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PROFILE OF RA:

Chronic and debilitating,rheumatoid arthritis (RA) affects almost 2 million Americans. Although this painful and often disabling illness can develop at any time,it commonly begins between the ages of 35 and 50,and strikes women three times more than men. Although the cause of this disease remains unknown, it now appears that a unknown antigen (perhaps a bacteria or virus) initiates the autoimmune response that results in RA.

This means that the body's immune system attack healthy joint tissue,resulting in inflammation and subsequent joint damage. In the disease's early stages, people experience general fatigue,soreness,stiffness and aching. As the RA progressess,joints become swollen,painful and stiff,making movement difficult.

Many people who have RA go through alternating periods of remission (when the disease is inactive) and exacerbations ("flare-ups"). However, the earlier this disease is diagnosed and treatment begun,the better. While there is still no cue for RA or what causes it,a lot can be done to manage the condition and control the pain, including medications for pain relief,disease-modifying drugs and biologic agents (anti-TNFalpha class) which alter the progress of the disease, exercise, lifestyle changes and surgery.

DRUG-COMPANIES INFLUENCE ON THERAPY AND EDUCATION:

It begins on the first day of medical school and lasts through to retirement,and it is the only reliable "cradle to grave" benefit that doctors can truly count on any more. Even in this era of medical-ledger watching world-wide,there is little evidence to expect it will ever end. In fact,it may even be growing,it starts slowly and insidiously,like an addiction,and can end up influencing the very nature of medical decision-making and practise.

It first appears harmless enough: a textbook here,a penlight there,and progresses to stethoscopes and black bags,until eventually come nights "on the town" at academic conventions and all-expenses paid "educational symposia" in luxury resorts.

Attempt to influence the judgement of doctors by commercial interests serving the medical-industrial complex are nothing if not thorough. Unfortunetly,they seem to work. Studies have shown that prescribing patterns are influenced by advertising and other marketing activities. If this were not the case,why would industry spend hundred of millions of dollars on promotion?

Advertising sustains industry,and no industry,not even the medical one,can avoid its reach. So it is not the fact of marketing that is in question here. It is the form in which it comes. Surely,no one would mistake a pen with a corporate logo as anything but promotion. Nor would any suggest that a stuffed animal with a brand-named drug attached to its fur is of any great medical value. But when the line between medical education or marketing is blurred,there is a problem.

A recent study completed by the US watchdog Public Citizen documents the relation between medical education activities,the pharmaceutical industry,and medical education services suppliers (MESS),which are private businesses that provide medical education. The study stems from a survey data published in December,1999 issue of Medical/Marketing & Media,an industry periodical. MM&M surveyed 123 MESS about their 1998 and 1999 operations. 80 returned questionnaires.

In summary,the data suggest that supplying medical education can,in this form, be a very lucurative exercise,whose most consistent client is the pharmaceutical industry.

Of the 43 companies that answered questions on finances,total revenue amounted to $643 million in 1999 alone,a 19 % increase from 1998. Extrapolating this to the entire industry.

Public Citizen predicts that the MESS industry is worth a t least $1 billion annually. An outstanding $116 million was billed by MESS to their clients on grand rounds alone;$114 million on symposia; $64 million on advisory boards,and another $60 million on publications. 66 (85%) of MESSs provided data on their client mix

On average 76% of respodents'c clients were drug manufacturers,26% of the MESS reported that at least 90% of their clients were pharmaceutical companies.

It cannot be said that the quality of any of these educational activities was compromised by the ultimate patronage of the pharmaceutical industry. Indeed,43% of the 80 MESS respondents reported being accredited by the Accreditation Council of Continuing Medical Education (ACCME) and an additional 5% said their accreditation was pending.

Of course, that also means that over half the MESS surveyed do not have ACCME accreditation. While one cannot be certain that lack of accreditation necessary connotes poor educational quality. It does att least suggest the possibility that industry may be able in these situations to exert even greater influence over what material is presented and what is left out.

What is of most concern here is the fact that so much continuing medical education comes through the filter of industry. To ensure the integrity,and the appearance of integrity,of the process of learning in medicine,physicians should do more to pay for CME themselves,just as many other professionals have to do.

Enbrel VS Remicade:

Etanercept and Infliximab Treatment in the Stockholm Tumor Necrosis Factor (TNF)-Alpha Antagonist Registry:

A Comparison of Two TNF-Alpha Antagonists RF van Vollenhoven, A Harju, J Bratt, S Ernestam, S Brannemark, E Gullstrom, L Klareskog

Objective: To compare the clinical results in the treatment of rheumatoid arthritis (RA) with etanercept (EBL) and infliximab (RMC).

