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欧洲抗风湿病联盟2005年会热点
Highlights of the European League Against Rheumatism (EULAR) 2005 Annual Meeting
2005年6月8－11日
奥地利维也纳
June 8 - 11, 2005, Vienna, Austria Treating RA: Recent Evidence from the European League Against Rheumatism (EULAR) 2005 Annual Meeting
Stanley B. Cohen, MD
This year's European League Against Rheumatism (EULAR) meeting was held in Vienna, Austria, on June 8-11. As with most of the recent major conferences, presentations varied from basic research evaluating factors initiating a dysregulated immune response to clinical trial data on presently available treatments as well as novel treatments under development. This review will highlight several of the important abstracts from this years meeting focusing on issues relevant to clinicians involved in care for patients with rheumatic diseases.
Several symposia focused on reviews of basic research. Areas of interest included the role of innate and adaptive immunity on the development of the autoantibody response, epitope shedding in Lupus, the role of antineutrophil cytoplasmic autoantibodies (ANCA) as a pathogenic factor in vasculitis, and the role of receptor activator of NFkappaB (RANK) ligand and osteoprotegerin (OPG) in cartilage and bone destruction. Although these were excellent reviews, very little new information was presented. Several presentations focused on the role of synovial fibroblasts in rheumatoid arthritis pannus formation and joint damage. One study Van der Helm-van Mil and colleagues evaluated synovial tissue from 72 rheumatoid arthritis (RA) patients and 50 osteoarthritis patients and evaluated the migration rate of the fibroblasts through a gel matrix (Matrigel), which the authors believed might correlate with tissue invasiveness.[1] A correlation between the rate of migration and the degree of radiographic destruction was also assessed.[1] Compared with the osteoarthritis patients, synovial fibroblasts from RA patients demonstrated greater invasiveness as determined by the gel migration. Additionally, a correlation was noted between invasiveness and radiographic progression. The 18 patients with the least invasiveness had Total Sharp Score (TSS) of 4.0/year compared with the 18 patients with the most invasiveness of 21.8 TSS/year. A study presented by Neumann and colleagues[2] evaluated the migratory and invasive capacity of RA synovial fibroblasts in a SCID mouse model. Synovial fibroblasts obtained from 2 RA patients at surgery were tagged with green fluorescent protein and implanted with normal cartilage in 1 flank. In the other flank, cartilage alone was implanted. After killing the animals at day 60, it was noted that the RA synovial fibroblasts had migrated to the contralateral flank and that these cells were also noted in the spleen and blood. This finding would support the hypothesis that synovial fibroblasts could migrate through the circulation in additional to local generation in the activated synovium.
Several papers focused on the role of dendritic cells and autoimmune disease. Dendritic cells are efficient antigen presenting cells and are crucial to the initiation and perpetuation of T-cell mediated immune response. In lupus, alpha interferon has been demonstrated to activate dendritic cells and enhance B-cell differentiation into antibody secreting plasma cells.[3] The role of alpha interferon in tumor necrosis factor (TNF) inhibitor-induced ANA development was assessed in 60 RA patients on infliximab. ANA+ RA patients on infliximab were found to have significantly higher interferon levels than patients persistently ANA-negative. Additionally, lower levels of plasmacytoid dendritic cells were found in ANA-positive patients, and increased numbers of plasma cells were generated in cell cultures of peripheral blood mononuclear cells after exposure to infliximab compared with controls. The authors concluded that ANA + infliximab RA patients have a "lupus-like" state characterized by decreased plasmacytoid dendritic cells, elevated interferon levels, and increased plasma cell generation.
Two abstracts evaluated toll-like receptor (TLR) expression in cells involved in adaptive and innate immunity. The first by Roelofs and colleagues looked at TLRs on dendritic cells from RA synovium and found markedly increased expression of TLRs 2, 3, 4, and 7.[4] RA dendritic cells produced higher levels of TNF and interleukin (IL) 6 after stimulation of TLR2/4 compared with controls. The second by Rudnicka and coworkers found that bone marrow-derived B cells from RA patients expressed TLR9 protein.[5] After exposure to CpG oligodeoxynucleotides which stimulate TLR9, B cells underwent proliferation and upregulated expression of CD54 and CD86 molecules, markers of adhesion and costimulation. These studies further confirm the role of dendritic cells in the initiation of the autoimmune process in RA.
