Christian Antoni

Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis

OBJECTIVE To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26. RESULTS Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P < 0.001 versus placebo). Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 (median duration 2.6 weeks; P=0.126 versus placebo). However, coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic, prolonging the duration of the 20% response in >60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients. CONCLUSION Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.

Psoriatic arthritis: epidemiology, clinical features, course, and outcome

Psoriatic arthritis (PsA) has been defined as a unique inflammatory arthritis associated with psoriasis. Its exact prevalence is unknown, but estimates vary from 0.3% to 1% of the population. The clinical features described initially are recognised by most experienced clinicians, although they are most distinct in early disease. Initially, PsA typically presents as an oligoarticular and mild disease. However, with time PsA becomes polyarticular, and it is a severe disease in at least 20% of patients. Patients with PsA who present with polyarticular disease are at risk for disease progression. In addition to progression of clinical and radiological damage, health related quality of life is reduced among patients with PsA. It important to note that patients included in recent drug trials resemble patients followed prospectively in a clinic.

The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): Results of radiographic analyses after 1 year

Objective: Infliximab is effective in improving signs and symptoms of joint/skin involvement, functional status, and quality of life in patients with psoriatic arthritis (PsA). Using IMPACT trial data, we assessed the effect of infliximab (IFX) on structural damage in PsA. Methods: Patients with active PsA were randomly assigned to receive placebo (PBO/IFX) or infliximab 5 mg/kg (IFX/IFX) at weeks 0, 2, 6, and 14, with the primary endpoint at week 16. The PBO group received infliximab loading doses at weeks 16, 18, and 22. Thereafter, all patients received infliximab 5 mg/kg every 8 weeks through week 50. Hand/feet radiographs were obtained at weeks 0 and 50. Total radiographic scores were determined using the PsA modified van der Heijde-Sharp (vdH-S) score. Projected annual rate of progression was calculated by dividing x ray score by disease duration (years). Results: As reported previously, 65% of infliximab treated patients versus 10% of PBO treated patients achieved an ACR20 response at week 16 (p<0.001). At week 50, 69% of patients achieved an ACR20 response. Radiographs (baseline and week 50) were available for 72/104 patients. At baseline, estimated mean annual rate of progression was 5.8 modified vdH-S points/year. Mean (median) changes from baseline to week 50 in the total modified vdH-S score were −1.95 (−0.50) for PBO/IFX and −1.52 (−0.50) for IFX/IFX patients (p = NS). At week 50, 85% and 84% of patients in the PBO/IFX and IFX/IFX groups had no worsening in the total modified vdH-S score. Conclusion: Infliximab inhibits radiographic progression in patients with PsA through week 50.

Psoriatic arthritis assessment tools in clinical trials

In order to measure disease activity, progression, and change with therapy in psoriatic arthritis (PsA), it is important to use accurate, reliable, and feasible outcome measures that can ideally be employed in longitudinal cohorts, clinical trials, and clinical practice. Until recently, there has been little focus on this methodology in PsA. Clinical trials and long term clinical registries have used disparate outcome measures. With emerging therapies, the focus on the methodology of outcome assessment has increased to ensure that discriminant and responsive instruments are used. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), in conjunction with the society, Outcome Measures in Rheumatology (OMERACT), is focused on refining and developing outcome measures for a variety of disease domains reviewed in this report. Key domains to assess include joints, skin, enthesitis, dactylitis, spine, joint damage as assessed radiologically, quality of life, and function. These domains can be assessed by individual and composite measures. A number of measures have been “borrowed” from the fields of rheumatoid arthritis, ankylosing spondylitis, and psoriasis and adapted to PsA. Others are being developed specifically for PsA. Few are validated but most have been shown to perform well in distinguishing placebo from treatment response. This report reviews the current state of the art of assessment in PsA and points toward future directions of development of this field.

