Sock's Toxicity And Drugs In RA:
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Dr Edward Keystone a professor of medicine at the University of Toronto who had been doing research on a new drug called adalimumab (D2E7) introduced it at the annual ACR meeting.
"The advance is really the ease of administeration"  said Dr.Keystone.
He further said " We have a new agent which has the efficacy at least as good as the other TNF blockers"--"Given the ability to administer it every second week it appears to have a better ease of administeration compared to the other two TNF agents".
The compound adalimumab is the first fully human monoclonal antibody that inhibits an immune system protein,TNF. TNF is produced in excess  in RA patients.
Other drugs in this category include  Enbrel delivered in twice weekly injections,and Remicade delivered via IV infusion. Dr. Keystone introduced it in Canada earlier under the "Armada Trial Test".
The drug adalimumab (injectable)or a placebo was administered once every 2 weeks for 24 weeks to 271 patients with an inadequate response  to the current standard treatment of the drug methotrexate.
 The study was funded by Abbott Laboratories.Of the patients who received the higher doses of the drug 65% showed a reduction of at least 20% of symptoms such as joint swelling and tenderness compared to 14% in the placebo group.
NB: DE27 was recently approved by the FDA,now known as Humira.
Pharmacia Corporation and Pfizer Inc. recently announced that the FDA has approved Bextra (valdecoxib tablets)  a Cox-2 specific inhibitor,for treating the signs and symptoms of OA and adult RA and the treatment of pain associated with menstrual cramping.
According to a company release Bextra which is indicated for arthritis in a once-a-day 10mg dose offers 24-hour arthritis pain relief. In global clinical trials involving more than 5,000 patients
Bextra demonstrated comparable efficacy while offering an improved gastrointenstinal safety and tolerablity profile versus  conventional NSAIDs studied specifically   naproxen,ibuprofen,and diclofenac.
In controlled trials the use of Bextra at the recommended dose has not been associated with any increased risk of cardiovascular or renal complications versus NSAIDs studied.
For menstrual pain the recommended dose is 20mg  administered twice daily as needed. Approximately 80% of women in the trials required only one dose of medication within the first 24 hours.
The drug valdecoxib (Bextra) offers "tighter binding to the cyclooxygenase-2 enzyme than the girst-generation coxibs," explains Dr. Bill Benson,a rheumatoligist at St. Joseph's Hospital in Hamilton. This translates to more powerful pain relief,he says.
"So far,studies are showing it effective for pain of any cause. It's an exciting new development. New developments come at a price,of course. Celebrex--$80/month supply--$14/month for equivalent supply of Naprosen.
Bextra was also recently approved by the FDA.
There's always the wild card factor--the idiosyncratic,not quite predictable response of each person to medication/coxibs offer an alternative.
Prostaglandins are chemicals that are important contributors to the inflammation of arthritis,which causes the pain,fever,swelling,and tenderness.
Valdecoxib blocks the enzyme that makes prostaglandins (specifically cyclooxygenase 2 or Cox-2) resulting in lower concentrations  of postaglandins.
As a consequence inflammation and its accompanying pain, fever, swelling, and tenderness is reduced. Cox-2 inhibitors differ from traditional NSAIDs in that they cause less inflamation and ulceration of the stomach and intestine and do not interfere with the clotting of blood.  
It is similar to naproxen (at 500 mg twice daily) in effectiveness. At the lower doses it showed less stomach irritation than naprosyn.
Etoricoxib is another Cox-2 NSAID that is being investigated for the treatment of RA. Previous studies have demonstrated its effectiveness in relieving the signs and symptoms of joint inflammation.
Fewer patients treated with etoricoxib had to discontinue the medication   because of gastrointestinal complications as compared with the traditional NSAIDs,voltaren,and naprosyn.
 Because it is classified as a Cox-2 inhibitor,etoricoxib should and apparently seems to  have advantages  with references to the stomach and intestine protection.----Recently approved.

According to the "T cell centric" theory of RA,activation of CD4 + cells would trigger and maintain the inflammatory process in the rheumatoid joint. Although large numbers of CD4 + cells persist in the synovium throughout the disease course,they appear to be inactive in the chronic phase of the disease.