There were multiple abstracts presented to further support the development of antibody response to citrullinated protein (anti-CCP) hypothesis. Most of these studies reported on the utility of anti-CCP in early RA as well as the association of these antibodies with long-term negative outcomes. A report by Kyriazis and colleagues on the diagnostic sensitivity of anti-CCP in early RA (< 12 months) compared with established RA demonstrated a greater frequency of CCP antibodies (55.5%) than IgM rheumatoid factor (RF, 41.7%) in early disease and similar frequency in established disease.[6] Results from 129 patients from an "Early Arthritis" clinic demonstrated a sensitivity of 76.7% and specificity of 69.7% for anti-CCP antibodies for the diagnosis of RA.[7] Anti-CCP antibodies were also found to be more prevalent and at higher titer in patients with extra-articular manifestations of RA compared with those without.[8]
Smoking as been suggested as a possible factor in the development of RA. An evaluation of the CORRONA database involving over 5000 patients reported that smokers had more swollen and tender joints than nonsmokers, a finding that achieved statistical significance. Additionally, smokers were significantly more likely to have a positive RF, subcutaneous nodules, biologic treatment, and higher HAQ scores than nonsmokers.[9] Another case controlled study of 913 recent-onset RA patients and 631 controls evaluated a possible interaction between an environmental risk factor, smoking, and genetic susceptibility factors, the "Shared Epitope". As reported by Klareskog and colleagues, smoking significantly increased the risk of the development of rheumatoid arthritis in patients positive for CCP antibodies who carry the "Shared Epitope" compared with CCP antibody-positive, "Shared Epitope" nonsmokers.[10]
Several abstracts reported on the increased mortality seen in RA patients. An Australian study by Lassere and colleagues demonstrated that higher functional disability as measured by HAQ and prednisone use were associated with a shortened life span.[11] A Danish patient cohort of early RA patients followed from disease onset found that the higher the DAS28, the higher the risk of cardiovascular disease (HR = 1.7; P = .04).[12] Welsing and colleagues showed that methotrexate (MTX) reduced cardiovascular risk as previously reported (HR = 0.3; P = .03) A report from the National Data Bank for Rheumatic Diseases on long-term mortality demonstrated that anti-TNF therapies reduced mortality primarily due to fewer cardiovascular disorders and that as reported at last year's EULAR meeting, prednisone was associated with increased mortality.[13]
Results from several clinical trials were presented for rituximab and abatacept as well as results from several smaller pilot studies evaluating these new therapies in other rheumatic diseases. The DANCER trial was designed to confirm the efficacy of rituximab (Rituxan) in patients with active RA, despite ongoing MTX treatment.[14] This study by Emery and colleagues evaluated the efficacy and safety of 2 doses of rituximab 500 mg and 1000 mg as well as the role of the peri-infusional and oral corticosteroid treatment (960 mg) that was used in the previously reported phase 2 trial.[14] The primary endpoint for this study was the American College or Rheumatology (ACR) 20 response at 24 weeks in RF-positive patients. The ACR responses for both doses of rituximab were statistically superior to placebo at 6 months -- placebo ACR20-28%, ACR50-13%, ACR 70-5%; rituximab 500 mg ACR20-55%, ACR50-33%, ACR70-13%; rituximab 1000 mg ACR20-54%, ACR50-34%, ACR70-20%. No difference between the 2 rituximab doses was seen, and analysis of the utility of the pretreatment and oral corticosteroids revealed no significant impact on ACR response.[15] No difference in reported serious adverse events and serious infectious events were seen between the placebo and rituximab-treated patients. Infusion reactions occurred in 39% to 46% of patients receiving rituximab and no steroids, 26%-35% receiving rituximab and steroids compared with 17% placebo and no steroids, and 25% on placebo plus steroids. Human antichimeric antibodies (HACAs) were reported in 2.7% to 4.9% of patients. The results of this study document the efficacy of a single treatment of rituximab for RA and demonstrate that corticosteroids are not necessary for this benefit, although the peri-infusional corticosteroids did reduce the frequency of infusion reactions. Phase 3 studies are planned for further evaluation of rituximab in RA.
