Rheumatoid Arthritis - Treatments

Rheumatoid arthritis is a chronic disorder for which there is no known cure. It therefore 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. The major goals of treatment of the arthritis are to reduce pain and discomfort, prevent deformities and loss of joint function, and maintain a productive and active life. Inflammation must be suppressed and mechanical and structural abnormalities corrected or compensated by assistive devices. Treatment options include reduction of joint stress, physical and occupational therapy, drug therapy, and surgical intervention.
Pharmacological Strategies

There are three general classes of drugs commonly used in the treatment of rheumatoid arthritis: non-steroidal anti-inflammatory agents (NSAIDs), corticosteroids, and remittive agents or 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, leflunomide (Arava™), etanercept (Enbrel™), infliximab (Remicade™), adalimumab (Humira™), anakinra (Kineret™), antimalarials, gold salts, sulfasalazine, d-penicillamine, cyclosporin A, cyclophosphamide and azathioprine. Because cartilage damage and bony erosions frequently occur within the first two years of disease, rheumatologists now move more aggressively to a DMARD agent. In some cases, analgesic drugs may also be helpful. A summary table of how to monitor drug treatment in rheumatoid arthritis is included (see table in ACR Guidelines).

Non-steroidal Anti-inflammatory Agents Corticosteroids Disease Modifying Anti-rheumatic Drugs (Agents with Delayed Onset of Action) Analgesic Drugs

Non-steroidal Anti-inflammatory Agents
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.

Aspirin is the oldest drug of the non-steroidal class, and it remains an economical, effective choice. However, because of its higher rate of GI toxicity, its 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levels and the inconvenience of multiple daily doses, aspirin's use as the initial choice of drug therapy has largely been replaced by the newer NSAIDs. There are now a large number of NSAIDs from which to choose, and at full dosage 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. Long acting NSAIDs that allow daily or twice daily dosing will improve compliance and help with morning stiffness.

Mechanism: NSAIDs inhibit prostaglandin synthesis by blocking cyclooxygenase enzymes, COX-1 and COX-2. The COX-2 selective inhibitors selectively block prostaglandins generated via COX-2. Prostaglandins are important mediators of both pain and inflammation.

Dosage: If there is active inflammation, a full dosage of an NSAID should be prescribed. 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.

Usual Time to Effect: Although these agents have anti-inflammatory effect within hours, a reasonable trial period is 1 month.

Side Effects: The most common toxicity of NSAIDs is gastrointestinal disturbance. Selective COX-2 inhibitors exhibit safer GI profiles than conventional non-selective NSAIDs. Because prostaglandins play a role in the regulation of renal blood flow and maintenance of glomerular filtration, NSAIDs can also impair renal function in certain patients. The patients at highest risk are those with fluid imbalances or with compromised renal function (e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency).

Corticosteroids
Corticosteroids have both anti-inflammatory and immunoregulatory activity. They can be given systemically or can be injected intra-articularly. 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 is very difficult to discontinue and even at low doses. Tapering of prednisone should be done slowly over a few weeks and symptoms may reoccur with small changes in the prednisone dose.

Weight gain and cushingoid appearance is a frequent problem and source of patient complaints. Recent studies have raised concern over accelerated osteoporosis associated with low dose prednisone particularly at doses above 10 mg daily. Patients with and without osteoporosis risk factors on low dose prednisone should undergo bone densitometry to assess fracture risk. Bisphosphonates are recommended to prevent and/or treat osteoporosis. Prednisone can also raise blood pressure and blod sugar levels. Recent studies suggest, however, that low dose prednisone maybe effective as a "disease modifying" agent in RA.

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 bid or tid. 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., 40mg of triamcinolone in a knee, 20mg in a shoulder, or 2mg in a finger) are effective for controlling a local flare in a joint without changing the overall drug regimen.