E.G., expression of surface antigens (such as IL-2 and transferring receptors),and secretion of specific cytokine (e.g.,IL-2,IL-4,and g-IFN),that are associated with an activated T cell state are very low.
In contrast,cytokines known to be produced primarily by "effector" cells (macrophages) and connective tissue cells (fibroblasts) are expressed in abundance in RA synovium and synovial fluid,as measured by ELISA or mRNA studies.
These cytokines include IL-1,IL-6,TNF,IL-8 and GM-CSF. According to the alternative theory (the "macrophage-fibroblast theory") of  RA, these two cell types appear to be largely responsible for creating a self-perpetuating state of chronic inflammation in which T cell participation may no longer be critical.
 In this scenario,the activated macrophage continuously secreates IL-1 and TNF which maintain the synovial fibroblast in an activated state. The fibroblast in turn,secreates a large amounts of: a)cytokines-IL-6,IL-8, and GM-CSF; b) prostagandins;and c) protease enzymes. GM-CSF feeds back to promote the maturation of newely recruited monocytes to macrophages.
 IL-6 and IL-8 contribute to the recruitement and/or activation of yet other cell populations,while the prostaglandins and proteases act directly to erode and destroy nearby connective tissues such as bone and cartilage.
In addition to activating synovial cells to secrete inflammatory mediators,IL-1 and TNF have profound systemic effects. E.G.,increased systemic levels of TNF and IL-1 are associated with fever,muscle wasting and decreased appetite. Some of these effects are mediated via the induction of IL-6 synthesis.

The cytokine chemical interleukin-1 (IL--1),along with TNF-alpha,is considered to be central to the inflammatory and destructive process of RA. In fact,IL-1 can induce the production of TNA-alpha,and vice versa.
Included among the undesirable effects of IL-1 are an increase in COX-2,the enzyme that enhances inflammation (and is the target of Celebrex). IL-1 also stimulates the production of molecules that line the blood vessels and grab onto passing white blood cells,luring them to enter the irritated tissues and contribute to the inflammation.
This cytokine also contributes to the eventual breakdown of bone tissue in the joints. Its action goes beyond the joints and contribute to more general reactions such as loss of appetitie and fatigue.
It's important to recognize that all these effects of this cytokine and others released by the body's immune system are part of a natural,complex set of events designed to defend against injury and infection. When these reponses are excessive and prolonged,as in the case of RA,they provoke and maintain inflammatory disease.
Just as in  the case of TNF-alpha,IL-1 acts by being recognized by special receptors on cell surfaces. Those receptors which are proteins,will act as a lock into which the IL-1 molecules easily fits. Once this meeting takes pplace,a cascade of reactions is set off inside the cell,genes are turned on,and then the cell then can make substances that contribute to inflammation,such as destructive enzymes.
The body makes another slightly different form of IL-1,which also can fit the receptor locks. This form is interleukin-1 receptor antagonist (IL-ra). the crucial differences between IL-1 and IL-1ra is that when IL-1ra fits into the receptors,the cascade of reactions does not take place inside the cell.
 IL-ra is a natural control,the body uses to balance the inflammatory effects of IL-1. It competes for the receptor sites sought out by IL-1. It's as though the IL-1 receptor sites were reserved parking garages. The IL-1ra molecules park there instead,leaving nowhere for the IL-1 molecules to park and get on their work of inflammation.
However,it takes relatively high concentrations of IL-ra to counteract the effects of IL-1. Studies have shown that the natural levels of IL-1ra in people with RA are not sufficient to control the disease. 

Dr. Larry Moreland,associate dean of medicine for clinical research at the University of  Alabama-Birmingham presented findings on costimulation blockers,a new type of compund that slows the activation of an inflammatory response by T cells,which can result in RA.
"This is a new method of inhibiting the immune system," Moreland said. "This was the first study in patients with RA with costimulatory blockers".
The researchers followed 214 patients who had failed to show improvement after traditional RA therapy.The patients were randomely assigned to receive four infusions of one of the two drugs-CTLA4lg and LEA29Y-at three different  doseage levels,or an inactive placebo,over a 2-month trial period. The patients were then followed for nearly 6 months.
