Rheumatoid arthritis is a chronic disorder for which there is no known cure. Fortunately in the last few years, a shift in strategy toward the earlier institution of disease modifying drugs and the availability of new classes of medications have greatly improved the outcomes that can be expected by most patients. The goal of treatment now aims toward achieving the lowest possible level of arthritis disease activity and remission if possible, minimizing joint damage, and enhancing physical function and quality of life. The optimal treatment of RA requires a comprehensive program that combines medical, social, and emotional support for the patient. It is essential that the patient and the patient’s family be educated about the nature and course of the disease. Treatment options include medications, reduction of joint stress, physical and occupational therapy, and surgical intervention.
- Pharmacological Strategies
- Methotrexate (Rheumatrex®, Trexall®)
- Hydroxychloroquine (Plaquenil ®)
- Sulfasalazine (Azulfidine®)
- Leflunomide (Arava®)
- Tumor Necrosis Factor Inhibitors— etanercept (Enbrel®, adalimumab (Humira ®), and infliximab (Remicade®)
- T-cell Costimulatory Blocking Agents—abatacept (Orencia®)
- B cell Depleting Agents—rituximab (Rituxan®)
- Interleukin-1 (IL-1) Receptor Antagonist Therapy—anakinra (Kineret®)
- Other Immunomodulatory and Cytotoxic agents— azathioprine (Imuran®), cyclophosphamide, and cyclosporine A(Neoral®, Sandimmune®)
- Treatment during pregnancy
- Reduction of joint stress
- Surgical approaches
There are three general classes of drugs commonly used in the treatment of rheumatoid arthritis: non-steroidal anti-inflammatory agents (NSAIDs), corticosteroids, and disease modifying anti-rheumatic drugs (DMARDs). NSAIDs and corticosteroids have a short onset of action while DMARDs can take several weeks or months to demonstrate a clinical effect. DMARDs include methotrexate, sulfasalazine, leflunomide (Arava®), etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), abatacept (Orencia®), rituximab (Rituxan®), tocilizumab (Actemra®), anakinra (Kineret®), antimalarials (e.g. Plaquenil®). Other immunomodulators are occasionally used including azathioprine (Imuran) and cyclosporine. Because cartilage damage and bony erosions frequently occur within the first two years of disease, rheumatologists now move aggressively to a DMARD agent early in the course of disease, usually as soon as a diagnosis is confirmed. Analgesic drugs are also sometimes helpful in decreasing pain until DMARDs take effect. A summary table of how to monitor drug treatment in rheumatoid arthritis is included.
The major effect of these agents is to reduce acute inflammation thereby decreasing pain and improving function. All of these drugs also have mild to moderate analgesic properties independent of their anti-inflammatory effect. It is important to note however that these drugs alone do not change the course of the disease of rheumatoid arthritis or prevent joint destruction.
Aspirin is the oldest drug of the non-steroidal class, but because of its high rate of GI toxicity, a narrow window between toxic and anti-inflammatory serum levels, and the inconvenience of multiple daily doses, aspirin’s use as the initial choice of drug therapy has largely been replaced by other NSAIDs. There are a large number of NSAIDs from which to choose, and at full dosages all are potentially equally effective. Likewise, the toxicities of the currently available NSAIDs are similar. However, there is a great deal of variation in tolerance and response to a particular NSAID. Many different NSAIDS are available, some over the counter including ibuprofen (Advil ®, Motrin®, Nuprin ®) and naproxen (Alleve®) and many others are available by prescription including meloxicam (Mobic®), etodolac (Lodine®), nabumetone (Relafen®), sulindac (Clinoril®), tolementin (Tolectin®), choline magnesium salicylate (Trilasate®), diclofenac (Cataflam®, Voltaren®, Arthrotec®), diflusinal (Dolobid®), indomethacin (Indocin®), ketoprofen (Orudis®, Oruvail®), meloxicam (Mobic®), oxaprozin (Daypro®), and piroxicam (Feldene®). Longer acting NSAIDs that allow daily or twice daily dosing may improve compliance. The NSAID class also includes drugs known as COX-2 inhibitors that are also effective in controlling inflammation. Only one of these agents is currently available in the United States (celecoxib, Celebrex®) while additional compounds are available in other countries (etoricoxib, Arcoxia®; lumiracoxib, Prexige®). These drugs were designed to decrease the gastrointestinal risk of NSAIDS, but concerns of possible increases in cardiovascular risk with these agents has led to the withdrawal of two of these drugs from the market (rofecoxib, Vioxx®; valdecoxib, Bextra®).
NSAIDs inhibit the generation of prostaglandins by blocking cyclooxygenase enzymes, COX-1 and COX-2. Prostaglandins are mediators of inflammation and pain but also have important roles in maintenance of normal body functions including protection from stomach acid, maintenance of kidney blood flow, and contributing to platelet stickiness and vascular function. COX-2 selective inhibitors selectively block prostaglandins generated via COX-2 which have prominent roles in inflammation.
While in some cases, lower doses of NSAIDS are effective, in rheumatoid arthritis and other forms of inflammatory arthritis a higher dose is often required to decrease inflammation. A lower dosage can initially be used if inflammation is mild, if mechanical pain is the major problem, if the patient is elderly or if the patient suffers from conditions that increase the risk for toxicity (see below). If a particular preparation is ineffective after a 4-week trial or is not tolerated, then another NSAID can be initiated. No one NSAID has been demonstrated to be better than another for the treatment of rheumatoid arthritis nor have the COX-2 agents been shown to be superior to traditional NSAIDS in terms of effectiveness.