One of the important questions that relates to rituximab is how safe and effective will re-treatment be? A report on 162 patients from the original phase 2 studies who received at least 1 re-treatment was presented by Pavelka and colleagues.[16] The ACR response rates in 68 patients who received re-treatment at a mean of 96 weeks after initial treatment was similar to the original response (ACR20-63%, ACR50-31%, ACR70-10%). One additional infusion reaction occurred with the repeat infusion, and serious infectious events were rare. HACAs were noted in 6 of 50 patients.
Rituximab was also evaluated in a small open-label trial of 8 patients with primary Sjogren's syndrome and 7 patients with primary Sjogren's syndrome and Mucosa-Associated Lymphatic Tissue (MALT) lymphoma localized to the parotid gland.[17] Rituximab was administered as 4 weekly infusions of 375 mg/m2. Five of the eight primary Sjogren's syndrome patients and two of the seven MALT/primary Sjogren's syndrome patients reported subjective improvement in salivary gland function. RF levels declined along with the B-cell depletion. Three patients developed a transient serum sickness after treatment, and these three patients were positive for HACAs. Larger formal trials are planned evaluating rituximab in Sjogren's syndrome.
The results of a safety study evaluating abatacept (10 mg/kg) in patients with active RA on 1 or more conventional and/or biologic disease-modifying antirheumatic drugs (DMARDs) was reported (ASSURE trial).[18] One thousand, four hundred forty-one patients were enrolled in this placebo controlled trial predominantly on nonbiologic DMARDs, with 167 being on concomitant biologics. The primary finding of this study was a significantly higher rate of serious adverse events (22.3%) on abatacept/biologic combination compared with abatacept/nonbiologic DMARD (11.7%) or biologic/placebo (12.5%). The serious infection rate on the abatacept/biologic combination was 5.8% compared with 1.6% to 2.6% for the other treatment cohorts. These findings showing a greater infection risk are comparable to that previously reported with combination etanercept/anakinra. On the basis of the data presented, the study authors recommended that abatacept should not be used in combination with other biologics.
A separate presentation reported the results of the impact of abatacept on prevention of radiographic progression in patients with active disease, despite methotrexate. The abatacept in incomplete responders to methotrexate (AIM) study involved 443 patients who received abatacept 10 mg/kg for 12 months and 219 patients continued with methotrexate alone.[19] The radiographs were analyzed using the Genant-Sharp methodology. Patients who did not receive abatacept worsened by 2.32 units compared with 1.21 units for the abatacept-treated cohort, (P = .012).
Several subanalyses of the AIM study and ATTAIN (abatacept trial in treatment of anti-TNF inadequate responders) study were presented.[20,21] An evaluation of the response of individual components of the ACR response to abatacept in the AIM study demonstrated statistical superiority to placebo for all components. All the components improved at least 48%, except for the HAQ, which improved a mean of 37.3% and C-reactive protein (CRP), which improved 29%. Using a DAS 28 score less than 2.6 as the definition of remission, 23.8% of abatacept-treated patients were in remission and only 1.9% of placebo patients were in remission. A study of the change in biomarkers in both studies demonstrated a statistically significant reduction in IL-6, MMP-3, TNF alpha, sIL-2R, and RF in abatacept-treated patients compared with the placebo-treated patients.[22]
A pilot dose ranging study of a monoclonal antibody to the IL-6 receptor (tocilizumab) in systemic-onset juvenile idiopathic arthritis (JIA) was presented.[23] Eighteen patients received a single 2, 4, or 8 mg/kg MRA (TOCILIZUMAB) by infusion, and methotrexate was the only concomitant DMARD allowed. Response occurred in all patients by 48 hours, and 70% of the patients achieved a JIA 30 within the first week. The greatest and most prolonged clinical efficacy was seen in the 4-mg dose group. As expected, there was a sharp drop in CRP levels. There were 5 serious adverse events, including chicken pox, transient pancytopenia, 2 episodes of disease flares, and 1 patient with herpes simplex. Three patients had transient liver function test abnormalities. A phase 3 trial in JIA is ongoing and will provide more information on the efficacy and safety of this treatment.