The study,which was designed primarily to determine safe dosage levels of the drug,was supported by Bristol-Myers Squibb.
More than half the patients receiving the highest dose of the two drugs had a 20% improvement in areas such as pain and swollen joints and tender joints, compared with nearly one third of the patients receiving the placebo medication.  Only 5% to 9% of the patients taking the high dose of the two medications,discontinued treatment due to flare-ups,compared with nearly one-third of those taking placebo drugs.
"There was no unexpected adverse effects," Mooreland said. However, because the drug inhibits the response of the immune system,patients may be more susceptible to infections and will need to be carefully monitored in the future,he said.
Raritan,NJ- 8/20/01--The FDA has approved Ulltracet,Tm (37.5 mg tramodol hydrochloride/325 mg acetaminophen tablets.A new centrally acting prescription  medication. Ultracet combine Ultran- reg/tm-tramadol hydrochloride.a leading prescription pain reliever,with acetaminophen,the most commonly recommended prescription pain treatment.
Clinical trials demonstrated that the combination offers better pain relief over either medication alone. In the trials,Ultracet consistently began working faster than Tramadol alone,and pain relief with Ultracet lasted signaficantly longer than with Acetaminophen alone. Ultracet should not be used concomitantly with alcohol.
According to results from a Phase II study presented recently at the American College of Rheumatology (ACR) scientific meeting, the novel investigational biologic agent, CTLA4Ig, may have potential for treating rheumatoid arthritis patients who do not respond adequately to etanercept (Enbrel) alone.
CTLA4Ig is the first in a new class of treatments called costimulation blockers and is being developed by Bristol-Myers Squibb Company. Researchers found that people who inadequately responded to etanercept alone showed significant improvement from baseline in ACR 20 and 70 response rates with the addition of once monthly infusions of CTLA4Ig compared with placebo plus etanercept over a six-month period.
The primary endpoint of the study was the proportion of patients meeting the ACR 20 criteria, a way of measuring patient improvement using American College of Rheumatology (ACR) guidelines.  By achieving ACR 20, a patient has at least a 20 percent improvement in multiple measures of disease activity. In this study of people with active rheumatoid arthritis despite treatment with etanercept, 85 people received a once-monthly infusion of a 2 milligram per kilogram (mg/kg) dose of CTLA4Ig and twice-weekly injections of etanercept. Another 36 people studied received a placebo in addition to the twice-weekly etanercept injections.
Of the 85 patients receiving CTLA4Ig 2 mg/kg plus etanercept, 41 (48.2 percent) achieved ACR 20.  Of the 36 patients receiving placebo and etanercept, only 10 (27.8 percent) achieved ACR 20. Also, researchers found that 9 of the 85 patients (10.6 percent) receiving CTLA4Ig 2 mg/kg achieved ACR 70 -- a 70 percent improvement in symptoms. No patient receiving placebo plus etanercept achieved ACR 70.
Bristol-Myers Squibb plans to initiate CTLA4Ig phase III development in rheumatoid arthritis later this year. 

Investigational Therapy:
Genmab A/S recently announced that HuMax (TM)-IL 15,a human monoclonal antibody that targets a cytokine known as IL-15,demonstrated potent activity in arresting inflammation in a preclinical trial study. HuMax IL 15 was shown effective in neutralizing IL 15 activity in various cellular models,as well as mice engrafted with inflammatory tissue from RA patients.
According to a press release from the company,IL 15 is an important disease target because it is an immune system signalling molecule that appears early in the chain of events that ultimately leads to inflammatory disease. IL 15 induces both the production of TNF alpha, another cytokine that has shown to play a pivotal role in inflammation,as well as the recruitment of inflammatory T cells. These T cells in turn promote the production of more IL 15,and the cycle escalates.
"HuMax-IL 15 may be the first of a new generation of anti-inflammatory agents that work via a unique 3-prolonged approach,stopping both mediators of inflammation and neovascularisation", said Professor Jan G.J.van de Winkel,Chief Scientific Officer of Genmab.
The study's authors explain that inflammatory diseases where IL-15 plays a role include arthritis,inflammatory bowel disease,celiac diseases and psoriasis. Il-15 is also involved in the development of new blood vessels, or neovascularisation,that can support both inflammation and cancer. Genmab in collaboration with Immunex Corporation,is currently preparing HuMax IL-15 for human clinical trials,which are expected to start,later this year. 