Usual Time to Effect:
Although these agents have anti-inflammatory effect within hours, a reasonable trial period is a few weeks to 1 month.
The most common toxicity of NSAIDs is gastrointestinal disturbance which may clinically include burning, belching, or irritation, but which can represent irritation of the lining of the stomach, erosions, and even ulcerations that can result in bleeding. While taking the medication with food may eliminate some of these symptoms, this does not decrease a risk of bleeding. The co-administration of medications known as proton pump inhibitors such as omeprazole (Prilosec®), Lansoprazole (Prevacid®), Esomeprazole (Nexium®), Pantoprazole (Protonix®), and Rabeprazole (Aciphex®), and a medication that provides back protective prostaglandins called misoprostol (Cytotec®) can also decrease gastrointestinal bleeding associated with these medications. Misoprostol is combined in a single pill with the NSAID diclofenac (Arthrotec®). Selective COX-2 inhibitors exhibit safer GI profiles than conventional non-selective NSAIDs.
Because prostaglandins play a role in the regulation of the blood flow in the kidneys and maintenance of glomerular filtration, NSAIDs can also impair renal function in certain patients leading to salt retention, edema, and increased blood pressure. The patients at highest risk are those with fluid imbalances or with compromised kidney function (e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency). NSAIDs may also increase cardiovascular risks by their effects on blood pressure and additional effects on vascular beds. Thus the use of this class of medications must into account their relative risks in an individual patient of gastrointestinal damage versus potential cardiovascular risk factors.
Corticosteroids (such as prednisone; methylprenisolone, Medrol®) have both anti-inflammatory and immunoregulatory activity. They can be given orally, intravenously, intramuscularly or can be injected directly into the joint. Corticosteroids are useful in early disease as temporary adjunctive therapy while waiting for DMARDs to exert their antiinflammatory effects. Corticosteroids are also useful as chronic adjunctive therapy in patients with severe disease that is not well controlled on NSAIDs and DMARDs. The usual dose of predinisone is 5 to 10mg daily. Although prednisone can be started at higher doses (15 to 20mg daily), attempts should be made to taper the dose over a few weeks to less than 10mg daily. Once started, corticosteroid therapy may be difficult to discontinue and even at low doses. Some patients are very sensitive to the tapering of prednisone which may be done slowly over a few weeks.
Weight gain and a cushingoid appearance (increased fat deposition around the face, redness of the cheeks, development of a “buffalo hump” over the neck) is a frequent problem and source of patient complaints. Other side effects of prednisone include weight gain, increased blood pressure, increased blood sugar, increased risk of cataracts, and avascular necrosis of bones.
Steroid medications are also associated with accelerated osteoporosis even with relatively low dose prednisone at doses of 10 mg daily. Patients with and without osteoporosis risk factors on low dose prednisone should undergo bone densitometry (DEXA Scan) to assess fracture risk. Bisphosphonates such as alendronate (Fosamax®), risedronate (Actonel®), ibandronate (Boniva®) are recommended to prevent and/or treat osteoporosis in addition to adequate calcium and vitamin D supplementation.
Higher doses of prednisone are rarely necessary unless there is a life-threatening complication of RA and, if used for prolonged periods, may lead to serious steroid toxicity. Although a few patients can tolerate every other day dosing of corticosteroids which may reduce side effects, most require corticosteroids daily to avoid symptoms. Once a day dosing of prednisone is associated with fewer side effects than the equivalent dose given twice or three times daily. Generally steroids are given in the morning upon wakening to mimic the body’s own steroid surge. Repetitive short courses of high-dose corticosteroids, intermittent intramuscular injections, adrenocorticotropic hormone injections, and the use of corticosteroids as the sole therapeutic agent are all to be avoided.
Intra-articular corticosteroids (e.g., triamcinolone or methylprednisolone and others) are effective for controlling a local flare in a joint without changing the overall drug regimen.
Disease Modifying Anti-rheumatic Drugs (DMARDS)
Although both NSAIDs and DMARD agents improve symptoms of active rheumatoid arthritis, only DMARD agents have been shown to alter the disease course and improve radiographic outcomes. DMARDs have an effect upon rheumatoid arthritis that is different and may be slower. In most cases, when the diagnosis of rheumatoid arthritis is confirmed, DMARD agents should be started. The presence of erosions or joint space narrowing on x-rays of the involved joints is a clear indication for DMARD therapy, however one should not wait for x-ray changes to occur. The currently available drugs include:
- Methotrexate (Rheumatrex®, Trexall®)
- Hydroxychloroquine (Plaquenil ®)
- Sulfasalazine (Azulfidine®)
- Leflunomide (Arava®)
- Tumor Necrosis Factor Inhibitors— etanercept (Enbrel®, adalimumab (Humira ®), and infliximab (Remicade®), certolizumab pegol (Cimzia®), golimumab (Simponi®)
- T-cell Costimulatory Blocking Agents—abatacept (Orencia®)
- B cell Depleting Agents—rituximab (Rituxan®)
- Interleukin-6 (IL-6) Inhibitors– tocilizumab (Actemra®)
- Interleukin-1 (IL-1) Receptor Antagonist Therapy—anakinra (Kineret®)
- Intramuscular Gold
- Other Immunomodulatory and Cytotoxic agents— azathioprine (Imuran®) and cyclosporine A(Neoral®, Sandimmune®)
Methotrexate is now considered the first-line DMARD agent for most patients with RA. It has a relatively rapid onset of action at therapeutic doses (6-8 weeks), good efficacy, favorable toxicity profile, ease of administration, and relatively low cost. When looking at groups of patients on different DMARDS, the majority of patients continue to take Methotrexate after 5 years, far more than other therapies reflecting both its efficacy and tolerability. Methotrexate is effective in reducing the signs and symptoms of RA, as well as slowing or halting radiographic damage. It was as effective as leflunomide and sulfasalazine in one study, and its effectiveness given early and in higher doses approached the efficacy of etanercept and adalimumab as single therapies in terms of signs and symptom improvement. Methotrexate is also effective in many other forms of inflammatory arthritis including psoriatic arthritis and other spondyloarthopathies, and is used in many other autoimmune diseases.
