Biologic Therapy

Biologic response modifiers act by binding TNF a dominant cytokine that plays a prominent role in inflammation which is responsible for the pain and swelling seen in RA patients.After a connection between TNF and joint erosion was established by research,scientists were able to engineer a TNF antibody (Remicade) that destroys TNF,and in the case of Enbrel (protein) "sops up" excessive TNF.

Biotechnology is the industry that has found ways to create new drugs from molecules that naturally exist in the human body. It is a type of technology that has allowed researchers to identify how disease states normally occur,and how they can actually devise drugs to treat disease states that was not possible in the past.

Biologic drugs are the genes, proteins, or cells that are found to be involved in disease environments that can be controlled, to use in attacking and help preventing the disease.

A great many of these products are produced in the body and re- produced in minute amounts-to make them in sufficient amounts so that they can be used for clinically testing-they have to use what is called recombient genetic engineering.

What scientists do with that content,is to isolate the gene that is providing the information to the cells by which these complex molecules are formed. That gene is tailored,and divided in a smaller organism-the machinery by which genes are translated into complex molecules are known as proteins is common to all organism in the planet.

Scientists harness that knowledge to put the gene that encodes TNF receptor-into a cell or another organism to control to a much greater extent for the production of these biologics. A conventional drug like methotrexate,may be composed of 20 carbon atoms and a bio- technology drug is composed of thousands of carbon atoms that are put together to create these molecular complexities.

The major reason that cytokines (TNF & IL-1) are the appropiate targets for biologic therapy is that they're found in excess amounts in people with rheumatoid arthritis. What happens,is they get painful but very swollen joints. And their joints,when felt,they feel like bread-dough:they're squishy. That squishiness or "bread-dough" feeling is actually the joint lining,which normally,in people without RA,a microscope is required to see,and normally can't be felt. In RA patients,it becomes very thick,and this thick joint lining then starts causing the pain and associated inflammation,and eats away at the bone and cartilage. Rheumatologists are trained at medical school to feel this manisfestation.

When this thick synovium or joint lining is analyzed,it's enriched with all of those little proteins or cytokines,and that's why targetting is important .Those cytokines are not seen in patients with many other arthritic diseases,including Osteoarthritis.

The two main cytokines,or proteins,or "e-mails" of the immune system are (tumour necrosis factor) and IL-1 (interleukin-1) Both of these have been demonstrated to be increased,in people with RA. That is why it was chosen as one of the proteins to target through bio-technology and the use of genetic engineering.

One of the advantages of biologic drugs (BRMs)is they act specifically to neutralize cytokine proteins,and unlike traditional DMARDs,they are not processed by the organs of the human body,(stomach) resulting in potentially less side effects.

Cytokines are a group of proteins that regulate the immune system's activity. In general cytokines can either stimulate or stifle the immune response. Two important cytokines,Tumour Necrosis Factor (TNF)-alpha and Interleukin-1 (IL-1),help orchestrate the active phases of RA. Note,these cytokines are found in the joints of all RA patients. Research aimed at inhibiting the activity of these cytokines has resulted in a number of new drugs for RA treatment.

TNF-alpha plays a central role in initiating events that lead to inflammation and destruction of joints. It stimulates the production of molecules necessary to attract white blood cells to joint spaces. It also stimulates the release of other enzymes with the ability to breakdown components of the joint (like collagen,cartilage,and bone). Inhibiting the ability of TNF-alpha to initiate these events could dampen the destructive processes in RA. Many TNF-alpha inhibitors are in development. Recently,the FDA approved two TNF-alpha inhibitors. These inhibitors block TNF activity by blocking production of TNF or by preventing TNF from binding to its receptor.