Enbrel "absorbs" excessive TNF. Remicade is called a monoclonal antibody,meaning it is a protein against TNF where it sticks to TNF like a magnet would stick to a piece of iron. It's made,however,with a mouse part,and a human protein is added to make it less allergic or immunogenic. So it works a bit differently,and it has the possibility that that one could be allergic to the mouse part of Remicade. But,giving methotrexate,with it,decreases the reaction.  Chimeric means it's made of two animals,one is mouse and the other is human.
Standard therapy today is early intervention with either a biologic, arava, or methotrexate. Every drug has possible side effects. One can't drink alcohol with mtx because of liver concerns,and other problems. It can affect the kidneys on rare occassions,it can affect the bone marrow on rare occassions and some patients may encounter mouth sores or in the nose.
Biologics are quicker acting,and has  less side effects. MTX requires more monitoring,then say,Enbrel.  Biologics agents seem to show less x-ray damage down more than MTX.  In a Enbrel trial of early RA patients it showed faster response and better response,but the response was better for Enbrel (-ACR response in patient with early RA) In the longer term the ACR response was approximately + 10 % more efficacious in the longer term.
At the Albany Medical Centre it has been shown that Arava can be combined with the biollogics safely. Kineret will probably be used in patients who are not quite doing as well on either one of the biologic agents such as Enbrel and Remicade or methotrexate.
In placebo contolled trials,meaning the patients and the doctors don't know if the trial participants are getting methotrexate or a placebo. (sugar composition). comparative studies such as comparing head to head,clinical trials with data that have been published,show that 40 % of patients do not respond to methotrexate. Enbrel has a little better response and more likely to work then MTX.
Reserchers combined anakinra or Kineret with Enbrel,and there was a increased risk of infection. They are studying if that's dose related or how to adjust the dose so they can be used safely. The combination is not a standard recommendation,currently.
Mixing Kineret with MTX or with Leflunomide (Arava) has been show to be efficacious and safe in certain patients.
Minocycline is an anti-biotic that has shown to be effective in treating patients with early,very mild arthritis,but most rheumatologist will skip minocycline,and go to MTX or a biologic for patients with long-standing or severe rheumatoid arthritis. There have been 59 cases of lupus induced by the use of this medication in the U.S.
Methotrexate is the "gold standard" currently in North America. SSZ used previously more in Europe is being used more often. Biologics is a wonderful drug for those not respondent to MTX. But cost,is the main current limitations. We do not have a 10 year long term history regarding biologic therapy like we do on methotrexate.
It is only in the late 90's that full-dose-subcutaneous injection was commonly introduced as being more efficacious and with lesser side effects then the pill form. The use of methotrexate is not "dead" in North America.
DE27 (Adamilumab),Humira has a feature of easier administeration. It has recently,recieved FDA approval. Scientists are working on a biologic that can be administered in pill form. Many future studies are being conducted.

When rheumatologists in this country were surveyed in 1999, 47% of them viewed combination DMARDs as appropriate initial therapy, and 46% of that group had used combination DMARDs for more than 30% of their patients. Aggressive therapy, usually in combination, may be appropriate for some patients.
That is counterbalanced by a second survey of Canadian and US rheumatologists in 1996, where there was some preference expressed for a single agent, if possible, in the treatment of rheumatoid arthritis.
With our new drugs, we have changed our vocabulary and our goals when we think of treatment for rheumatoid arthritis. Our goals are: no constitutional symptoms, returning to work, minimizing the impact of this disease on daily living, and changing the course of disease progression. We have made our biggest leap in the last several years with discussion about slowing, stopping, and perhaps even reversing this previously relentless chronic disease.
Ideally, you would like a drug that is effective not just for symptoms, but one that inhibits disease progression, has that efficacy sustained over long periods of time, and is safe and well tolerated with minimal monitoring required. We would like that to be simple, perhaps monotherapy.
