Drug Treatment is Disappointing
A 1997 survey of 1,000 Canadian Arthritis sufferers showed that 60% developed the disease after age 40; 62% of those dissatisfied with the care they received cited "not getting better" as their chief complaint. Arthritis was one of the most reasons for visiting the family doctor in Canada and is the third most common reason for prescription drug use. The annual cost of Arthritis health care in Canada is $14.3 billion.
Overview of Standard Medical Treatment
Arthritis is usually treated with drugs and physiotherapy. Drug treatment of arthritis is often unsatisfactory. If you critically examine treatment regimens, there has some progress beyond the basic drugs, aspirin and prednisone but the newer immunosuppressant drugs have serious negative effects.
Aspirin (ASA) has been imitated by many other agents that have similar benefits, side effects and similar toxicity. There are two groups of ASA substitutes:
1. Non-steroidal anti-inflammatory drugs (NSAIDs)
2.; Selective COX-2 inhibitors.
The mechanism of ASA and the other drugs is the inhibition of the enzyme, cyclooxygenase (COX), responsible for the production of pro-inflammatory prostaglandins. NSAIDs were once considered controlled drugs, available only on prescription, but many NSAIDs have been removed from the prescription list and are available as over-the-counter drugs: Advil and Motrin are examples.
COX 2 Inhibitors, Expensive and Not Safe
The newest class of pain–relieving drugs, the selective COX-2 inhibitors were; marketed aggressively and outsold older less expensive drugs. All these drugs alleviate the pain of active arthritis but do not favorably affect the outcome of the disease. Advertising for the newer “selective COX-2 inhibitors” led the casual reader to believe that these drugs were the newest and best drugs for arthritis. Because they are prescription drugs and more expensive, patients may be tempted to believe they are better than ASA, ibuprofen, diclofenac or naproxen but this is not true. The claimed advantage of the newer COX-2 inhibitors, slightly lower incidence of gastrointestinal irritation is supported by some but not all studies Cox-2 inhibitors have no advantage in terms of pain relief and anti-inflammatory effects.
A growing controversy surrounds the use of Cox-2 inhibitors. The drug companies involved; competed to secure a large share of the multi-billion-dollar-a-year market for pain-relieving anti-inflammatory drugs. A news report in 2002, for example, warned people that: "Elderly patients taking Vioxx, the most popular arthritis drug in Canada, are twice as likely to be hospitalized with major gastrointestinal bleeding than those taking its pharmaceutical competitor, Celebrex. In 2002, 3.4 million prescriptions for Vioxx were filled across Canada; 3.1 million for Celebrex. What is surprising about this expensive and unproven class of drugs is that physicians; prescribed them so quickly and frequently. They and their patients were obedient consumers responding to clever advertising campaigns.
Many years ago I worked with biochemist, Dr. Alan Burton, on the applications of glucosamine when it was virtually unknown. We became the inventors cited in a US patent on the use of acetyl glucosamine in the treatment of food allergic diseases, including inflammatory arthritis. Burton was one of the few scientists with any knowledge about or interest in glucosamine and in the mid-1980s proposed a therapeutic use in Crohn's disease. I realized that glucosamine was an important building block of the digestive tract seals and may be useful in reducing gut permeability. I was working on our current theory that arthritis occurred when gut permeability increased giving access to food and bacterial antigens that made their way to joints, triggering inflammation. The ideas were interesting enough that Al Fowler championed the project at the University of British Columbia and applied for and received a US patent. Burton's writing on the subject was used to popularize the sale of glucosamine and successful glucosamine marketing efforts followed. Subsequently, many companies and promoters went into the glucosamine business.
The marketing efforts were based entirely on speculation and not on known efficacy. The disappointing discovery for us was that preliminary clinical trials with acetyl glucosamine showed mixed results and I raised the question of the pharmacokinetics of glucosamine. Does it get absorbed? Is it broken down in the gut or liver? Does orally ingested glucosamine reach tissues such as joints where it might be helpful?
