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Inflammatory Arthritis - RA

Remicade
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In November 1999, the Food & Drug Administration (FDA) approved infliximab for use in rheumatoid arthritis (RA). Infliximab is the second tumor necrosis factor (TNF) inhibitor to be approved for use in RA (etanercept was approved in November 1998).  Infliximab was FDA-approved in 1998 for use in fistulizing and moderate to severe Crohn's disease. Based on Crohn's data and updated RA clinical studies, the FDA extended the indication to include RA patients who have not responded to an adequate trial of methotrexate (MTX). Infliximab is given as an intravenous infusion every eight weeks.
 
Biologic effects. Infliximab is a chimeric IgG1 monoclonal antibody that binds with great affinity to cell-bound and circulating TNFa, but does not bind to TNFb. TNFa is a pleiotropic proinflammatory cytokine that has local and systemic effects on a variety of cells and tissues. By binding to circulating and cell-bound TNF, infliximab abrogates the biologic effects of TNF.  More than 600 RA patients have received infliximab in clinical trials. The results of placebo-controlled trials showed significant ACR20 response rates for infliximab-treated patients when compared to placebo.  Most of these studies were conducted in RA patients with longstanding, severe disease. Whereas early protocols tested the efficacy and safety of infliximab alone, recent trials have tested the combination of infliximab and MTX in MTX non- or partial-responders.
 
FDA approval for RA followed the completion of the large multicenter, multinational ATTRACT (Anti-TNF Therapy in Rheumatoid Arthritis patients on Concomitant Therapy) trial. The ATTRACT trial studied 428 MTX-treated patients randomized to five treatment groups: placebo, 3 mg/kg every 4 or 8 weeks, or 10 mg/kg every 4 or 8 weeks.  All patients received the same induction regimen with infliximab or sham infusions at day 0, week 2, and week 6, then every 4 weeks according to treatment assignment. The clinical results of the first 30 weeks were presented at the 1998 ACR annual meeting and the one-year clinical and radiographic data were presented at the 1999 ACR annual meeting in Boston.  The week 30 data demonstrated highly significant improvement in all infliximab-treated groups, such that the lowest dose and least frequent dosing (3 mg/kg every 8 weeks) demonstrated an ACR20 of 50% compared with a 20% placebo response. Analysis after one year of blinded therapy confirmed the statistical superiority of all methotrexate plus infliximab treatment groups compared to placebo, with the group receiving 10 mg/kg every 8 weeks demonstrating the best responses after a year.
 
Radiographic results, based on 81% of the study population, demonstrated negligible or no change for the majority of infliximab-treated patients (a minority progressed despite therapy), while the patients treated with only MTX showed x-ray worsening. These results were unaffected by disease duration or responder status. The FDA has approved infliximab for use in RA patients with an inadequate response to MTX alone. Patients should be maintained on weekly methotrexate at a clinically effective and tolerable dose. It appears that patients on methotrexate are less likely to have an immunogenic response to the drug.
 
 The standard starting dose is 3 mg/kg with a loading regimen at weeks 0, 2 and 6 and thereafter every eight weeks. Most patients will receive 200 mg (~3 mg/kg) IV per infusion. Nearly half of those responding will improve with their first infusion and in most, the efficacy of the drug can be determined by the week 6 infusion. Patients not responding to the induction protocol should consult their rheumatologist to consider a change in therapy or escalate the dose of infliximab.  Although higher doses may be more effective in some, dose escalation should only be considered after discussing the risks, benefits and costs with the patient. As with etanercept, caution should be exercised when considering the initiation of TNF inhibition in patients with an increased risk of infection (IDDM, CHF, renal insufficiency, debility, etc.) and should be avoided in those with active serious infections (e.g., sepsis, tuberculosis) or chronic and recurrent infections.
 
Patients who develop serious infections requiring hospitalization, acute or chronic antibiotic therapy should have their TNF-inhibitor suspended until resolution of the infection and careful reevaluation.  Infliximab is generally well tolerated. A small number of patients may develop headache, rash, minor upper respiratory tract infections or infusion-related reactions. For the nearly 600 patients treated thus far, there has been no increased risk of serious infections, malignancies or death when compared to the control populations and historic controls (such as the NIH SEER cancer database).
 