Rheumatologists are moving from that first treatment paradigm to this. Our current approach still may be initial treatment with traditional DMARDs, but then quickly adding drugs, including a biologic agent. That evolution emphasizes early aggressive treatment, biologics, monotherapy if possible, or combinations for non- or partial responders, and the potential to reduce or discontinue our previous drug.
What is the paradigm change in terms of therapy for rheumatoid arthritis? In the last few years, we understand the severity and the nature of rheumatoid arthritis more than we ever have. What are those paradigm shifts? (1) we're using disease modifying antirheumatic drugs (DMARDs) earlier; (2) we're using aggressive methotrexate therapy; (3) we're using combination therapy; and (4) we're using biologics.
In terms of early DMARD use, there are 2 issues that most physicians want to address. If I use a DMARD early, will it make a long-term difference to my patients? And, if I use a DMARD early, will I have a better clinical response? The concept that initiating a DMARD early may have a longer-term benefit on the patient. Are there any data to support that? There are at least 2 studies to suggest it.
The first is a study by Lard. He took a group of patients who, within 2 weeks after presenting with their diagnosis, were started on a DMARD. He took another group of patients and waited a mean of 4 months and then started a DMARD. The delay, on average, is about 4 months. These populations weren't exactly matched, but they were pretty closely matched.
If you look at the radiological outcome, the Sharp score, those patients who were treated early had a reasonable reduction in Sharp score, whereas those patients who were only 4 months delayed on average had quite a significant increase in Sharp score over time. That suggests earlier treatment will have a long-term benefit.
The second study has to do with disability outcomes. This study by comes out of British Columbia. They did a hydroxychloroquine (Plaquenil) trial. They did a 9-month, double-blind, placebo-controlled trial. At the end of 9 months, they put the placebo patients on Plaquenil. They watched the patients who got Plaquenil at the beginning of the study, and watched those patients receiving Plaquenil 9 months later, ie a delay, to see whether, long term, there would be a difference.
If you look at improvement in those patients who got Plaquenil at the beginning, in terms of disability, there is a 57, 58, and 60 in standard deviation units. The patient population that started 9 months later, out to 33 months later, didn't match their counterparts. They still had more disability after 3 to 4 years and were not up to the base of those individuals who started on Plaquenil initially. Aggressive, early therapy could make a long-term difference. We've seen it radiologically and in terms of clinical outcomes.
What about methotrexate? What about better response to DMARDs in early versus late disease? If I use a DMARD early, will I have a better response than late? There are not a lot of data to support that. I'm going to give you 2 pieces of data that are certainly suggestive, but not definitive.
One of these pieces of data comes from the trials with etanercept. They looked at the Stanford Health Assessment Questionnaire (HAQ) outcomes, the disability outcomes, in patients in the Moreland trial, which was monotherapy late disease, an average of about 10 to 12 years of disease, versus the outcomes in the Early Rheumatoid Arthritis (ERA) trial in patients who were treated with under 3 years of disease. Other than disease activity, for the baseline outcomes of tender joints, swollen joints, etc, they were comparable.
Investigators had 2 comparable populations, 1 early, 1 late, and they asked the question: Using the same dose of etanercept, do you have a better response? These data show, in the ERA trial, there was a difference between these 2 populations, a better improvement in HAQ if you treated early.
The second study is a meta-analysis. This is a study by Anderson. It's probably the only study done in terms of asking the question, "Earlier treatment, better response?" This is published in Arthritis and Rheumatism.
There were various DMARDs used. They looked at Plaquenil, azathioprine (Imuran), and methotrexate. They even looked at Prosorba (protein A-based extracorporeal immunoadsorption, silica).
 The concept is, if you treat people with a short disease duration, regardless of their treatments, in general, your sedimentation rate is improved, your swollen joint count is improved, and your tender joint count is improved. This is the proportion of those people who are improving by at least 20%.
If you treat them late, if they're treated at 5 to 10 years, there is a significant difference. Suggestive, but not definitive, data indicate if you treat earlier, you're more likely to have a response.
What about aggressive methotrexate dosing? Are there any data to say that higher doses of methotrexate make a difference versus lower doses? Dan Furst did a study. He asked the question whether 20 mg of methotrexate over 14 weeks is any better than 10 mg over 14 weeks.
