DCommon adverse effects

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i. Gastrointestinal intolerance. Nausea and vomiting occur in nearly 20% of patients, usually those on oral MTX. This can be avoided in most cases by switching to SC, IM, or IV administration. Diarrhea occurs in 10% of patients and may be avoided by altering the route of administration.

ii. Stomatitis occurs in 6% to 10% of patients and may be avoided with the use of between 1 and 5 mg of oral folic acid daily.

iii. Hypersensitivity pneumonitis. This acute pulmonary disorder, manifested by cough, dyspnea, eosinophilia, and diffuse pulmonary infiltrates, can occur in as many as 5% of MTX-treated patients. It can be quite severe, always requires the discontinuation of MTX, and may necessitate a course of high doses of steroids. Rechallenge is not recommended. This problem may be more common in patients who smoke or have had interstitial lung disease associated with RA.

iv. Teratogenicity and induction of abortion. MTX must be discontinued 3 months before any male or female patient attempts to have a child. MTX is an abortifacient, and women taking it should be made aware of this fact and counseled regarding the need to use appropriate birth control techniques while taking this medication.

v. Oncogenicity. Based on longitudinal data from large studies of patients treated with MTX for psoriasis and choriocarcinoma, MTX was not thought to be oncogenic. However, more than 50 cases of non-Hodgkin's B-cell lymphomas have been reported worldwide in patients taking MTX. In eight of these patients, discontinuation of MTX led to spontaneous disappearance of the lymphoma, without a need for chemotherapy. Although the exact incidence of this association is unknown, it is probably low but should be discussed with patients. It must be appreciated that RA patients already have an inherent increased risk for the development of lymphoproliferative disorders. MTX may be a cofactor, along with Epstein-Barr virus, in altering immunosurveillance capability and triggering lymphomas in some RA patients.

vi. Bone marrow toxicity. This can occur on low-dose, weekly MTX but is uncommon. The synergistic toxic effects on bone marrow of taking antibiotics that contain sulfa along with MTX should be appreciated.

vii. Hepatic toxicity. The following information is important in guiding hepatic surveillance in RA patients treated with methotrexate:

Methotrexate is relatively safe for the liver, and SGOT levels correlate with liver biopsy grade. Despite prior concepts regarding the inability of liver function test abnormalities to predict MTX-induced liver disease, recent studies in RA patients support the fact that serial elevations of aminotransferases [AST (SGOT) and ALT (SGPT)] and decreases in albumin have been found to correlate with the progression of histologic abnormalities defined by serial liver biopsies. In such liver biopsy studies, Kremer found that the overall hepatic histologic grade does increase with time. In the patients reported, minimal fibrosis was developing; however, almost half the patients had fibrosis that was not present at baseline. Among 13 patients with RA treated with MTX in whom Kremer identified fibrosis, some lost fibrosis on follow-up, seven showed fluctuation in grading, and none showed progression of fibrosis. Hence, fibrosis appeared to be an inconsistent and inconsequential feature. There were statistically significant correlations between liver function test abnormalities and liver biopsy grade after approximately 8 years of

MTX. It is important to note that the extent of fibrosis correlates poorly with the extent of hepatic dysfunction.

Note: Alcohol should be completely avoided in patients treated with MTX. The use of alcohol adds an unacceptable risk for the development of liver inflammation and damage.

MTX-induced cirrhosis and liver failure are uncommon in RA patients. In a survey of more than 2,200 members of the American College of Rheumatology (ACR) who had treated 16,600 patients with MTX, Walker et al. found 24 cases of cirrhosis and liver failure, giving a 5-year cumulative incidence of approximately 1 in 1,000 treated patients. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease.

Given the above data and the risks and cost of liver biopsy, the following indications for liver biopsy have been formulated:

The ACR has published a position paper regarding liver biopsy in MTX-treated RA patients. With their interpretation of the above data, they do not recommend baseline or follow-up biopsies unless the patient, in every 6-weekly liver function test, demonstrates persistent or recurrent elevations (even minor) of transaminases or decreases in albumin. This is a clear shift in position from prior (not from the ACR) recommendations for a biopsy between a cumulative dose of 1.5 to 5.0 g or after 3 to 5 years of treatment. The physician should be aware that this stance differs greatly from that taken by dermatologists in their treatment of psoriasis with MTX, and also does not address similar questions regarding the use of MTX for psoriatic arthritis.

If a patient is an alcoholic or has known alcoholic liver disease and every other drug has failed to control the disease, a biopsy should be performed before initiation of MTX treatment to guide therapeutic decisions.

For patients with baseline abnormal liver function test results of unknown cause, a biopsy would be performed to define the following disorders: hepatotoxin-induced liver disease, liver damage from prior or ongoing viral infections, and "occult" alcoholic liver disease. viii. Opportunistic infections have been reported in some RA patients treated with weekly, low-dose MTX. The combined immunosuppression of corticosteroids and MTX may contribute to the risk for such infection. Appropriate immunizations should be offered to RA patients taking MTX. ix. Nodulosis. The development of multiple, new, small, painful nodules on the hands and elsewhere can be quite uncomfortable and functionally limiting. These often occur despite excellent disease control elsewhere. The addition of hydroxychloroquine or colchicine has, in rare patients, led to some control of the development of nodules.