Background: The Stockholm registry for patients receiving TNF-alpha antagonist therapy (STURE) provides systematically collected efficacy and safety data for all patients treated with EBL and RMC at the Karolinska and Huddinge Hospitals. This allows comparisons of efficacy and safety of the 2 treatments in population-based cohorts.

Methods: Since May 1999, 312 patients have been entered into this follow-up program, 202 of whom received RMC, and 110 EBL. Clinical measures corresponding to the American College of Rheumatology (ACR) outcome criteria and the DAS were collected at 0, 3, 6, 12 months and semiannually thereafter.

Results: While the 2 groups of patients were not randomized, the demographic backgrounds, RA backgrounds, and the baseline RA activity measures in the 2 groups were very well matched. Ninety-two percent of the patients who received RMC, and 62% of patients on EBL, received concomitant methotrexate (MTX) therapy.

The clinical responses after 3 to 12 months of treatment were also very similar for the EBL- and RMC-treated patients. However, there was a trend to somewhat greater clinical efficacy at 3 months in the RMC group. For example, the ACR20 response criteria at 3 months were met by 57.3% of patients on EBL and by 70.2% of patients on RMC.

However, the difference was not statistically significant. Similar results were seen for individual disease activity indices. Infusion reactions were seen frequently in the RMC group (approximately 7% of all infusions; 25% of patients; 13 discontinuations due to more severe infusion reactions), but other adverse events were similar between the 2 groups.

Discussion: In these population-based cohorts, EBL and RMC have similar efficacy, with a trend towards a somewhat greater improvement at 3 months with RMC. With the exception of infusion reactions, adverse events are similar.

Inflammation in RA is a very complex process. Scientists believe it starts when one of the class of cells that guards the body against foreign invaders( in ordinary inflammation these are usually viruses or bacteria )comes into contact with something that triggers the alarm. One form the alarm takes is a whole battery of chemical messengers,called cytokines,that are released into the joint.

These recruit other cells,the white blood cells that attack and kill other cells and bacteria. One form this killing takes is the release into the immediate area of very "corrosive"" chemicals. Joint tissue,an innocent bystander,is damaged. Furthermore,cytokines stimulate the lining of the joint to grow and produce other chemicals that break down cartilage.

Cytokines are released into the blood stream,and cause fever and fatigue. Because the body is so finely balanced,there are also cytokines released that tend to damp down the inflammation. Unfortunately,in the RA joint these "good" cytokines tend to become overwhelmed by the "bad" or pro-inflammatory cyctokines.

One of the key cytokines that promotes inflammation is a substance called TNF-alpha. Produced by both the "guard" cells (macrophages) and the joint lining tissues,it is released into the surrounding tissues,joint fluid,and blood. It stimulates other while blood cells to expand the inflammatory reaction. To do this it must attach itself to the other cells a a specific binding site-like a key in a lock.

Etanercept (Enbrel) and infliximab (Remicade) have been designed to interfere with this stimulatory action of TNF-alpha. Etanercept does this very cleverly;it's a molecule that looks exactly like the keyhole. As long as there is enough of it in circulation (it has to be self-injected twice weekly under the skin ),it will prevent enough keys from finding the lock they were intended for,and the inflammation will be damped down. It absobs excessive TNF.

Infliximab has a similar effect,but it consists of an antibody ( a protein specifically designed to attach to another protein ) against TNF-alpha. Once the key has a antibody stuck to it,it no longer fits the lock. Infliximab too has to be given by needle-in this case into a vien-once every two months.

Infliximab is called a monoclonal antibody,meaning it's a protein made with a mouse part,and a human protein is added to make it less allergic or immunogenic. Methotrexate is added because it decreases the mouse part reaction. Chimeric definition means,it's made of two animals,one is mouse and one is human. It "kills" excessive TNF-alpha (tumour necrosis factor.).

Leflunomide (Arava) is different. It doesn't block TNF-alpha,but it interferes with the normal functioning-one of the key cells ( the lymphocyte) affected by TNF-alpha,and thus interferes with the development of joint inflammation.

People with rheumatoid arthritis tend to have excess TNF-alpha. DE-27 (TNF-inhibitor) is going through final clinical trials. Easier administeration is the reported feature. There is a family of Interleukins,involved in the disease process,too. IL-1,Il-2,IL-'s etc.

Anakinra or Kineret inhibits IL-1 alpha. Scientists are working on a pill form of TNF inhibitors. Not everyone,will benefit from biological therapy,and some patients will not react favourably to conventional disease modifying medication.

