All immune-mediated or hypersensitivity diseases can be treated by immunosuppressant drugs. All inflammatory arthritis will respond to immune suppression. In theory, if you found the right combination of drugs you could arrest the disease. Immune activity involves complex sequences and can be blocked in a variety of ways. The mechanisms of action of imunosuppressants are multiple and include preventing/inhibiting:
Immune cell activation, Cytokine production and expression, Cell differentiation, and/or proliferation.
Immunosuppressants can also work by stimulating the expression of immunosuppressive molecules and/or cells. Because immune suppressant drugs have a host of negative consequences, trials of their use in immune-mediated diseases were slow and cautious; however, recently, more aggressive treatments with increasingly potent agents have become more popular. There is a danger that aggressive therapies may run amok for several years before study results show the real benefit to cost to risk ratios.
In organ transplant programs, however, immunosuppression is essential to success and many powerful drug combinations have been tried. Lifelong prednisone has been the mainstay of transplant programs. The protocols used in most transplant centers involve the use of multiple drugs, each directed at different mechanisms in the T-cell activation cascade and each with distinct side effects. Cyclosporine, azathioprine, corticosteroids, tacrolimus, and mycophenolate mofetil have been used. Other agents have been introduced to treat immune mediated diseases. The strategy of drug companies has been varied, but the goal with each new agent is to block immune activation at some level or another. While there may be benefits, the research and product hype can be distracting. There is no easy and safe way to block immune activity. The more effective immune blockers are, the more damage they can do. New immunosuppressants come with penalties:
The drugs are often expensive.
Immune Blocking Antibodies
Tumor necrosis factor (TNF) is a cytokine, a signaling chemical released by immune cells to activate other immune cells. TNF blockers are immunosuppressive agents approved to treat immune system diseases, including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn's disease, and ankylosing spondylitis. Etanercept (Enbrel) infliximab (Remicade), Efalizumab and Adalimumab (Humira) block the action of tumor necrosis factor, and can reduce disease activity in patients with inflammatory diseases. . Enbrel is administered by injection twice a week and Remicade is given in hospital by IV infusion every eight weeks. Etanercept is a recombinant DNA version of the P75 TNF receptor that is linked to IgG1. In a study by Bathon et al: “632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months… patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having greater improvement in disease activity during the first six months (P<0.05). As compared with oral methotrexate, subcutaneous etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis. “Klareskog followed 371 RA patients who received etanercept 25 mg twice daily for 3 years. Disease Activity Score fell from 5.1 at baseline to 3.0 after 3 months in the initial study and to 2.6 at 3 years. There was a sustained improvement in Health Assessment Questionnaire scores over the course of the study. The researchers concluded: "etanercept showed sustained efficacy and a favorable safety profile" and is an option for long-term treatment in clinical practice. . Goldsmith et al reported: ”Etanercept, a tumor necrosis factor-alpha antagonist produced by recombinant technology, is approved for use in the US as subcutaneous monotherapy in adults with moderate-to-severe psoriasis who are candidates for systemic therapy or phototherapy. The drug is also indicated in patients with psoriatic arthritis. In well designed trials in patients with moderate-to-severe psoriasis, short-term etanercept therapy (typically 25 or 50 mg twice weekly) significantly increased the proportion of patients achieving a 75% reduction in the Psoriasis Area and Severity Index score compared with placebo. Short-term etanercept therapy was well tolerated in patients with psoriasis or psoriatic arthritis. “
Infliximab is a chimeric mouse/human IgG1 monoclonal antibody that binds to tumor necrosis factor and prevents it from acting on immune cell receptors. It is administered IV at 5 mg/kg every 8 weeks. While anti-TNF antibody looks like a smart strategy for blocking immune activation, the proposal to use this treatment long-term for more immune-mediated diseases is worrisome. THF blocking invites many complications and hazards that have not been well explored. There are differences between using THF blockers for single or short-term treatments and using it long-term. In my opinion, if this approach works well long-tem without significant adverse effects, it will be a stroke of luck more than intelligent design.
