Page 1782 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 126: Rheumatology in the ICU 1251

corticosteroids on alternate days is associated with some decrease in cells recycle purine precursors through salvage pathways and are not
chronic drug morbidity but has limited clinical utility and is not used dependent on de novo purine synthesis, in contrast to proliferating T
frequently. In the urgent setting of the critically ill patient, the greater and B lymphocytes, which are completely dependent on the de novo
effectiveness of daily or split daily doses of steroids recommends such pathway. This difference confers selectivity on MMF and makes it an
a dosing schedule. attractive choice for preventing allograft rejection. MMF is rapidly sup-
■ CYCLOPHOSPHAMIDE planting azathioprine in multiagent immunosuppressive protocols used
in heart, lung, and renal transplantation. The conventional daily dose of
Cyclophosphamide (CTX) is an alkylating agent with broad immunosup- MMF is usually 2 to 3 g and greater therapeutic effects are not usually
pressive properties. It is generally embraced as the drug of choice for sup- found with higher doses. Mild reversible leukopenia and mild gastro-
pression of progressive, life-threatening autoimmune disease unresponsive intestinal side effects have occurred with MMF, and dose adjustments
to corticosteroids alone. Effectiveness has been reported in a broad spec- should be made when a patient has a glomerular filtration rate less than
trum of systemic autoimmune diseases and primary vasculitides, includ- 25% of predicted value. There is a low incidence of opportunistic infec-
ing SLE, GPA and polyarteritis nodosa. CTX causes broad suppression of tion that can be directly attributed to MMF when used at less than 3 g
B- and T-cell function and acts as a potent inhibitor of antibody produc- daily. In most clinical scenarios, plasma levels of its active metabolite,
tion. Anti-inflammatory effects have also been described. The drug is rap- mycophenolic acid, do not need to be monitored to achieve therapeutic
idly absorbed orally. It is inert until metabolized in the liver. Extravasation effects. Based on its selectivity, ease of administration, and low side-
of the drug (when used intravenously) is not caustic to soft tissues. Sixty effect profile, there is increasing interest in using MMF for the treatment
percent of the drug is excreted in the urine in the form of active metabo- of patients with autoimmune diseases.
lites. Impaired excretion of these active metabolites because of renal insuf- ■ METHOTREXATE
ficiency can potentiate the therapeutic and toxic effects of a given dose of
drug. The drug can be given orally, usually at a dose of 2 mg/kg per day, Although methotrexate was introduced for the treatment of rheumatoid
or intravenously. To circumvent toxic effects associated with chronic drug arthritis more than 30 years ago, methotrexate remains the remitting
exposure, intravenous bolus CTX therapy is commonly used in critically agent of first choice in rheumatoid arthritis for many rheumatologists.
ill patients at doses of 0.5 to 1.0 g/m . The onset of immunosuppressive The drug is accepted as effective for the peripheral joint inflammation
2
activity of CTX is estimated at 10 to 14 days following initiation of therapy. in psoriatic arthritis and reactive arthritis. Experience is being gained
Although unproved in rigorous clinical trials, there is an operational with its use in SLE and scleroderma. Use of methotrexate in the criti-
principle that immunosuppression can be achieved more rapidly with cally ill rheumatic disease patient is currently limited to patients with
intravenous bolus therapy. Hence bolus CTX is most often given in the polymyositis/dermatomyositis that is refractory to corticosteroids.
setting of progressive life-threatening disease requiring immunosuppres- Methotrexate is a folic acid analogue and the major folic acid antago-
sion. A major short-term side effect of bolus therapy is a predictable white nist in clinical use. The drug is absorbed after oral ingestion but with
blood cell count nadir 7 to 10 days after drug infusion. Leukocyte count significant variability. More predictable serum levels can be achieved by
levels typically recover in 2 to 3 days. However, if the patient has a concur- subcutaneous, intramuscular, or intravenous administration. High-dose
rent bacterial infection during the nadir period, the consequences of even methotrexate can alter antibody production and cellular immunity.