The answers to these questions are still uncertain, but there are serious doubts that oral doses of glucosamine survive transit through the gut and liver. Casual pharmacokinetic studies done at UBC were unable to identify glucosamine in the blood 20 minutes after ingestion. This means that little or no glucosamine actually reaches the joints where it may do some good. None of the vendors of glucosamine has, to our knowledge, conducted pharmacokinetic studies, and all the claims of benefit in arthritis are speculative and doubtful. A Cochrane group reviewed all randomized controlled trials (RCTs) evaluating the effectiveness and toxicity of glucosamine in Osteoarthritis (OA). Eight studies failed to show consistent and statistically significant benefit of glucosamine for pain and functional improvement. Only one preparation of crystalline glucosamine sulfate (Rotta Pharm) showed a little benefit
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.
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)
Examples from the Literature
Gotzsche_PC; Johansen_HKochrane Database Syst Rev, 2000 01, : 2, CD000189
Abstract BACKGROUND: The effect of low dose corticosteroids, equivalent to 15 mg prednisolone daily or less, in patients with rheumatoid arthritis has been questioned. We therefore performed a systematic review of trials which compared corticosteroids with placebo or non-steroidal, anti-inflammatory drugs. OBJECTIVES: To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and nonsteroidal, antiinflammatory drugs in patients with rheumatoid arthritis. SEARCH STRATEGY: Medline Silverplatter, The Cochrane Controlled Trials Register, reference lists and a personal archive. SELECTION CRITERIA: All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a nonsteroidal, antiinflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. DATA.RESULTS: Ten studies, involving 320 patients, were included in the meta-analysis. Prednisolone had a marked effect over placebo on joint tenderness pain and grip strength. Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mm Hg (5 to 40) for grip strength. Prednisolone also had a greater effect than nonsteroidal, antiinflammatory drugs on joint tenderness and pain whereas the difference in grip strength was not significant. Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mm Hg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable. REVIEWER'S CONCLUSIONS: Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.
COX 2 Inhibitors and Heart Attack Risk
MSNBC News April 18 2002 http://www.msnbc.com/news/740542.asp?0si=-
“Evidence is prompting scientists to study users of new painkillers called cox-2 inhibitors to determine whether their hearts are at risk. At issue is whether people with heart disease — not healthy people — increase their risk of heart attacks even more by taking Vioxx or Celebrex. The study by University of Pennsylvania researchers, in Friday’s edition of the journal Science, suggests, how the drugs could cause such side effects.A leading heart expert called the new research a very important step in explaining an earlier study that found certain Vioxx users suffered twice the risk of heart attacks as users of NSAIDs, COX-1 inhibitors). There are two forms of an enzyme that plays a role in pain-causing inflammation and blood clotting.
One of the enzymes, Cox-1, makes thromboxane, which causes blood vessels to constrict and platelets to become sticky, steps important in a heart attack or stroke. The other, Cox-2, is a major source of prostacyclin, which dilates blood vessels and prevents platelets from clumping together. In a healthy person, the two coxes are thought to balance each other so blood doesn’t excessively clot.In people at risk of heart attack, aspirin helps because it thins the blood by blocking cox-1; it also slightly blocks cox-2. Vioxx and Celebrex, in contrast, block only cox-2... Topol and other doctors reported more Vioxx users than users ofnaproxen suffered heart attacks.”
Azathioprine for rheumatoid arthritis.