Multiple presentations on the safety and efficacy of approved therapies were reported. The 2-year follow-up of the BeSt trial was presented.[24] The BeSt trial is evaluating 4 treatment strategies in early RA patients: Sequential monotherapy; Step-up combination therapy ("Triple Therapy"); Step-down therapy (Cobra type); and infliximab/methotrexate combination therapy. Adjustments in treatment are directed based on the DAS44 calculation every 3 months with scores greater than or equal to 2.4 resulting in a change in treatment. Additionally, if the DAS44 remained less than 2.4 for at least 2 evaluations, treatments are tapered. At the end of 2 years, the COBRA-type therapy and infliximab combination cohort had a statistically lower HAQ then the sequential monotherapy or step-up groups and less radiographic progression (Sharp van der Heide score -- mean 2.5, 2.6 vs 5.2, 9.0 units; median 1.0 vs 2.0). No difference was seen in the frequency of patients in remission (DAS < 1.6), with approximately 42% achieving that benchmark. Of interest, 55% of patients with early RA who discontinued infliximab maintained their clinical benefit with methotrexate alone. No difference was reported for adverse events between the groups. These data would suggest that aggressive intervention targeting a treatment outcome will result in good patient response over 2 years with modestly better improvements seen with initial biologic/methotrexate or high-dose corticosteroid/DMARD treatment compared with conventional treatments. These patients will be followed up for 10 years, and we look forward to determining whether these findings will persist with long-term follow-up.
TNF inhibitors have demonstrated substantial efficacy in the spondyloarthropathies and are approved for that indication.[25] Several abstracts further characterized the clinical response. A meta-analysis of 7 randomized placebo controlled clinical trials evaluating etanercept and infliximab in ankylosing spondylitis (AS) explored the impact on the frequency of anterior uveitis flares. Of the 717 (32%) AS patients, 229 reported uveitis at study entry. During the study, the incidence of uveitis flares was 3.4/100 pt. years for patients on infliximab, 6.4/100 patient years for etanercept, and 16.2/100 patient years for placebo treatment and this difference was statistically significant (P = .001). The difference between etanercept and infliximab did not reach statistical significance.
Two studies were presented on longer-term follow-up of the IMPACT study evaluating infliximab in psoriatic arthritis. Presented were year 2 results of the previously reported 12-month study.[26] Seventy-eight patients entered year 2 and received infliximab 5 mg/kg every 8 weeks. A total of 69 (88.5%) completed the study, and the ACR 20 response at 24 months was 61.5% compared with 73% at 12 months. ACR 50 (44.9%) and 70 (34.6%) responses were similar to the 12-month responses. Improvements in skin disease activity was maintained, with 64% of patients at year 2 having more than or equal to 75% improvement in their PASI scores. A second analysis of this database evaluated impact of infliximab on radiographic outcomes at 12 months.[27] As previously reported with etanercept, no progression was seen in the infliximab-treated patients. Before study entry, the mean annual rate of progression for the study population was 5.8 modified vdH-S-points/year. Mean (median) changes from baseline to week 50 in the total radiographic score was -1.52 (-0.50) point/year in the infliximab group.
Similar results were reported with adalimumab administered in a standard manner 40 mg every 14 days in psoriatic arthritis. Three hundred thirteen patients were enrolled in a placebo controlled trial, and radiographic progression at 48 weeks was inhibited (mTSS -0.2) in adalimumab-treated patients compared with placebo(mTSS 1.0; P < .001).[28]
Multiple abstracts reported on continued efficacy and safety of infliximab, adalimumab, and etanercept in ankylosing spondylitis patients.[29-32] One abstract reported that 41 of 42 ankylosing spondylitis patients who discontinued infliximab relapsed after a mean 17.5 weeks.[33] Fortunately, readministration of infliximab resulted in efficacy similar to that seen before treatment discontinuation.
Significant progress is being made in our understanding of the long-term risks and benefits of our newer therapies for rheumatic diseases as reflected in the EULAR presentations. The role of CCP antibodies continues to intrigue us as to its place in the pathogenesis of RA, as does the relationship of smoking to RA. As emphasized in the basic research symposia of this conference, further understanding of the role of innate immunity in the development of autoimmune disease will lead to newer strategies for modulation of the disease process. We look forward to further data on the efficacy and safety of abatacept and rituximab in rheumatoid arthritis and other disease such as Sjogren's syndrome and lupus.