Interleukin-1 (IL-1),activates several inflammatory cells and stimulates those cells to release other pro-inflammatory substances. Several IL-1 inhibitors designed to block Il-1's pro-inflammatory effects have shown promise in animal studies. Recently,the FDA aprroved Kineret. These inhibitors block IL-1 activity by one of three main mechanisms: by preventing Il-1 from binding to its receptor,by blocking production of IL-1 or by blocking intracellular signaling once IL-1 has bound to its receptor. (Scientists say inflammatory cells "talk-to-each-other",or signal-each-other in the inflammatory orchestration.)

Etanercept is a synthetic protein that essentially acts as a decoy for the TNF circulating in the blood stream. It binds with TNF molecules,thereby preventing them from penetrating the cells to continue the process of inflammation. By capturing TNF in this way,etanercept supplements the body's naturally occurring TNF regulators so that they are not so overwhelmed.

Etanercept is used in people who have active rheumatoid arthritis and have not significantly improved after treatment with DMARDs. The rheumatoligist may also recommend that it to be used before other therapies are tried. Enbrel also appears to boost the effectiveness of traditional DMARD therapy. Adding Enbrel to standard methotrexate therapy,e.g.,resulted in a 75% improvement in the number of tender joints--almost double that provided to people taking MTX alone.

The drug works quickly,in as little as two weeks,although it may take up to three months to feel the full effects Studies that have being ongoing for the last 5 years show that the drug continues to work as long as the medication is taken,and X-rays show that it slows damage to the joint.

In adults, etanercept is taken twice per week in 25-milligram (mg) injections underneath the skin in the thigh, abdomen or upper arm. You can inject the drug yourself, or have the injections given by a partner or caregiver. The drug must be kept refrigerated because it is a natural protein that can break down at room temperature

Another biological agent,Infliximab (Remicade) also targets TNF but in a different way from Enbrel Rather then absorbing excessive TNF,infliximab uses a monoclonal antibody,that hunts down TNF and neutralizes it so that it has no effect. The antibody is produced in mouse,humanized and used in humans.

Infliximab is administered intravenously. The exact dose is based on your weight. A health professional experienced in giving infusions administers the drug directly into your vein. The infusion process, which takes about two hours, can be done at a infusion center. After a initial three infusions,over the course of six week--then a maintenance dose received every other month. In the first year the patient should expect about eight infusions;therafter,about six doses per year. This medication is given in conjunction with methotrexate.

Anakinra is taken on a daily basis in 100-mg injections underneath the skin. You can inject the drug yourself, or have the injections given by a partner or caregiver. Anakinra should not be used in combination with TNF inhibitors. Kineret is a IL-1 inhibitor. It may be more suitable to use this drug with another DMARD.

BRM's affect the immune system, etanercept, infliximab and anakinra have the potential to make patients vulnerable to infections. Safeguards, such as not beginning therapy during an infection or modifying the dose should an infection develop, have made the risk of more serious infection with these drugs small. However, serious infections have been associated with these BRMs. If you develop symptoms of infection while using etanercept, infliximab or anakinra, call you doctor so you can receive proper evaluation and treatment.

People taking them should not receive live vaccinations such as oral polio, chickenpox or the measles-mumps-rubella vaccine. Discuss these risks with your doctor to determine if the benefits of taking a BRM outweigh the potential side effects and risks.Patients should not take BRMs if they have an active, serious infection. People who are getting adequate relief from other treatments probably will not need to take a BRM.

Due to the groundbreaking research and development required to produce BRMs, these drugs cost more than some other medications. Check with your insurance provider to find out if these medications are covered. Currently,BRMs are not for everyone.

A New DMARD: Leflunomide (ARAVA)

Leflunomide,marked under the brand name Arava,is a type of immunosuppressant that belongs to the family of DMARDs. Although its exact action in rhematoid arthritis is unclear (the manufacturer has a web site explanation one the drug),this new medication appears to work by inhibiting immune cells that are rapidly dividing which promote inflammation in joints.

