The Modern Day Treatment of Rheumatoid Arthritis
by Hope Starkman, MD
Board Certified Rheumatologist
The treatment of Rheumatoid Arthritis is an ever evolving area in medicine. I graduated medical school in 1989 and during my last year at Albany Medical College I was fortunate enough to gain my first experience in the Department of Rheumatology at Albany Medical College with Dr. Richard Rynes and Dr. Joel Kremer. At that time the armamentarium of therapies to combat this disease was extremely limited.
The initial treatments for Rheumatoid arthritis have, forever, been combinations of therapies In 1989 we used NSAIDs (Non-steroidal Anti inflammatory Drugs) such as Ibuprofen and Naprosyn. These therapies can help a little but have many gastrointestinal and kidney related adverse effects. NSAIDS also are not thought to alter the progression of Rheumatoid Arthritis to prevent deformities and r xray changes. There have also always been steroids such as Prednisone which give almost immediate relief but, long term, can cause weight gain, glaucoma, cataracts, diabetes, fatty redistribution, infections, immune suppression, stretch marks, thrush, osteoporosis, hypertension, and osteonecrosis or bone death due to circulation issues within bone. Most patients feel great on steroids initially but then cannot wait to get off of them.
In 1989, there was also Plaquenil or Hydroxychloroquine , an anti malarial antibiotic, which sometimes also helps with inflammation. Plaquenil is a fairly safe therapy but it is more useful in mild cases of Rheumatoid arthritis and other autoimmune disorders. It’s used as an oral daily therapy. Rarely, chronic Plaquenil use can result in retinal issues causing blurred vision and peripheral vision loss, therefore baseline eye examinations as well as biannual to annual ophthalmology follow ups are indicated in patients who are treated with Plaquenil. Rarely patients with Plaqunenil use may develop anemia, skin pigment issues and nerve and muscle issues and therefore patient’s with Plaquenil use must be monitored regularly.
In 1989, when I was rotating thru the arthritis clinics at Albany Medical College, it was commonplace to treat with Oral and Injectable Gold. In fact, we had a large Gold clinic at least weekly. It is not common to treat patient’s with Rheumatoid arthritis with gold anymore.
Methotrexate has replaced Gold as the standard of care for the treatment of Rheumatoid Arthritis, for the most part. Methotrexate, like Gold, can be given orally as a weekly dose of 1-10 pills or by weekly self injection. Since the use of Methotrexate can affect liver function, labs must be monitored anywhere from 6 weeks to 3 months intervals. Methotrexate can cause nausea, vomiting, diarrhea, oral sores, liver dysfunction, pulmonary issues, immunologic issues leading to infections and even cancer(although it is a chemotherapy used to treat some cancers). Close monitoring of patients being treated with Methotrexate is always warranted.
Since Methotrexate has become the current gold standard for the treatment of Rheumatoid arthritis, all other therapies are compared to Methotrexate in clinical research studies. In fact, it is considered unethical to compare a new product to complete placebo without Methotrexate since we know Methotrexate works. Therefore, most clinical trials of new drugs have a placebo arm containing Methotrexate and many studies look at the new drug in combination with Methotrexate.
Other DMARDS (Disease Modifying Anti Rheumatic Drugs) include Imuran which is also an oral chemotherapy and anti organ transplant anti rejection drug, Arava which is , like Methotrexate an anti folate drug and Sulfsalazine which has an antibiotic and aspirin component. Arava is also called Leflunamide and works a lot like Methotrexate but the advantages are that it usually is not contraindicated in lung disease and it may be immediately bound out of the blood using Cholestryramine. Regardless of the DMARD chosen, it must be custom chosen to fit each patient’s individual needs and the benefits must always outweigh the risks.
In individuals who may not have access to more advanced biologic therapies, combination therapies with various DMARDS may work well. Triple therapy with Plaquenil, Methotrexate and Sulfasalazine has proven, in some studies, to be highly effective and may be more safe in some patients with chronic infections for example infected prosthetic devices.