Here is the percentage of patients with American College of Rheumatology (ACR) 50 and with improvement of at least 50%. The 20-mg dose improved more at tender joint count, swollen joint count, global joint count, and activities of daily living (ADLs) relative to 10 mg.
These data say higher doses work better than lower doses, that 20 mg is better than 10 mg. The median dose of methotrexate used about 3 years ago, when they did a pharmaceutical survey in the United States, was 11 mg. Another study that suggests the possibility that methotrexate works well is the Early Rheumatoid Arthritis trial. We think about etanercept as one of the gold standards.
Can we take methotrexate, which is our gold standard, raise the dose in 2 months to 20 mg, and compete with etanercept? In the first 4 months, you don't compete. To an extent, etanercept worked quicker. By 12 months, the 2 look almost identical. There is only a 5% difference between etanercept and methotrexate in terms of clinical outcomes at 1 year. These are very good outcomes. Most of the other disease modifiers and biologics aren't going to beat methotrexate.
So why use it? Or, why not use it? Here is the concept. Radiologically, at 2 years, there was a minor difference between etanercept and methotrexate. The Sharp score point differences were about 2.
However, it's clear that, over time, radiological outcomes are linear. It was thought to be only 6 years, but now we're talking 15 to 20 years. The concept is, if these 2 curves continue to diverge, by 5 years, there is going to be a 5 Sharp score point difference and at least that from then on.
How long does it take to notice a difference, radiologically, in terms of change in Sharp score? Nobody knows, but I'll give you a number anyway. About a 50 Sharp score point difference and your grandmother can tell the difference between those 2 x-rays.
Therefore, if it's 5 years, it doesn't take very long for those 2 x-rays to be different. If you continue methotrexate, you will have different x-rays than if you were on etanercept.
Over time, the tolerability isn't as good with methotrexate, so that 74% of the patients stay on etanercept for 24 months, and 59% of the patients stay on methotrexate. There is a difference between the two. Methotrexate makes some people feel sick. Etanercept makes them feel good. If the cost would come down, everybody would be switching to etanercept.

What about combination therapy? There are 3 ways to combine DMARDs. You can add a DMARD in those partially responsive. That's called step up. We can use them in parallel from the beginning, or we can use step down. We can use multiple DMARDs at the beginning and, as the patient responds, keep removing DMARDs until you're back down to baseline, maybe with monotherapy. That's the induction and maintenance concept.
I'm showing you one piece of data. You've seen lots of add-on therapies, because that's the way the trials are being designed. The step-up therapy here is leflunomide. In patients who are partially responsive to methotrexate, the combination is a 51 ACR 20 compared with methotrexate alone, which means you continue on it. There is quite a difference. There appears to be a clinical added benefit to adding leflunomide in patients who are partially responsive to methotrexate. These are some data that suggest combination therapy is not bad.
What about parallel design? Two studies recently asked the following question: At the beginning, if I initiate methotrexate and sulfasalazine, will it be better than either alone? Two studies say no. Initiating sulfasalazine and methotrexate at the same time is not better than either methotrexate or sulfasalazine alone.
These are data using the Disease Activity Score (DAS) and the ACR 20 scores. What about triple therapy? Jim Ardell added triple therapy at the beginning and asked whether it was better than Plaquenil, sulfasalazine, or methotrexate alone. He had striking results. The triple therapy at the beginning was much better than the others.
There were a couple of problems with the study. It was pretty long. There were long-duration patients, about 10 years. The number of patients who were methotrexate na´ve was quite considerable, and most of the patients failed about .9 DMARDs.
It's an unusual population, but these studies were done a number of years ago when methotrexate wasn't on everybody's "radar screen." It's still an unusual population. This study is critical to be reproduced in early rheumatoid arthritis because it says that the toxicity wasn't any different whether you were on triple, double, or single therapy.
There are a couple of open-label trials. There is a triple therapy trial -- methotrexate, sulfasalazine, and Plaquenil versus methotrexate and sulfasalazine, or methotrexate and Plaquenil. It was triple therapy versus double therapy versus single therapy. The single therapy was methotrexate.
They showed triple therapy worked quite well. The problem in this study is they used methotrexate at low doses up to 15 mg. I don't know that triple therapy is better than high-dose methotrexate. I don't think we'll ever see the study.