In early clinical trials leflunomide worked as well as the more standard DMARDs, methotrexate and sulfasalazine. As such,it may provide another option for RA patients This medication alleviates pain and swelling,and reduces the total number of tender joints in some patients. Studies have shown that it slows the progression of the disease. Arava must be prescribed It may take at least one month and up to three months for results. Arava does not work for all patients like any other medication.

The most common side effects are abdominal pain,diarrhea,rash, and hair loss(but these end when medication is stopped. While taking this drug the blood will be tested regularily to test for drug toxicity. There is a 3 day loading dose of 100 mg/daily and thereafter a daily dose of 10 mg or 25 mg/daily depending upon patient.

Leflunomide can cause birth defects. It also remains in the body long after the last pill was taken (up to 2 years). If a patient wants to become pregnant speak to the physician. He/she can best advise how to discontinue the drug and eliminate it from the body.

The Prosoba Column: A Blood-filtering Device ( It is not a BRM )

If you have moderate to severe rheumatoid arthritis and have not benifited from treatment with one or more DMARDs,another option may be the Prosoba column,a blood filterig device approved by the FDA in 3/99.

The Prosorba column function much like a kidney dialysis machine. The patient is connected to the machine,the blood is withdrawn through a tube,filtered through the column,removing certain substances involved in rheumatoid arthritis,and then returned to the bloodstream.

The procedure takes about 2 hours and is usually done once a week for 12 weeks. It can be done in a out-patient basis. Clinical studies showed that it generally took all 12 treatments before people noticed any benifit.

Side effects most commonly reported are chills,mild fever,nausea,and joint pain (similar to that of flu) for a day or two,after treatment. Other side effects include headache,anemia,sore throat,abdominal pain,rash,and dizziness.

There are many new questions to be addressed in use and treatment of biologics in RA: 1)How much better is combination therapy based on the data we have? 2)How much better is combination than monotherapy? 3)Are you thinking about using these drugs as monotherapy? 4)Do we want combinations with traditional DMARDS? 5) Do we reach for a step up or step down ? Most of the research data suggests a affirmative answer.

Nearly every combination trial we have "HARD DATA " on is a biologic plus methotrexate trial, which brings the question of whether that's the optimal combination, or whether we're going to move on and try more combinations of biologics. The cost of a single biologic prohibits it's use widely.

Some trials have been tried and it appears to work in certain very small trials, (we need larger trials ),but with Kineret (IL-1),more data suggests not to use it with biologics in combination. Toxicity seems to be the major problem.

Every trial we've looked at has evaluated patients on methotrexate. We add a biologic. Seventy-five percent to 80% of our patients have relentless disease, and at this point in time, we do not know who's going to go on to have the worst disease except for some easy predictors -- nodules at presentation, erosions at presentation, more than 20 joints. (Polyarthritis is defined as arthritis in 4 or more joints)

Let's consider patients with polyarticular disease that's seropositive with or without nodule, the people you think have definite RA. Should we be treating them all with biologics, methotrexate, and corticosteroids,or are we going to continue to gradually add medications.

How do you make a decision now about who gets what drug? Who do you put on infliximab or enbrel? The usual answer is people who can convince the "special access board" in Ontario Canada.

More questions to be considered is that a lot of important informative data is presented by the drug manufacturers themselves. Clinical trials are sponsored by the manufacturers. They are in business to make much profit as possible.

Is too much hype,patient selection,or over-promotion of the product itself,entering into the equation,even thought the product itself is basically sound and effective ? Are we getting the answers we really require ?

The current practise is those who do not respond to,or cannot tolerate conventional drugs is put on biologics. There are also patients who do not respond to biologics.

It has to do not with efficacy or what you know about the drugs. It's about who's going to pay and how easy it is for them to get the drug. It shouldn't be based just on your insurance type, but are there characteristics of disease where one patient is going to respond better than another?

Preexisting liver disease with methotrexate, if on leflunomide, limit their use. What are the issues with one biologic? An example is pregnancy where we don't know. Also, renal failure where we don't know. Think of different situations, different conditions, where we may want data.