Treatment of psoriatic arthritis with antitumour necrosis factor-α antibody clears skin lesions of psoriasis resistant to treatment with methotrexate

Background  In inflamed skin, keratinocytes and inflammatory cells both produce large amounts of tumour necrosis factor (TNF) ‐α, a cytokine with broad effects that are relevant to inflammation. Blockade of this proinflammatory cytokine by a monoclonal anti‐TNF‐α antibody might be effectively used in the treatment of inflammatory skin diseases.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial

Objective: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. Methods: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. Results: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin’s lymphoma (infliximab). Conclusion: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

Successful treatment of a small cohort of patients with adult onset of Still's disease with infliximab: first experiences

OBJECTIVE To test the efficacy of infliximab in the treatment of patients with severe and active adult onset Stills syndrome (AOSD) despite conventional immunosuppressive therapy. PATIENTS AND METHODS Six patients with the diagnosis of AOSD according to the Yamagushi criteria of 1992 were treated with infliximab. All patients had severe disease with high clinical and serological activity. Patients were treated initially with high dose steroids or more intensive immunosuppressive therapy. Two patients had a history of multiple disease modifying antirheumatic drug (DMARD) treatments. One patient had a history of three years of AOSD with fever, chills, pleural and pericardial effusions, and hepatosplenomegaly. Despite these treatments, he developed increasing serological signs of inflammation and arthritis of both hips and peripheral joints. Another patient had a history of five years of AOSD with oligoarthritis, myalgias, and recurrent fever despite multiple DMARD treatment, including cyclophosphamide pulse therapy. Our patients with AOSD presented with massive polyarthralgias, polyarthritis, splenomegaly or hepatomegaly, the typical rash, sore throat, weight loss, serositis, continuing fever, leucocytosis, and raised C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and ferritin levels. Four patients with early onset of the disease, fulfilling the diagnostic criteria for AOSD and a clinical and serological high disease activity, were included in our pilot study without any further DMARD treatment apart from the initial steroid treatment. Reduction of established treatment, mainly with steroids, caused a relapse of the disease in all our patients. Patients then received 3–5 mg/kg infliximab on weeks 0, 2, and 6, continuing with intervals of 6–8 weeks depending on the patients individual disease activity. RESULTS In all patients, fever, arthralgias, myalgias, hepatosplenomegaly, and the rash resolved after the first courses of treatment with infliximab. All serological variables (CRP, ESR, hyperferritinaemia) returned to normal. After three courses of infliximab infusions, splenomegaly could not be detected in any of our patients. One patient still had severe pain in the left hip caused by hip postarthritic osteoarthrosis, requiring hip replacement. After three courses of treatment with infliximab, splenomegaly could not be detected in any of our patients. Up to now, our patients have received infliximab infusion treatment for between five and 28 months. Throughout this period all patients have continued to benefit from this treatment, with improvement in their clinical symptoms, joint counts, and serological disease activity. One of our patients had a moderate infusion reaction during the second treatment. The infusion was discontinued for one hour and then was resumed with no further problems. CONCLUSION The disease improved remarkably in all six patients with AOSD after treatment with infliximab, also in the early stage of AOSD. These preliminary data suggest the potential therapeutic benefit of anti-tumour necrosis factor α treatment in AOSD.

Infliximab improves health-related quality of life and physical function in patients with psoriatic arthritis