 The impact of infliximab in patients with established neoplasia is unknown. Although some drug study patients have received infliximab for over two years, the long-term consequences of chronic TNF-inhibition with infliximab are not known.  "Infusion reactions" were more common in early trials (without MTX) when compared with more recent trials conducted in patients on background MTX therapy. Findings of pruritis, rash, urticaria, nausea, headache, flushing, sweating, tachycardia, and dyspnea have been reported, but serious bronchospasm, hypotension, hemodynamic instability and anaphylaxis have not been seen in RA patients on MTX and are rare in the Crohn's population where infusions are only given intermittently during active disease and often without background immunosuppression.
 
Most infusion reactions can be managed by slowing the rate of infusion and employing symptomatic therapies with the initial reaction and as pretreatment for subsequent infusions. It is postulated that infusion reactions may be related to the development of human anti-chimeric antibodies (HACA) seen in fewer than 10% of patients. Infusion reactions are quite uncommon in patients receiving concomitant MTX (possibly by suppressing HACA formation), may occur at any time, do not increase in frequency over time and are not associated with reduced efficacy.  There is a 9% incidence of anti-dsDNA antibodies, and for most these do not appear to be pathogenic and other autoantibodies have not been reported. Three patients have developed a drug-induced lupus-like illness (migratory arthritis, pleuropericarditis, malar rash) while on drug.  The average wholesale price of infliximab is roughly $611 per 100 mg vial. The average purchase price is $482 per vial, or $964 per infusion for an average patient. Infusion costs vary widely and are at the discretion of the clinic or infusion site.

The scientists at Centocor Inc., used a very different strategy to make an antibody that could grab onto TNF-alpha and inactivate it. The researchers injected mice with human TNF-alpha and the mice made antibodies toward it. Removing just the portion of the antibody molecule that physically binds to the TNF-alpha,they fused it to a piece of a human antibody molecule. This meant that they had created antibody molecules that were mouse-human hybrids. Their reasoning was that the mouse portion would bind to TNF-alpha,while having about 75 percent of the hybrid from a human source would reduce the chances of the human recipient with RA recognizing the mouse portion and reject the mouse-human molecules. The kinds of antibodies that the mouse make against human TNF-alpha are called monoclonal antibodies (Mabs).

Infliximab (Remicade) Infliximab, in combination with methotrexate, is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate. Infliximab is a chimeric monoclonal antibody that binds TNFa with high affinity and specificity. During development infliximab was also called cA2.  The antibody binding site for TNF is of mouse origin, with the remaining 75% of the infliximab antibody derived from a human IgG1k antibody sequence. Infliximab is a chimeric TNF-alpha monoclonal antibody (mAb) comprising about 75% human and 25% mouse protein. It has a half-life of 8 to 10 days and is administered intravenously in combination with MTX every 4 to 8 weeks (at a dose of 3 to 10 mg/kg).
 
Infliximab, originally available for the treatment of refractory inflammatory bowel disease, is now approved by the FDA for use in rheumatoid arthritis. The safety and efficacy of infliximab given in conjunction with methotrxate were assessed in a multicenter, randomized, double-blind, placebo-controlled study of 428 patients.  Patients with rheumatoid arthritis of 6 months duration or more who were active despite methotrexate therapy were randomized to one of five treatment groups: placebo; infliximab 3 mg/kg every 4 or 8 weeks; infliximab 10 mg/kg every 4 or 8 weeks, intravenously. Patients in all five groups received methotrexate >12.5 mg/week.  Fifty-nine percent of patients receiving the 10 mg/kg dose of infliximab achieved ACR 20 response, as did >42% of patients receiving the 3 mg/kg dose compared to only 17% in the placebo (methotrexate only) group. Radiograpic changes in the study above were also monitored. Placebo treated patients exhibited radiographic progression at an average rate of 4.0 Sharp units per year while the four infliximab groups progressed at average rates ranging from -0.5 to 0.5. These data confirm that the combination of infliximab/methotrexate has a significant disease modifying effect compared to methotrexate alone.
 
Infliximab is expected to bind TNF-a in the circulation, preventing its interaction with TNF-a receptors on the surface of inflammatory cells, and eventually clearing TNF-a from the circulation. (slide) Like etanercept, infliximab inhibits the activity of TNF.  Since infliximab contains 25% mouse sequence, a major concern is the development of human anti-chimeric antibodies (HACA) which would block infliximab from binding TNF-a. HACA would be expected after repeated administration and would result in diminished therapeutic response over time.  Methotrexate appears to diminish HACA. Monoclonal antibody therapy has also been associated with "cytokine release syndrome" a clinical syndrome of fever, chills headache associated with the infusion of the antibody.  The frequency of this syndrome has diminished with the use of chimeric and humanized antibodies that contain less mouse sequence and slower infusion rates.
 