transient profound neutropenia can be disastrous. Gross hematuria may Low-dose oral methotrexate (25 mg/wk or less), as used in rheumatoid
signal the development of hemorrhagic cystitis or bladder malignancy. arthritis, may be mainly anti-inflammatory or directly inhibiting to
Bladder problems are related to duration of therapy and total cumulative synovial lining cells. Low-dose methotrexate is given in rheumatoid
dose administered. Many of the other side effects of therapy with CTX arthritis in initial doses of 10 to 15 mg and may be gradually increased
are related to chronic use, including gonadal suppression, oncogenesis, to levels of 25 mg/wk. Methotrexate for rheumatic disorders is delivered
pulmonary interstitial fibrosis, and hypogammaglobulinemia. on a weekly basis. This regimen is associated with less toxicity than
■ AZATHIOPRINE Most patients will respond at doses between 15 and 20 mg weekly.
when the drug is given more frequently, particularly hepatotoxicity.
Azathioprine is a commonly used immunomodulating drug with mild Adverse reactions forcing discontinuation of the drug in short-term
trials with rheumatoid arthritis occur in 5% to 31% of patients. Most
to moderate immunosuppressive properties that may in large part be toxicity is relatively minor and associated with advanced age, malnu-
explained by a preferential reduction of natural killer cells. Onset of trition, and impaired renal function. Nausea, vomiting, oral ulcers,
action is slow, probably taking months. It is often used concurrently with rash, leukopenia, thrombocytopenia, and pancytopenia all may occur.
corticosteroids in patients requiring unacceptably high doses of steroids, Cirrhosis may occur in some patients treated for long periods and
to reduce the steroid dose. Azathioprine is not the drug of choice when appears to be related to cumulative dose and probably the nature of
significant immunosuppressive effect is needed on an urgent basis. Risk the underlying disease being treated. The risk is asserted to be greater
for infection is modest in the absence of leukopenia. Azathioprine is in psoriatic arthritis than rheumatoid arthritis. Ethanol potentiates the
metabolized in the liver to the active metabolite, 6-mercaptopurine, a hepatotoxicity of methotrexate. Pretreatment screening for hepatitis
purine analogue. The drug interferes with purine biosynthesis and is B and C is usually done. Baseline liver biopsy is not indicated in the
ultimately metabolized by xanthine oxidase. Allopurinol (which inhibits absence of risk factors for existing liver disease. The concurrent use
xanthine oxidase) should be avoided in a patient on azathioprine as this of other antifolates (eg, sulfonamides) increases toxicity. Pancytopenia
may result in very high serum azathioprine levels and a fatal outcome. has been reported in some patients receiving methotrexate and trime-
Dose range for this drug is approximately 2 mg/kg per day. The drug is thoprim-sulfamethoxazole together. Patients with ascites and large effu-
primarily metabolized in the liver, but the need for dose adjustment in the sions are at greater risk for methotrexate toxicity. Folic acid, 1 mg daily,
presence of liver disease is variable and may be unnecessary. Drug half- has been recommended as a means of preventing adverse reactions and
life can increase in renal failure but may not prove clinically significant. particularly hematologic side effects in patients treated for rheumatoid
Cautious observation for the development of cytopenia is indicated in the arthritis. The use of folic acid does not appear to significantly reduce
73
presence of hepatic or renal failure. The drug is well absorbed orally and effectiveness of the drug. In serious episodes of pancytopenia, leu-
may be given intravenously in doses equivalent to the oral form. covorin may be used. Opportunistic infections with herpes zoster and
■ MYCOPHENOLATE MOFETIL Pneumocystis (carinii) jiroveci have been reported even with low-dose
methotrexate, although they are uncommon. Finally, an acute hyper-
Mycophenolate mofetil (MMF) interferes with de novo purine synthesis sensitivity pneumonitis as discussed earlier occurs infrequently but may
by inhibiting inosine monophosphate dehydrogenase. Nonlymphocytic result in profound hypoxemia.

section11.indd 1251 1/19/2015 10:52:17 AM