Disease Modifying Anti-rheumatic Drugs (Agents with Delayed Onset of Action)
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 more delayed in onset than either NSAIDs or corticosteroids. Once persistent disease activity (chronic synovitis) is established, a DMARD agent should be considered. The development 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
* hydroxychloroquine and sulfasalazine
* leflunomide
* tumor necrosis factor inhibitors
* soluble interleukin-1 (IL-1) receptor therapy
* intramuscular gold
* cytotoxic agents (azathioprine, cyclophosphamide, and cyclosporine A)

Methotrexate has become the most popular first-line DMARD agent because of its early onset of action (4-6 weeks), good efficacy, favorable toxicity profile, ease of administration, and relatively low cost. Methotrexate is the only conventional DMARD agent in which the majority of patients continue on therapy after 5 years. 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 nearly as effective as etanercept in another study.

Mechanism: Although the immunosuppressive and cytotoxic effects of methotrexate are due to the inhibition of dihydrofolate reductase, the anti-inflammatory effects in rheumatoid arthritis appear to be related at least in part to interruption of adenosine and TNF pathways.

Dosage: In a study comparing methotrexate to etanercept in early RA, methotrexate was begun at a dose of 10 mg per week, and increased to 20 mg per week by week 8. This dosing regimen is now fairly well accepted in clinical practice. Maximal dose is usually 25 mg per week. 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 should be carefully selected not to have renal insufficiency, acute or chronic liver disease, alcohol abuse, leukopenia, thrombocytopenia, 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. Salicylates (and other NSAIDs) and trimethoprim (Bactrim, Septra) block the renal excretion of methotrexate and leads to higher serum levels and potential toxicity. If alternatives exist, concomitant use of methotrexate and trimethoprim is to be avoided. NSAIDs and methotrexate are routinely used together with safety.

Usual Time to Effect: The onset of action is 4 to 6 weeks, with 70% of patients having some response. A trial of 3 to 6 months is suggested.

Side Effects: Fortunately the most serious complications of methotrexate therapy: hepatic cirrhosis, interstitial pneumonitis and severe myelosuppression are rare. Stomatitis, mild alopecia and GI upset may occur and are related to folic acid antagonism and can be improved with folic acid supplementation. Folic acid 1mg daily does not diminish the efficacy of methotrexate and is routinely given. Before starting methotrexate, baseline studies should include complete blood count, liver chemistries, serum creatinine, hepatitis B and C serologies and chest radiography. Routine toxicity monitoring should include a CBC, liver profile, serum albumin and serum creatinine every 4-8 weeks.

Hepatotoxicity has not been significant if patients with pre-existing liver disease, alcohol abuse, or hepatic dysfunction are excluded from treatment. Patients are instructed to limit alcohol containing beverages to no more than two per week. Baseline or surveillance liver biopsies are not indicated unless pre-existing iver disease is suspected. Elevated liver enzymes do not directly correlate with toxicity but therapy should be stopped if transaminases are elevated to 3 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 rare (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.

Myelosuppression is also rare at the low doses of methotrexate utilized for rheumatoid arthritis. Increased renal insufficiency from other causes or use of trimethoprim (Bactrim, Septra) frequently raises methotrexate levels and may cause myelosuppression.

In the absence of leukopenia, 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.

Although there are case reports of lymphoma associated with methotrexate therapy including a case where the lymphoma resolved after cessation of therapy, increased occurrence of malignancy has not been found in large population based studies. Nor have there been noted effects on sperm production or ovarian function. Women of childbearing potential or men with partners of child bearing potential must understand that methotrexate has potential for teratogenesis and should practice effective birth control. Women must discontinue methotrexate for one ovulatory cycle prior to attempting conception, while men should wait 3 months.

Methotrexate can be combined safely with nearly every other FDA approved DMARD for RA, including sulfasalazine, hydroxychloroquine, TNF inhibitors, anakinra and leflunomide. In all clinical trials combining methotrexate with one of these DMARDs, no unexpected toxicities or synergistic toxicities were observed.

