EDITORIAL - Mycophenolate Mofetil: A Magic Bullet for Lupus?

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Journal of Rheumatology

June 2005

Editorial

Mycophenolate Mofetil: A Magic Bullet for Lupus?

W. JOSEPH McCUNE, MD,

University of Michigan Medical Center;

MONA M. RISKALLA, MD, MS,

Lecturer in Pediatric Rheumatology,

University of Michigan, Ann Arbor, Michigan, USA.

Address reprint requests to Dr. W.J. McCune, 3918 Taubman Center, 1500 E.

Medical Center Drive, Ann Arbor, MI 48109-0358. E-mail: jmccune@...

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Mycophenolic acid, the parent drug from which mycophenolate mofetil (MMF)

was synthesized, was isolated from Penicillium species in 18961 at about the

same time that quinine was first used for the treatment of cutaneous lupus.

Like quinine, widespread application of mycophenolic acid (MPA) to lupus

awaited synthesis of a more effective and better tolerated derivative, but

the timetable was slower. During the decades between 1920 and 1960, the

quinine derivatives quinacrine, chloroquine, and hydroxychloroquine were

synthesized and gained wide acceptance for treatment of lupus, particularly

cutaneous lupus. Much later, in the 1960s, MPA was found to have antifungal

and anticancer properties.

Mycophenolic acid was first extensively studied for treatment of psoriasis

in the 1970s, employing heroic doses of 4- 9 grams per day2. Although MPA

was shown to be an effective treatment for psoriasis, its erratic

absorption, short half-life in the blood, and extremely high incidence of

gastrointestinal toxicity precluded widespread use. In retrospect,

unrecognized enzymes in the skin that resynthesize the active compound, MPA,

from the circulating inactive metabolite mycophenolic acid glucuronide

(MPAG) may have contributed to the effectiveness of MPA in psoriasis.

Introduction of MMF, which is more consistently absorbed than MPA and is

hydrolyzed to MPA in vivo, enabled maintenance of therapeutic serum levels

of MPA utilizing lower and better tolerated daily doses - usually 2 to 3

grams of MMF. The improved efficacy and markedly reduced toxicity of MMF led

to its widespread use as an immunosuppressive. Nonetheless, individual

differences in the rates of hepatic metabolism of MPA to MPAG and the renal

excretion, deglucuronidation, and reactivation of MPAG in tissues, including

the intestine and skin, led to substantial variation of MPA concentrations

in individual patients taking MMF. Unfortunately, determining

pharmacokinetics or comparing effective drug levels in individual patients

or clinical trials at this time remains cumbersome and expensive3.

MMF initially " earned its spurs " by establishing itself as an effective

antirejection drug in renal transplantation and was subsequently found to be

effective in heart, lung, and other solid organ transplants. Two large

trials comparing MMF versus azathioprine (AZA) and a third comparing MMF

versus placebo in allogeneic renal transplant established its efficacy by

showing a statistically significant reduction of the incidence of rejection

and corticosteroid use4-6. One successful protocol for allogeneic renal

transplant utilizing MMF included no prednisone7. MMF may be particularly

well suited for renal transplant because decreased creatinine clearance

resulting from rejection results in reduced excretion of MPAG, resulting in

increased deglucuronidation of MPAG and increased MPA levels, thereby

" self-treating " the rejection episode! Renal transplant trials suggested

that there was no difference in rates of rejection between regimens

utilizing MMF at 2 versus 3 g per day, but that the rate of toxicity,

particularly gastrointestinal toxicity, was increased in the 3 g per day

groups. These results lent support to doses of about 2 g per day for

transplantation and other indications, and were the basis for initial

selection of 2 g per day as the target dose for lupus patients in our

institution. Since then, controversy over higher dose requirements in

individuals of African descent possibly due to a more rapid metabolism of

MMF has arisen8-10.

In addition to successfully preventing rejection and reducing corticosteroid

use in transplantation, MMF's known and emerging benefits may increase

efficacy and decrease toxicity in the treatment of systemic lupus

erythematosus (SLE) compared with currently used medications. The

observation of decreased antibody levels in response to immunization in MMF

versus AZA treated transplant patients suggests that autoantibody synthesis

might be similarly suppressed more by MMF than AZA11. Although inhibition of

antibody production may be MMF's obvious benefit in SLE, other immunologic

mechanisms such as decreased recruitment of mononuclear cells to areas of

inflammation -- likely via decreased expression of adhesion molecules12 -

may confer benefit as well. Studies in mouse models of lupus nephritis (LN)

suggest a decrease in nitric oxide production may underlie the effectiveness

of MMF in LN, perhaps independent of its immunosuppressive properties13.