Suarez_Almazor_ME; Spooner_C; Belseck_E. Cochrane Database Syst Rev, 2000 01, : 2, CD001461
Abstract OBJECTIVES: To assess the short-term effects of azathioprine for the treatment of rheumatoid arthritis (RA). SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, Medline up to and including July 1998 and Embase from 1988-1998. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. All randomized controlled trials and controlled clinical trials comparing azathioprine against placebo in patients with rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: Data was extracted independently by two reviewers (CS, EB); disagreements were resolved by discussion or third party adjudication (MS). The same reviewers (CS, EB) assessed the methodological quality of the trials using a validated quality assessment tool. Rheumatoid arthritis outcome measures were extracted from the publications for the six-month endpoint. The pooled analysis was performed using standardized mean differences for joint counts, pain and functional status assessments. Weighted mean differences were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals and for adverse reactions. MAIN RESULTS: Three trials with a total of 81 patients were included in the analysis. Forty patients were randomized to azathioprine and forty-one to placebo. A pooled estimate was calculated for two outcomes. A statistically significant benefit was observed for azathioprine when compared to placebo for tender joint scores. The standardized weighted mean difference between treatment and placebo was -0.98 (95% CI -1.45, -0.50). Withdrawals from adverse reactions were significantly higher in the azathioprine group OR=4.56 (95% CI 1.16, 17.85). REVIEWER'S CONCLUSIONS: Azathioprine appears to have a statistically significant benefit on the disease activity in joints of patients with RA. This evidence however is based on a small number of patients, included in older trials. Its effects on long-term functional status and radiological progression were not assessed due to lack of data. Toxicity is shown to be higher and more serious than that observed with other disease-modifying anti-rheumatic drugs (DMARDs). Given this high risk to benefit ratio, there is no evidence to recommend the use of azathioprine over other DMARDs.
Cyclophosphamide for rheumatoid arthritis.
Suarez_Almazor_ME; Belseck_E; Shea_B; Wells_G; Tugwell_P
Cochrane Database Syst Rev, 2000 01, : 2, CD001157
To estimate the short-term effects of cyclophosphamide for the treatment of rheumatoid arthritis. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's Register, the Cochrane Controlled Trials Register, Medline and Embase up to and including July 1997. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. SELECTION CRITERIA: All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing oral cyclophosphamide against placebo (or an active drug at a dosage considered to be ineffective) in patients with rheumatoid arthritis. DATA COLLECTION AND ANALYSIS: Data abstraction was carried out independently by two reviewers. The same two reviewers using Jadad's scale (Jadad 1995) assessed the methodological quality of the RCTs and CCTs. Rheumatoid arthritis outcome measures were extracted from the publications for baseline and end-of-study. MAIN RESULTS: A total of 70 patients were included in the pooled analysis of two trials, 31 receiving cyclophosphamide. A statistically significant benefit was observed for cyclophosphamide when compared to placebo for tender and swollen joint scores: SMDs were -0.57 and -0.59 respectively. The difference in ESR also favoured the active drug but did not reach statistical significance (-12 mm, 95%CI: -26 to 2.5). One trial reported the number of patients developing new or worse erosions: the OR for cyclophosphamide compared to placebo was 0.17 (95% CI: 0.05 to 0.57). Patients receiving placebo were six times more likely to discontinue treatment because of lack of efficacy than patients receiving cyclophosphamide. Withdrawals from adverse reactions were higher in the cyclophosphamide group (Odds ratio=2.9), although this difference was not statistically significant. Side effects from cyclophosphamide included hemorrhagic cystitis, nausea, vomiting, leucopenia, thrombocytopenia, alopecia, amenorrhea and herpes zoster infections. REVIEWER'S CONCLUSIONS: Cyclophosphamide appears to have a clinically and statistically significant benefit on the disease activity of patients with RA, similar to some disease modifying antirheumatic drugs (DMARDs) such as antimalarials or sulfasalazine, but lower than methotrexate. Toxicity however is severe, limiting its use given the low benefit-risk ratio compared to other antirheumatic agents.
Antimalarials for rheumatoid arthritis.