Hydroxychloroquine and Sulfasalazine
Antimalarials such as hydroxychloroquine and chloroquine are rapidly absorbed, relatively safe, well-tolerated and often effective remittive agents for the treatment of rheumatoid arthritis, particularly mild to moderate disease.

Mechanism: The mechanism of action of antimalarials in the treatment of patients with rheumatoid arthritis is unknown.

Dosage: Hydroxychloroquine (Plaquenil, 200mg tablets) is the drug of choice among antimalarials. Chloroquine is no longer recommended because of its greater ocular toxicity. The usual dose is 400mg/day (6mg/kg) but 600mg/day is sometimes used. Normally it is prescribed as a single nighttime dose to avoid gastrointestinal symptoms.

Usual Time to Effect: A period of 2 to 4 months is usual. A 6-month period without clinical effect should be considered a drug failure.

Side Effects: The most important toxicities are ocular: corneal deposits, extraocular muscular weakness, loss of accommodation, and a retinopathy that may progress to irreversible visual loss. Ocular toxicity is only 1 out of 40,000 patients treated at the doses recommended, but a baseline ophthalmologic examination and a follow-up examination every 12 months are recommended during the period of treatment.

Sulfasalazine is another effective DMARD for the treatment of RA. Its mechanism of action in RA is unknown. Like the other DMARDs, it has been shown not only to reduce the signs and symptoms of RA but also to slow or halt radiographic progression. It can cause hypersensitivity reactions due to sulfa allergy, mild gastrointestinal, and occasionally, mild cytopenias. The usual dose is 2-3 grams per day in a twice daily dosing regimen. Blood monitoring is every 1-3 months depending on dose. Sulfasalazine is a good alternative to methotrexate for patients with liver disease.

Leflunomide (Arava™)
Leflunomide was approved by the FDA and became available as a new DMARD agent for rheumatoid arthritis in October 1998. In clinical trials, its efficacy was similar to that of methotrexate and it represents a viable alternative to patients who have failed or are intolerant to methotrexate. Leflunomide has been demonstrated to slow radiographic progression and damage in RA. It can also be combined with methotrexate in patients with no preexisting liver disease, as long as the liver function tests are carefully monitored.

Mechanism: The mechanism of action of leflunomide is not fully understood but may be related to its ability to inhibit tyrosine kinase activity and inhibit de novo pyrimidine biosynthesis through the inhibition of the enzyme dihydroorotate dehydrogenase. In vitro studies have demonstrated the inhibition of mitogen and IL-2 stimulated T cells.

Dosage: The half-life of the active metabolite of leflunomide is 15 days. Leflunomide and its active metabolite are extensively protein bound and undergo further metabolism before excretion in the urine and in the feces (direct biliary excretion). To achieve steady state, a loading dose of 100mg daily for three days can be given followed by 20 mg daily. However, more recent recommendations are for a starting dose of 20mg daily. The dose may be reduced to 10mg daily if not tolerated or in patients having difficulty metabolizing or excreting the drug.

Usual Time to Effect: Onset of action 4-8 weeks, with some evidence that onset of action may be sooner than methotrexate.

Side Effects: In clinical trials, leflunomide has been associated with a 2-4% incidence of liver transaminase elevations 3 times the upper limit of normal that reversed with cessation of the drug. Routine monitoring should include complete blood count and hepatic panel every 2 weeks for the first month and then on a monthly basis. Other toxicities have included mild diarrhea, GI upset and alopecia of insufficient severity to cause cessation of the drug. Because of the potential for teratogenic effects, 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 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-a) 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. The pro-inflammatory effects of TNF-asuggests that inhibition of TNF-awould be clinically useful in rheumatoid arthritis. Indeed extensive clinical trial data have confirmed the efficacy of all three currently available TNF inhibitors in relieving the signs and symptoms of RA, and in slowing or halting radiographic damage. The long-term safety of these agents is still relatively unknown. Cost and insurance reimbursement may limit availability for some patients.

Read a comprehensive discussion about Anti-TNF therapy.