Given the impact of cardiovascular disease on longterm survival of patients

with lupus, it is intriguing and timely that MMF's success in reducing

transplant rejection may be based on a mechanism of reduced endothelial

injury and vascular damage, again, independent of its immunosuppressive

properties. In the rat aortic allograft model, MMF appeared to inhibit

vascular smooth muscle cell proliferation by inhibition of endothelin-114.

In human cardiac allograft patients, Weis and colleagues showed decreased

markers of endothelial damage early in the transplant period in

MMF-containing posttransplant immunosuppression regimens compared with

AZA15. As noted by Pisoni, et al16 in this issue of The Journal, since MMF

preferentially targets activated lymphocytes, MMF may be less toxic to other

bone marrow cell lines than immunosuppressive agents such as AZA. In

comparison with cyclophosphamide (CYC), MMF lacks gonadal toxicity and

appears to be associated with fewer secondary malignancies. Based on

anecdotal experience, MMF appears less toxic than CYC during pregnancy. The

overall rate of adverse events in this study as well as that from our

group17 appears to be 30- 40%, but most problems were minor.

Published clinical trials have focused on the use of MMF in LN. Open trials

have almost uniformly shown control of the inflammatory response and

induction of remission over the short term when administered to patients who

have continued active disease after taking CYC or those who have not

tolerated CYC. Use of MMF as a first-line agent for active LN has been the

subject of several controlled trials, some of which illustrate the

complexity of applying such data to clinical practice. The study by Chan, et

al randomized patients with moderately active lupus to a complex regimen of

daily oral CYC followed by AZA, or to initial MMF followed by AZA. The short

term results18, which suggested no difference in the MMF group compared with

daily CYC, do not actually permit comparison of MMF with monthly bolus CYC.

In particular, comparisons of toxicity cannot be extrapolated to monthly

bolus CYC because of higher cumulative doses in patients treated with daily

versus monthly bolus CYC. It is encouraging that their more recent report

after a mean of 63 months continued to show no difference between the

groups19.

The recent study by Ginzler, et al20, which randomized patients at the time

they presented with severe active LN to either MMF or monthly bolus CYC,

used a higher dose of MMF, 3 g per day, than in some series, including the

current study by Pisoni, et al16. Their report of equivalent to superior

results with MMF versus monthly bolus CYC and of reduced toxicity in the MMF

group after 6 months' followup should be viewed in the context of the high

dose of MMF used. It is noteworthy that in this non-blinded trial, MMF at 3

g per day was well tolerated by most patients, in contrast to other series,

including our own17. It is tempting to speculate that the immediate prospect

of being switched to monthly bolus CYC if MMF was not tolerated led these

patients to consider frequently encountered issues such as gastrointestinal

complaints to be less significant. Finally, the study by Hu, et al21, which

reported efficacy of MMF versus monthly bolus CYC for LN in a randomized

open trial, is noteworthy because of the data from serial renal biopsies

that were obtained from a subset of patients. These data suggested a greater

fall in disease activity indexes in the MMF versus monthly bolus CYC group

and also a trend toward greater improvement of vascular lesions ( " renal

vasculitis or necrotizing vasculopathy " ) in the MMF group (Table 1).

Chronicity indexes worsened only slightly in both groups. The reported

improvement of histological signs of vascular injury is noteworthy in the

context of MMF's favorable influence on the outcome of endothelial injury in

transplantation as discussed above. These results make it plausible that MMF

may have at least equivalent efficacy compared with monthly bolus CYC in new

LN, and that favorable short term clinical improvement may not be, as some

fear, masking histological disease progression that will become clinically

significant in 5- 10 years. Finally, it is arguable that monthly bolus CYC

plus monthly bolus methylprednisolone, which has been reported to be more

effective than monthly bolus CYC alone22, may be considered the gold

standard.