In August 2004, U.S. health officials said 12 Californians who had taken Remicade or Enbrel had tested positive for tuberculosis. Two of those infected died. Other patients revealed blood-related disorders such as leukopenia and thrombocytopenia. In October 2004, Johnson & Johnson warned MDs that patients taking Remicade have a three-fold increase in the risk of developing lymphoma. Swale et al reported: “TNF is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis.
A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.” In small study preliminary study 20 patients were treated with a combination of three treatments designed to deplete B-lymphocytes. Two drugs, prednisoline and cyclophosphyamide, and a monoclonal antibody targeted to B-lymphocytes. The antibody preparation, Mabthera (rituximab), which triggers the destruction of B lymphocytes by other lymphocytes, appeared to have the best short-term benefit. Anakinra (Kineret) is a recombinant DNA version of the interleukin-1 receptor antagonist that blocks the action of IL-1. It is administered by daily subcutaneous injections. The administration of antibodies by injection is a potentially hazardous procedure. The anti-TNF antibody, for example, will excite antibody production against itself. The anti-anti-TNF antibodies can have activity similar to TNF itself.
The immune response to foreign antibodies can produce allergy, both immediate and delayed. Short-term benefits have been demonstrated, but the same benefits are available from oral prednisone, which blocks the production of TNF. The negative effects of prednisone are well known and can be mitigated by equally well-known procedures. The long term effects and anti-TNF are not known. The US FDA issued a warning in 2008 about life-threatening complications in children taking Enbrel (ethercept) for psoriasis and arthritis. The FDA examined 949 reports of serious complications in children ages 4 to 17, finding 14 deaths and 76 other life-threatening cases.
In May 2009, the US Food and Drug Administration (FDA) issued a reminder warning that there is risk of serious fungal infections associated with all tumor necrosis factor-alpha (TNF-alpha) inhibitors. The reminder was issued because " histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking TNF-α blockers. Delays in instituting antifungal treatment may be fatal. The drugs included in this warning were Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab) and golimumab (Simponi, Centocor Ortho-Biotech Inc )" Waknine reported that makers of tumor necrosis factor (TNF)-blocking agents were ordered to strengthen warnings regarding the risk for histoplasmosis and other invasive fungal infections by the US Food and Drug Administration. Since the initial approval of the 4 TNF blockers, the prescribing information for these drugs has included information about the risk of serious infections, including fungal infections; however physician are not recognizing cases of histoplasmosis and other invasive fungal infections, leading to delays in treatment. The US FDA has received 240 reports of histoplasmosis in patients receiving infliximab (Remicade) 207 cases, etanercept (Enbrel) 17 cases, and adalimumab (Humira) 16 cases; 1 case occurred during treatment with certolizumab pegol (Cimziac), approved in 2008. Missed diagnoses in 21 patients led to treatment delays and 12 deaths. Fatal cases of coccidioidomycosis and blastomycosis have also been reported. Healthcare professionals are advised to closely monitor patients for signs and symptoms of fungal infection during and after treatment with anti-TNF drugs. Patients who develop fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates on X-ray, or serious systemic illness should undergo a complete diagnostic workup. A high index of suspicion should be maintained for invasive fungal infections in symptomatic patients. If possible, the decision to initiate empiric antifungal therapy should be made in conjunction with an infectious diseases specialist. An infectious disease consultation is also recommended when determining the duration of antifungal therapy and whether anti-TNF therapy should be resumed on recovery, particularly for patients who reside in regions of endemic mycoses. “ Efalizumab was used for the treatment of chronic moderate to severe plaque psoriasis. In April 2009 Efalizumab (Raptiva, Genentech, Inc) was withdrawn from the US markets because of a potential risk to patients of developing progressive multifocal leukoencephalopathy (PML). According to a US Food and Drug Administration (FDA) statement, the risk that an individual patient taking efalizumab will develop PML is generally associated with long-term use. PML leads to an irreversible decline in neurologic function and death.