The anti-inflammatory effects of methotrexate in rheumatoid arthritis appear to be related at least in part to interruption of adenosine and possible effects on other inflammatory and immunoregulatory pathways. The immunosuppressive and toxic effects of methotrexate are due to the inhibition of an enzyme involved in the metabolism of folic acid, dihydrofolate reductase.
Dosing typically begins at 12.5-15 mg once per week. A dose escalation to 20 mg within the first three months is now fairly well accepted in clinical practice. Maximal dose is usually 25 mg per week but is sometimes increased further to 30 mg. Methotrexate can be given orally or by subcutaneous injection. The latter route of administration can be advantageous for patients who have methotrexate-associated nausea. Patients starting methotrexate should be carefully evaluated for renal insufficiency, acute or chronic liver disease, significant alcohol intake or alcohol abuse, leukopenia (low white blood cell counts), thrombocytopenia (low platelet counts), or untreated folate deficiency. Obesity, diabetes and history of hepatitis B or C are factors that have been suggested but not confirmed to increase methotrexate hepatotoxicity (liver injury). Salicylates (and other NSAIDs) and the antibiotic trimethoprim (Bactrim®, Septra®) block the renal excretion of methotrexate and increase serum levels with an increased risk of toxicity. If alternatives exist, concomitant use of methotrexate and trimethoprim is to be avoided. The coadministration of NSAIDS with methotrexate is routine in patients with rheumatoid arthritis and is considered safe by rheumatologists as long as liver function tests and blood counts are closely monitored.
Usual Time to Effect:
The onset of action is seen in as early as 4 to 6 weeks. However the dose required to achieve a response is variable in individual patients and may require 4-6 weeks after a dose increase to determine if the drug is working. A trial of 3 to 6 months at an increased dose (e.g. 20 mg/wk) is suggested. In patients with partial responses to methotrexate, additional medications are usually added to rather than substituted for methotrexate to achieve combination therapies.
Fortunately the most serious complications of methotrexate therapy: hepatic cirrhosis, interstitial pneumonitis, and severe myelosuppression are quite rare, especially with proper monitoring. Stomatitis and oral ulcers, mild alopecia and hair thinning, and GI upset may occur and are related to folic acid antagonism. These side effects can be improved with folic acid supplementation. Folic acid given at a dose of 1mg daily does not diminish the efficacy of methotrexate and is routinely given with methotrexate to decrease these side effects. Some patients complain of headache, fatigue, and feeling “wiped out” (also called methotrexate “fog”). These side effects can often be overcome by increasing folic acid or using an activated form of folic acid known as folinic acid (leukovorin®) given as a 5mg dose 12 hours and sometimes 24 hours after methotrexate is given. Some patients complain of GI upset (nausea or diarrhea) with oral methotrexate. This may be lessened when methotrexate is taken at night. In most cases this is completely eliminated when methotrexate is given by subcutaneous administration.
Before starting methotrexate, baseline studies should include complete blood count, liver chemistries, serum creatinine, hepatitis B and C serologies, and chest X-ray. Routine toxicity monitoring should include a CBC, liver profile, serum albumin and serum creatinine every 4-8 weeks.
Methotrexate can be combined safely with nearly every other FDA-approved DMARDs for RA, including sulfasalazine, hydroxychloroquine, TNF inhibitors, abatacept, rituximab, tocilizumab, anakinra, and leflunomide. In all clinical trials combining methotrexate with one of these DMARDs, no unexpected toxicities or synergistic toxicities were observed with the exception of higher liver toxicity with leflunomide which is also metabolized by the liver.
Hepatotoxicity (liver injury) has not been significant if patients with pre-existing liver disease, alcohol abuse, or hepatic dysfunction are excluded from treatment with methotrexate. Patients are instructed to limit alcohol containing beverages to no more than one-two per week. Baseline or surveillance liver biopsies are not indicated unless pre-existing liver disease is suspected. Elevated liver enzymes do not directly correlate with toxicity but therapy should be stopped and doses of methotrexate reduced if transaminases are elevated to 2 times the upper limit of normal. Liver biopsy should be done if elevated liver enzymes persist or if methotrexate therapy is to be continued.
Interstitial pneumonitis is a rare complication of methotrexate (<2%), but the clinician should be alert to symptoms of cough or shortness of breath that may herald the onset of this severe complication. Methotrexate pneumonitis may occur at any time during therapy and is not dose related. A baseline chest x-ray is useful for comparison. Patients with poor pulmonary reserve from other causes may be excluded from therapy over concerns of increased morbidity if methotrexate pneumonitis occurs. A more chronic form of interstitial lung disease and fibrosis is also seen in patients with rheumatoid arthritis. This may be increased with methotrexate.
Myelosuppression (lowering of blood counts) is also rare at the low doses of methotrexate utilized for rheumatoid arthritis. Patients at particular risk include those with renal insufficiency from other causes or use of trimethoprim (Bactrim®, Septra®) which increases levels of methotrexate. In the absence of leukopenia (lowered white blood cell counts), there has not been conclusive information to link methotrexate use in rheumatoid arthritis with increased risk of infection. The exception is a slight increased risk of localized herpes zoster infection (shingles).
