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International Journal of Dermatology 1999, 38, 310–314 © 1999 Blackwell Science Ltd

Pharmacology and therapeutics

Long-term administration of cyclosporin A to HCV-antibody-positive patients with dermatologic diseases

Hiroyuki Miura, MD, Yuka Itoh, MD, Yoshiko Matsumoto, MD, Mamori Tani, MD,Noboru Tanabe, MD, Masaaki Isonokami, MD, Kishirou Kurachi, MD, andTakahito Kozuka, MD

From the Department of Dermatology Abstractand Allergology, Osaka National Background Cyclosporine A (CYA) is an immunosuppressive agent which is being usedHospital, and Department of in the treatment of an increasingly wide range of dermatologic diseases, but its use hasDermatology, Osaka University,

been avoided in carriers of hepatitis C virus (HCV).School of Medicine, Osaka, JapanMethods We administered small doses of CYA (maximum, 3 mg/kg/day) for a long time

Correspondence to treat dermatologic diseases in one HCV-antibody-positive patient with no HCV-RNA inHiroyuki Miura, MD the blood, one patient with a small amount of HCV-RNA in the blood, and two patientsDepartment of Dermatology with large amounts of HCV-RNA in the blood.Osaka University

Results Skin lesions improved in all patients, but recurred upon complete or partialSchool of Medicinewithdrawal of CYA. In the absence of HCV-RNA in the blood, or when only a small2–2 Yamadaoka, Suita-shi

Osaka 565–0871 quantity of HCV-RNA was present in the blood, HCV-RNA load showed no apparentJapan change. In one patient with a large blood HCV-RNA load, CYA dosage reduction was

followed by increases in alanine aminotransferase (ALT) levels and decreases in bloodDrug name

HCV-RNA. Aggravation of hepatitis due to immunologic reactivation was suspected in thiscyclosporine: Sandimmunepatient.

Conclusions The reduction of CYA dosage is a key element in the use of this agent for

cutaneous diseases.

Introduction

Cyclosporine A (CYA) is a well-known immunosuppressive

agent and has been used to treat a wide range of dermato-

logic diseases in recent years.1 Hepatitis C virus (HCV),

an RNA virus, accounts for 60% of chronic hepatitis

viruses in Japan, and about 1–2% of the total population

are believed to be carriers of it.2,3 It is therefore not rare

to encounter HCV carriers in daily medical practice in

Japan. Although the exact mechanism by which hepatitis

C occurs is not yet well understood, the use of immuno-

suppressive agents, including CYA, is inevitable in organ

transplantation patients even if they carry HCV. Because

precipitate aggravation of hepatitis is occasionally

reported following administration of CYA,4–7 however,

dermatologists have refrained from using CYA in HCV-

antibody-positive patients. In the present study, we adminis-

tered small doses of CYA for long periods to treat severe

dermatologic diseases in four HCV-antibody-positive

patients: the first patient had nummular dermatitis and

autosensitization dermatitis, the second psoriasis vulgaris,

the third psoriasis pustulosa, and the fourth prurigo nodu-

laris. CYA therapy was initiated at dose of 3 mg/kg or

lower, and hepatic function was monitored based on alanine

aminotransferase (ALT) levels (normal, 13–33 IU/L). Blood

HCV-RNA load was monitored quantitatively by the

branched DNA probe method and qualitatively by the

polymerase chain reaction method.8,9

Case reports

Case 1A 61-year-old man had nothing significant in particular in

his medical history except mild diabetes. He had not

undergone blood transfusions. Tests for anti-HCV antibody

were positive. Because blood HCV-RNA was negative,

however, it was thought that the HCV infection had not

become chronic. He had had nummular dermatitis, mainly

in the extremities, for about 5 years before first visiting

our hospital. He was treated with topical steroids and oral

antihistamines by his family doctor. Drug therapy caused

temporary remission, but then the dermatitis had returned.

He visited us because the dermatitis had been spreading

Miura et al. Cyclosporin A and HCV Pharmacology and therapeutics 311

Figure 1 Clinical course of four

HCV-antibody-positive patients with

dermatologic disease: A, nummular

dermatitis and autosensitization; B,

psoriasis vulgaris; C, psoriasis

pustulosa; D, prurigo nodularis;

CYA 5 cyclosporine A; ALT 5

alanine aminotransferase.

over his entire body, starting several months earlier.