There are currently three TNF inhibitors FDA approved in the treatment of RA; etanercept (Enbrel™), infliximab (Remicade™), and adalimumab (Humira™).

Etanercept (Enbrel™) Etanercept is a human fusion protein that combines two extracellular binding domains of the p75 form of the TNF receptor to the Fc portion of a human IgG1 antibody molecule. The protein is entirely human and anti-etanercept antibodies are relatively uncommon. In a series of clinical trials, etanercept proved to be safe and effective 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. Etanercept is also FDA approved for the treatment of psoriatic arthritis and for ankylosing spondylitis.

Mechanism: Etanercept binds TNF-ain the circulation and in the joint, preventing interaction with cell surface TNF-areceptors thereby reducing TNF activity.

Dosing: Etanercept has a half-life of 70 hours after a standard 25mg dose. It is currently available in a 25mg dose and is given by self-administered subcutaneous (SC) injection twice weekly. Also available is a 50mg pre-filled syringe administered once weekly. Intermittent or occasional dosing has not been studied.

Usual Time to Effect: Etanercept has an onset of action of 1 to 4 weeks.

Side Effects: In the clinical trials, adverse events were mild and relatively infrequent. There was an increase frequency of injection site reactions in the etanercept groups, 37% Vs 10% in the placebo group. The injection site reactions were mild. There was not an overall difference between the etanercept group and the placebo groups in the rates of serious infection, cancer, or death from any cause. There was an increase in mild upper respiratory infection symptoms in the etanercept group. No increase was seen in the frequency of anti-ds-DNA antibodies and no patients developed clinical SLE as has been seen with studies with monoclonal antibodies against TNF. Approximately 1% of patients developed anti-etanercept antibodies but these antibodies were non-neutralizing. A study adding etanercept to methotrexate showed no additional toxicities.

Post-marketing experience has indicated an enhanced risk for serious and opportunistic infections in patients treated with etanercept or infliximab. Although disseminated tuberculosis due to reactivation of latent disease was seen more commonly with infliximab than etanercept, screening for latent TB is nonetheless prudent before treatment with any TNF inhibitor. In some of the clinical trials, 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. [RA itself is a risk factor for non-Hodgkins lymphomas.] Etanercept and other TNF inhibitors are not recommended in patients with demyelinating disease or with congestive heart failure. Transient neutropenia or other blood dyscrasias have been reported with etanercept and the other TNF inhibitors.

Infliximab (Remicade™)Infliximab, in combination with methotrexate, is FDA approved for the treatment of RA. Infliximab is also approved for the treatment of Crohn's disease. Infliximab is a chimeric monoclonal antibody that binds TNF-awith high affinity and specificity. The antibody binding site for TNF is of mouse origin, with the remaining 75% of the infliximab antibody derived from a human IgG1kantibody sequence.

Infliximab has been studied extensively in clinical trials. It is effective as monotherapy in reducing the signs and symptoms of RA but anti-infliximab antibodies can develop which can, in turn, reduce the durability of the response. Co-treatment with methotrexate reduces the frequency of these antibodies and is therefore recommended along with infliximab. The combination of infliximab and methotrexate is very effective in reducing clinical manifestations of disease, as well as in slowing or halting radiographic progression of disease in RA. Infliximab also has demonstrated efficacy in clinical trials of ankylosing spondylitis.

Mechanism: Infliximab is binds TNF-ain the joint and in the circulation, preventing its interaction with TNF-areceptors on the surface of inflammatory cells, and eventually clearing TNF-afrom the circulation. Like etanercept, infliximab inhibits the activity of TNF.

Dosing: The recommended starting dose of infliximab is 3 mg/kg given as an intravenous infusion followed by additional dosing at 2 and 6 weeks, then every 8 weeks thereafter. Infliximab should be given in combination with methotrexate. If the clinical response is inadequate at this dose, infliximab can be increased to a maximum of 10 mg/kg and the frequency of infusion increased to every 4-6 weeks.

Usual Time to Effect: Days to weeks.