Some of that data are already available and we need to mine it so we can make some decisions using evidence-based medicine,not rely on intelligent guessing,which doctors often use successfully,in current practise.

The use of biologics in RA has already revolutionized treatment options, and further studies will be necessary to clarify which patients with RA should actually,receive which drug and when. The future of these drugs looks exciting and promising,except for the cost factor.

But if they are really effective (short term)as Immunex (sold out to SP)paints the picture and is efficacious as reported by them. The long term cost of treating RA patients may be more cost effective in the long run when cost factor involved in the long -term treatment by conventional therapy is compared to biologic therapy short term. It doesn't take a genius to figure that out.

Perhaps we have to wait until we find the real cause and cure of rheumatoid arthritis for all the answers.

There is a study of anakinra plus etanercept. Schiff et al studied 58 patients with RA in a safety trial. This was a tolerability trial and 21 patients discontinued the drug. They reported something and were taken off. Twenty-eight of the 58 had infections. There were 48 infections, but only 4 patients had serious infections. Maybe that's a lot, but they weren't opportunistic infections or TB. In fact, they were serious infections because it was a safety trial. If they reported something, they were thrown in the hospital. What they had was cellulitis and community-acquired pneumonia. They responded very nicely to typical treatment.

But this is part of what the FDA evaluated when considering anakinra safety. Therefore, there is a rider in the package insert about not using combinations of biologics, and it's based on this safety trial. It suggests combinations of biologics may be too toxic, but the science community says a few other trials are necessary.

BRMs:

Tumor necrosis factor alpha (TNF-a) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in large quantities in the rheumatoid joint and is produced locally in the joint by synovial macrophages and lymphocytes infiltrating the joint synovium. The pro-inflammatory effects of TNF-a suggests that inhibition of TNF-a would be clinically useful in rheumatoid arthritis.

Despite excellent clinical trial data, there remain questions regarding long term use of the anti-TNF agents discussed below. The effect of these agents on rates of infection, cancer or the clinical recognition of these problems has yet to be answered in the general rheumatoid arthritis population. Cost and insurance reimbursement may limit availability. Whether these agents should or will replace methotrexate as the DMARD of first choice is to be answered only as the use of these agents increases.

Etanercept is a human fusion protein that combines two extracellular binding domains of the p75 form of the TNF receptor to the Fc portion of a human IgG1 antibody molecule. The protein is entirely human and thus has a low potential for immunogenicity (anti-etanercept antibodies).

A naturally occurring soluble form of the p75 TNF receptor is found in the circulation and may be part of a pathway to limit TNF activity in the inflammatory response to infection. The resultant fusion protein is a soluble molecule that binds TNF-a at high affinity. A number of placebo controlled clinical trials have shown the efficacy of etanercept in patients with active rheumatoid arthritis who have failed prior DMARD therapy.

Using the 25mg dose SC twice weekly, 59-75% of patients were found to improve by ACR 20 (20% improvement), and 40-57% improved by ACR 50 criteria (50% improvement). Long term-sustained efficacy has also been shown in an ongoing open label trial. At 18 months, patients have maintained their clinical improvement. Entanercept is also approved by the FDA for use in patients with polyarticular juvenile rheumatoid arthritis.

Radiographic studies in rheumatoid arthritis have tested the ability of etanercept to prevent or slow radiographic erosions. 832 patients were an average disease duration of one year were randomized to receive etanercept 25 mg, etanercept 10 mg, or methotrexate (mean dose, 18.3 mg/week). After one year of treatment, Sharp scores had only increased by 0.8, 1.4 and 1.3 units, respectively. All three treatment groups dramatically reduced the rate of radiographic progression, confirming the ability of etanercept alone to slow the progression of rheumatoid arthritis.