This session reviewed some of the recent advances in managing the patient with rheumatoid arthritis (RA). As outlined in Figure 1, one needs to understand the "embryology" of RA to diagnose it as early as possible and treat it effectively. It is likely that RA "begins" earlier than the time at which the patient either first notes pain and inflammation or presents to a physician. This likelihood is important, because there appears to be a therapeutic "window of opportunity" in each patient which is that period in which optimal treatment will yield the best outcome and beyond which there will be therapeutic diminishing returns. Thus defining when RA starts to have its damaging effects upon the joints, soft tissues, blood vessels, and bones is key to the decision as to when therapy should start and what it should be. If RA "hits the ground running" because it has been smoldering immunologically and pathologically for some time, RA does indeed become a medical emergency, demanding immediate and aggressive therapy to alter its intrinsically aggressive personality. No physician would wait for a month or more to treat active diabetes, hypertension, infection, asthma, or angina, and neither should they wait to treat active RA.
Figure 1. The embryology of rheumatoid arthritis.
Figure 2 demonstrates that each patient's tissues is subject to the cumulative, minute-by-minute effect of inflammation that has a cumulative, negative effect and leads to not only joint damage, deformity, and functional limitation but also premature atherosclerosis and myocardial infarctions, osteoporosis, amyloidosis, and non-Hodgkin's lymphoma. So, " striking while the iron is hot" and continuing to demand a "No evidence of disease or inflammation" disease status is mandatory. Therapy should be based upon the well-recognized RA traits, as listed in the Table.
Figure 2. Cumulative inflammatory burden of early arthritis and RA.
Rx = prescription; NED = no evidence of disease
Stephen Paget, MD, who co-chaired the session, highlighted the importance of safer and more sensitive treatment modalities for RA. His analysis of the modern concepts used in fine tuning and safely crafting RA treatments in 2005 included:
The use of pharmacogenomics in guiding more effective and safer treatment with immunosuppressive agents such as azathioprine and methotrexate;
The use of sensitive imaging techniques such as ultrasound and magnetic resonance imaging to:
allow for the earliest possible diagnosis of arthritis and guided therapy during the "window of opportunity"
define the aggressiveness and erosive potential of RA
characterize clinical response in drug trials and real-world care of RA patients
prognosticate;
Infection risk in RA patients treated with anti-tumor necrosis factor (TNF) medications is present but is acceptable and controllable by optimal screening and treatment;
Limiting RA-related comorbidities such as myocardial infarction; and
Optimal measurement of pain
TNF-alpha plays a commanding and dominant role in the ability of the immune system to wall off Mycobacterium tuberculosis (TB) in granuloma by means of its effect upon the dendritic cell, the adaptive immune response, apoptosis of macrophages, upregulation of nitric oxide, and interferon gamma. Actually, the granuloma is an active site of TB infection control. Thus it should be easily understood why the effective, new anti-TNF biologic agents might lead to the development of TB reactivation in patients treated with these amazing new medications. Perez and colleagues[1] presented data that defined the fact that RA itself leads to a 2-fold increased incidence of TB and the addition of anti-TNF medications increase that risk 4-fold. The risk appears to be highest with infliximab and less so with etanercept and adalimumab, probably a reflection of the immunologic characteristics of the biologic and the countries in which the drugs are used. This study presented the European and United States cumulative data of over 14,500 patient years and involved patients who were treated with adalimumab (Humira; the fully humanized monoclonal anti-TNF) during pre- and postscreening for TB. Screening varied from a 5 tuberculin units purified protein derivative (PPD) alone to a PPD + chest x-ray. Patients were considered to test positive for TB if they had a PPD of 5 mm or more, and in those treated with BCG, a PPD of 10 mm or more indicated a positive TB test result. With screening before instituting the anti-TNF and the institution of 9 months of isoniazid (INH) + vitamin B6, TB events per 100 patient years went from 1.3 prescreening to 0.19 postscreening. Most rheumatologists begin the anti-TNF immediately or soon after the institution of INH. It is clear that each locality must define their own optimal screening procedures, because TB appears to be more endemic in Europe than the United States and more in countries like Spain than England.