Cancer risk with methotrexate. Although there are case reports of lymphoma associated with methotrexate therapy including cases where the lymphoma resolved after cessation of therapy, increased occurrence of malignancy has not been found in large population-based studies. It is important to recognize that patient with rheumatoid arthritis have an increased risk of developing lymphoma as a consequence of their autoimmune disease, independently from any potential medication effects.
Pregnancy and Conception with methotrexate. There have not been any notable effects on sperm production or ovarian function after the prolonged administration of methotrexate. However, methotrexate is considered a teratogen; therefore, women of childbearing potential or men with partners of childbearing potential must practice effective birth control. Women should discontinue methotrexate for at least one ovulatory cycle prior to attempting conception, while men should wait 3 months.
Hydroxychloroquine is an antimalarial drug which is relatively safe and well-tolerated agent for the treatment of rheumatoid arthritis. Chloroquine is another antimalarial agent that is also sometimes used. Because these drugs have limited ability to prevent joint damage on their own, their use should probably be limited to patients with very mild, seronegative, and nonerosive disease. Hydroxychloroquine is sometimes combined with methotrexate for additive benefits for signs and symptoms or as part of a regimen of “triple therapy” with methotrexate and sulfasalazine.
The mechanism of action of antimalarials in the treatment of patients with rheumatoid arthritis is unknown but is thought to involve changes in antigen presentation or effects on the innate immune system.
Dosage: Hydroxychloroquine (Plaquenil®) is the drug of choice among antimalarials. Chloroquine is not commonly used because of greater toxicity on the eye. The usual dose of Plaquenil is 400mg/day but 600mg/day is sometimes used as part of an induction regimen. It may be prescribed as a single daily dose or in divided doses twice per day.
Usual Time to Effect:
A period of 2 to 4 months is usual. Most agree that if a patient shows no response after 5-6 months that this should be considered a drug failure.
The most important toxicities are on the eyes: corneal deposits, extraocular muscular weakness, loss of accommodation (and sensitivity to light), and a retinopathy that may progress to irreversible visual loss. Ocular toxicity is exceedingly rare, occurring in only 1 out of 40,000 patients treated at the doses recommended. Patients with underlying retinopathies or risks may not be good candidates for antimalarial drugs. Baseline ophthalmologic examination and a follow-up examination every 12 months are recommended during the period of treatment.
Sulfasalazine (Azulfidine®) is an effective DMARD for the treatment of RA. Its effectiveness overall is somewhat less than that methotrexate, but it has been shown to reduce signs and symptoms and slow radiographic damage. It is also given in conjunction with methotrexate and hydroxychloroquine as part of a regimen of “triple therapy” which has been shown to provide benefits to patients who have had inadequate responses to methotrexate alone. Sulfasalazine is also used in the treatment of inflammatory bowel disease and spondyloarthropathies. Its mechanism of action in RA is unknown. Some of its effects may be due to folate depletion.
The usual dose is 2-3 grams per day in a twice daily dosing regimen. The dose may be initiated at 1 gram per day and increased as tolerated.
Usual Time to Effect:
It may take 6 weeks to 3 months to see the effects of sulfasalazine.
Sulfasalazine may cause hypersensitivity and allergic reactions in patients who have experienced reactions to sulfa medications. Mild gastrointestinal complaints are commonly seen and these can be decreased by using enteric coated formulations or administration of the medication with meals. Occasionally, mild cytopenias are seen. Patients may be screened before the use of sulfasalazine for a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) which may predispose patients to red blood cell hemolysis and anemia. Blood monitoring is typically every 1-3 months depending on dose. Though sulfasalazine may cause increases in liver function tests, it is generally considered a preferable agent to methotrexate in patients with liver disease or in patients who have hepatitis B or C.
Leflunomide is also an effective DMARD. Its efficacy is similar to methotrexate in terms of signs and symptoms, and is a viable alternative to patients who have failed or are intolerant to methotrexate. Leflunomide has been demonstrated to slow radiographic progression. Studies have demonstrated that it can also be carefully combined with methotrexate in patients with no preexisting liver disease, as long as the liver function tests are carefully monitored. Leflunomide has also been studied in psoriatic arthritis with some efficacy demonstrated.
The mechanism of action of leflunomide is not fully understood but may be related to its ability to inhibit de novo pyrimidine biosynthesis through the inhibition of the enzyme dihydroorotate dehydrogenase. Laboratory studies have demonstrated that it also has effects on stimulated T cells.
The half-life of the active metabolite of leflunomide is very long. Leflunomide and its metabolites are extensively protein bound and undergo further metabolism before excretion. When initially approved, the medication was given using a loading dose of 100mg daily for three days then followed by 20 mg daily. Due to a significant incidence of GI side effects and diarrhea, most practitioners now use a shorter loading period with lower doses or initiate treatment at 10-20 mg/day with no loading dose,. The dose may be reduced to 10mg daily if not tolerated at the 20 mg dose.
Usual Time to Effect:
The onset of action is relatively rapid within 4-8 weeks. The onset of action of Arava may be seen earlier than methotrexate when using a loading dose.
Leflunomide has been associated with liver transaminase elevations that reversed with cessation of the drug in clinical trials. Routine monitoring should include complete blood count and hepatic panel more frequently at the beginning of therapy then on a regular basis (at least every 2 months). Other toxicities that are common include mild diarrhea, GI upset and alopecia and hair thinning sometimes of sufficient severity to cause cessation of the drug.
