CHAPTER 62 IMMUNOSUPPRESSIVE DRUGS 993
Many drugs such as erythromycin, azole antifungal drugs,
and some calcium channel antagonists that inhibit CYP3A4
(inhibiting the metabolism of cyclosporine) also inhibit
Pgp. Drug interactions mediated by these dual mechanisms
may result in a twofold to fivefold increase in cyclosporine
concentrations. Azithromycin, in contrast to erythromycin
and clarithromycin, seems unlikely to alter cyclosporine
levels. The plasma concentrations and clinical toxicity of
several statin lipid-lowering agents are increased substan-
tially by cyclosporine, but the pharmacokinetics of fluvas-
tatin and pravastatin, because they are not metabolized
primarily by CYP3A4, are altered less by cyclosporine.98
Nevertheless, the pravastatin AUC curve, a measure of drug
exposure, was five times higher in patients also receiving
cyclosporine.99 Of the calcium channel antagonists, dil-
tiazem, nicardipine, and verapamil increase cyclosporine
concentrations; nifedipine and amlodipine have variable
effects; and isradipine and nitrendipine do not generally
affect concentrations.100 It is controversial whether nonste-
roidal anti-inflammatory drugs (NSAIDs) increase cyclo-
sporine nephrotoxicity. In many clinical studies, cyclosporine
and NSAIDs have been safely co-administered79,101; how-
ever, increased cyclosporine-associated nephrotoxicity with
NSAIDs has been reported. Currently, many patients start-
ing cyclosporine also take an NSAID. If the creatinine
increases, in addition to decreasing the dose of cyclosporine,
discontinuation of the NSAID may be tried. Grapefruit
juice increases plasma concentrations of cyclosporine, so
patients should be warned to avoid consuming grapefruit.
TACROLIMUS (FK506)
Structure
Tacrolimus, previously known as FK506, is a macrolide
derived from an actinomycete and is widely used in organ
transplantation as an alternative to cyclosporine. Studies in
rheumatic autoimmune disease are less advanced.
Mechanisms of Action
Tacrolimus is about 100 times more potent than cyclospo-
rine and, although structurally different, is also a calcineurin
inhibitor. Tacrolimus binds to an intra-cellular binding
protein (FK binding protein), and this drug-immunophilin
complex, in association with calcineurin, suppresses tran-
scription of cytokines such as IL-2, inhibiting the early steps
of T lymphocyte activation (see Figure 62-3).74
Pharmacology
Absorption of tacrolimus after oral administration is
poor and highly variable (range, 4% to 93%; average,
25%).102 Tacrolimus is lipophilic, is widely distributed in
tissues, and is almost completely metabolized, with an elimi-
nation half-life of 5 to 16 hours.103 As with cyclosporine,
Pgp and CYP3A4 in the liver and gut are important deter-
minants of the metabolism and disposition of tacrolimus.
Drugs that inhibit CYP3A4 or Pgp can increase tacrolimus
concentrations (see Table 62-4).102 Impaired hepatic func-
tion, but not impaired renal function, increases tacrolimus
concentrations.103
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Dosage
Tacrolimus is not routinely used for rheumatologic condi-
tions. Different dosages have been used in clinical studies
(see the next paragraph).