In 1998, the FDA approved Enbrel (Etanercept- generic) as the first biologic drug to treat Rheumatoid Arthritis. This drug works at a cellular level to inhibit a chemical called tumor necrosis factor,. This chemical known to cause inflammation and destruction at the cellular level in rheumatoid joints and tissues. Enbrel is administered weekly by either a prefilled syringe or auto-injector pen. Because Enbrel, like the other anti tnf and biologic drugs, can cause immune suppression, infections, fluid retention, flares of chronic obstructive pulmonary disease, lupus, like reactions, multiple sclerosis like reactions, reactivation of tuberculosis and Hepatitis B and C, strict monitoring and pre screening are imperative. Patients should have screening tests for prior exposure to TB and Hepatitis B and c. Patients who are to be treated with Enbrel , like other anti tnf and biologic drugs should receive flu shots and pneumonia shot, chest radiographs, blood counts and chemistry evaluations but may not receive live vaccines such as the shingles shot once started on these types of drugs. Baseline radiographs of both hands, wrists feet ankles and other afflicted joints should be obtained prior to the start of these medications as well as bone density testing (DEXA) scans. Patients who are prescribed anti tnf and biologic drugs need to be monitored with frequency for potential adverse effects. There have been reports of increases in certain types of cancers especially skin cancers and lymphomas, especially when used in combination with Methotrexate, but this increased risk has been debated and is not a proven fact. It is known that patient’s with inflammatory conditions are at increased risk to develop malignancies even in the absence of DMARDS and biologic drugs, and , therefore treatment might actually ultimately decrease cancer risk in some patients. Still monitoring on a regular basis is advised.
Kineret(Anakinra-generic) is another biologic drug working to inhibit the interleukin inflammatory chemical pathway. This option is less often used because it is a daily injecion and other options are more convenient.
In August of 1999, Remicade ( Infliximab-generic) was FDA approved to treat rheumatoid arthritis. It was the second biologic agent approved for this indication as an infused IV drug administered every 4-8 weeks. It has a similar risk profile but is better used in combination with Methotrexte.
Humira, (Adalimumab-generic) soon followed these two anti tf drugs, again with similar adverse risk profile and administered sub cutaneous like Enbrel every two weeks. Then followed Simponi(Golimumab generic-2009) and Cimzia(Certolizumab generic pegol-2009). The “pegolation” is an attached component to the drug that make antibody production to the drug less likely to occur. At this time , there are 5 anti tnf drugs FDA approved to treat Rheumatoid Arthritis. Usually if one does not help the patient a second may still be of benefit but if two anti tnf drugs do not work, a drug with a different mechanism of action is preferred. Each drugs, is a little different from the others.
Other than anti tnf drugs, other biologics are available including Orencia(Abetacept-generic) This drug interferes with T cell receptor function and limits there activation which plays a role inflammation. It is either infused monthly or injected weekly. Orencia is said to have less risk of TB reactivation and does not have the same black box warning that the anti tnf drugs above have. It may also have a lower propensity to cause infection but this is not proven and even patients treated with Orencia have developed reactivated TB and infection. The manufacturer of Orencia discusses risk in their labeling and packaging.
Actemra( Tocilizumab-generic) is another type of inject able biologic drug for the treatment of Rheumatoid Arthritis. This drug works on a different area of the immune system the interleukin 6 (IL-6) receptor as an antagonist. It may also increase the risk of infections and tuberculosis reactivation.
Rituxan is interesting because it is also used to treat multiple malignancies such as breast cancer and lymphoma and is given twice- two weeks apart and every 6 months in this way. It is a B lymphocyte inhibitor and may have lasting effects for at least 6 months. In addition to infection risk, there is also a risk of activation of a virus called the JC virus which, although rare, can affect the neuromuscular system and cause severe decompensation. Due to risk of infection and reactivation potential of TB and Hepatitis, screening tests prior to the start of this drug and close ongoing monitoring while taking the treatment is advised. It may be a good treatment option for patients with rheumatoid arthritis who also have lymphoma and breast cancer.
Finally, as of 2016, there is one oral biologic drug called Xeljanz (Tofacitinib) This drug works on a new component of inflammation called Jak-2, considered a small molecule. Like the other biologic therapies, Xeljanz requires pre screening and close monitoring in the same way as the other biologic drugs. It may be taken as a twice a day or daily therapy by mouth.
Clearly, since I graduated medical school in 1989 and even completed my rheumatology fellowship in 1994, there has been remarkable progress in the treatment of rheumatoid arthritis. There continues to need to be better therapies with less adverse effects and improved cost as some of these therapies can cost more than eight thousand dollars or more a month. This year biologically similar drugs (bio-similar) drugs were approved which may lower costs and improve accessibility.
The lesson to be taken away is that there are many treatment options for rheumatoid arthritis which are evolving every day. The treatment needs to be tailored to the specific patient and their individual needs. The risks of the treatments must outweigh the benefits and the patients will always require close monitoring by their physicians.
Patient’s with Rheumatoid arthritis, like patients with any other chronic illness need to have a close and open relationship with their Rheumatologists and primary care physicians and physician’s office staff. This communication is essential.
Since rheumatoid internationally affects 0.4 to 1.3% of the population and since at least 1.5 million US adults have rheumatoid arthritis and the incidence is increasing, if you have been diagnosed with this condition, you are certainly not alone. Everyday, new advances are being made to treat Rheumatoid Arthritis. As a patient you should keep informed of all the newest treatments and developments and feel comfortable discussing the best options for you with your physician.