Similar to a monoclonal antibody, etanercept when given as a therapeutic agent, binds TNF-a in the circulation, preventing interaction with the cell surface TNF-a receptors and clears TNF-a from the circulation. Etanercept inhibits TNF activity.

Etanercept has a long half-life of 70 hours after a standard 25mg dose. It is currently available only in a 25mg dose and is given by self-administered subcutaneous (SC) injection twice weekly. Intermittent or occasional dosing has not been studied.

Etanercept has a rapid onset of action within the first 1-2 weeks of therapy with some continued improvement over the next 4 weeks.

Adverse events were mild throughout the clinical trials. There was an increase frequency of injection site reactions in the etanercept groups, 37% Vs 10% in the placebo group. The injection site reactions were mild. There was not an overall difference between the etanercept group and the placebo groups in the rates of infection, cancer, or death from any cause.

There was an increase in mild upper respiratory infection symptoms in the etanercept group. No increase was seen in the frequency of anti-ds-DNA antibodies and no patients developed clinical SLE as has been seen with studies with monoclonal antibodies against TNF.

Approximately 1% of patients developed anti-etanercept antibodies but these antibodies were non-neutralizing. A study adding etanercept to methotrexate showed no additional toxicity’s.

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 TNF–a 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, 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 , 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. Like etanercept, infliximab inhibits the activity of TNF.

The recommended dose of infliximab is 3 mg/kg given as an intravenous infusion followed with additional 3 mg/kg doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Infliximab should be given in combination with methotrexate.

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 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 TNF–blocking 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 immunosuppressive 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.

When it comes to the pain and debilitation of arthritis, the body can be its own worst enemy. The immune system – which generally protects the body from the constant barrage of bacteria, viruses and assorted poisons presented by the world – has become a prime suspect in the search for the cause of joint swelling and inflammation. An overactive immune reaction could lie at the heart of this condition, a defensive response which the body somehow fails to “turn off.”

Researchers at two American biotechnology companies are rapidly revealing the workings behind this “on/off” switch, with optimistic implications for arthritis sufferers. The proteins operating this switch should be manipulated by a new compound, which is expected to enter clinical trials this fall. Eventually, an entirely new class of agents could be available to treat the underlying causes of certain arthritic disorders rather than simply the obvious symptoms.

Moreover, arthritis is only one of many disorders which may be treated at its most fundamental level. Others include multiple sclerosis, diabetes, blood diseases and the ongoing problem of preventing the rejection of transplanted organs.

The excitement surrounds a protein called interleukin-1 or IL-1, one of several related proteins that the body manufactures for specific tasks. An IL-3 protein, for example, stimulates the production of platelets essential to blood clotting. Others control the behaviour of “killer” cells, the front-line troops waging the body’s battles with disease.

Proteins like IL-1 are relatively recent discoveries, products of new genetic technology enabling biochemists to isolate particular parts of complex organic molecules. Once isolated, these tiny strands of matter can be cloned, replicated in numbers large enough to fill test tubes and permit formal experiments.

Such work has been necessary to achieve any deeper understanding of the immune system, an intricate chemical network lacking any physically defined structure like the body’s circulatory or nervous systems.

What has emerged is a picture of a precision mechanism defining our very survival. Immunity is our defence against the less intrusion of foreign and often hostile organisms into the most intimate corners of our biological lives. Without our immune system we would fall prey to the simplest of maladies, such as the growth of microorganisms contained in the food we eat; with our immune system in place, however, we can muster strategies to repulse invaders the body has never before encountered.

Consider a venomous snake bite, injecting into the body some poison that destroys tissue or interferes with nerve signals vital to breathing or heartbeat. These effects can be countered by the introduction of antibodies, proteins specifically tailored to bind with venom molecules and neutralize them. Those antibodies can be cultivated in an animal by injecting small amounts of the venom and allowing the animal’s immune system to build up a set of antibodies; blood taken from the animal then serves as a snake-bite serum, so rich in antibodies that an injection into a bite victim counteracts the poison.