Erythema and papulae were observed all over the body, and

the diagnosis of nummular dermatitis and autosensitization

dermatitis was made. CYA therapy was initiated because

all previous therapies had been ineffective. To date, CYA

therapy has been continued for 26 months with a maximum

dose of 3 mg/kg (200 mg) (Fig. 1A). Skin eruptions

subsided during CYA therapy, but became aggravated upon

discontinuation, so maintenance therapy at 100 mg is being

continued. The oral dose of CYA was drastically decreased

by mistake by the patient 5 and 13 months after starting

treatment. ALT levels increased slightly in the latter period,

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 310–314

but no blood HCV-RNA was detected and no other sign

of hepatitis was observed.

Case 2An 81-year-old woman had had osteoarthritis of the hip

and had undergone blood transfusions during prosthesis

replacement. ALT levels remained between 50 and

100 IU/L before starting CYA therapy. Blood HCV-RNA

was qualitatively positive and the virus subtype was 2A,

but quantitatively it was below the limit of determination

(0.05 meq/L). Chronic hepatitis with a small amount of

HCV was suspected. CYA was administered for 24 months

312 Pharmacology and therapeutics Cyclosporin A and HCV Miura et al.

to deal with psoriasis vulgaris in this patient (Fig. 1B). ALT

levels increased 7 months after starting treatment. Whether

or not this increase was transient is unknown because ALT

levels were not determined immediately before or after the

increase. Thereafter, ALT levels did not increase over

100 IU/L. Quantitatively, the HCV-RNA level was under

0.05 mEq/L throughout the observation period. No sign

was observed which suggested aggravation of hepatitis.

Skin eruptions have been well controlled since starting

CYA therapy. At present, the patient is being observed with

CYA doses of about 50 mg.

Case 3A 49-year-old man had undergone blood transfusions to

deal with intraperitoneal bleeding due to a traffic accident.

He had chronic hepatitis and blood HCV-RNA was detected

before starting CYA therapy. The virus subtype was 1B.

CYA was administered up to 3 mg/kg (200 mg) for 34

months to deal with psoriasis pustulosa in this patient (Fig.

1C). Pustulae disappeared gradually. Psoriasis lesions did

not disappear completely but improved. During the first

14 months, the initial dose was maintained, and ALT and

RNA loads remained unchanged. The HCV-RNA load

showed changes upon reduction in the dose of CYA, but

the CYA dose and RNA load were not correlated. ALT

levels increased slightly with the reduction in the CYA dose

22 months after the start of therapy, but returned to

baseline with increases in the CYA dose.

Case 4A 55-year-old woman had undergone blood transfusions

to deal with massive bleeding during delivery due to

hysteromyoma. As in Case 3, the virus subtype in this

patient was 1B, and a large amount of HCV-RNA was

detected in the blood. CYA (3 mg/kg or 150 mg) has been

administered for 33 months to deal with prurigo nodularis

in this patient (Fig. 1D). The blood HCV-RNA level before

starting CYA therapy was determined by a different method,

not shown in the figure, and was equal to 3.2 mEq/mL.

HCV-RNA levels changed between 4 and 22 mEq/mL

during the first 17 months after CYA therapy was initiated;

this increase might have been caused by the CYA therapy.

During this period, however, ALT levels did not increase

over 50 IU/L and no other sign of hepatitis was observed.

The HCV-RNA load decreased and the ALT levels increased

as the CYA dose was gradually reduced with the improve-

ment of skin lesions. The ALT levels decreased and the

HCV-RNA load increased when CYA therapy was resumed

following recurrence of skin eruptions.

Discussion

CYA, a member of the family of cyclic peptides acquired

from fungi, is an immunosuppressive agent very useful for

International Journal of Dermatology 1999, 38, 310–314 © 1999 Blackwell Science Ltd

preventing transplant rejection.10 It is also indicated for

dermatologic diseases, such as psoriasis, alopecia areata,

and ichthyosis, and is most generally used for severe

psoriasis.1 The dosage for psoriasis is relatively low (3–

5 mg/kg), and the drug is generally used alone for this

indication; it is usually coadministered with other immuno-

suppressive agents in organ transplant patients.

The exact mechanism of action by which CYA exerts

therapeutic effects for these diseases is unknown, but the

therapeutic benefits of CYA have generally been ascribed

to its effects on T-cell activation, because CYA has been

shown to inhibit the gene expression of a variety of

cytokines, such as interleukin-1 (IL-1), IL-2, IL-6, and

interferon-gamma, in T cells.11–13 The presence of many

cytokines, including IL-6, has been reported in psoriatic

skin,14–17 and so CYA may reduce their production.