Although more work is required to establish MMF as the standard of care for

initial treatment of LN, it is our opinion that, following monthly bolus CYC

to induce remission, MMF (and possibly AZA) as maintenance therapy for LN

will soon become the standard of care, at least for adults. This is

supported by the study of Contreras, et al23, in which maintenance therapy

with MMF was found to be superior to maintenance with quarterly bolus CYC in

terms of renal outcome and mortality and with overall lower toxicity. It

should be noted, however, that mortality in the quarterly bolus CYC group

was surprisingly high, perhaps reflecting the relatively small number of

patients in each group.

No study has convincingly established superiority of MMF versus AZA for

maintenance therapy of LN after monthly bolus CYC; AZA, like MMF, is much

less toxic than monthly bolus CYC. For example, the recent Euro Lupus

Nephritis Trial, which compared low dose to high dose intravenous CYC, used

AZA as maintenance therapy and reported good results in both short24 and

longterm followup25. AZA currently has the advantage of being less expensive

than MMF. It may reasonably be concluded that when monthly bolus CYC is

employed, sequential therapy will be here to stay, especially when avoidance

of gonadal toxicity is a consideration. In addition, combining sequential

therapy with ovarian protection from CYC-induced damage utilizing

gonadotropin-releasing hormone agonists has been proposed by our group and

others26.

The study by Pisoni, et al16 adds further support to the use of MMF in

patients with both renal and non-renal SLE. The study includes " real-life "

patients treated in a lupus center for a variety of disease manifestations

that had not remitted despite immunosuppressive agents, including, in some

cases, prior treatment with CYC. The favorable response of the majority of

these patients suggests MMF can be used in refractory cases with

satisfactory response and acceptable toxicity. In the absence of a control

group the rate of disease improvement that might have occurred due to

" regression toward the mean " or as a result of increased corticosteroid

dosage is unknown, but it is clear that patients improved and that in many

cases toxicity from CYC was avoided.

At this stage in our understanding of MMF for treatment of lupus we propose

the following:

1. MMF levels are unpredictable, particularly in individuals with renal

insufficiency; in the setting of significant renal failure, guidelines for

using bolus CYC are better tested. Methods to cost effectively follow MMF

levels in clinical trials need to be developed.

2. As with many lupus therapies, the benefits of MMF may be organ-specific.

For example, MMF could be highly effective in the kidney and skin, but not

particularly effective for synovitis. Individual patients may respond

differently to different immunosuppressive regimens - one immunosuppressive

will not fit all.

3. MMF 3 g per day as first-line therapy of LN has, thus far, been

equivalent to bolus monthly CYC (without monthly bolus methylprednisolone)

in relatively short term controlled trials. MMF is a candidate to become

first-line therapy for LN on the basis of additional studies and sufficient

longterm data for comparison.

4. Based on the above studies suggesting MMF is comparable to monthly bolus

CYC in initial therapy of LN, the finding that MMF is equivalent or superior

to quarterly bolus CYC for maintenance of remission of LN is highly

plausible. The role of MMF in sequential therapy of LN needs further study,

but in the absence of more data this is a reasonable strategy to use in many

clinical situations.

5. MMF has not been shown to be superior as a maintenance drug to AZA after

monthly bolus CYC for LN. The expense of MMF compared to AZA makes this an

important consideration.

In conclusion, intriguing questions remain:

1. When used without corticosteroids, will MMF prove more effective than

other immunosuppressives such as AZA, as suggested in renal transplantation?

Improved ability to taper prednisone to zero during maintenance

immunosuppression would be a substantial benefit.

2. What is the role of MMF for treatment of severe lupus flares during

pregnancy? There are insufficient data to justify use in pregnancy, but

there is no reason to believe MMF will prove more dangerous than other

immunosuppressives used in renal transplantation, such as AZA or

cyclosporine. The answer may come from the transplant experience.

3. Is MMF faster acting than AZA for lupus? Older trials comparing AZA with

CYC suggest inferiority of AZA when used de novo for active nephritis; this

might reflect slower onset of action during rapid disease progression.

4. Will MMF help protect lupus patients from vascular damage independently

of its direct effects on lupus activity? This would make MMF a " triple

threat " : immunosuppressive, corticosteroid and cyclophosphamide-sparing, and

cardioprotective.

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