Infliximab is administered with MTX by IV infusion over 2 hours to prevent these symptoms. In clinical trials with infliximab, approximately 8% of patients developed anti-double stranded DNA antibodies (anti-ds DNA), antibodies with high specificity for systemic lupus erythematosus (SLE). There are several reported cases of clinical SLE that resolved after stopping the drug. The nature of this reaction is unclear. Serious infections, including sepsis and disseminated tuberculosis, have been reported in patients receiving TNFblocking agents, including infliximab. Some of these infections have been fatal.  Many of the serious infections in patients treated with infliximab have occurred in patients on concomitant immuno suppressive therapy that could predispose them to infections. Caution should be exercised when considering the use of infliximab in patients with a chronic infection or a history of recurrent infections.
 
Tumor necrosis factor (TNF) blockers: All three of the available TNF blockers have led to clinical improvement over that obtained with methotrexate alone. Infections, such as tuberculosis, and other medical problems, such as low blood counts, have recently been reported. Monitoring with blood counts and TB skin tests is appropriate and should be guided by the physician. How ever, despite the necessity for caution and increased monitoring, the benefits of these drugs continue to outweigh their risks. Multiple issues, including effectiveness, safety, route of administration, likelihood of compliance, and costs/insurance coverage, need to be considered before prescribing because important differences exist between these three agents.
 
Although etanercept is composed entirely of human sequence, neoepitopes might be generated at the joining regions of the TNF receptor and the immunoglobulin Fc region which could elicit an anti-etanercept antibody response. This does not appear to be relevant. In the two published trials, non-blocking anti-etanercept antibodies were found in only 2 patients and did not have a notable effect on efficacy.  Of unclear etiology and clinical signficance is the development of low titers of anti-double stranded DNA (anti-ds-DNA) antibodies in patients treated with infliximab and etanercept. Anti-ds-DNA antibodies are considered to be specific for systemic lupus erythematosus. However, in generall, patients treated with infliximab or etanercept who developed these antibodies do not exhibit lupus like illnesses
 
Infliximab is a chimeric human/mouse monoclonal anti-TNFa antibody composed of the constant regions of human (Hu) IgG1?, coupled to the Fv region of a high-affinity neutralizing murine anti-HuTNFa antibody. The antibody exhibits high affinity (Ka 1010/mol) for recombinant and natural huTNFa, and neutralizes TNF-mediated cytotoxicity and other functions in vitro.  This chimeric monoclonal molecule is composed of 3/4 human and 1/4 mouse proteins and is an antibody to TNF itself. Thus, it either binds TNF in the blood or as it attaches to its receptor and, by doing so, stops its downstream pro-inflammatory and tissue damaging actions.  Cells expressing transmembrane TNF bound by infliximab can be lysed in vitro by complement or effector T cells. Infliximab leads to both clinical improvement and a major trial showed a halting of erosion development and joint space narrowing. At this time, infliximab is approved only for use in combination with MTX.
 
More than 80 cases of Mycobacterium tuberculosis have been reported worldwide in patients who have been treated with infliximab. The infection appears to occur soon after the institution of infliximab, and some patients have developed disseminated disease.  Thus, a PPD must be performed prior to starting infliximab and, if positive, a chest X-ray. If the chest X-ray is normal, then infliximab can be used along with a nine month course of isoniazid and Vitamin B6 .  To date the reported infection and tumor risk is not greater in patients treated with infliximab than in RA patients not treated with this medication. Caution in infliximab use in patients with open skin ulcerations and/or diabetes would, however, be in order.
 
The U.S. Food and Drug Administration's Arthritis Drugs Advisory Committee heard updated postmarketing adverse event data on August 17, 2001 from Centocor and Immunex on their TNF-alpha antagonists, infliximab (Remicade) and etanercept (Enbrel), respectively. The reports reflected updated information since FDA's approval of etanercept in 1998 and infliximab in 1999.  The FDA reporting system is a passive one, meaning that physicians may or may not report their patients' adverse drug reactions to the FDA directly or via the manufacturer. This type of system tends to lead to under-reporting, poor standardization of diagnosis, poor comparative data, little information about causality, and none about the denominator.  Initial signals from the MedWatch  Program that suggest a causal association require epidemiologic confirmation.
 