Side Effects: Monoclonal antibody therapy has been associated with cytokine release syndrome, a clinical syndrome of fever, chills and headache associated with the infusion of the antibody. In clinical trials, these symptoms were observed with infliximab but at relatively low frequency. If they do occur, it is usually with the first infusion and decline with subsequent infusions. The symptoms can be reduced or prevented by slowing the infusion rate. Anti-infliximab antibodies can occur in 10-30% of patients depending on the dosage and frequency of infusion but are suppressed by concomitant methotrexate therapy. In clinical trials with infliximab, approximately 8% of patients developed anti-double stranded DNA antibodies, antibodies with high specificity for systemic lupus erythematosus (SLE). There are several cases of mild clinical SLE that resolved after stopping the drug.

In clinical trials, the frequency of serious infections was not increased in the infliximab + methotrexate groups compared to the methotrexate alone group. However, post-FDA approval, a number of cases of sepsis and disseminated tuberculosis and other opportunistic infections have been reported for patients treated with infliximab or etanercept. The risk for disseminated TB appears to be higher for infliximab than etanercept, perhaps because of its longer half-life. However, all patients should be screened for latent TB before initiation of any TNF inhibitor. All patients receiving a TNF inhibitor should be carefully monitored for signs of infection. Like etanercept, infliximab is not recommended in patients with congestive heart failure or with demyelinating disease.

Adalimumab (Humira™) Adalimumab is a recently approved anti-TNF mAb that differs from infliximab in that its sequences are entirely human. Generated by phase display technology with amino acid sequences only from the human germline, it is indistinguishable in structure and function from natural human IgG1. Adalimumab also has high specificity for TNFa and a half-life of approximately 2 weeks. Like the other TNF antagonists, it has been shown to be effective, both as monotherapy and in combination with methotrexate, to be effective in reducing signs and symptoms of RA, as well as slowing or halting radiographic progression of disease. It is administered by subcutaneous injection every two weeks but can be increased to weekly, if needed.

Mechanism: Adalimumab binds specifically to TNF-aand blocks its interaction with the p55 and p75 cell surface TNF receptors, thereby interfering with endogenous TNF-aactivity.

Dosing: Adalimumab has a long half-life of approximately 2 weeks (ranging from 10-20 days) after a standard 40 mg dose. It is currently available in a 40 mg dose and is given by self-administered subcutaneous (SC) injection every other week. If response to this dose is inadequate, the frequency of injections can be increased to weekly.

Usual Time to Effect: 1 to 4 weeks.

Side Effects: In clinical trials, the most common adverse event was injection site reactions. 20% in the adalimumab group Vs 14% in the placebo group. The injection site reactions were mild and generally did not result in drug discontinuation. The infection rate was 1 per patient year in patients treated with adalimumab compared with 0.9 per patient year in patients treated with placebo. Infections consisted primarily of upper respiratory tract infections, bronchitis and urinary tract infection. Thirteen cases of tuberculosis occurred in the early clinical trials of adalimumab and appeared to be due to reactivation of latent disease (consistent with what was seen with infliximab and etanercept). In these studies, doses of adalimumab 20-40 fold higher than the current FDA recommended starting dose were utilized and patients were not prescreened with PPDs prior to treatment. In subsequent trials using lower drug doses and PPDs to pre-screen for TB, this problem was eradicated. Because adalimumab was just recently approved by the FDA, there are no postmarketing safety data available. As with the other TNF inhibitors, however, patients treated with adalimumab should be carefully monitored for signs of infection, and adalimumab is not recommended for patients with concurrent demyelinating disease or congestive heart failure.

12% of patients treated with adalimumab developed positive ANA titers by week 24 compared to only 7% of placebo-treated patients. No patient developed lupus nephritis or central nervous system symptoms. Lymphomas occurred more frequently in adalimumab treated patients than placebo but the incidence did not appear to be higher than background incidence of lymphoma in RA patients not on TNF inhibitors.