Because leflunomide and its metabolites are a teratogen, extreme care must be taken for treatment of women of child bearing potential. Women must be warned about the possible risk to the fetus and cautioned to use adequate birth control. Women wishing to become pregnant must take cholestyramine 8gm 3 times daily for 11 days and then have two leflunomide metabolite levels drawn 14 days apart to document serum concentration less than 0.02mg/L. Leflunomide treatment does not appear to be associated with an increased risk for infection.
Tumor necrosis factor (TNF) inhibitors
Tumor necrosis factor alpha (TNF) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in large quantities in the rheumatoid joint and is produced locally in the joint by synovial macrophages and lymphocytes infiltrating the joint synovium. TNF is one of the critical cytokines that mediate joint damage and destruction due to its activities on many cells in the joint as well as effects on other organs and body systems. TNF antagonists were the first of the biological DMARDS to be approved for the treatment of RA. These drugs began to enter the market for rheumatoid arthritis in 1999 and are now considered a part the ACR recommendations for treatment of RA. There are currently five TNF inhibitors FDA approved for the treatment of RA (listed in order of their approval for RA); etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), and golimumab (Simponi®). Etanercept if a soluble TNF receptor-Fc immunoglobulin fusion construct; infliximab, adalimumab, and golimumab are monoclonal antibodies; and certolizumab pegol is an anti-TNF antigen binding domain-polyethylene glycol construct. While differing in structure, the efficacy and safety of the drugs is similar across the class in reducing the signs and symptoms of RA, as well as in slowing or halting radiographic damage, when used either as monotherapy or in combination with methotrexate.
Usual Time to Effect: TNF inhibitors have a rapid onset of action sometimes with improvements seen within 2 to 4 weeks. However, additional improvements can be seen over 3-6 months.
Side Effects: With all TNF antagonists, there is an increased risk of infection both mild and severe. The most common are upper respiratory infections, pneumonia, urinary tract infections, and skin infections. Studies are currently ongoing regarding the practice of temporarily holding the administration of any biologic DMARD in the presence of infection and use of antibiotics. However, many rheumatology practices are following that practice.
In addition to routine infections, opportunistic infections have been seen. Disseminated tuberculosis due to reactivation of latent disease has been seen with all TNF inhibitors; therefore, screening for latent TB is prudent before treatment with any TNF inhibitor. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis have all been seen in patients receiving TNF inhibitors. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.13 Because reactivation of Hepatitis B has been seen with TNF use, patients should be screened before beginning TNF therapy.
In some clinical trials of TNF antagonists, lymphomas were more commonly observed in patients treated with TNF inhibitors compared to placebo controls but the incidence rates do not appear, at this time, to exceed those reported in the RA population prior to the availability of TNF inhibitors. It is important to note that RA itself is a risk factor for Non-Hodgkins lymphomas. Other malignancies have been seen in patients taking TNF inhibitors. There does appear to be an increase in nonmelanoma skin cancer (basal and squamous cell) in patients receiving these agents. Regular dermatologic assessment is recommended with any suspicious lesions promptly evaluated. The administration of TNF inhibitors in patients with a prior malignancy should be discussed with the patient and their oncologist to assess potential risk and benefit. TNF inhibitors are not recommended in patients with demyelinating disease or with congestive heart failure. Transient neutropenia (lowering of white blood cell counts) or other blood dyscrasias have been reported with TNF inhibitors. Some patients develop positive antinuclear antibodies (ANA), and cases of clinical lupus are reported but rare. The new onset of psoriasis has also been seen.
T-cell Costimulatory blockade
Abatacept is the first of a class of agents known as T-cell costimulatory blockers. These agent interfere with the interactions between antigen-presenting cells and T lymphocytes and affect early stages in the pathogenic cascade of events in rheumatoid arthritis. T lymphocytes become activated due to an unknown stimulus but likely involving the interaction between antigen presented in the context of the Class II Major Histocompatability Complex molecule on the surface of antigen presenting cells. T cells recognize antigens as foreign and if they receive a second stimulus, will become active, proliferate, traffic to inflamed sites, and secrete proinflammatory cytokines including TNF. One of the important second signals for T cell activation is mediated by the molecules CD80 and CD86 found on antigen presenting cells and the CD28 molecule on the T cell surface.
Mechanism of action:
Abatacept is a fusion protein that combines the extracellular domain of the molecule CTLA4 (CD154) with the Fc portion of a human immunoglobulin molecule. CTLA4 has very high affinity for CD28. When abatacept binds to CD28 on the T cell surface, it prevents the second signal from being delivered, thus turning down the T cell response. Additional effects are decreasing the production of T cell derived cytokines including TNF.
Abatacept is administered either via IV or subcutaneously. When given by intravenous infusion it is used once per month after initial doses at baseline, 2 weeks, and 4 weeks. The IV dose is based on body weight, with patients <60 kg receiving 500 mg, 60-100 kg receiving 750 mg, and >100 kg receiving 1000 mg. The medication is administered over a period of approximately 30 minutes to one hour. The subcutaneous version, a fixed dose of 125 mg regardless of weight, is administered once weekly with or without an intravenous loading dose based on body weight as above.
Time to Effect:
Responses are typically seen within 3 months. In clinical trials, patients with initial responses continued to show improvements through the first year.
As with other biological DMARDS infections are increased in patients receiving abatacept. These have ranged from mild to severe. Respiratory infections including pneumonia were more common in clinical trials in patients with underlying COPD, thus extreme caution is suggested in this population. Opportunistic infections have been seen, though only a few cases of TB have been seen to date. TB screening is recommended. Malignancies have been seen in clinical trials but the rates appear to be similar for those expected in patients with rheumatoid arthritis. Infusion reactions have been seen in clinical trials that are typically mild.