Askling and colleagues[2] provided data on the risk and characteristics of TB after use of TNF-blockers in clinical practice. In this study involving a cohort of Swedish patients with RA, over a 2-year period (1999-2001), the authors assessed age-adjusted relative risks of hospitalization due to TB in patients with RA not treated with a TNF blocker (n = 31,185) and also in those patients treated with TNF blockers (n = 2510). This finding was compared with hospitalized non-RA individuals in the general population (n = 83,007). Compared with the general population, the risk of hospitalization was doubled in the RA patients not treated with TNF inhibitors. This risk increases to 9-fold in RA patients treated with TNF inhibitors. This study demonstrates that, at least in Sweden, patients with RA are at increased risk of TB when treated with anti-TNF therapy, which may persist over time on treatment.
This important study focuses on the fact that RA is associated with some very dire facts regarding the "collateral damage" that is attendant to this systemic illness: A patient with RA is 2 times more likely to have a myocardial infarction; 70% more likely to have a stroke; 70% more likely to develop an infection; has a 25-fold increased incidence of lymphoma; mortality rates 41% higher for women; and life expectancy decreased by 18 years. Michaud and Wolfe's long-term outcome RA database assessed 63,811 patient years of follow-up, during which 1129 deaths were noted in 19,850 patients.[3] Cardiovascular disorders accounted for 33% of deaths, malignancies for 22%, and lung disorders for 19%. After adjusting for disease severity, comorbidity, and demographic differences, the use of methotrexate (MTX) and anti-TNF medications was associated with a reduction in mortality risk. The primary cause of the decrease was related to cardiovascular risk. Prednisone actually was associated with an increased risk. This finding suggests that, even in more severe RA, treatment with anti-TNF therapy and MTX does make a difference, not only with regard to clinical manifestations but also to mortality.
Individual variability to drug response is related to age; gender; pharmacokinetics; disease severity; concomitant diseases; environmental factors; and genetic differences such as drug metabolism and or cellular drug targets. Pharmacogenetics focuses on genetic variations in genes responsible for drug metabolism, drug transport, and drug targets. For any given gene, there may be sequence variations between individuals, termed allelic variants. An example of this variation is the mutation that causes nonfunctional proteins such as in the cystic fibrosis transmembrane regulator gene. Gene variations are common, and there are 3 million single nucleotide polymorphisms (SNPs). We make use of one of these variations in our treatment with azathioprine (Imuran). Figure 3 demonstrates the metabolism of azathioprine and its metabolite 6-mercaptopurine (6-MP). Thiopurine methyltransferase (TPMT) inactivates 6-MP. Ninety percent of patients have high activity of this enzyme; 10% with intermediate activity and 0.03% are deficient. Studies have demonstrated that the use of routine doses of azathioprine used in low-enzyme patients commonly led to more side effects such as leucopenia because of the high levels of the drug due to low metabolism. Thus before starting azathioprine, it is wise to assess for TPMT activity by a simple blood test. Similarly, methotrexate metabolism (Figure 4) involves enzymes with such polymorphisms, and this study focuses on that feature. The associations of treatment efficacy and toxicity with SNPs in genes coding for the folate pathway enzymes, methylene tetrahydrofolate reductase (MTHFR) and dihydrofolate reductase, and reduced folate carrier in patients with early RA was demonstrated in the study presented by Wessels and colleagues.[4] The study compared 4 treatment strategies in 205 patients with newly diagnosed active RA (ACR 1987 criteria, < 2 years symptoms, >/= 6/66 swollen joints, >/= 6/68 tender joints, erythrocyte sedimentation rate >/= 28 mm/hour or visual analogue scale (VAS) global health >= 20 mm). Patients were treated with MTX (initial dose of 7.5 mg/week and increased to 15 mg/week after 4 weeks), in combination with folic acid (1 mg/day). The efficacy of MTX was evaluated at 3 and 6 months by comparing the genotype distribution with clinical response in 3 analyses: patients with and without good clinical response; patients with and without good improvement; and patients with and without moderate improvement. These investigators demonstrated that patients with early RA show greater clinical improvement when treated with methotrexate if they have MTHFR 1298 AA or MTHFR 677 CC genotype. Patients with other genotypes had more side effects. Thus genotype testing can guide physicians in their choice of RA medications, leading to safer and more effective treatment.
