Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory disease that leads to irreversible joint damage, chronic pain, stiffness, and functional impairment. The pain associated with arthritis can be disabling and profoundly affects the individual’s quality of life. Non medication approaches to managing RA include patient education, weight reduction, various alternative therapies, and exercise. In most cases a pharmacologic approach is also used to manage both the disease and the pain associated with the disease. Despite their effectiveness in reducing pain and inflammation, the first line types of medications often used- the non-steroidal anti-inflammatory drugs (NSAIDs)- are potentially dangerous compounds.
Issues surrounding both cardiovascular (CV) and gastrointestinal (GI) effects have caused concern. Some of the first-generation cyclooxygenase (COX)-2 inhibitors have emerged as safer alternatives; however, CV risk in some patients has resulted in limitation of their use.
An increased risk for gastrointestinal and CV side effects has been identified with traditional non-steroidal drugs in both patients with RA and osteoarthritis. The main issue with the traditional non-steroidal drugs, which initiated the entrance of COX-2’s to the marketplace, was gastrointestinal (GI) bleeding that led to an excess of hospitalizations, morbidity, and mortality. There was a need to develop compounds that could provide pain relief but also protect the GI lining.
The mechanism of action of NSAIDS is to block an enzyme called cyclooxygenase. Cyclooxygenase is required for the production of prostaglandins. Cyclooxygenase is divided into two types.
Cyclooxygnases 1 is responsible for prostaglandins that are required for normal functions like protecting the gastrointestinal tract and maintaining normal blood flow to the kidneys. Cyclooxygenase 2 is responsible for inflammation. COX -2 selective drugs were developed in order to reduce inflammation without causing untoward side effects with the GI system and kidneys. COX-2 drugs work by selectively blocking only the COX-2 isoenzyme rather than indiscriminately blocking both the COX-1 and COX-2 isoenzymes, as is the case with traditional NSAIDs.
As a result of selectively blocking the COX-2 pathway, there is inhibition of prostacyclin, another prostaglandin that is responsible for keeping the blood thin. By blocking prostacyclin, a prothrombotic environment is created, which predisposes the patient to clotting problems. By blocking prostacyclin, there is also an increase in blood pressure and therefore concern for risk of heart attack and stroke in these patients. We know that patients with RA already have an increased risk for heart attack. The concern here is that by blocking COX-2, there may be acceleration of this phenomenon so that patients are having a cardiac event at a younger age.
RA is in itself a risk factor for cardiovascular (CV) disease; however, patients who have had a prior CV event or patients who are at high risk for CV disease, such as diabetic patients, are particularly at risk. Because patients at high risk for a CV event are typically prescribed aspirin, these patients may in fact respond differently to treatment because of the interaction of aspirin with non-steroidal drugs. One very important finding by the FDA (US Food and Drug Administration) recently is that ibuprofen appears to block the CV protective effect of aspirin. So for patients at high risk for a CV event and receiving aspirin, the addition of ibuprofen can block the effect of aspirin and cause an increased incidence of cardiovascular events. This has been seen in multiple observational studies and has resulted in the FDA issuing a warning about the use of ibuprofen in conjunction with aspirin.
So here are the steps that should be followed:
First, patients need to be educated regarding the risks. Second, physicians need to be educated to look for CV and GI risk. Third, physicians should try, if possible, to avoid ibuprofen and other NSAIDS in patients taking aspirin. This may be very difficult though in arthritis patients who require an NSAID for their arthritis. Fourth, COX-2 inhibitors, according to the FDA regulations and black box warning, should be used cautiously in patients who have a history of ischemic heart disease. Fifth, it may be that the combination of aspirin, with COX-2’s might be a potentially safe alternative. Finally, more data and study is needed to examine this problem.
Nathan Wei, MD, FACP, FACR is a rheumatologist and Director of the Arthritis and Osteoporosis Center of Maryland (http://www.aocm.org). He is a Clinical Assistant Professor of Medicine at the University of Maryland School of Medicine and consultant to the National Institutes of Health. For more info: Arthritis Treatment