B cells are an important inflammatory cell with multiple functions in the immune response. They serve as antigen presenting cells, directly interact with T-cells and others, can secrete cytokines, and differentiate into antibody-forming plasma cells. The depletion of B cells has been shown to be effective in reducing signs and symptoms of RA and in slowing radiographic progression. One B cell depleting agent, Rituximab, is currently available for the treatment of rheumatoid arthritis. Rituximab (Rituxan®) was originally developed to treat non-Hodgkin’s lymphoma. Ritxuimab causes a rapid and sustained depletion of circulating B cells in the circulation with clinical improvements in many patients. Clinical trials have demonstrated that Rituximab is effective in decreasing signs and symptoms and in slowing radiographic progression in RA patients who have failed other DMARD therapies. The agent is currently approved in the US, however, only in patients who have failed TNF antagonists.
Rituximab is a chimeric monoclonal antibody that binds to the CD20 molecule on the B cell surface leading to the removal of B cells from the circulation. A single course of ritximab (2 infusions of 1000 mg each given 2 weeks apart) leads to a rapid and sustained depletion of B lymphocytes in the peripheral blood. This effect is sustained for 6 months to 1 year or even longer. The levels of the autoantibody rheumatoid factor decrease, but the levels of other antibodies typically remain within the normal range after the first infusion, but may drop with subsequent courses.
Time to onset:
Effects from rituximab are not seen for up to 3 months after an infusion. Effects however may last 6 months and up to 2 years following a single infusion course.
The currently approved dose is 1000 mg administered intravenously over 3-4 hours with two doses given 2 weeks apart. Patients receive intravenous corticosteroids 30 minutes prior to each infusion. The optimal time for readministration is not yet clear. Some have advocated treatment every 6 months, while others wait for a return of symptoms to redoes. Doses of 500 mg have also been studied and appear to have similar clinical efficacy in patients who have failed to respond to DMARDS.
Infusion reactions are seen in patients who receive Rituximab infusions. These may include hives, itching, swelling, difficualty breathing, fever, chills, and changes in blood pressure. These are usually mild and respond to slowing the infusion rate or additional medication (such as antihistamines) but may be severe. These are reactions were the most common with the first infusion.
As with other immunomodulatory therapies, infections may be increased in patients who are receiving rituximab. Rituximab may lead to the reactivation of viral infections that were dormant including hepatitis B. Cases of progressive multifocal leukoencephalopathy (PML), a severe and potentially fatal brain infection, have been seen in patients with autoimmune disease who receive rituximab though this condition has also been seen in patients with autoimmune diseases who are not administered rituximab. Immunizations should be completed before starting therapy with rituximab and live virus vaccinations avoided. Repeat administration of rituximab has been associated with decreases in levels of IgG and IgM antibodies with subsequent courese. Whether these decreases are clinically important is under study.
Tocilizumab is the first approved drug in a class of IL-6 inhibitors. Clinical studies have shown that tocilizumab is effective in decreasing signs and symptoms and in slowing radiographic progression in RA patients who have failed other DMARD therapies. The agent is currently approved in the US, however, only in patients who have failed TNF antagonists.
Mechanism of action: Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis
Dosage: When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response
Usual time to effect: 4 to 8 weeks
Side effects: As with other biological DMARDs, an increase risk of infection and serious infection is present with tocilizumab. Because of a risk of GI perforation, patients with a history of diverticulitis should not receive tocilizumab. Tocilizumab has been associated with reduced platelet count, elevations in liver transaminases, increased lipid parameters (total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol) and neutropenia. Monitoring for any of these side effects should be considered every 4 to 8 weeks while on therapy.
IL-1 is another proinflammatory cytokine implicated in the pathogenesis of RA. IL-1 receptor antagonist (IL1ra) is an endogenous blocker of the cytokine. Evidence supporting an anti-inflammatory role of IL-1ra in vivo is demonstrated by the observation that IL-1ra deficient mice spontaneously develop autoimmune diseases similar to rheumatoid arthritis as well as vasculitis. IL1 has effects on cartilage degradation leading to damage as well as inhibiting repair, and is a potent stimulus to osteoclasts leading to bone erosion. One IL1 antagonist, anakinra (Kineret®), is currenly approved for the treatment of RA. Other agents have been studied as well in RA.
Anakinra, a human recombinant IL-1 receptor antagonist (hu rIL-1ra), is approved for the treatment of RA. Anakinra can be used alone or in combination with non-biologic DMARDs.
Mechanism: Anakinra is a recombinant human IL-1ra that differs from native IL-1ra by the addition of an N-terminal methionine. Anakinra blocks the biologic activity of IL-1 by binding to IL-1R type I with the same affinity as IL-1 beta.
Dosage: The recommended dose of anakinra is 100 mg/day administered daily by subcutaneous injection. The dose should be administered at approximately the same time each day. An autoinjection system is available for the medication.
Usual Time to Effect: 2 to 4 weeks.
Side Effects: The most commonly observed side effect in all of the clinical trials with anakinra is injection site reactions, occurring in approximately two-thirds of patients. These reactions are present as erythema, itching, and discomfort and typically resolve over one to two months. In some patients these reactions can be severe leading to drug discontinuation.
A modest increase in the risk of serious infection was observed in RA patients in clinical trials treated with anakinra in combination with DMARDS other than TNF inhibitors, compared to placebo with DMARDs (2 % vs 1%). Opportunistic infections including tuberculosis are less common with anakinra than with TNF antagonists. Mild to moderate decreases in absolute neutrophil counts were seen more commonly in anakinra treated patients in clinical trials, some severe. The rate of malignancies reported for anakinra was not increased relative to expected rates in the general population.