We have often heard about one of the cytokines central to RA-tumor necrosis factor-alpha,(TNF-alpha) TNF-alpha is a vital member of the group of many other different cytokines that drive the destructive reactions in RA.

These cytokines play an important role in maintaining normal health. They are produced in response to infection or energy and stimulate our immune systems to fight back. Unfortunately,in RA,the natural control mechanisms that normally turn off the immune response after it has done its job are unable to do so.

Scientists do not yet know all the details of why this happens,but they do know,e.g.,that uncontrolled TNF-alpha is a serious problem. It can transform cells in the synovium,the delicate membrane lining the joints,into a growing, invading mass of tissue-the pannus-that eats away at the cartilage and bone. It also attracts more inflammatory cells to the area,aids in the formation of additional small blood vessels,and helps make enzymes that can break down cartilage and bone.

The major source of TNF-alpha are the macrophages-plentiful,active cells that move aroun in the joint tissues. The macrophages' normal job is to pick up material in the tissues that the body recognizes as foreign and dangerous to it,like bacteria or perhaps pieces of injured cells. The macrophages,carrying these foreign fragments-called antigens-come in contact with special kinds of white blood cells,the T cells.

This meeting stimulates the T cells to make cytokines that attract other T cells and macrophages to the sit. Soon there is an abundant supply of TNF-alpha coming from the macrophages,which can transform joint cells to divide and destroy. In addition,TNF-alpha induces other cells in the area to make inflammatory cytokines,like interleukin-1 (IL-1) and interleukin-6 (IL-6).

Under ordinary conditions,if we develop a minor bacterial infection in a hand,for example,we may experience some local redness,swelling,and pain tht may last for a few days,and then disappear. The macrophages,T cells,and the cytokines have done their work,and then they slow down until the next invasion. The exact trigger(s) that begin this inflammatory process in RA is yet unknown but we do know that our challenge is to slow down its abnormal destructive continuation.

When molecules of TNF-alpha are released by cells like macrophages,the soluable molecules can attach to special protein receptors on the surface of cells in the joint,such as cells in the synovial membrane,or cells that line the tiny blood vessels in the area. Once attached to the receptors on these cells,the TNF-alpha induces the cells (by turning on some of their genes) to keep the inflammation going.

In the fluid surrounding these cells there is a variable amount of those protein TNF-alpha receptors that are fre-floating. these are part of the natural control system,because they can grab onto TNF-alpha and thereby not allow it to bind to receptors on cells which cause the inflammation.

This allows some "fine tuning" of the effects of TNF-alpha. However, in the joints of someone with RA,even though there are increased amounts of these dissoved receptors grabbing TNF-alpha and keeping it from making trouble, they are unable to stop it from prodding the immune system down the path of RA.

The development of genetically engineered biologic agents that selectively block cytokines (anticytokine therapy) in the short term,represents a major advance in the treatment of RA. Etanercept is a recombinant soluable TNF-fc fusion protein,and infliximab is a chimeric (mouse-human ) anti-TNF monoclono antibody.

Infliximab is currently recommended for use only with concomitant MTX therapy. MTX may be used with etanercept or used alone. Several randomized trials have demonstrated that patients with etanercept alone or with infliximab plus MTX have less radiographic progression after 1 year rhan patients treated with MTX alone.

In the trial with patients made up of early RA patients,the symptoms and signs of RA improved more rapidly over the first 6 months,with compareable efficacy of the two agents at 12 months.

The ACR guidlines for monitoring liver toxicity in patients recieving MTX is that a liver biopsy should be performed in patients who develop abnormal findindings on liver function studies,that persist during treatment or upon discontinuing the drug. Liver toxicity with MTX is rare.

Although data from randomized trials have not shown an increased frequency of adverse effects,such as infections or malignancies,for either anti-TNF agent,concerns about the short-term and long-term safety of these agents continue. Enbrel was recently given a 5 year safety approval in clinical trials.

Clinical trials have demonstrated the efficacy of infliximab and etanercept in improving clinical symptoms and signs in patients with RA,according to the ACR 20,50,and ACR 70 improvement criteria. Patients with early active RA and those that had failed previous conventional therapy showed improvements.

Anti-TNF agents should be used with caution in patients susceptible to infection or a history of T.B.,should be avoided in patients with significant chronic infections and should be discontinued,temporarily in all patients with acute infection

Postmarketing surveillance has yielded reports of septis,tuberculosis.a typical mycobacterial infections,but it not common. At this time there appears to be no need of routine laboratory testing. Not all patients will respond to TNF therapy. The main disadavantage is high cost and parental administration.