A Better Approach
Part of the problem with arthritis therapy has been complacency attached to dogma. No one understands the cause of arthritis and the mechanisms that initiate and then maintain inflammation remain obscure. The treatments are inadequate and the suffering is great. Apparently, it has been easy for institutions to focus on coping with the ravages of arthritis - you have resources to help people cope with pain and loss of function. Pain control is seldom adequate and loss of function is often progressive and disabling. No resources are applied to prevention or emergency care of the arthritis attack.
Our attitude is different. What if you took the point of view that any an all inflammatory attacks on joints is a medical emergency. You got into the ambulance and were rushed to the joint ICU. Hours count. The onset of joint swelling and pain should be treated as an urgent problem to be solved. Inflammation damages joints and they cannot be repaired. Some can be replaced but this is hardly a satisfactory strategy.
What if the attitude was - there has to be an immediate investigation into the cause so that the problem can be stopped at its source. You ask important questions about the possible cause, even if you are not sure. Is the cause in the Food? In the Air? Water?
What if the attitude was - in the face of uncertainty, why not make some simple assumptions and try simple, safe experiments to see if the problem can be avoided? We propose diet revision as the experiment - not casual, haphazard, silly diet revision, but complete, thorough, thoughtful, disciplined diet revision. Drugs may play a role in controlling the disease, but again the casual use of drugs without understanding, without a clearly-defined strategy, without goal and end-points to measure efficacy, drug use can be a great disappointment and a source of further suffering and disease.
Quick Action to stop inflammation
Our preference is to try to stop the inflammatory activity as soon as possible. All inflammation is likened to a fire. You get out the fire extinguishers and go to work. Drugs are used as short-term tools. Diet revision is used to control the disease long-term. No matter what pattern the immune attack assumes, our standard defense can be tried:
Prednisone is often a magic drug that relieves terrible pain and suffering often in the first 48-72 hours of therapy. The problems with prednisone arise with long-term use. The secret of success is to use this drug for brief periods and attempt to control the disease with diet revision in the long-term. A medium to high dose of prednisone (20 - 60 mg per day) may be required for several days and then is reduced to an effective short-term maintenance level between 5 and 20 mg/day.
After pain and swelling have subsided, slow food reintroduction follows the Alpha Nutrition Program. Each food is carefully screened for arthritis-triggering effects. You hope that food allergy caused the problem and that food control can be successful controlling the disease in the long-term. Unfortunately, we do not have good data on how many un-selected patients would respond to this approach, but nothing is lost by taking this approach and complete control of the disease has been obtained. If strict food control proves to be inadequate, then other drug treatments - step 1 and 2 can be instituted to replace prednisone in the longer term.
Tom Arnold. Study Links Arthritis Drugs To Bleeding: Vioxx And Nsaids: (A2) Competing Medication Results In Less Hospitalization. National Post, Friday, September 20, 2002
The Therapeutics Initiative Newsletter in BC. Do journal publications tell the full story? January 31, 2002. http://www.ti.ubc.ca/pages/letter43.htm
US FDA News, FDA Issues Public Health Advisory on Vioxx as its Manufacturer Voluntarily Withdraws the Product. Sept 30 2004. Online http://www.fda.gov/bbs/topics/news/2004/NEW01122.html
Topol, E.J. Failing the Public Health — Rofecoxib, Merck, and the FDA. n engl j med. 351;17 October 21, 2004. 1708
Barclay, L. Vioxx Withdrawal Prompts Reevaluation of COX-2 Inhibitor Safety.; Medscape Medical News Oct. 2004. http://www.medscape.com/viewarticle/490979?src=mp
Jeffrey M. Drazen, M.D.; COX-2 Inhibitors -- A Lesson in Unexpected Problems. Published at www.nejm.org February 15, 2005 (10.1056/NEJMe058038)
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