Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (7 page)
In the past 25 years, new medications given early on in the course of disease have made a major difference in the lives of RA patients, boosting life expectancy by a decade to age 86.7,
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a normal lifespan for most women. Researchers say one of the factors that has led to the decline in RA-related deaths is the use of new medications that reduce inflammation, notably “biological” drugs.
Treatment usually involves combinations of drugs to attack the disease on several fronts, not only to control symptoms but also to lower disease activity, ideally to put RA into remission and prevent future joint damage. This treatment strategy is called “treat to target.”
Diagnostic and lab tests can help determine a target (see
pages 32
to
33
), but how you feel and how you function every day are just as important, if not more so, in treatment decisions you and your rheumatologist will make together.
“The most important outcome for our patient is maintaining function,” says NYU’s Dr. Yusuf Yazici. “But to maintain function, we need to control their pain, the inflammation in the joints, we need to control the swelling. So all our treatments are geared towards making sure the patient at least maintains the function they have, and if we can reverse the disease, sometimes we can improve their function also.”
The choice of medication takes into consideration a number of factors: whether you have established or “early” RA (symptoms for less than 6 months), how active your disease is, how severe your symptoms are, the proven effectiveness of a drug in similar cases, how a drug is given, how much it costs (including the cost of monitoring its use, such as lab tests), how long it will take to work, and its side effects and risks. Some treatments can contribute to premature cardiovascular disease or cause osteoporosis (see
pages 55
to
58
). If you want to have children, this may restrict your choices, since some medications cause birth defects; you may have to modify your treatment regimen during pregnancy and breastfeeding (see
pages 50
to
51
).
Ideally, your treatment target should be remission or low disease activity. This is determined by the number of painful and swollen joints (joint counts), the amount of erosion on x-rays, levels of inflammatory blood markers such as C-reactive protein (CRP), and scores on clinical assessment tools you doctor may use. These may include the Disease Activity Score in 28 joints (DAS28), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID3). For example, on the widely used DAS28, remission is defined as a score below 2.6 and low disease activity a score at or above 2.6 to below 3.2. Also taken into consideration are instruments such as the Health Assessment Questionnaire (HAQ), which asks about pain and difficulty in everyday functioning like bathing or getting in and out of bed. These are terms you may see in your medical file.
To help select the right medications and to monitor your progress, your rheumatologist may refer to guidelines from the American College of Rheumatology (ACR) and/or the European League Against Rheumatism (EULAR). You can read the latest ACR Treatment Guidelines at
www.rheumatology.org
, under Rheumatoid Arthritis, “Clinical Practice Guidelines” and the EULAR guidelines at
www.EULAR.org
, under “Recommendations for Management.” These are guidelines only – not hard and fast rules. Ultimately, your rheumatologist will rely on his or her judgement and your input. And your input is critical.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the drugs your rheumatologist will likely reach for first to treat joint pain and swelling. They include aspirin and aspirin-like drugs such as over-the-counter
ibuprofen (Motrin, Advil)
and
naproxen (Aleve)
, prescription-only
naproxen (Naprosyn, Anaprox)
,
naproxen sodium (Naprelan)
, and
diclofenac sodium (Voltaren)
.
NSAIDs have both painkilling and anti-inflammatory properties, but they can also raise heart risk and cause gastrointestinal symptoms such as upset stomach or, in some cases, bleeding ulcers.
That’s because they work by blocking enzymes in the body called
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
. While the COX-2 enzyme is related to inflammation, COX-1 protects the lining of the stomach and helps platelets to form clots. Because most NSAIDs block both COX
enzymes, they can erode the stomach lining and lead to bleeding, especially among women using corticosteroids and women over age 75 who may have a thinned stomach lining. These complications can be minimized by taking NSAIDs with meals and using acid reducers like
omeprazole (Prilosec, Nexium)
or
cimetidine (Tagamet)
, or a prostaglandin such as
misoprostol (Cytotec)
.
However, recent research suggests prescription-strength Nexium (40 mg) can lead to bone thinning, so discuss its use with your rheumatologist.
NSAIDs that only block the COX-2 enzyme have a slightly reduced risk of serious gastrointestinal side effects (such as bleeding ulcers), but studies show around the same incidence of minor GI problems as the nonselective drugs. COX-2 inhibitors are also much more expensive. Prescription selective COX-2 inhibitors include celecoxib (Celebrex) and meloxicam (Mobic), a less selective COX-2 inhibitor.
Because COX-2 inhibitors don’t have the blood-thinning properties of aspirin, they do not lower the risk of blood clots and heart attack (and may potentially increase it). This is a special concern for women, since RA can lead to early heart disease (see
pages 55
to
57
). If you already have heart disease and need antiplatelet therapy, the ACR recommends using low-dose aspirin (81 mg a day).
Nonaspirin NSAIDs in general can raise your risk of heart attack and other cardiovascular problems—even as early as the first week you take them, according to the FDA.