Biologic Treatment Schedule
|Etanercept||Prefilled syringeAutoinject pen||50 mg subcutaneous||Once per week|
|Adalimumab||Prefilled syringeAutoinject pen||40 mg subcutaneous||Once every 2 weeks (may ↑ to weekly)|
|Infliximab||IV infusion||3mg/kg -10 mg/kg||Day 1, 14, 42 then every 8 wks (interim can be as short as every 4 weeks)||2-3 hours|
|Abatacept||IV infusion||<60 kg/500 mg 60 to 100 kg/750 mg >100 kg /1 gram||Day 1, 14, 28 and every 4 weeks thereafter||30 minutes|
|Prefilled Syringe||125 mg||With or without initial single IV infusion, then every month|
|Rituximab||IV infusion||1000mg (500 mg also shown to be effective in DMARD inadequate responders)||Day 1 and 14||4 ½ hours|
|Certolizumab Pegol||Prefilled syringe||200mg per syringe||Loading dose 400 mg at baseline, 2 weeks, 4 weeks then either 200 mg every other week or 400 mg every month|
|Golimumab||Prefilled syringe Autoinject pen||50 mg||Every 4 weeks|
|Tocilizumab||IV infusion||4 mg/kg or 8mg/kg||Every 4 weeks||1 hour|
Patients receiving infused biological agents including may develop a clinical syndrome of fever, chills, body aches, and headache associated with the infusion of biologics. The symptoms can often be reduced or prevented by slowing the infusion rate, administration of diphenhydramine, acetaminophen, and sometimes corticosteroids before the infusion. Injection site reactions may be seen with injectable biologics. These are typically mild and generally do not result in drug discontinuation.
Other Immunomodulatory and Cytotoxic Agents
Some additional immunomodulatory drugs are used in RA including azathioprine (Imuran®), and cyclosporin A (Sandimmune®, Neoral®). Rarely cyclophosphamide (Cytoxan®) and d-Penicillamine are used. Because the potential of high toxicity, these agents are typically utilized for life-threatening extra-articular manifestations of RA such as systemic vasculitis or with severe articular disease that is refractory to other therapy.
Azathioprine (Imuran®) has some activity in rheumatoid arthritis but may take 8-12 weeks to see an effect. It is a purine analog that can cause bone marrow suppression and lowering of blood cell counts (white blood cells, red blood cells, and platelets) particularly in patients with renal insufficiency or when used concomitantly with allopurinol or ACE inhibitors. Increased risk of secondary malignancy due to azathioprine is controversial. Screening for levels of the enzyme thiopurine methyltransferase (TPMT) is recommended before initiating therapy with azathioprine. Certain individuals have deficiencies in this enzyme that metabolizes azathioprine with a concomitantly increased risk of toxicitiy for the medication. Side effects include nausea, and alopecia. Blood tests to monitor blood counts and liver function tests are necessary for patients on azathioprine.
Cyclosporine (Sandimmune®, Neoral®) has some activity as a disease modifying therapy in rhematoid arthritis. Studies have demonstrated that cyclosporine can be combined with methotrexate in RA patients to capture clinical responses. It is an immunosuppressive agent approved for use in preventing renal and liver transplant rejection and also has activity in psoriasis and other autoimmune diseases. Cyclosporine inhibits T cell function by inhibiting transcription of interleukin-2. Main toxicities include infection and renal insufficiency. Increase in blood pressure is common and may require treatment. Careful monitoring of renal function and blood pressure is needed for the entire time a patient is taking cyclosporine. Numerous medication interactions may affect blood levels of cyclosporine and lead to more toxicity. The package insert contains important information concerning these medication interactions. Cyclosporine increases risks of infection and may also increase the risk of malignancies including lymphoma.
Cyclophosphamide (Cytoxan®) is a potent immunosuppressive agent that is reserved for severe cases of refractory rheumatoid arthritis and those with manifestations such as vasculitis. It is used in the treatment of other autoimmune conditions including lupus and vasculitis. Cyclophosphamide is an alkylating agent with serious toxicities including bone marrow suppression, hemorrhagic cystitis, premature ovarian failure, infection and secondary malignancy particularly an increased risk of bladder cancer. Blood counts must be carefully monitored with this medication.
d-Penicillamine (Cuprimine®, Depen®) historically has some activity as a treatment for rheumatoid arthritis. It is prescribed primarily for patients with persistent aggressive disease who have failed other available DMARDS. Like gold it is a relatively toxic drug that has limited utility due to issues of tolerability and efficacy that is not as robust as other currently available agents. Major side effects include severe rash and effects on renal function. Careful monitoring of kidney function is required with this drug. Patients may develop a lupus like illness or other autoimmune diseases when taking d-Penicillamine.
Gold is effective in the treatment of rheumatoid arthritis when it is given intramuscularly. Intramuscular gold salts were, until the 1990’s, the most often used DMARD agents but have been replaced by Methotrexate and other DMARDS as the preferred agents to treat RA. Two injectable compounds are available, (Myochrysine® and Solganal®). Gold compounds are rarely used now due to their numerous side effects and monitoring requirments, their limited efficacy, and very slow onset of action. An oral gold compound (Auranofin®) is also available but its efficacy is even more limited than injectable compounds.
A number of mechanisms have been postulated, but how gold works in patients with rheumatoid arthritis remains unknown.