Clinical Indications
Tacrolimus has been studied in a number of rheumatic con-
ditions with variable success. In RA, tacrolimus showed
only modest efficacy, and with the availability of a plethora
of effective conventional and biologic disease-modifying
anti-rheumatic drugs, the need for a novel immunosuppres-
sant such as tacrolimus has waned.104,105 Topical 1% tacro-
limus has been used with moderate success in patients with
resistant skin disease resulting from SLE, subacute cutane-
ous lupus erythematosus, and discoid lupus erythemato-
sus.106 A large open-label, randomized, controlled trial in
150 patients with biopsy-confirmed active lupus nephritis
showed that remission induction with tacrolimus (0.6 mg/
kg/day) was not inferior to MMF (2-3 g/day) when given
with prednisolone (0.6 mg/kg/day) for 6 weeks and followed
by azathioprine maintenance, with major infectious epi-
sodes occurring in 5.4% versus 9.2% of patients, respec-
tively.107 In a retrospective study in patients who had
interstitial lung disease associated with polymyositis or der-
matomyositis, patients treated with tacrolimus in addition
to conventional therapy had a significantly improved sur-
vival compared with patients who were treated with con-
ventional therapy alone.108
Toxicity
The adverse effects of tacrolimus are dose related and
include nephrotoxicity, hypertension, hyperkalemia, hyper-
uricemia, tremor, hyperglycemia, and gastrointestinal intol-
erance.102 Among patients with RA who took 3 mg of
tacrolimus daily for more than 1 year, 59% experienced an
adverse effect, probably or possibly due to the drug, includ-
ing diarrhea (15%); nausea (10%); tremor (9%); headache
(9%); abdominal pain (8%); increased creatinine (7%);
hypertension (5%); and pneumonia, pancreatitis, hypergly-
cemia, and diabetes mellitus (all <1%). A creatinine
increase of greater than 30% from baseline to the end of the
study was found in 40%.109
MYCOPHENOLATE MOFETIL
Structure
MMF, a prodrug, is the inactive 2-morpholinoester of myco-
phenolic acid, which is hydrolyzed to the active mycophe-
nolic acid (MPA), an antibiotic with immunosuppressive
effects.110
Mechanism of Action
Two pathways exist for the synthesis of guanine nucleotides:
the de novo pathway and the salvage pathway. MPA revers-
ibly inhibits inosine monophosphate dehydrogenase, a
crucial enzyme for the de novo synthesis of guanosine
purines.110,111 Lymphocytes, in contrast to many other cells,
994 PART 8 PHARMACOLOGY OF ANTI-RHEUMATIC DRUGS
are critically dependent on the de novo purine synthesis
pathway and are a relatively selective target for MPA,
accounting for the ability of the drug to inhibit reversibly
B cell and T cell proliferation without myelotoxicity.112
MPA results in decreased guanine synthesis and decreased
DNA synthesis, decreased lymphocyte proliferation, altered
microRNA expression, and decreased antibody produc-
tion.111-114 MPA also inhibits proliferation of fibroblasts,
endothelial cells, and arterial smooth muscle cells and pre-
vents deposition and contraction of collagen, extra-cellular
matrix proteins, and smooth muscle actin.115
Pharmacology
MMF is rapidly and completely absorbed and de-esterified
to the active MPA, which is highly (98%) protein bound.
Most MPA (>99%) is found in plasma, with little in cells;
most is glucuronidated to the poorly active, stable phenolic
glucuronide, which is eliminated in the urine (Figure
62-4).116 Minor metabolites, some of which may be active,
have also been described. Peak levels of MPA occur 1 to 2
hours after administration, and secondary peaks, thought to
be due to enterohepatic circulation, can be seen. The half-
life of MPA is 16 hours.116 MPA concentrations may vary
fivefold to tenfold in persons receiving the same dose.117 A
small amount of this variability may be due to genetic varia-
tion in uridine-glucuronosyltransferase enzymes.118 Renal
disease and liver disease have relatively minor effects on the
disposition of the active drug, MPA. Generally, dosage
adjustments are not required,116 but because free MPA con-
centrations are approximately doubled in patients with
severe renal impairment (creatinine clearance <20 to
30 mL/min),119 they may be necessary sometimes. A retro-
spective study in 16 patients with lupus nephritis showed
that concentration-controlled dose adjustments with a
target MPA-AUC (from intake until 12 hours after inges-
tion) of 60 to 90 mg*h/L was associated with optimized
MPA exposure and excellent renal outcome at 12 months,
although adverse effects were reported in one third of
patients, resulting in a switch to azathioprine in two
Mycophenolate mofetil
MPA (active)
Enterohepatic UGT1A9 UGT2B7
circulation
MPAG (inactive) AcMPAG (active)
Renal excretion
Figure 62-4 Mycophenolate mofetil is converted to mycophenolic
acid (MPA) and is subsequently metabolized to its glucuronide (Glu)
conjugates, MPAG and AcMPAG, by different isoforms of UDP glucuroni-
dyl transferases (UGT) in the liver. Pathways of enterohepatic circulation
of MPA via the glucuronide conjugate metabolites are shown. The major-
ity of MPAG is excreted in urine.
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patients.120 Another observational study also pointed to the
potential benefits of therapeutic monitoring in 34 patients
with lupus nephritis when dosing was adjusted to achieve
an AUC of 30 to 60 mg*h/L.121 In this study MPA exposure
was not associated with adverse events, and patients
with an AUC of 30 mg*h/L or greater had a greater renal
response at 1 year. The major glucuronide metabolite of
MPA accumulates in patients with impaired renal function
and may cause increased gastrointestinal adverse effects.