Suarez_Almazor_ME; Belseck_E; Shea_B; Homik_J; Wells_G; Tugwell_P
Cochrane Database Syst Rev, 2000 01, : 2, CD000959
Abstract OBJECTIVES: To estimate the short-term efficacy and toxicity of antimalarials for the treatment of rheumatoid arthritis (RA). SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, Medline and Embase up to and including July 1997. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. SELECTION CRITERIA: All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing antimalarials against placebo in patients with RA DATA COLLECTION AND ANALYSIS: Data abstraction was carried out independently by two reviewers. The same two reviewers using Jadad's scale (Jadad 1995) assessed the methodological quality of the RCTs and CCTs. Rheumatoid arthritis outcome measures were extracted from the publications for the 6-month endpoint. The pooled analysis was performed using standardized mean differences for joint counts, pain and global assessments. Weighted mean differences were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout. MAIN RESULTS: We found four trials, with 300 patients randomized to hydrochloroquine and 292 to placebo. Only trials evaluating hydroxychloroquine could be pooled in the analysis. A statistically significant benefit was observed when hydroxychloroquine was compared to placebo. The standardized mean differences for the various outcome measures ranged from -0.33 to -0. 52, and were statistically significant. Statistically significant differences were also observed for ESR. Overall withdrawals and withdrawals due to lack of efficacy were significantly more frequent in the placebo group. No differences were observed in withdrawals due to toxicity. REVIEWER'S CONCLUSIONS: Hydroxychloroquine appears to be efficacious for the treatment of RA. Its overall effect appears to be moderate, but its low toxicity profile should be considered when treating patients with RA.
Sulfasalazine for rheumatoid arthritis.
Suarez_Almazor_ME; Belseck_E; Shea_B; Wells_G; Tugwell_Pochrane Database Syst Rev, 2000 01, : 2, CD000958
Abstract OBJECTIVES: To estimate the short-term efficacy and toxicity of sulfasalazine for the treatment of rheumatoid arthritis (RA). SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to July 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). Key experts in the area were contacted for further published and unpublished articles.
DATA COLLECTION AND ANALYSIS: Two reviewers determined the studies to be included based on inclusion and exclusion criteria (GW, MSA). Data were independently abstracted by two reviewers (EB, MSA), and checked by a third reviewer (BS) using a pre-developed form for the rheumatoid arthritis sub-group of the Cochrane Musculoskeletal Group. The same two reviewers, using a validated scale (Jadad 1996) assessed the methodological quality of the RCTs and CCTs independently. Rheumatoid arthritis outcome measures were extracted from the publications. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts, pain, and global and functional assessments. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios (OR) for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout and random effects for outcomes showing heterogeneity. MAIN RESULTS: Six trials, including 468 patients were included. A statistically significant benefit was observed for sulfasalazine when compared to placebo for tender and swollen joint scores, pain and ESR. The standardized weighted mean difference between treatment and placebo was -0.49 for tender and swollen joint scores, and -0.42 for pain. The difference for ESR was -17.6mm. Withdrawals from adverse reactions were significantly higher in the sulfasalazine group (OR=3.0). Patients receiving placebo were four times more likely to discontinue treatment because of lack of efficacy than patients receiving sulfasalazine. REVIEWER'S CONCLUSIONS: Sulfasalazine appears to have a clinically and statistically significant benefit on the disease activity of patients with RA. Its effects on overall health status and radiological progression are not clear at this time, but would appear to be modest.