This procedure is perhaps nothing short of miraculous, given that neither animal nor human need to have previously encountered the snake venom to produce just the right antidote. The secret lies in the body’s remarkable variety of antibodies, a range of proteins so diverse as to combine with any set of invading molecules or antigens. Even more impressive, therefore, are the control mechanisms telling the various antibody-producing cells what to produce and when.

Such control begins with macrophages, white blood cells patrolling the body for foreign substances, consuming whatever does not belong and displaying various parts of it to attract antibody-producing cells.

“Macrophages have a key a role in the immune response,” says Cindy Jacobs, a staff scientist with Immunex, a Seattle-based biotechnology company. “They’re the beginning cell that takes something foreign and presents it to the immune system. It says, ‘Here, see this? You better respond to this, and I’m going to give you factors to respond to it, like IL-1’.”

IL-1 was discovered in 1984, in connection with this function of macrophages. The protein attaches itself to receptors on the surface of antibody-producing cells, directing those cells to attack whatever has been indentified as undesirable. “Youcall it an immune response when the response is good,” says Jacobs. “The system sees a foreign substance, responds to it and removes it, then everything goes back to a normal condition. If, for whatever reason, this process gets out of control, or it can’t get rid of the antigen, it can now start causing tissue injury. At that point, you stop calling it an immune response and start calling it an inflammatory response.”

This inflammatory response serves as a model for arthritis, giving researchers fresh insight into the disease process and how it might be halted. If the root of the problem lies with a signal that continues long after it is needed, the solution is to stop the signal.

Just last year Immunex came up with one technique for stopping IL-1’s immune signals. The company developed IL-1 receptors that remain in the solution around cells, competing with the receptors on the cell surface. Protein binding to cells can cause the cell to produce more of the enzymes generating inflammation; if the protein binds with the soluble receptors, then nothing happens. By adding these “decoy” receptors to an area where IL-1is active, the protein’s call for immune activity can be muted.

“The idea is to use the soluble IL-1 receptors to mop up the excess IL-1,” says Jacobs, who views this approach as a precisely targeted method of getting the protein to interfere with itself. “We found that these soluble receptors are naturally produced,” she adds. “This was very surprising. You’d think this is something that just came out of the lab, but when you go and look, you find soluble receptors. This maybe a way the body has of tuning down the immune response.”

Synergen, a biotechnology firm based in Boulder, Colorado, has taken a different approach to the same goal. Rather than diverting IL-1, this group of researchers has isolated a substance that interferes with the binding process itself. “This is a naturally occurring protein, which we believe just sits in the receptor and blocks IL-1 from docking with the receptor,” says Synergen spokesperson Ken Collins. “We’re in the process of developing this as a therapy for inflammatory diseases, and rheumatoid arthritisis the first target we’re going after.”

The blocking protein has been dubbed IL-1ra, the last two letters standing for “receptor antagonist.” Collins says Synergen expects a selected number of clinics to begin testing the medicaluse of IL-1ra this fall. Those tests represent the first step toward approval by the American Food and Drug Administration, which may be years away.

Ultimately, IL-1ra could take the form of an injection taken to alleviate recurring episodes of rheumatoid arthritis. While not a cure, this treatment would deal with the underlying causes of the ailment more directly than anything done so far. And because the active agent occurs normally within the body, few related problems are anticipated.

“It’s far better to treat our body with something that’s naturally produced to turn off the immune system, rather than going with artificial chemicals that have a lot of side effects,”says Jacobs.

By exploring the immune system in detail, scientists have now laid bare the manner in which the body protects each of us for a life time from a world that would otherwise prove fatal. IL-1and other proteins are crucial elements of that protection, which can turn against us or fail altogether. Knowing they are there, however, enables us to take immunity into our own hands and possibly overcome its apparent shortcomings.