Objectives: To evaluate the effect of infliximab on health related quality of life (HRQoL) and physical function in patients with active psoriatic arthritis (PsA) in the IMPACT 2 trial. Methods: 200 patients with PsA unresponsive to conventional treatment were randomised to intravenous infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22; patients with inadequate response entered early escape at week 16. HRQoL was assessed using the Short Form-36 (SF-36) at weeks 0, 14, and 24. Functional disability was assessed using the Health Assessment Questionnaire (HAQ) at every visit through week 24. Associations between changes in quality of life (SF-36) and articular (American College of Rheumatology (ACR)) and dermatological (Psoriasis Area and Severity Index (PASI)) responses were examined. Results: Mean percentage improvement from baseline in HAQ was 48.6% in the infliximab group compared with worsening of 18.4% in the placebo group at week 14 (p<0.001). Furthermore, 58.6% and 19.4% of infliximab and placebo treated patients, respectively, achieved a clinically meaningful improvement in HAQ (that is, ⩾0.3 unit decrease) at week 14 (p<0.001). Increases in physical and mental component summary (PCS and MCS) scores and all eight scales of the SF-36 in the infliximab group were greater than those in the placebo group at week 14 (p⩽0.001). These benefits were sustained through week 24. Patients achieving ACR20 and PASI75 responses had the greatest improvements in PCS and MCS scores. Conclusions: In patients with PsA, infliximab 5 mg/kg significantly improved HRQoL and physical function compared with placebo through 24 weeks.

Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases (May 2002)

A s in previous years, the consensus group to consider the use of biological agents was formed by an organising committee constituted of rheumatologists from the Universities of Erlangen, Leiden, and Vienna in Europe in cooperation with universities in the United States, Canada, and Europe. Pharmaceutical industry support was obtained from a number of companies, but these institutions had no part in the decisions about the specific programme or about the academic participants at this conference. The 158 rheumatologists and bioscientists from 22 countries who attended the consensus conference were chosen from a worldwide group of people felt to have experience or interest in the use of biological agents for the treatment of rheumatoid arthritis (RA) and other rheumatic diseases. Unfortunately, the number of attendees and participants was limited so that not everyone who might have been appropriate could be invited. Additional information has come to light in the past year, both corroborating the major positive effect these drugs have had in RA and documenting possible new and unexpected adverse events. In addition, the first of a new class of targeted biological agents, interleukin 1 (IL1) blocking agents, has become available. Therefore an update of the previous consensus statement1 seems both appropriate and necessary. In the present update the consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 3.2 All participants reviewed relevant clinical published articles relating to tumour necrosis factor (TNF) and IL1 blocking agents. They were given a draft consensus statement and were asked to revise the document in small discussion groups; open discussion of the revisions led to a final document, representing this updated consensus statement. Individual patients differ in the aggressiveness of their …

NMR monitoring of rheumatoid arthritis patients receiving anti-TNF-α monoclonal antibody therapy

The aim of this study was to investigate if dynamic gadolinium-DTPA-supported magnetic resonance (MR) imaging can monitor the therapeutic effect of a fast-acting immuno-modulating drug like anti-tumour necrosis factor alpha (anti-TNF-α) monoclonal antibody (moab) in patients with rheumatoid arthritis (RA). Dynamic MR imaging was performed on 64 joints in a total of 18 patients before and after infusion with either a placebo or 1 or 10 mg/kg of anti-TNF-α moab. Additionally, treating the placebo group and reinfusing the verum group with either 3 or 10 mg/kg was monitored by quantitative nuclear magnetic resonance (NMR). Time-dependent signal intensity changes were then correlated with a total of five Paulus criteria and with ESR and C-reactive protein (CRP). No changes in either the gadolinium uptake or clinical parameters were seen after the infusion of a placebo. Therapy with 1 mg/kg anti-TNF-α moab resulted in a significant decrease in clinical disease activity, as well as in gadolinium-DTPA uptake in dynamic NMR studies. However, correlations between signal intensity changes and Paulus criteria were only demonstrated for the variable “doctors evaluation of disease activity”. Patients given 10 mg/kg moab demonstrated a very significant improvement in all clinical manifestations of their disease, as well as a high significant reduction in gadolinium uptake (P=0.004). In addition, the latter group showed significant correlations between time-dependent signal intensity changes and five Paulus criteria: “number of swollen joints”, “number of painful joints”, “duration of morning stiffness”, “doctors evaluation of disease activity” and “patients evaluation of disease activity”. No differences and correlations were seen for ESR and CRP. We concluded that dynamic NMR studies are suitable to monitor inflammatory activity in RA patients under therapy with biological response modifiers such as anti-TNF-α moab.