Penicillamine for Rheumatoid Arthritis
Suarez-Almazor ME, Spooner C, Belseck E. Penicillamine for rheumatoid arthritis (Cochrane Review). In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software
Background and objectives: To estimate the short-term effects of D-penicillamine for the treatment of rheumatoid arthritis (RA). Data collection and analysis: The methodological quality of the trials was assessed independently by two reviewers (CS, EB) and checked by a third (MS) using a validated quality assessment tool. Rheumatoid arthritis outcome measures were extracted from the publications for the six-month endpoint and stratified according to D-penicillamine dosages: low ( <500mg/day), moderate (500 to <1000mg/day) and high (1000 mg/day or greater). Reviewers' conclusions: D-penicillamine appears to have a clinically and statistically significant benefit on the disease activity of patients with rheumatoid arthritis. Its efficacy appears to be similar to that of other disease modifying anti-rheumatic drugs (DMARDs), but with a significantly higher toxicity. Its effects on long-term functional status and radiological progression are not clear from this review. Main results: Six trials were identified, with 425 patients randomized to D-penacillamine and 258 to placebo. A statistically significant benefit was observed for D-penicillamine when compared to placebo for all three-dose ranges and for most outcome measures including: tender joint counts, pain, physician's global assessments and ESR. The standardized weighted mean differences between treatment and placebo in moderate doses were -0.51 [95% CI -0.88, -0.14] for tender joint counts, -0.56 (95% CI -0.87, -0.26) for pain and -0.97 (95% CI -1.25, -0.70) for global assessment. The difference for ESR was -10.6 mm/hr. Similar results were observed for the higher dose group. Total withdrawals were significantly higher in the moderate and high dosage D-penicillamine groups (OR=1.63 and 2.13 respectively), mostly due to increased adverse reactions (OR = 2.60 and 4.95 respectively), including renal and hematological abnormalities.
Methotrexate for rheumatoid arthritis.
Suarez_Almazor_ME; Belseck_E; Shea_B; Wells_G; Tugwell_P
Cochrane Database Syst Rev, 2000 01, : 2, CD000957
OBJECTIVES: To estimate the short-term efficacy and toxicity of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). We searched the Cochrane Musculoskeletal Group trials register, and Medline, up to July 1997, using the search strategy developed by the Cochrane Collaboration (Dickersin 1994). The search was complemented with bibliography searching of the reference list of the trials retrieved from the electronic search. Key experts in the area were contacted for further published and unpublished articles. MAIN RESULTS: Five trials and 300 patients were included. A statistically significant benefit was observed for MTX when compared to placebo. Statistically significant differences were observed for all measures except ESR. The standardized weighted difference (effect size) between MTX and placebo for the various outcome measures varied between -0.43 and -1.5. No differences were observed in the total number of withdrawals and dropouts (OR = 0.95), although patients on MTX were three times more likely to discontinue treatment because of adverse reactions (OR=3.47) and four times less likely to withdraw due to lack of response (OR=0.22). REVIEWER'S CONCLUSIONS: Twenty-two percent of people on MTX withdrew due to adverse effects compared to seven percent of the placebo group. MTX has a substantial clinically and statistically significant benefit in the short term treatment of patients with RA.
Cox-2 inhibitors have been oversold to physicians and patients. The only real benefit claimed for their use was a reduction in the incidence of digestive tract bleeding, the main negative effect of ASA and other NSAIDs. This benefit may have been overstated, and other risks may be attached to the use of these newer drugs. In addition several different drugs have been marketed under the banner of Cox-2; evidence is emerging that each agent has its own merits and risk, so that drug class generalizations are always appropriate. Here is a reasonable summary by Robert W. Griffith, MD (HealthandAge.com, from the Novartis Foundation for Gerontology)
“NSAIDs and the COX-2 inhibitors are equally effective in relieving the symptoms of pain and inflammation in osteo-arthritis and rheumatoid arthritis. This is because the NSAIDs have both COX-1 and COX-2 inhibitory properties, and it is generally accepted that the COX-2 enzyme is the one responsible for inflammatory effects. It's clear, therefore, that the beneficial effects of both COX-2 inhibitors and NSAIDs in arthritis are due to their inhibitory effects on COX-2. Inhibition of COX-1 doesn't counter the effects of inflammation. To date, there's no evidence that the COX-2 inhibitors are any better than NSAIDs with regard to effectiveness. Side effects of NSAIDs involving the gastrointestinal tract include heartburn, stomachache, vomiting, diarrhea, and occasionally, stomach ulcers that can bleed. They are considered to be due to the NSAIDs' COX-1 inhibition effect….there is no such thing as a 'pure' COX-2 inhibitors (at least, not yet); the most specific, or precise, COX-2 inhibitor available, rofecoxib, is over 50 times more active on COX-2 than on COX-1 enzymes, while most NSAIDs are far less than 5 times as active on COX-2 than on COX-1 enzymes. This lab test shows that there is a middle group of drugs that are between 5 and 50 times 'selective' for COX-2 over COX-1. This group contains celecoxib, meloxicam, nabumetone and etodolac, which were previously classified as 'regular' NSAIDs.
