Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy

OBJECTIVE: To evaluate the safety and efficacy of single and multiple doses of a chimeric anti-TNF-alpha monoclonal antibody (infliximab) in patients with rheumatoid arthritis (RA) who had active disease despite therapy with methotrexate (MTX). METHODS: Twenty-eight patients with active RA despite receiving therapy with 10 mg/week of MTX were randomized to receive a single, blinded infusion of either placebo or 5, 10, or 20 mg/kg infliximab. Twenty-three patients who completed the blinded study entered an open, multiple dose extension study in which they received up to 3 additional infusions of 10 mg/kg infliximab at Weeks 12, 20, and 28. Safety, efficacy, and pharmacokinetics were evaluated during the blinded and open trial. RESULTS: There were no serious infusion related reactions. In the blinded phase, 17 (81.0%) of 21 patients receiving infliximab achieved an American College of Rheumatology (ACR) 20% response at some point during the 12 weeks of followup compared to one (14.3%) of 7 patients receiving placebo (p = 0.003). Clinical improvement was evident by the first week and was sustained through Week 12. For the 19 patients who received infliximab during the blinded part of the trial and continued into the open label trial, 53% maintained an ACR 20% response with multiple infusions of 10 mg/kg infliximab through Week 40. Three patients withdrew from the trial during the open continuation phase because of adverse events: cellulitis, infusion related dizziness and headache, and vasculitic rash. Infliximab in doses of 5 to 20 mg/kg had a mean terminal half-life ranging from 9 to 12 days and was detectable in sera from most patients 8 to 12 weeks after dosing. CONCLUSION: Infliximab is generally well tolerated during 40 weeks of therapy. A single infusion of 5 to 20 mg/kg infliximab significantly decreases the signs and symptoms of RA compared to placebo in patients with active disease receiving MTX. Multiple doses of infliximab produce sustained clinical benefit for up to 40 weeks.     

Neutrophil migration and production of reactive oxygen species during treatment with a fully human anti-tumor necrosis factor-alpha monoclonal antibody in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the effects of therapy with a fully human anti-tumor necrosis factor (TNF)-alpha monoclonal antibody on the production of superoxide and other reactive oxygen species (ROS) and on the migration capacity of neutrophils in patients with rheumatoid arthritis (RA). METHODS: A total of 29 patients with active RA and 25 healthy controls participated. Assessments were performed at baseline and 2 weeks after the first administration of anti-TNF-alpha. The production of ROS was studied in unstimulated conditions and after stimulation of receptor dependent (serum treated zymosan, STZ) and receptor independent (phorbol mystrate acetate, PMA) pathways by luminol enhanced chemiluminescence. As well, the PMA induced burst production of superoxide was measured using the cytochrome-c reduction assay. Potential changes in neutrophil migration to joints were assessed by scintigraphy with autologous leukocytes. RESULTS: Baseline production of ROS (both spontaneously and after STZ stimulation) and superoxide and the ex vivo chemotaxis were similar in RA patients (n = 25) and controls (n = 25) and remained unchanged after administration of anti-TNF-alpha. The production of ROS after PMA stimulation was slightly higher in patients than in controls (p = 0.04) and this difference disappeared 2 weeks after the first dose of anti-TNF-alpha (p < 0.05). The scintigraphic study showed that a single dose of anti-TNF-alpha, but not placebo, markedly decreased the influx of leukocytes to inflamed joints. CONCLUSION: In patients with RA, anti-TNF-alpha therapy rapidly decreases the influx of leukocytes into inflamed joints but does not impair neutrophil chemotaxis and production of ROS.     

Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis

The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment, especially in the first 6 weeks.     