Minocycline have shown efficacy in certain early,milder type RA patients. Surprisingly it showed efficacy in a subset of patients who were positive for the HLA shared epitope (HLA-DR4+)(--A.S.) conclusion is further testing should be done on tetracyclines.

Intramuscular gold treatment is effective,but injections are required every week for 22 weeks before less-frequent maintaince dose is started. Oralgold althought more convenient has proved less efficacious and is now not commonly used.

Cyclosporine is beneficial and has short-term efficacy to that of D-Pen (not used frequently). the use of cyclosporine,however,has been limited by its toxicity,expecially hypertension and dose-related renal function 20 %loss of renal function appears to be reversible for renal function loss,but not entirely.

Dose calculation to avoid renal toxicity is more critical with cyclosporine than with any other DMARD. Cyclosporine plus MTX was found to be more effective than MTX alone but long-term follow up revealed the development of hypertension and elevated creatinine levels

Low-dose oral glucocorticoids (<10 mg of prednisone daily,or the equivalent) and local injections of glucocortoids are highly effective for relieving symptoms in patients with active RA. A patient disabled by active polyarthritis may experience marked and rapid improvement in functional status within a matter of a short period.

Frequently,disabling synovitis recurs when steriods are discontinued,even in patients who are receiving combination therapy. However, many patients are functionally dependent on steriods and continue them long-term.

Recent evidence suggest that low-dose glucocorticoids slow the rate of joint damage and appear to have disease-modifying potential Joint damage may increase on discontinuation, Previously it was thought they did nothing to stop disese progression.

The benefits of low-dose glucocorticoids,should always be weighed against their adverse effects which are well documented elsewhere.

Combination therapy with traditional DMARDs is often used in the management of patients with RA. However, such treatment is frequently limited by complicated drug regimens, low compliance associated with high pill burden, high incidence of side effects, requirement for complicated monitoring procedures, and the development of constitutional symptoms that can result in reduced quality of life (QOL), particularly in patients who are being treated with MTX.These limitations have led to the need for alternatives to existing treatment regimen.

Biologic DMARDs: Elucidation of the key role of TNF-alpha in the pathogenesis of RA has led to the development of biologic DMARDs that block the activity of this cytokine. The use of these new preparations for the treatment of RA has a number of potential advantages over therapy with traditional DMARDs, including highly specific binding to target molecules that have key roles in the disease process, rapid onset of clinical action, reduced nonspecific toxicity, dosing intervals as long as every other week subcutaneously or every other month intravenously, possible long-term immunomodulatory effects, and improved QOL.

Effectiveness of biologic DMARDs in the treatment of early RA is particularly important for slowing and even potentially halting disease progression. The results of Genovese and colleagues provide strong support for the use of etanercept, the human recombinant version of TNFR1 that is linked to the Fc receptor of human immunoglobulin G1 (IgG1), in patients with early RA.

These investigators compared clinical and radiographic outcomes in 632 patients who received monotherapy with either etanercept or MTX for 2 years. Following at least 1 year of double-blind treatment, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner.

At the end of 2 years, patients who received 25 mg etanercept twice weekly had a higher ACR20 response rate than patients who received 20 mg/week MTX . Evaluation of radiologic disease progression over 2 years also indicated significant superiority of 25 mg etanercept over MTX.

Results from this study showed further that significantly more patients in the 25 mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the HAQ disability index. In addition, fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events.

Since the initial studies with etanercept, there has been significant evolution in TNF-alpha antagonists . Monoclonal antibodies to TNF-alpha, which bind selectively to TNF-alpha but not to TNF-beta, are now available for the treatment of RA. Infliximab, a chimeric monoclonal antibody, is currently approved for use in combination with MTX. Adalimumab, the first fully human anti-TNF-alpha monoclonal antibody, is currently under regulatory review for the treatment of RA either in combination with MTX or other DMARDs or as monotherapy.

The efficacy and safety of adalimumab have been demonstrated in the Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Patients with Rheumatoid Arthritis (ARMADA) trial. This double-blind, placebo-controlled study included 271 patients with active RA who were partial-responders to MTX. They were randomized to receive placebo or adalimumab (20, 40, or 80 mg, injected subcutaneously every other week, for 24 weeks) with continued MTX.

Addition of 20, 40, or 80 mg adalimumab, respectively, to MTX resulted in ACR20 responses in 48%, 66%, and 66% of patients; ACR50 responses in 32%, 54%, and 43%; and ACR70 responses in 10%, 27%, and 19%. The ACR20, ACR50, and ACR70 response rates for patients who had placebo added to continued MTX were 15%, 8%, and 5%, respectively .