NSAIDs may have harmful effects on kidney function. This appears to be due to the COX-2 inhibition that NSAIDs possess - it's been found that both rofecoxib and celecoxib produce similar effects on kidney function to those caused by NSAIDs.
The two COX enzymes have different roles in the blood clotting process, which more or less balance out. Nonselective NSAIDs, since they inhibit COX-1 and COX-2, don't upset this balance. However, COX-2 inhibitors seem to tip this balance in favor of an increased tendency to thrombosis. In August 2001, an analysis of published clinical studies suggested there was an increased risk of developing a heart attack or myocardial infarction (an MI), unstable angina, sudden heart death, a stroke, or a transient ischemic attack (TIA) - with use of the COX-2 inhibitor rofecoxib. Celcoxib didn't show this effect. In a study in patients with both high blood pressure and osteoarthritis, both rofecoxib and celecoxib were found to increase blood pressures to a slight degree -- rofecoxib more so than celecoxib.”
Bjarnason I, Peters TJ.
Baillieres Clin Rheumatol 1996 Feb;10(1):165-76
There is great interest in the association between intestinal inflammation and the various arthropathies. However, most studies assessing intestinal function in these diseases are confounded by the fact that non-steroidal anti-inflammatory drugs (NSAIDs) have profound effects on the small intestine. Hence NSAIDs cause quite distinct and severe biochemical damage during drug absorption (uncoupling of mitochondrial oxidative phosphorylation proving to be most important) which results in increased intestinal permeability. All commonly used NSAIDs, apart from aspirin and nabumetone, are associated with increased intestinal permeability in man. Whilst reversible in the short term, it may take months to improve following prolonged NSAID use. Increased intestinal permeability appears to be the central mechanism of converting the biochemical damage to an inflammatory tissue reaction (NSAID enteropathy). The inflammatory enteropathy is not, however, unique to NSAIDs but similar changes are found with other permeability breakers. In intestinal infections and in diseases associated with reduced mucosal defence, suggesting that the small intestinal inflammation represents a common final pathway for a number of intestinal injuries. Spondylarthropathies are associated with a high prevalence of terminal ileitis, but as most patients have been receiving NSAIDs it has been difficult to dissociate the effects of NSAIDs on intestinal function from that of the ileitis itself. Nevertheless, two studies suggest that increased intestinal permeability in spondylarthropathies occur independently of NSAID ingestion. Whilst these findings may have implications for the development of arthritis, the permeability changes in spondylarthropathy do not differ quantitatively or qualitatively from that of NSAIDs or other permeability breakers. NSAID enteropathy can be differentiated from spondylarthropathic enteropathy by differences in location of disease and lack of predilection of certain HLA types. However, as the two may coexist both enteroscopy and ileocolonoscopy may be necessary for this distinction.
GI permeability, anti-inflammatory drugs
Smecuol E, Bai JC, Sugai E, Vazquez H, Niveloni S, Pedreira S, Maurino E, Meddings J. Gut 2001 Nov;49(5):650-5
Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New anti-inflammatory drugs have been developed in an attempt to improve their gastrointestinal side effect profile. Our objective was to compare the effect on gastrointestinal permeability of acute equieffective doses of four different NSAIDs; three were designed to reduce gastrointestinal mucosal injury. Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. RESULTS: Gastric permeability was significantly affected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. CONCLUSION: Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side effect profile.
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