Factors associated with toxicity,final dose,and efficacy of methotrexate in patients with rheumatoid arthritis

OBJECTIVE: To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: Data were used from a randomised clinical 48 week trial on 411 patients with RA all treated with MTX, comparing folates and placebo. Logistic regression was used to study the relation between baseline variables and various dependent factors, including hepatotoxicity (alanine aminotransferase >/=3 x upper limit of normal), MTX withdrawal, final MTX dose >/=15 mg/week, and MTX efficacy. RESULTS: Addition of folates to MTX treatment was strongly related to the lack of hepatotoxicity. Next to this, high body mass index was related to the occurrence of hepatotoxicity. Prior gastrointestinal (GI) events and younger age were related to the adverse event, diarrhoea. Hepatotoxicity and GI adverse events were the main reason for MTX withdrawal, which in turn was associated with the absence of folate supplementation, body mass index, prior GI events, and female sex. Renal function (creatinine clearance >/=50 ml/min) was not associated with toxicity. Reaching a final dose of MTX of >/=15 mg/week was related to folate supplementation and the absence of prior GI events. Efficacy of MTX treatment was associated with low disease activity at baseline, male sex, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lower creatinine clearance. CONCLUSIONS: MTX toxicity, final dose, and efficacy are influenced by folate supplementation. Baseline characteristics predicting the outcome of MTX treatment are mainly prior GI events, body mass index, sex, use of NSAIDs, and creatinine clearance.     

Adalimumab,a fully human anti-tumor necrosis factor alpha monoclonal antibody,for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

OBJECTIVE: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. METHODS: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. RESULTS: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. CONCLUSION: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.     

The impact of escalating conventional therapy in rheumatoid arthritis patients referred for anti-tumour necrosis factor-alpha therapy

OBJECTIVE: To assess the impact of escalating conventional therapy in patients with RA who satisfy BSR/NICE criteria for biologics. METHODS: A total of 308 consecutive patients referred to a tertiary centre for biological therapy between January 1999 and February 2001 were studied prospectively. They were considered by their own consultant to have failed standard therapy. Prior to biologics, conventional therapy was escalated to include combination and parenteral methotrexate treatment. Patients were assessed at 12-weekly intervals for 1 yr and therapy was changed if response was not satisfactory. The subsequently released BSR/NICE biologic eligibility criteria were applied retrospectively. Response (disease activity, disability and quality of life) to escalated therapy in those patients who did or did not satisfy current eligibility criteria were compared. RESULTS: In total, 159 satisfied BSR/NICE criteria and would have been eligible for immediate treatment with biologics [DAS28 > 5.1, failed methotrexate (20 mg/week or lower dose owing to toxicity) and one other DMARD]; however, 93 of these responded to escalated conventional therapy and did not require biologics [significant improvement (P < 0.01) in disease activity, disability and quality of life]. However, mild disease activity (DAS28 < 3.2) was only achieved in 7% of these patients at 12 months. CONCLUSIONS: Although over half the patients who satisfied standard criteria for biologics responded satisfactorily to escalated therapy, only a minority achieved mild disease activity. The savings achieved by treating with conventional therapies need to be weighed against the risk of persistent disease activity.     

A single dose,placebo controlled study of the fully human anti-tumor necrosis factor-alpha antibody adalimumab (D2E7) in patients with rheumatoid arthritis

OBJECTIVE: To assess the pharmacokinetics, safety profile, and efficacy of the fully human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody adalimumab (D2E7) in patients with long-standing, active rheumatoid arthritis (RA). METHODS: This was a randomized, double blind, placebo controlled study of single intravenous injections of ascending doses (0.5 to 10 mg/kg) of adalimumab in 5 cohorts of 24 patients each (18 adalimumab and 6 placebo in all cohorts except the 0.5 mg/kg cohort of 17 adalimumab, 7 placebo). A total of 120 patients participated (adalimumab 89, placebo 31). The clinical response was measured by changes in composite scores defined by the criteria of the European League Against Rheumatism (EULAR) and the American College of Rheumatology. RESULTS: Single doses of adalimumab showed a rapid onset of clinical effect (24 hours to 1 week), with peak efficacy at 1 to 2 weeks that was sustained for at least 4 weeks and for as long as 3 months in some patients. EULAR response was seen at least once during the 4 week period after drug injection in 29% of patients in the placebo group as well as in 41%, 78%, 72%, 89%, and 100% in the 0.5, 1, 3, 5, and 10 mg/kg groups, respectively. No dose related increases in adverse events were observed in the adalimumab patients compared with the placebo group. Adalimumab systemic drug exposure (AUC0-( )) increased linearly with an increase in dose. The mean total serum clearance was 0.012 to 0.017 l/h, and the steady-state volume of distribution ranged from 4.7 to 5.5 l. The estimated mean terminal half-life ranged from 10.0 to 13.6 days for the 5 cohorts, with an overall mean half-life of 12 days. CONCLUSION: Treatment with the fully human Mab adalimumab was safe and well tolerated when administered as a single intravenous injection at doses up to 10 mg/kg, and was associated with a clinically significant improvement in the signs and symptoms of active RA.     

Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis

Weekly treatment with low-dose oral methotrexate (MTX) was compared with daily auranofin (AUR) treatment in a 36-week double-blind, randomized, multicenter study of 281 patients with active, adult-onset rheumatoid arthritis. Both treatment groups showed significant improvement by the usual measures of clinical efficacy. The response with MTX occurred earlier and was consistently greater than that with AUR. An intent-to-treat analysis showed significantly greater improvement (P < 0.01) with MTX for painful and swollen joint counts and physician and patient global assessments of disease activity. Adverse reactions were reported more frequently in the AUR group, and more AUR-treated patients were withdrawn from the study because of toxicity. MTX was thus more effective and better tolerated than AUR in this study.     

Iguratimod combination therapy compared with methotrexate monotherapy for the treatment of rheumatoid arthritis: a systematic review and meta-analysis

Clinical Rheumatology - We estimated the relative efficacy and safety of iguratimod combination therapy compared with methotrexate monotherapy for the treatment of rheumatoid arthritis. We...     

Anti-tumor necrosis factor-alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis

The aim of this study was to analyze the change of serum chemokins levels of CXCL16, CX3CL1/Fractalkine, and CXCL10/interferon-gamma inducible protein-10 (IP-10) with rheumatoid arthritis (RA), by infliximab treatment. The effects of infliximab treatment were studied in 23 patients with RA, over a period of 30 weeks. The serum levels of CXCL16, Fractalkine, and IP-10, were measured at the baseline, just before initial treatment, and at 14 and 30 weeks after the initial treatment, with infliximab by ELISA. The higher levels of serum CXCL16 in the RA patients before treatment with infliximab significantly decreased at 14 and 30 weeks after the initial treatment with infliximab, but the serum Fractalkine and IP-10 levels did not decrease significantly. Infliximab treatment significantly lowered the serum levels of CXCL16 in patients with RA. CXCL16 is one of the crucial chemokines regulated by infliximab treatment.     

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis

OBJECTIVE: To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA). METHODS: Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty-four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS < or = 2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients. RESULTS: The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of < or = 3.5 had a true positive response rate of 95%. Scores of > or = 6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results. CONCLUSION: This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better-tailored initial treatment decisions in patients with RA.     

Requirement of methotrexate in combination with anti-tumor necrosis factor-alpha therapy for adequate suppression of osteoclastogenesis in rheumatoid arthritis

OBJECTIVE: To determine that concomitant use of methotrexate (MTX) is required to achieve adequate suppression of bone destruction in treating rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-alpha)-inhibiting biologic therapy. We quantitatively compared the suppressive effects of treatment with a combination of infliximab and MTX and treatment with each of these 2 agents alone on bone destruction in SCID-HuRAg-pit mice. METHODS: Tissue derived from human RA pannus was implanted with a slice of dentin subcutaneously in the backs of SCID mice (SCID-HuRAg-pit model). Infliximab was administered daily to SCID-HuRAg-pit mice using an osmotic pump for 2 weeks with or without oral administration of MTX. Histological changes in tissue and the pits formed on the dentin slice were examined 8 weeks after transplant. Serum concentrations of TNF-alpha and interleukin 6 (IL-6) were also measured. RESULTS: Treatment with a combination of infliximab and MTX suppressed pit formation significantly, while treatment with neither infliximab alone nor MTX alone had a significant effect on pit formation. Synovial inflammation and serum TNF-alpha and IL-6 levels were suppressed by infliximab with or without MTX. CONCLUSION: This is the first evidence in an animal model of arthritis that concomitant use of MTX is required to achieve adequate suppression of bone destruction when treating RA with a TNF-alpha-inhibiting biologic. Our findings suggest that infliximab suppresses bone destruction through a mechanism of action different from that mediating its antiinflammatory effects in the treatment of RA.     