This is another trial. In this trial they used combination therapy along with corticosteroids versus corticosteroids and sulfasalazine. It was actually quadruple therapy versus sulfasalazine, plus or minus cortisone. You didn't have to add cortisone. The results were very good.
The combination therapy was excellent. The problem is their comparator was sulfasalazine and I'm not sure this combination is any better than high-dose methotrexate.
There is step-down. The key trial for step-down was the COBRA trial (comparison of combined step-down prednisolone, methotrexate and sulfasalazine with sulfasalazine alone in early rheumatoid arthritis). It was high-dose steroids for a short period of time and then eventually tapered off.
They used a methotrexate combination, and a sulfasalazine combination. All triple therapy was compared with sulfasalazine alone. Notice the clinical results. Patients on triple therapy did extremely well until you stopped the prednisone. Then they came back to the baseline. They came back to what sulfasalazine alone looked like. After you dropped the steroids, they looked clinically alike.
 The only difference was a significant difference in the radiologic outcomes when you added low-dose methotrexate along with sulfasalazine, and the prednisone versus sulfasalazine alone. This is triple therapy slowing progression relative to sulfasalazine. At 1 year, the patients on sulfasalazine were allowed to go onto any therapy they wanted.
Over the next 5 years, those patients on sulfasalazine never caught up. That may have to do with the DMARDs they went on, but the sulfasalazine group never caught up to the triple-therapy group. At this point, remember, you're only on sulfasalazine. You've already stopped the prednisone and the methotrexate. It's an interesting concept that with early aggressive therapy, tapering off "the bad guys," and leaving a simple drug on, you may end up with a significant difference radiologically.
Biologic therapy says that if you fail methotrexate and you add a disease modifier, like a biologic, you have good data. There are good ACR 20s and 50s in combination: etanercept versus methotrexate.
 With infliximab you have to use methotrexate, good data. Anakinra (Kineret) just came on the market recently. What you see, again, are reasonable data.
These time courses are a little different. You can't compare study with study but, in general, it says if doctors add a biologic to those patients partially responsive to methotrexate, they have additional clinical benefit. This is not a positively established fact.
In these trials, you never had the biologic arm alone. You had the methotrexate arm. You had the combination arm. But, you never had the biologic arm. How do doctors know that you really need methotrexate?
There is an uncanny concept with the ACR 20 outcomes. If you used etanercept as monotherapy, the ACR 20 was 60. If you used it and added methotrexate, the ACR 20 outcome was 71, not very different.
Leflunomide as monotherapy, the ACR 20 outcome was 46. In those patients who were partially responsive to methotrexate, it was 46.
If you look at anakinra (Kineret), it was 38 by monotherapy, and adding methotrexate, it was 37. You've got to wonder whether you really needed the methotrexate if those numbers look alike. Those are the data. It's food for thought.
What's new? Scientists have made great gains in terms of the clinical and radiological outcomes with tumor necrosis factor (TNF) antagonists. The next new agent to come out in terms of TNF-Humira (Adalimumab). This is a fully human anti-TNF monoclonal antibody with a half-life of about 2 weeks. It fixes complement.
It's able to lyse cells like infliximab. It kills those cells that actually make TNF. It was given subcutaneously once a week as monotherapy. The results were quite good. The ACR 20s were comparable to anything else we've seen, around 55%. The ACR 20s were about 25% or 30%. That is good. This is once-weekly subcutaneous administration in a severe population of patients.
What happens if I have a partial response patient population on methotrexate? Using an average dose of about 16.8 mg, patient disease duration was 12.3 years.
What happens when you add subcutaneous Humira (DE 27-formerly )every second week in those patients who were partially responsive? ACR 20 is about 65%. Reasonable. ACR 50 at the 40-mg dose was quite high at 53%, and ACR 20 was 26.9%. This value was higher than we see in most studies, but notice the 80-mg dose was slightly less, in terms of efficacy, than the 40-mg for reasons that are unclear.
This study was not powered to tell the difference between doses, so we still don't know what the minimally effective dose is. At least we can say there is good benefit if you give subcutaneous D2E7 every second week.----Keystone.