ASPIRE Trial (Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset)
The efficacy and safety of long-term therapy
with infliximab in moderately-to-severely active early rheumatoid
arthritis (ERA) was evaluated in the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE)
trial. This was an international, multicenter, randomized, double-blind
trial of 1,049 patients with active, early RA (disease duration ≥3
months but ≤3 years). Active disease was defined as swollen
joint count
Patients were randomized to 1 of 3 treatment
groups: infusion of infliximab
The primary end point in assessing improvement in signs and symptoms was the ACR-N at Week 54. Secondary end points included proportion of patients in each group achieving an ACR20, 50, and 70 response. Components of the ACR criteria include tender and swollen joint counts, physician and patient global assessments of disease, pain assessment, physical function, and levels of serologic inflammatory markers. The ACR-N represents the least percentage of improvement from baseline in (1) the number of swollen joints, and (2) the number of tender joints, and (3) the medians of the following: physician and patient global assessments, pain assessment, physical function [HAQ score], and level of serologic markers of inflammation.3218, 3219
All analyses were based on evaluable data for
1,004 patients. For the primary end point of ACR-N, patients were
considered nonresponders (i.e., Week 54 ACR-N score was set to 0 regardless
of actual response) if any of the following occurred: protocol prohibited
changes in medications,
Baseline demographics were similar between the 3 groups. Enrolled patients had active, progressive disease as evidenced by baseline swollen and tender joint counts and vdH-S scores.3218
Clinical Response
Both infliximab plus methotrexate (MTX) regimens
resulted in statistically significant improvement in signs and symptoms
of rheumatoid arthritis (RA), as measured by American College of Rheumatology
(ACR-N) scores at Week 54, compared with patients receiving MTX alone.
Significantly more infliximab plus methotrexate (MTX) treated patients
achieved an ACR20, ACR50, and ACR70 response at Week 54, compared
with patients treated with MTX alone. In a retrospective subanalysis,
17% of patients in the infliximab
Figure 700 – Median American College of Rheumatology Improvements at Week 54
Centocor. Data on file. 2003.
Some figures may not display clearly when rendered as a PDF or printed.
Figure 701 – Clinical Response Through Week 54
Centocor. Data on file. 2003.
Some figures may not display clearly when rendered as a PDF or printed.
Patients treated with infliximab plus methotrexate
(MTX) had greater reductions in Disease Activity Scores (DAS)28, compared
with patients treated with MTX alone. Additionally, higher remission
rates were observed in the patients receiving infliximab
Figure 702 – Disease Activity Score in 28 Joints Values at Baseline and Week 54
Centocor. Data on file. 2003.
Some figures may not display clearly when rendered as a PDF or printed.
Radiographic Results
The ASPIRE trial also evaluated the effects of
infliximab in combination with methotrexate (MTX) on radiographic
progression in patients with early rheumatoid arthritis (ERA). Significant
inhibition in the progression of joint damage was observed in infliximab
plus MTX-treated patients relative to patients treated with MTX alone.
The mean change from baseline in van der Heijde modification of the
Sharp score (vdH-S) at Week 54 for the patients treated with infliximab
Of the patients receiving infliximab plus MTX,
59% had no progression (vdH-S score
Physical Function
In the ASPIRE trial, improvement in physical
disability was assessed using the change in the health assessment
questionnaire (HAQ) disability index score averaged over time from
Week 30 to Week 54. Significantly greater improvement in median HAQ
scores averaged over time were observed from Week 30 to Week 54 in
patients receiving both infliximab
Results–ASPIRE Exploratory Analyses
While early aggressive treatment with the goal of achieving remission has become the standard of care in the treatment of moderate to severe rheumatoid arthritis (RA), not all patients require initial treatment with biologics. It is therefore of interest to ascertain if it is possible to predict which patients are at greatest risk for significant and progressive disease.
Smolen, et al, conducted an exploratory analysis of the ASPIRE trial to identify predictors of radiographic progression of joint damage in order to identify subgroups of patients who would derive greater benefit from infliximab plus methotrexate (MTX) therapy. Univariate and multivariate analyses were used to correlate radiographic progression of joint damage to baseline disease and demographic characteristics.3225
Higher baseline swollen joint counts (SJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF) levels were significantly correlated with increasing progression of joint damage from baseline to Week 54 in patients treated with MTX only. The highest correlations were observed with baseline ESR and CRP values. However, the addition of infliximab inhibited radiographic progression regardless of baseline disease characteristics. Furthermore, infliximab-treated patients baseline vdH-S scores were inversely correlated with changes in vdH-S scores from baseline to Week 54.3225
Figure 706 – Correlation Between Baseline Clinical Characteristics and Change in Sharp/van der Heijde Score at Week 54
Table 1, Page 705, Arthritis Rheum. 2006;54:(3):702-710, reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
Some figures may not display clearly when rendered as a PDF or printed.
A treatment benefit with infliximab plus methotrexate
(MTX) vs. MTX alone in early rheumatoid arthritis (ERA) was most evident
in patients with high baseline C-reactive protein (CRP
Also of relevance is the finding of a retrospective
exploratory analysis that patients with
Figure 707 – Median Change in Sharp Score
Centocor. Data on file. 2003.
Some figures may not display clearly when rendered as a PDF or printed.
Content on this page was last reviewed on March 31, 2008.
Content on this page was last changed on March 19, 2009.
References:| 3204. | Remicade [prescribing information]. Malvern, PA: Centocor Ortho Biotech Inc.; November 2009. |
| 3211. | Centocor. Data on file. 2004. |
| 3213. | Smolen JS, Han C, Bala M, et al. Evidence of radiographic benefit of treatment with infliximab plus MTX in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum. 2005;52(4):1020-1030. |
| 3218. | St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: A randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432-3443. |
| 3219. | Schiff M, Weaver A, Keystone E, Moreland L, Spencer-Green G. Comparison of ACR response, numeric ACR, and ACR AUC as measures of clinical improvement in RA clinical trials. Arthritis Rheum. 1999;42(9 Suppl.):S81. |
| 3225. | Smolen JS, van der Heijde DM, St Clair EW, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose MTX with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006;54(3):702-710. |
| 3226. | St Clair EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46(6):1451-1459. |
| 8276. | Centocor. Data on file. 2003. |
| 8279. | Centocor. Data on file. 2003. |
| 8283. | Centocor. Data on file. 2003. |
| 8284. | Centocor. Data on file. 2003. |
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Prescribing Information and Medication Guide
REMICADE® (infliximab) Indications and Important Safety Information
INDICATIONS AND USAGE
Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
Ulcerative Colitis
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
IMPORTANT SAFETY INFORMATION
RISK OF INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®. 1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE®. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE® in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and anakinra was associated with a higher risk of serious infections, therefore the use of REMICADE® in combination with anakinra is not recommended. Live vaccines should not be given with REMICADE®. Bring pediatric Crohn's patients up to date with all vaccinations prior to initiating REMICADE®.
Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.