2. Azathioprine. This purine analog has had an excellent track record in terms of both effectiveness and safety in patients with RA. Through the years, it has been used as a second- or third-line drug for the treatment of moderate to severe RA. Presently, it is considered for patients who have failed other

DMARDs, such as MTX, and may be used in combination with other medications, such as hydroxychloroquine.

a. Indications. For established RA after failure of several DMARDs, or as a steroid-sparing and disease-controlling agent in rheumatoid vasculitis.

b. Mechanism of action. Reduction in circulating lymphocytes, mixed lymphocyte reactivity, and immunoglobulin synthesis have been demonstrated. These are probably caused by suppression of inosinic acid synthesis and inhibition of IL-2 secretion.

c. Therapeutic approach. AZA is an effective drug in the treatment of RA, with many studies demonstrating its similarity in efficacy to IM gold, D-penicillamine, MTX, and other DMARDs. Its use is somewhat limited by its potential oncogenicity. The long-term experience with AZA in patients with RA has proved that this drug in this population has an acceptable profile of toxicity. However, the overall oncogenic potential of this drug must be considered before it is prescribed to treat a nonmalignant disorder.

d. Administration. AZA is available in 50-mg tablets. Therapy is begun with 50 mg/d, and the dosage is increased by weekly 50-mg increments until a maintenance dose of 2 to 3 mg/kg is reached. The usual daily dose is 100 mg. Close monitoring is indicated and includes complete blood cell counts with platelet and differential counts weekly for 1 to 2 months, then every 2 weeks for 1 to 2 months, and eventually monthly. Liver function tests should be carried out every 1 to 2 months if the patient has excessive nausea or vomiting or if a fever develops. If gastrointestinal symptoms occur following administration of the drug, it may be given in a single daily dose before bedtime to minimize this effect. If a hypersensitivity reaction develops manifested by fever, hypotension, and liver function test abnormalities, the drug should be stopped immediately and never started again. Reinstitution of AZA in this situation can be fatal.

Caution: Allopurinol inhibits the metabolic breakdown of AZA, and if the drugs are used concomitantly, potentially toxic levels of AZA and its metabolites may accumulate. Thus, this drug combination should be avoided because of the potential for severe bone marrow suppression. If it is essential that the drugs be used together, the dose of AZA should be decreased to one-third of the usual dose. Even then, close hematologic monitoring should be carried out.

e. Common adverse effects include the following:

i. Dose-related bone marrow suppression with leukopenia and thrombocytopenia.

ii. Increased susceptibility to infection, primarily viral, such as herpes zoster, but also bacterial, and gastrointestinal intolerance, such as nausea and vomiting. aZa can lead to liver enzyme abnormalities and even clinically significant hepatitis. At times, hepatitis may be part of a hypersensitivity reaction with associated fever and hypotension. If this occurs, AZA should be stopped permanently. Pancreatitis may occur and clears when the drug is stopped.

iii. Oncogenicity. A 50-fold increase in relative risk for malignant disease, primarily non-Hodgkin's lymphoma, has been demonstrated in renal transplant patients treated with AZA. In RA, however, the related risk for lymphoma is confounded by an increased relative risk secondary to RA per se or the coexistence of Sjogren's syndrome. Overall, there appears to be a small added risk (relative risk, 1.3) for malignancy when AZA is used in patients with RA.

iv. Teratogenicity. Although there is mounting evidence demonstrating the safe use of AZA during pregnancy in patients with active SLE, the recommendation is that AZA not be used during pregnancy.

3. Cyclophosphamide. CTX is an extraordinarily effective disease-modifying agent for the treatment of RA. However, because of its significant potential toxicities, its role is now limited to use in the most severe, refractory cases of RA or in those associated with life- and organ-threatening RA vasculitis.

Only physicians experienced in the indications for and monitoring of CTX should administer this drug.

a. Indications. Treatment with CTX should be limited to those clinical situations in which RA continues to be active and destructive despite the use of many DMARDs, including MTX, CyA, AZA, and anti-TNF biologics. It is also an effective disease-modifying agent in patients with active rheumatoid vasculitis. The physician can use CTX initially, for 3 to 6 months, to gain control of the disease, and then switch back to another medication, such as 15 to 20 mg of MTX per week, to maintain disease suppression. In this way, one employs the best possible medication initially, then changes to a safer therapeutic choice. Daily oral CTX may be more effective than monthly IV CTX, but the choice is often dictated by practical clinical considerations and patient comorbidities.

b. Mechanism of action. The active metabolites of CTX, principally phosphoramide mustard, cross-link DNA so that it cannot replicate. CTX is cytotoxic to dividing and resting lymphocytes. It induces lymphocytopenia, with B cells more affected than T cells. It readily suppresses primary cellular and humoral immune responses. It suppresses many cell-mediated responses and also has antiinflammatory properties.

c. Therapeutic approach. When CTX is compared with other DMARDs, its clinical effectiveness is equal to that of AZA and IM gold. In two studies, it has been shown to retard bone destruction. Although no placebo-controlled studies have been performed, daily oral CTX is thought to be the drug of choice for the treatment of necrotizing vasculitis associated with RA, so-called "malignant" RA. Intermittent IV CTX is also being used, but this route of administration may not be as effective as daily oral treatment.

d. Administration. CTX (Cytoxan) tablets are 50 mg in size. The usual oral dose begins with 50 mg/d for 1 week, and then the dose is increased by 50 mg if the complete blood count is stable. The usual oral therapeutic dose is 2 mg/kg daily, or 75 to 125 mg/d. Higher doses may be needed in severe cases. Complete blood count, differential and platelet count, and urinalysis are assessed every 7 to 14 days initially, then every 2 to 4 weeks after 2 to 3 months of stable dosage. The IV regimen is 0.5 to 0.75 g/m2 monthly. Once the patient has responded to oral and IV CTX, a switch to a less toxic DMARD, such as MTX, is appropriate to decrease the potential for oncogenicity, sterility, and other side effects. Given the renal excretion of CTX metabolites, dose adjustments and careful hematologic monitoring are needed in patients with renal insufficiency.

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