These results thus show that the addition of a highly specific, fully human monoclonal anti-TNF-alpha antibody to continuing MTX in RA patients, who were partially responsive to this DMARD, provided clinically significant improvement in disease activity.

Results from the recently completed Safety Trial of Adalimumab in Rheumatoid Arthritis (STAR) trial also support the safety and effectiveness of adalimumab in patients with RA.The STAR trial is the first study designed to evaluate the safety of a biologic DMARD as part of standard antirheumatic care. It included 636 patients who had 40 mg adalimumab (injected subcutaneously every other week) or placebo added to ongoing therapy that included 1 or more conventional DMARDs in 83.5% of patients.

At the end of 24 weeks of follow-up, the ACR20, ACR50, and ACR70 response rates for patients who had adalimumab added to therapy were 52.8%, 29.2%, and 14.8%, respectively. The respective values for patients who received placebo in addition to their ongoing therapy were 34.9%, 11.1%, and 3.5%.

Safety data from the STAR trial also indicated that adalimumab was safe and well tolerated when used in combination with multiple traditional DMARDs.

Results from other recent publications and presentations support the improved safety of biologic vs conventional DMARDs. Geborek and colleagues used a survival-on-drug analysis and showed that the TNF-alpha antagonists etanercept and infliximab had significantly better tolerability than leflunomide .

At the end of 1 year, 82% of etanercept-treated patients remained on drug compared with only 36% of leflunomide-treated patients. In the above-cited 2-year comparison of etanercept and MTX carried out by Genovese and colleagues , 75% of patients remained on etanercept 25 mg compared with 59% of patients on MTX at the end of follow-up.

Taken together, the results summarized,indicate that addition or substitution of biologic DMARDs directed against TNF-alpha in the therapeutic regimens of patients with RA is significantly superior to continued MTX monotherapy for improving clinical and radiologic outcomes. Biologic DMARDs provide long-term improvement in signs and symptoms of RA, stop or greatly delay radiologic progression, and have a very good safety profile resulting in high patient compliance.

The efficacy, safety, and long administration intervals with these new preparations also support the prediction that they may become the treatment of choice, perhaps as monotherapy, for patients with early RA; new production processes that decrease their cost will increase their use. Treatment with highly specific biologic preparations also has the potential to revolutionize therapy for other difficult-to-treat conditions, such as ankylosing spondylitis.

Predicting responses to therapy. A number of issues regarding the optimal use of TNF-alpha antagonists remain incompletely defined, thereby providing key areas of focus for future research. For example, it has been demonstrated that some patients experience remission or near-remission as a result of using TNF-alpha antagonists.

On the other hand, for some patients these agents are ineffective. Being able to prospectively identify patients with a tendency to experience outcomes at both ends of the response spectrum would be a tremendous advantage. Relevant information in this regard may come from pharmacogenetics, or "personalized medicine," which involves identifying the genetic polymorphisms and other factors associated with particular outcomes.

Defining the most appropriate therapeutic options for the majority of patients who experience significant benefit from TNF-alpha antagonists but still have some residual disease activity is also an important area for further study.

Determining the best approaches to combination therapy. Perhaps one of the most important priorities for future RA-related anticytokine research is determining the best combinations of biologic and traditional disease modifying antirheumatic drugs (DMARDs) for the early aggressive treatment of disease.

Many different combinations of anticytokine therapies may be potentially useful. These include combinations of 2 anti-inflammatory molecules; anti-inflammatory plus immunomodulatory combinations (eg, inhibitors of co-stimulatory molecules, adhesion molecules, or angiogenesis). The potential benefits of such combination therapies include additive or synergistic efficacy that would permit treatment with low doses and reduced risk for toxicity and/or treatment resistance.

Exploration of combination anticytokine therapies is highly worthwhile because of their potential to completely suppress ongoing immune-driven inflammation, induce immunologic tolerance, prevent tissue damage, and promote healing. However, potential risks associated with these approaches include increased immunosuppression and elevated risk for both opportunistic infections and development of malignancies. There is also a potential for completely unanticipated outcomes due to the chaotic, nonlinear nature of cytokine networks/cascades.

Ultimately, the objective of TNF-alpha antagonism and other immunomodulatory approaches in treating patients with RA is to completely suppress immune-driven inflammation, induce immunologic tolerance, prevent damage, and promote tissue healing, while minimizing any treatment-related side effects. Further study will hopefully enable us to achieve these goals.