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The American College of Gastroenterology (ACG) and EULAR, among others, recommend that NSAIDs be used at the lowest possible dose for the shortest amount of time—and PPIs (or
misoprostol
) used for gastroprotection, even with COX-2 selective inhibitors.
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Disease-modifying antirheumatic drugs (DMARDs) can literally alter the course of RA, preventing damage and destruction of the joints, bones, and cartilage. While many of these drugs work in nonspecific ways to modulate the immune system, newer DMARDs known as biological agents target specific cytokines.
The standard of care is now treatment with DMARDs
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as soon as a diagnosis of RA is made, says Vivian P. Bykerk, MD, director of the Inflammatory
Arthritis Center of Excellence at the Hospital for Special Surgery in NYC and an associate professor of medicine at the Weill Cornell Medical College.
Early treatment can often slow the disease process and arrest further bone and joint destruction, improving function and reducing disability in RA, says Dr. Bykerk.
The DMARD most commonly used for early and established RA is
methotrexate (Trexall)
, often called MTX for short. MTX is the “anchor” drug used to treat RA, alone or in combination with other therapies.
“In RA, it works by inhibiting adenosine, interfering with the production of inflammatory cells and chemical mediators of inflammation with the net result of less inflammatory infiltrates in the joint,” explains Dr. Bykerk. “This lessens swelling, stiffness, pain, and disease-related damage.”
Because it’s both very effective and well tolerated, MTX is strongly recommended as “first-line” therapy in RA, the medication physicians should prescribe first.
The effective dose of MTX used to treat RA is 20 to 25 mg per week taken as either pills or subcutaneous injections under the skin. As is the case for nearly all medications, MTX can be associated with some side effects. These can include temporary mild nausea or diarrhea. It can cause irritation of liver cells, so it is generally recommend to not drink alcohol when starting MTX. It also cannot be used during pregnancy.
About 3 percent of people using MTX for RA report hair thinning, which may require dose reduction. Lung side effects are extremely rare. Most rheumatologists recommend taking supplements of the B vitamin folic acid to protect against side effects. MTX’s anti-inflammatory and immunosuppressant properties take effect fairly quickly.
“Initial treatment with methotrexate is associated with lower disease activity in the first three months, although full benefits may take as long as six months,” observes Dr. Bykerk.
MTX may enhance the effects of other DMARDs. The antimalarial
hydroxychloroquine (Plaquenil)
and sulfasalazine (Azulfidine), a sulfa drug that has anti-inflammatory properties, are added to MTX in “double” or “triple conventional DMARD therapy.”
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Sulfasalazine is an oral medication that requires some periodic monitoring with lab tests to detect low levels of white blood cells (
leukopenia
). In some cases, a corticosteroid (such as prednisone) may be added to DMARD monotherapy.
Biologicals such as
etanercept (Enbrel)
,
infliximab (Remicade)
, and adalimumab (Humira), may also be used with MTX.
Older DMARDs—such as
azathioprine (Imuran)
,
D-penicillamine (Cuprimine, Depen)
,
minocycline (Minocin)
, and
cyclosporine (Neoral)
—are now used less frequently.
Leflunomide (Arava)
is an oral DMARD that suppresses immune responses and also affects rapidly growing cells. It may take 4 to 12 weeks to start relieving symptoms. Side effects include an increased risk of infections; it can be toxic to the liver, and it also causes birth defects.“In patients new to DMARDs, regardless of disease activity, methotrexate is preferred over double or triple therapy. However, the ACR strongly recommends this approach in patients who start out with low disease activity,” says Jasvinder Singh, MD, MPH, lead author of the 2015 ACR treatment guidelines for RA. “If patients do not show a good response to methotrexate, with and/or without a corticosteroid, we will move on to combination DMARD therapy and or a biologic,” adds Dr. Singh, a professor of medicine at the University of Alabama, Birmingham. Some patients do start out with methotrexate alone, and in other cases, MTX will be combined with one or more DMARDs plus a corticosteroid, depending on the judgement of their physician, says Dr. Bykerk.
Recent studies do show that many early RA patients who start out on combination therapy achieve low disease activity or sustained remission earlier than patients treated with methotrexate alone.
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“Some patients need triple therapy, others don’t. But sustained remission is the goal for all our early RA patients. We’d like to get them down to zero swollen joints,” says Dr. Bykerk. “Sustained remission is important because that means better function.”
Biological RA drugs suppress specific inflammatory cytokines, chief among them
tumor necrosis factor alpha (TNFα)
, the cytokine that causes damage in most cases of RA. Some anti-TNF drugs have been used for more than a decade and have proven highly effective, especially when combined with other DMARDs.
The first TNFα blockers were infliximab and etanercept. Infliximab is a monoclonal antibody, a molecular “smart bomb” that targets TNFα and
inactivates it. (The names of drugs in this category have the suffix
-mab
, short for monoclonal antibody.)