Because MPA is highly protein bound, it is not cleared by
hemodialysis.122
Toxicity
MMF is generally well tolerated. The most common adverse
effects are gastrointestinal, such as diarrhea, nausea, abdom-
inal pain, and vomiting. Occasional infections, leukopenia,
lymphocytopenia, and elevated liver enzymes can occur. Of
54 patients with SLE treated with MMF over a 3-year
period, 16% withdrew because of adverse events, with
73% continuing treatment at 12 months.123 In patients with
lupus nephritis, diarrhea was more common and serious
infections were less common with MMF than with cyclo-
phosphamide.41 Enteric-coated mycophenolate sodium and
MMF have similar rates of adverse effects.124 Opportunistic
infections, including one that was fatal, occurred in 3 of 10
patients with idiopathic dermatomyositis who were treated
with glucocorticoids and MMF.125
Dosage
Effective daily dosages of MMF range from 0.5 to 1.5 g
twice a day. In 71 patients with lupus nephritis, the initial
dose was 1 g/day with a target of 3 g/day. The mean maxi-
mal dose was 2680 mg/day, and 63% of patients tolerated
3 g/day.39
Clinical Indications
MMF is used as a safer alternative to cytostatic agents in
the treatment of several rheumatic diseases, notably SLE,126
systemic sclerosis,127 vasculitis,128 and inflammatory muscle
disease.125,129 In a 24-week study in persons with lupus
nephritis, mycophenolate was more effective than monthly
pulse cyclophosphamide, with a failure rate (without com-
plete or partial remission at 24 weeks, plus those who
stopped treatment for any reason) of 34 of 71 (47.9%)
compared with 48 of 69 in the cyclophosphamide group
(69.6%; P = 0.01).39 In a systematic review of four trials
involving 618 patients, MMF was not superior to cyclophos-
phamide for renal remission, and there was no significant
difference for adverse events (infections, leukopenia, gastro-
intestinal symptoms, herpes zoster, end-stage renal disease,
and death) except for a lower incidence of alopecia and
amenorrhea with the use of MMF compared with cyclo-
phosphamide.130 Notwithstanding its appeal as a safer alter-
native to cyclophosphamide for remission induction therapy
of lupus nephritis, MMF is most commonly used for main-
tenance therapy of lupus nephritis, although systematic
reviews comparing its efficacy and safety with azathioprine
have not yielded consistent results.131,132 A study on repeat
kidney biopsies in 30 patients with lupus nephritis failed

to detect differences between azathioprine and MMF as
maintenance therapy after a short course of IV cyclophos-
phamide.133 MMF is an alternative remission induction
agent for patients with anti-neutrophil cytoplasmic
antibody–associated vasculitis and evidence of low disease
activity and who are not at risk of experiencing organ
damage.134 MMF was slightly less effective than azathioprine
in maintaining remission, however.134a In seven patients
with myositis, six had a good clinical and biochemical
response to mycophenolate,129 an observation that was con-
firmed in another study in six patients who had refractory
myositis.135 In addition, in three studies in patients who had
interstitial lung disease associated with dermatomyositis (n
= 4) or other connective tissue diseases, including RA (n =
10) and systemic sclerosis (n = 13), MMF was effective in
improving signs and symptoms of lung disease.136-138 MMF
may be useful as an alternative immunosuppressant to aza-
thioprine, particularly in patients with gout who require
therapy with allopurinol because, in contrast to azathio-
prine, it does not seem to interact significantly with allopu-
rinol.72,112 Mycophenolate, 1 g twice daily, was not more
effective than placebo in two clinical trials involving 443
patients with refractory RA139 as assessed with ACR20
responses, and a larger mycophenolate-cyclosporine trial
was stopped prematurely. Treatment-related adverse events
were experienced by 51.6%, 73.1%, and 36.1% of patients
receiving MMF, cyclosporine, and placebo, respectively.
Hypertension, increased serum creatinine, muscle cramps,
hirsutism, and hypertrichosis were more than twice as
common with cyclosporine as with MMF. In all three trials
the incidence of serious adverse events with MMF was
12.1% (compared with 11.3% and 7.5% for cyclosporine
and placebo, respectively). Although mycophenolate is
used in psoriasis as an effective alternative to methotrexate,
there are only anecdotal reports of its utility in persons with
psoriatic arthritis.
Pregnancy and Lactation
MMF is an FDA Pregnancy Category C drug. Mycophenolic
acid is associated with miscarriage and congenital malfor-
mations when used during pregnancy, and therefore it
should be avoided whenever possible by women trying to
conceive. Switching from MMF to azathioprine in 19
patients with SLE did not result in deterioration of global
disease activity, and another study in 54 patients with SLE
who had quiescent lupus nephritis showed that replacing
MMF with azathioprine rarely leads to renal flares, while
pregnancy outcomes were favorable.140,141 MMF is trans-
ferred into the mother’s milk, and extreme caution should
be used in women with childbearing potential and lactating
mothers.