Soluble Interleukin-1 (IL-1) Receptor Therapy
IL-1 is a cytokine that has immune and pro-inflammatory actions and has the ability to regulate its own expression by autoinduction. Evidence supports the fact that the level of disease activity in RA, and progression of joint destruction, correlate with plasma and synovial fluid levels of IL-1. IL-1ra is an endogenous receptor antagonist. Evidence supporting the 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 and arteritis. Hence, IL-1ra is a rational therapeutic target for use in the treatment of RA.

Read a comprehensive discussion about Interleukin-1

Anakinra (Kineret™) Anakinra, a human recombinant IL-1 receptor antagonist (hu rIL-1ra) is approved by the FDA for the treatment of RA. Anakinra can be used alone or in combination with DMARDs other than TNF blocking agents (Etanercept, Infliximab). Anakinra is not recommended for use in combination with TNF inhibitors.

Mechanism: Anakinra is a recombinant, nonglycosylated form of the human IL-1ra. It differs from the native nonglycosylated 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-1b.

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.

Usual Time to Effect: 2 to 4 weeks.

Side Effects: The most commonly observed side effect in all of the clinical trials with anakinra to date is injection site reactions, occurring in approximately two-thirds of patients at the FDA-approved daily dose of 100 mg administered subcutaneously. These reactions are generally mild, present as erythema, itching, and discomfort and resolve over one to two months.

A modest increase in the risk of serious infection was observed in RA patients treated with anakinra in combination with DMARDS other than TNF inhibitors, compared to placebo with DMARDs (2 % vs 1%). However, no opportunistic infections occurred. In particular, no cases of TB were reported in any clinical trial with anakinra. The risk of serious infections of anakinra in combination with a TNF inhibitor is approximately 7% and this combination of biologics is not recommended.

In the placebo-controlled trials, 8% of patients receiving anakinra had mild to moderate decreases in absolute neutrophil counts, compared to 2% in the placebo groups. 0.3% of anakinra treated patients experienced severe neutropenia (< 1x 109/L). In the combination anakinra/etanercept study, two of 58 points (3%) experienced severe neutropenia.

The rate of malignancies in anakinra treated patients was not increased relative to expected rates in the general population. Neutralizing antibodies were rare, and the presence of antibodies did not appear to correlate with clinical response or adverse events.

Intramuscular Gold (Myochrysine, Solganal)
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. They are rarely used now due to side effects and very slow onset of action. An oral gold compound (Auranofin) is also available but its efficacy is limited.

d-Penicillamine is also a relatively toxic drug and is, like injectable gold, prescribed primarily for patients with persistent aggressive disease who have failed to achieve remission with less toxic agents.

Mechanism: A number of mechanisms have been postulated, but how gold works in patients with rheumatoid arthritis remains unknown.

Dosage: 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.

Side Effects: Approximately 35% of patients on gold therapy experience side effects and this often leads 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.

Cytotoxic Agents
The most commonly used cytotoxic drugs are azathioprine (Imuran), cyclophosphamide (Cytoxan) and cyclosporin A. Because the potential of high toxicity, these agents are utilized for life-threatening extra-articular manifestations such as systemic vasculitis or severe articular disease refractory to other therapy. It is recommended that these agents be used under the direction of a rheumatologist.

Azathioprine is a purine analog that can cause severe bone marrow suppression 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.

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. For these reasons it is not used in the treatment of uncomplicated rheumatoid arthritis. Cyclophosphamide is used in rheumatoid vasculitis or lung disease.

Cyclosporine is an immunosuppressive agent approved for use in preventing renal and liver allograft rejection. Cyclosporine inhibits T cell function by inhibiting transcription of interleukin-2. Main toxicity’s include infection and renal insufficiency.

Analgesic Drugs
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 are 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. Methotrexate, because of evidence of potential teratogencity should be stopped in men and women planning conception (see above).

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, 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.

Surgical Approaches

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 ordinarily not recommended for patients with rheumatoid arthritis, primarily because 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 MCP 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.

References

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