Myochrysine or Solganal therapy is started at 10 mg intramuscularly, 25mg is then given the second week, then 50mg is given weekly until a response has occurred or until a total of 1 g has been given. If there is a favorable response, therapy is tapered to 50mg every 2 weeks for 3 months, then every 3 weeks for 3 months and then finally to a maintenance monthly dose. No response after a total of 1g should be considered a treatment failure. Monthly gold should be continued indefinitely.
Usual Time to Effect:
Effects are achieved within 4 to 6 months or after administration of 1g of gold.
Approximately 35% of patients on gold therapy experience side effects leading to discontinuation of the drug. Prior to each gold injection, patients should have a complete blood count and urine test for protein. The most common reaction is a rash, which can vary from a simple pruritic erythematous patch to a severe exfoliative dermatitis. Ulcerations and mucositis of the mouth, tongue, and pharynx can occur. If a mild mucocutaneous eruption occurs, therapy should be interrupted. If the eruption abates, therapy can be restarted at a 10-15mg weekly, titrating upwards to 50mg weekly with careful monitoring for further rash.
Up to 10% of patients have mild proteinuria due to a gold-induced membranous glomerulonephropathy that can progress to the nephrotic range. Patients with a positive urine dipstick for protein should be evaluated with a 24-hour urine collection and gold therapy stopped if proteinuria exceeds 500mg/24 hours. Mild proteinuria generally resolves with the cessation of therapy. Occasionally patients will have isolated microscopic hematuria on gold therapy. If monitored closely gold therapy can be continued but other causes of hematuria must be excluded.
Immune thrombocytopenia, granulocytopenia, and aplastic anemia occur uncommonly but are absolute indications for cessation of gold therapy. Myochrysine, and less often Solganal, can produce a nitritoid reaction (flushing, dizziness, or fainting) occurring immediately after the gold injection. Rarely, there is a paradoxical increase in musculoskeletal pain that requires discontinuation of treatment.Long term use of gold may result in a bluish discoloration of the skin to occur that is typically irreversible.
Pain caused by inflammation is best treated with an anti-inflammatory drug (see above), although occasionally the addition of acetaminophen can be helpful. Chronic narcotic therapy is not used routinely due to side effects such as diminished mental status, hypersomnolence, constipation, and dependency. Furthermore, they have no anti-inflammatory activity. They may be needed for patients with severe joint destruction who are not surgical candidates.
Treatment During Pregnancy
Rheumatoid arthritis therapy during pregnancy is complicated by the fact that none of the drugs discussed above have been shown to be safe in pregnant women with adequate, controlled studies. Although joint symptoms frequently remit during pregnancy, this effect is not universal. Treatment decisions require careful consideration of the risks and benefits to the mother and fetus.
All DMARD therapy should be stopped in women planning to conceive and in pregnant and lactating women. Evidence of the risks of these agents to the fetus either exists or cannot be ruled out. Hyrdoxychloroquine (Plaquenil®) is probably the safest DMARD for use during pregnancy. Methotrexate, because of evidence of potential teratogencity should be stopped in men and women planning conception (see above). Leflunomide is teratogenic, and women who are considering conception should undergo a washout of this drug and have 2 separate demonstrations of blood levels of the metabolite of the drug are low. TNF antagonists are currently pregnancy category B though studies are ongoing to evaluate the outcomes of pregnancies in patients treated with these agents.
Although safety has not been proven in controlled trials, no evidence exists for risks to the fetus of low dose prednisone (less than 20mg daily) or of NSAIDs used in the first two trimesters. If necessary, joint symptoms are best managed with the lowest possible dose of prednisone. Potential prednisone complications include worsening of maternal gestational diabetes, hypertension and intrauterine growth retardation. NSAIDs should be avoided in the third trimester because of the potential for premature closure of the ductus arteriosus, prolonged labor and peripartum hemorrhage. Although both NSAIDs and prednisone are excreted in the breast milk, both are considered compatible with breast-feeding by the American Academy of Pediatrics.
Reduction of joint stress
Because obesity stresses the musculoskeletal system, ideal body weight should be achieved and maintained. Rest, in general, is an important feature of management. When the joints are actively inflamed, vigorous activity should be avoided because of the danger of intensifying joint inflammation or causing traumatic injury to structures weakened by inflammation. On the other hand, patients should be urged to maintain a modest level of activity to prevent joint laxity and muscular atrophy. Splinting of acutely inflamed joints, particularly at night and the use of walking aids (canes, walkers) are all effective means of reducing stress on specific joints. A consultation with a physical and an occupational therapist is recommended early in the course.
Although rheumatoid arthritis is generally an inflammatory process of the synovium, structural or mechanical derangement is a frequent cause of pain or loss of joint function. Pain and joint mobility may be improved by a surgical approach. The primary physician, the rheumatologist, and the orthopedist all help the patient to understand the risks and benefits of the surgical procedure. The decision to have surgery is a complex one that must take into consideration the motivation and goals of the patient, their ability to undergo rehabilitation, and their general medical status.
Synovectomy is sometimes appropriate for patients with rheumatoid arthritis, though in many patients the relief is only transient. However, an exception is synovectomy of the wrist, which is recommended if intense synovitis is persistent despite medical treatment over 6 to 12 months. Persistent synovitis involving the dorsal compartments of the wrist can lead to extensor tendon sheath rupture resulting in severe disability of hand function.
Total joint arthroplasties, particularly of the knee, hip, wrist, and elbow, are highly successful. Arthroplasty of the metacarpophalangeal (knuckle) joints also can reduce pain and improve function. Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome), arthroscopic procedures, and, occasionally, removal of a symptomatic rheumatoid nodule.