Drug Interactions
Because MPA is glucuronidated and is not metabolized by
CYP oxidation, there are few clinically significant drug
interactions. Antacids reduce bioavailability by approxi-
mately 15%, and cholestyramine reduces bioavailability by
approximately 40%.142 Rifampin treatment reduced MPA
concentrations twofold to threefold.143 Co-administration
with azathioprine is not recommended.
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CHAPTER 62 IMMUNOSUPPRESSIVE DRUGS 995
CONCLUSION
Immunosuppressive drugs are key therapeutic tools in the
management of many rheumatic diseases. They include
alkylating agents such as cyclophosphamide and purine ana-
logue cytotoxic drugs such as azathioprine with a long
history of clinical use in rheumatology, as well as noncyto-
toxic immunosuppressants such as MMF. In contrast to
extra-cellular, exquisitely targeted therapeutics represented
by biologics, our understanding of the in vivo mechanism
of action of immunosuppressive drugs is still limited. In
contrast, their potential efficacy and safety profiles are gen-
erally well known, and serious toxicities can usually be
prevented by careful monitoring of laboratory tests for white
blood cell counts, liver and renal function, and electrolytes.
Nevertheless, vigilance is required, because the risk of
(opportunistic) infection is increased.144,145 As a general
rule, combination therapy of the different immunosuppres-
sants discussed earlier should be avoided. The individual
response to immunosuppressive therapy can be highly vari-
able, and decisions to continue a chosen immunosuppres-
sant should be revisited on a regular basis, weighing the
benefits and adverse effects.
Full references for this chapter can be found on
ExpertConsult.com.
SELECTED REFERENCES
1. de Jonge ME, Huitema AD, Rodenhuis S, et al: Clinical pharmaco-
kinetics of cyclophosphamide. Clin Pharmacokinet 44:1135–1164,
2005.
2. Fauci AS, Wolff SM, Johnson JS: Effect of cyclophosphamide upon
the immune response in Wegener’s granulomatosis. N Engl J Med
285:1493–1496, 1971.
3. Struck RF, Alberts DS, Horne K, et al: Plasma pharmacokinetics of
cyclophosphamide and its cytotoxic metabolites after intravenous
versus oral administration in a randomized, crossover trial. Cancer
Res 47:2723–2726, 1987.
4. Takada K, Arefayene M, Desta Z, et al: Cytochrome P450 pharma-
cogenetics as a predictor of toxicity and clinical response to pulse
cyclophosphamide in lupus nephritis. Arthritis Rheum 50:2202–2210,
2004.
5. Haubitz M, Bohnenstengel F, Brunkhorst R, et al: Cyclophosphamide
pharmacokinetics and dose requirements in patients with renal insuf-
ficiency. Kidney Int 61:1495–1501, 2002.
6. Moroni G, Raffiotta F, Trezzi B, et al: Rituximab vs mycophenolate
and vs cyclophosphamide pulses for induction therapy of active lupus
nephritis: a clinical observational study. Rheumatology (Oxford) 53:
1570–1577, 2014.
7. Illei GG, Austin HA, Crane M, et al: Combination therapy with
pulse cyclophosphamide plus pulse methylprednisolone improves
long-term renal outcome without adding toxicity in patients with
lupus nephritis. Ann Intern Med 135:248–257, 2001.
8. Houssiau FA, Vasconcelos C, D’Cruz D, et al: The 10-year follow-up
data of the Euro-Lupus Nephritis Trial comparing low-dose and
high-dose intravenous cyclophosphamide. Ann Rheum Dis 69:61–64,
2010.
9. Trevisani VF, Castro AA, Neves Neto JF, et al: Cyclophosphamide
versus methylprednisolone for treating neuropsychiatric involvement
in systemic lupus erythematosus. Cochrane Database Syst Rev 2:
CD002265, 2006.
10. Tashkin DP, Elashoff R, Clements PJ, et al: Cyclophosphamide versus
placebo in scleroderma lung disease. N Engl J Med 354:2655–2666,
2006.
11. Hoyles RK, Ellis RW, Wellsbury J, et al: A multicenter, prospective,
randomized, double-blind, placebo-controlled trial of corticosteroids
and intravenous cyclophosphamide followed by oral azathioprine for