Etanercept is a protein that inhibits TNFα and prevents it from locking onto receptors on cells. Both drugs prevent TNFα from promoting inflammation, and both have been shown to dramatically slow the progression of RA and stop joint erosion.
Both of these TNFα blockers are often given with methotrexate. Infliximab is given intravenously every four to eight weeks, and MTX is taken orally once a week. This drug combination could start to produce benefits in a few days, or it may take up to four months. Etanercept is given by self-injection into the skin (subcutaneous) twice a week; it can also take a few days to four months to take effect.
Adalimumab (Humira)
is a fully human antibody (infliximab is an antibody that’s partly human and partly mouse, a chimeric antibody). It works by binding up excessive molecules of TNF and removing them from the body. Adalimumab is administered by subcutaneous self-injection once every two weeks. Clinical trials showed that the drug produced improvement in almost 70 percent of patients.
Certolizumab pegol (Cimzia)
is a newer anti-TNFα agent, a “PEGylated Fab’ fragment of a humanized TNF inhibitor monoclonal antibody,” to be precise. Injections of this drug are given in a stepwise fashion, with a higher dose for the first month, then a lower dose injected every other week. In some women with RA it can be given as a maintenance drug every month. As with other TNFα blockers, it carries a risk of infections.
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Golimumab (Simponi)
is another newer TNF blocker, in this case an injectable, man-made protein that binds to TNFα. It can be used with MTX to treat moderate to severe RA. It’s available in a pen-shaped auto-injector.
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Anakinra (Kineret)
is a selective blocker of
interleukin-1 (IL-1)
, another inflammatory cytokine elevated in RA. It’s a version of a body’s natural molecule called the IL-1 receptor antagonist. In a normal joint this molecule prevents IL-1 from binding to cells; in RA there’s not enough of this antagonist molecule, so inflammation caused by IL-1 can lead to cartilage and bone erosion. By preventing IL-1 from locking onto cells, anakinra prevents joint damage. It’s also given by subcutaneous injection. A newer anti-interleukin agent is
tocilizumab (Actemra)
, a humanized monoclonal antibody that blocks the receptor for IL-6.
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Tofacitinib (Xeljanz)
is a synthetic DMARD that disrupts the signaling of Janus kinases (JAKs) and is used when people don’t respond well to MTX or are intolerant of the drug. Tofacitinib is an oral medication taken as one tablet twice a day. It can be used alone or in combination with MTX or nonbiologic DMARDs in moderate to severe RA.
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Abatacept (Orencia)
has a unique mode of action as a selective costimulation molecule. It’s a man-made fusion protein that attaches to the surface of antigen-presenting cells (APCs) and prevents them from signaling T cells to fully activate them. Abatacept is a “second-line” drug used when RA does not respond to one or more DMARDs, including MTX. It can enhance the effectiveness of other DMARDs.
These drugs also carry a high risk of serious bacterial, viral, or fungal infections and have been linked to malignancies, such as lymphoma. They can also be quite expensive compared to older DMARDs, costing thousands of dollars a year.
Rituximab (Rituxan)
is an intravenous anticancer drug used in combination with methotrexate to help people whose RA has not responded to TNFα blockers and other treatments. Rituximab selectively targets the antibody-producing B cells that that contribute to the disease process in RA, reducing the number of B cells. It is given in two infusions, 15 days apart, and this cycle may be repeated after six months.
In the treat-to-target approach, it’s recommended that various combinations of DMARDs and biologicals are given in specific sequences to bring RA into remission or at least reduce disease activity down to the lowest possible level.
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For example, if you’re diagnosed with early RA (symptoms for fewer than six months), you might be prescribed methotrexate and possibly short-term, low-dose glucocorticoids. If you reach remission or low disease activity within six months, this treatment may be continued. If your treatment doesn’t hit the target, produces adverse side effects, or you have moderate or high disease activity, you might then be started on double or triple therapy or one of the biological DMARDs in combination with MTX. Again, you’ll be monitored to see if the target is reached in six months. If treatment doesn’t prove effective, your rheumatologist might switch biologics or add a second one.
If you have established RA, the sequence may be similar except that if remission is reached, your rheumatologist may consider tapering down the
dose of medication, explains Dr. Singh. If you don’t reach remission, tofacitinib is now among the medications that may be added to MTX, instead of a TNFα blocker.
Depending on the treatment target, clinical trials show that between 31 and 82 percent of patients reach their target within six months using a treat-to-target treatment strategy.
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There are different ways of measuring disease activity and defining remission that use multiple factors including physical exams that evaluate the number of swollen joints—and the information you give your doctor at each visit about symptoms and how you’re doing (often with questionnaires like the HAQ), along with lab tests and x-rays. Without this information, there’s no way to make the best treatment decisions. “We measure and ask, ‘is your disease under control or is it not under control?’ It’s no more complicated than that,” stresses Dr. Singh.
But again, your input is vital. Under ACR guidelines, all treatment decisions must be
shared
decisions with patients.