The FDA has received 23,000 adverse event reports on infliximab (which has been taken by 147,000 patients worldwide); 26% of the reports were related to infections. There have been 18,500 reports on etanercept (with 102,000 patients treated worldwide), 22% of which were infections. Concomitant use of immunomodulatory drugs (i.e. methotrexate or steroids), which also increase infection risk, occurred in many patients. Highlights:
 
1) Opportunistic infections - 44 cases of histoplasmosis, listeriosis and Pneumocystic carinii pneumonia, including fatal cases, have been reported with these drugs;  2) Tuberculosis - Infliximab has been more closely associated than etanercept with TB, with 92 cases reported (including fatal cases), most commonly arising early after treatment onset (i.e. stimulation of a latent infection); 3) Multiple sclerosis - Enbrel has been more closely associated than infliximab with the new onset of MS; 
 
 4) Lymphoma - The 18 cases for etanercept and 10 for infliximab do not appear to be greater than would be expected in a normal population, especially in RA patients, who have a 2- to 24- fold increased incidence of lymphoma compared to normal cohorts;  5) Intestinal perforation - Cases have been reported;  6) Aplastic anemia and pancytopenia - Cases have been reported.  Interpretation and Commentary on the Findings Despite the necessity for caution in using these drugs, their benefits continue to outweigh their risks. However, despite the acknowledged problems with the FDA reporting system, we should incorporate the data into our clinical decision-making. Close monitoring for, treatment of, and prophylaxis against infections of all types has always been appropriate and is even more so given these reports.

Regarding tuberculosis: The following treatment algorithm is an appropriate one to follow:  PPD should be performed on all patients prior to starting Remicade. In those patients who have already started Remicade a PPD should also be performed but a negative tests may be due to immunosuppression and not a true negative.  Clinical follow-up for TB is thus indicated and a chest X-ray should be performed.  In patients starting or taking Enbrel, even though this drug has a much lower association with TB, high-risk patients for TB should also have a PPD.  In patients with a negative PPD, Remicade can be started and clinical monitoring for TD instituted.  In those patients with a positive PPD, a chest X-ray should be performed. If the chest X-ray is negative, then 9 months of 300 mg INH and 50 mgm of vitamin B6 should be given. Concomitant use of Remicade in this situation is appropriate. Observation for any infection is indicated.
 
If the PPD is positive and the chest X-ray shows apical disease typical of TB or calcified hilar nodes (Gohn complex), at least 3 months of INH and B6 are indicated prior to starting Remicade. Or, if active TB is clinically possible, a pulmonary or infectious disease consult is appropriate. Remember to follow liver function tests in patients started on INH especially those older than 50.  If the PPD is positive but the patient has already had a course of INH in the past for a known positive PPD, Remicade can be started with the usual clinical observation for infection.  Both medications should be stopped in the presence of any type of infection, be it a viral or bacterial (e.g. urinary tract infection, bronchitis). Both drugs can be restarted after mild infections that resolve quickly on their own or with oral antibiotics. However, patients who develop septicemia or opportunistic infections should not have their anti-TNF medications restarted.
 
Rheumatologists,generally, monitor complete blood counts, platelets and differential counts every six weeks, similarly to what is recommended for methotrexate. This makes sense and will pick up early downward trends in blood counts to avoid aplastic anemia or pancytopenia. Given these and earlier FDA reports, they avoid the use of anti-TNF agents in patients with multiple sclerosis and take great care in the use of these medications in patients with MS-like illnesses or ill-defined neuropathies.
 
Update on Remicade Use in Patients with both RA and Congestive Heart Failure In view of higher incidences of mortality and hospitalization in patients treated in studies with Remicade for congestive heart failure (CHF), a safety warning for patients with rheumatoid arthritis (RA) has been disseminated by the drug's manufacturer.
 
I) For patients with RA, Remicade should not be instituted in patients with congestive heart failure;  II) For patients with RA who are being treated with Remicade and who also have CHF, Remicade should be stopped and alternative disease-modifying drugs for RA instituted. 
 
III) As always, physicians should be prepared to discuss news reports about adverse events, which some patients may find alarming. Informed counsel will help patients understand how infrequent these adverse events are, as well as reinforce the importance of contacting the physician when any symptoms of infection or other problems arise.