The safety of anti-tumour necrosis factor therapy in rheumatoid arthritis

PURPOSE OF REVIEW: Anti-tumour necrosis factor therapy has proven effective as treatment against a series of autoimmune inflammatory diseases, and has displayed a rapidly increasing market penetration. The safety profile of these drugs is, however, both uncertain and debated, in particular with respect to infections and malignancy. Lack of uniform definitions and methods of analysis makes it difficult to directly compare data from randomized controlled trials, meta-analyses of trials, open-label extensions, data from spontaneous reporting, and particularly, observational cohort studies. RECENT FINDINGS: In this review, we provide a summary of currently published data on infection, malignancy, cardiovascular disease, interstitial lung disease, and death in relation to treatment of rheumatoid arthritis with anti-tumour necrosis factor agents. SUMMARY: Superficially contradictory data on infection display a more or less coherent pattern of an increased risk shortly after treatment starts. Available data on malignancy, cardiovascular disease, interstitial lung disease, and death do not exclude clinically important increased risks, nor do they refute beneficial effects. Harmonized methods of reporting safety data would greatly improve the interpretation and comparison of class and drug-specific risks.     

Chronic pulmonary toxicity of methotrexate and rheumatoid arthritis

SIR, Methotrexate (MTX) is the most frequently used second-linetherapy in rheumatoid arthritis (RA) and is used widely in manyother autoimmune disorders. Pulmonary toxicity has been reportedin 2–7% of patients receiving low-dose MTX [1], and acutehypersensitivity pneumonitis is the most feared complication[2]. It has also been suggested that chronic pulmonary fibrosiscan     

Peripheral blood lymphocytes from patients with rheumatoid arthritis are differentially sensitive to apoptosis induced by anti-tumour necrosis factor-alpha therapy

OBJECTIVE: The efficacy of anti-tumour necrosis factor-alpha (TNF-alpha) therapies in rheumatoid arthritis (RA) has been mainly attributed to TNF-alpha neutralisation. Other mechanism as immune cell apoptosis, which is impaired in RA, may also be induced by anti-TNF-alpha therapies. The aim of our study was to investigate whether TNF-alpha inhibitors could induce apoptosis in vitro of the peripheral blood lymphocytes of RA patients. METHODS: Peripheral blood mononuclear cells (PBMC) isolated from 24 patients with RA and 18 healthy donors were incubated with anti-TNF-alpha agents, infliximab or etanercept, in comparison with no agent and including an isotypic control, for 48 hours. Apoptosis was detected and quantified by annexin V labelling of phosphatidylserine externalization using cytofluorometric analysis and compared with PBMC production TNF-alpha in vitro. RESULTS: In healthy donors, induced apoptosis was observed in 0.3% to 3.8% of lymphocytes with both therapies. In RA patients the treatment induced lymphocyte apoptosis in 17 of 24 patients with a percentage of annexin V-positive lymphocytes ranging from 0.1% to 25%. Among these 17 RA patients, a significant in vitro lymphocyte apoptosis (> 4%) was observed in 11 patients (46%) compared with healthy donors (p < 0.01). The variability of the response to anti-TNF-alpha within the RA population was not dependent on TNF-alpha synthesis or disease activity. CONCLUSION: In vitro induction of lymphocyte apoptosis by anti-TNF-alpha was observed in a subgroup of RA patients. Based on these data, it would be of interest to further study the interindividual variations of sensitivity to apoptosis induced by TNF alpha inhibitors in relation to treatment efficacy or resistance observed in RA patients.