Figure 3. Cellular metabolism of azathioprine.
Figure 4. Cellular metabolism of methotrexate.
Infection is a potential source of serious adverse events in patients with rheumatic disease treated with anti-TNF agents. However, there are few data on the incidence of infections in routine clinical practice and no comparative data between drugs.
In this prospective UK study by Dixon and coworkers,[5] data were analyzed on 2602, 2871, and 915 consecutive patients treated, respectively, with etanercept (ETA), infliximab (INF), and adalimumab (ADA). Incidence of infections was ascertained by consultant and patient follow-up at 6-month intervals. Serious infections were defined as those requiring intravenous antibiotics, leading to a hospital admission, death, or that were in any way life-threatening. Although the rates of serious infection between the 3 anti-TNF agents did not differ significantly, the authors concluded that the incidence rate of serious infections on biologic agents is estimated at between 50 and 65 cases per 1000 person years follow-up. Such rates are lower than reported rates of infections requiring hospitalization in a recent retrospective longitudinal cohort study of RA patients in the United States. There were no important differences between the anti-TNF agents.
Pain associated with RA is one of the main reasons for physician visits. Despite this, there is no clear sense of the importance and tolerability of different levels of pain, the minimally clinically important difference (MCID) and the long-term effect of pain therapy. Pain and function are the primary patient outcomes in RA. Although function has been studied intensively, pain is usually investigated as part of an index in clinical studies.
In this 6-year longitudinal investigation involving 19,479 patients, pain was assessed with a 0-10 VAS and the SF-36 bodily pain scale.[6] Quality of life was assessed in utility units by the EuroQol. MCID was assessed by regression, using published values for the Health Assessment Questionnaire as a guide, and results were confirmed using the 15% change rule. The authors showed that, despite some gender and ethnic differences, anti-TNF therapy resulted in lower levels for pain in persons receiving anti-TNF therapy and pain levels were almost constant over RA duration.
Magnetic resonance imaging (MRI) is an important sensitive tool for monitoring the physical changes in early RA but has not yet been used as outcome measure in large randomized controlled clinical trials. The study by Ejbjerg and colleagues[7] used MRI-determined synovitis and bone erosion as outcome measures to investigate the additional effect of cyclosporine A (CyA) in early RA patients treated with MTX and intra-articular betamethasone (IAB). In this randomized double-blind, placebo-controlled trial, contrast-enhanced MRI was performed at 0, 6, and 12 months in 132 patients with early RA. These patients were randomized to either MTX + IAB + CyA 2.5 mg/kg (CYA group) or MTX + IAB + placebo (PLA group). Patients had IAB in all swollen joints at each visit (week 0, 2, 4, 6, 8, thereafter monthly up to 1 year). Magnetic resonance images were acquired and evaluated for synovitis, bone edema, and bone erosion. Overall, the results demonstrated that cyclosporine did not have additional damaging effects in patients with early RA treated with methotrexate and intra-articular betamethasone.
In early RA, high-frequency ultrasound was demonstrated to be a more effective indicator of early disease modification after infliximab therapy than radiographic monitoring of sequential change in erosion scores[8] This double-blinded study involved 24 patients with RA of less than 3 years duration randomized to infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and thereafter every 8 weeks. High-frequency ultrasound and radiographic images were used to assess erosion in the 2 treatment groups. At 18 weeks, high-frequency ultrasound detected significant reduction in bone erosion only in the MTX-treated group. In contrast, a change was seen with radiographic image only after 30 weeks. These observations are consistent with the hypothesis that soft tissue infill of cortical breaks, detectable by high-frequency ultrasound after only 18 weeks of treatment, is an early feature of the reversal of joint destructive mechanisms that precedes remineralization detectable after 54 weeks of treatment by plain radiography.
The field of rheumatology, in concert with industry, epidemiologists, radiologists, geneticists, molecular biologists, and immunologists, has made a giant step by developing and aggressively using new and effective treatment modalities in a disease that, without early and optimal treatment, is joint damaging, functionally limiting, and life shortening. An integrated clinical approach with constant monitoring of the effect of medications is demanded in a complex illness such as RA to achieve predictable and profound improvements in outcome.