markedly up regulated FcgammaRII. mDC from patients with active RA also lacked the physiological down regulation of FcgammaRII that occurs upon maturation in both control groups. RT-PCR analysis confirmed the increased expression of FcgammaRII in RA-especially marked for FcgammaRIIb. FcgammaR dependent stimulation of DC using antigen-IgG immune complexes (IC) significantly increased TNFalpha production by DC from healthy subjects, but significantly decreased TNFalpha by DC from patients with RA. Overlapping expression patterns between FcgammaRII and DC-LAMP in the synovial tissue of patients with RA imply that in vivo, also, mature DC express increased levels of FcgammaRIIb. CONCLUSION: The presence and altered characteristics of DC during active RA suggest that DC help to modulate autoimmunity in RA. Further studies should elucidate the role of local factors in altering the function of DC in RA and in increasing expression of FcgammaRII.

Antigen-Antibody Complex↗
PubMed2003

Adalimumab, a fully human anti-TNF-alpha monoclonal antibody, treatment does not influence experimental UV response in the skin of rheumatoid arthritis patients.

TNF-alpha is known to play an important role in UV-induced immunomodulation and photodamage. It plays a role in UVB-mediated induction of apoptosis and is a strong inducer of the c-Jun N-terminal kinase (JNK) pathway, which eventually leads to the loss of dermal collagen and elastin content. Recently chimeric anti-TNF-alpha has been introduced as a therapy for rheumatoid arthritis. The aim of the present study was to investigate the effect of anti-TNF-alpha treatment on UV-induced DNA damage, apoptosis, and induction of matrix metallo proteinases. Twelve patients with rheumatoid arthritis were included and irradiated with 2 MED broadband UVB before and after administration of 0.5 mg/kg anti-TNF-alpha monoclonal antibody. Twenty-four hours after irradiation biopsies were taken. Frozen and paraffin sections were stained for p53, c-Jun, phosphorylated c-Jun, sunburn cells and MMP-1. No significant changes were observed in the expression of p53 and sunburn cells and MMP-1 content after treatment with anti-TNF-alpha, whereas a slight but significant decrease in c-Jun and phosphorylated c-Jun expression was noted (P = 0.0250 and P = 0.0431, respectively). Our results showed no influence of anti-TNF-alpha on UV response at therapeutic doses in patients with rheumatoid arthritis.

Adalimumab↗
PubMed2003

Scintigraphic detection of tumour necrosis factor in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the biodistribution and specific targeting for tumour necrosis factor (TNF) of a fully human, radiolabelled anti-TNF monoclonal antibody (anti-TNF mAb) in patients with active rheumatoid arthritis (RA). To assess whether this agent is suitable for visualisation of synovitis. METHODS: Ten patients with RA underwent whole body scintigraphy after administration of a tracer-subtherapeutic dose of 100 microg (99m)Tc human anti-TNF mAb. After two weeks, the procedure was repeated to assess the specificity of the radiolabelled antibody for TNF and its sensitivity for changes in inflammation. Therefore, a competition study was performed in five patients, who received excess unlabelled anti-TNF mAb before the tracer dose of (99m)Tc-anti-TNF. Another five patients received 120 mg methylprednisolone two days before the second scintigraphy. RESULTS: Radiolabelled anti-TNF mAb allowed clear visualisation of inflamed joints in patients with active RA with a high specificity. Concomitant administration of excess unlabelled anti-TNF reduced the joint uptake of (99m)Tc-anti-TNF mAb by a median of 25% as a percentage of the injected dose after 24 hours, whereas uptake in liver and spleen remained unchanged. Systemic corticosteroids reduced the disease activity, which was mirrored by a decreased joint uptake of the tracer. The anti-TNF mAb retained its high affinity for TNF alpha after labelling and was cleared from the circulation with an elimination half life of 48 hours. The procedure was well tolerated. CONCLUSIONS: Radiolabelled human anti-TNF mAb allows visualisation of synovitis in patients with RA. Joint accumulation of this agent is partly due to specific TNF targeting and is highly predictive for inflammation.

Aged↗
PubMed2003

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.

Adult↗
PubMed2002

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.

Antibodies, Monoclonal↗
PubMed2002

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.

Adalimumab↗