The mechanisms of hepatitis C are also unknown in

many aspects, but two mechanisms must be considered in

discussing the findings obtained in our patients. First,

the hepatocytotoxic effects of HCV itself. Regarding this

mechanism, various experiments have been undertaken to

evaluate the relation between HCV-infected hepatocytes

and hepatic dysfunction using in situ hybridization and

immune staining techniques.18,19 The results of these experi-

ments have shown that hepatocellular HCV-RNA load is

correlated with blood HCV-RNA load, indicating that the

former can be indirectly estimated by determining the latter.

Because the determination of intrahepatic viral load is often

difficult in clinical settings, qualitative and quantitative

measurements of peripheral blood HCV-RNA load are

used as indices of hepatitis activity.8

Second, hepatocytes may be injured when the host’s

immune system tries to expel HCV-infected hepatocytes.

In fact, cytotoxic T cells have been reported to be increased

in hepatic tissues from hepatitis C patients, as well as in

hepatic tissues from hepatitis B patients, and these T cells

may be responsible for cytotoxicity.20–23

If these two mechanisms are responsible for the aggrava-

tion of hepatitis C, large doses of CYA should suppress the

immune mechanism involved in inhibiting viral activity in

HCV carriers, increase viruses, and aggravate hepatitis by

the first mechanism mentioned above. Moderate doses of

CYA, however, may decrease the activity of T cells, which

are believed to attack virus-infected hepatocytes, and

improve hepatic function. In expectation of this effect,

some investigators have been coadministering CYA with

interferon in patients with fulminant hepatitis C.24 Even if

no hepatic disorders occurs during treatment with moderate

doses of CYA, however, suppressed cytotoxic T cells may

be reactivated suddenly, and hepatic function may rapidly

deteriorate upon sudden withdrawal of CYA. Studies of

hepatitis C that aggravated after administration of immuno-

suppressive agents in organ transplant patients have shown

Miura et al. Cyclosporin A and HCV Pharmacology and therapeutics 313

that immunity was suppressed to a considerable extent in

these patients due to CYA and other immunosuppressive

agents, and that acute aggravation of hepatitis occurred

after rapid dosage reduction or withdrawal.4–7 These find-

ings are consistent with the above-mentioned mechanisms

for the aggravation of hepatitis C. Therefore, we established

the following rules: (i) CYA should be administered at

doses of 3 mg/kg or lower and should not be administered

with any other immunosuppressive drug; (ii) HCV load

should be monitored based on blood HCV-RNA load;

(iii) CYA dosage must be gradually reduced, paying close

attention to the aggravation of hepatitis.

These rules were useful in successfully treating dermato-

logic diseases with CYA in HCV-antibody-positive patients.

CYA was safely administered for more than 2 years in

Case 1, an HCV-positive patient in whom no HCV-RNA

was detected in the blood and in whom hepatitis did not

become chronic. In Case 2, ALT levels apparently increased,

but no symptom which suggested rapid aggravation of

hepatitis occurred, and a return to baseline was achieved.

HCV-RNA load was below the limit of determination

(0.05 mEq/L) throughout the observation period in this

patient. The increases in ALT levels were thought to be

due to hepatic dysfunction caused by the adverse effects of

CYA itself or other factors, rather than the activation of

hepatitis. The findings obtained in this case alone are

obviously not sufficient to draw any definite conclusion,

but suggest that CYA can be safely administered to patients

of this type as well, if the above-mentioned three rules are

followed. Cases 3 and 4 were chronic hepatitis patients with

large blood HCV-RNA loads. Hepatic function showed no

abnormal change as long as CYA doses were maintained

at certain levels. Because the reactivation of hepatitis was

expected when reducing the CYA dosage as mentioned

above, more than 1 month was spent reducing the CYA

dosage by 25 mg. Despite this precaution, elevation of ALT

levels and decreases in HCV-RNA load were noted during

dosage reduction and after discontinuation of the treatment,

suggesting that hepatitis showed a tendency to aggravate

due to reactivation of cytotoxic T cells following the second

of the above-mentioned mechanisms for the aggravation

of hepatitis. ALT levels decreased when CYA therapy was

resumed following aggravation of skin lesions. This finding

also supports the theory that cytotoxic T cells are related

to the aggravation of hepatitis. With changes in CYA doses

in Case 3, ALT levels showed less remarkable changes than

those observed in Case 4, and interpretation is difficult in

this case in which blood HCV-RNA showed no consist-

ent change.

Conclusion

We administered small doses of CYA to four patients with

different degrees of infection for an average of 29 months

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 310–314

and concluded that CYA could be safely administered to

patients with no or small blood HCV-RNA load, if all

necessary precautions were taken. No clear conclusion

could be drawn as to whether CYA was safe in the presence

of a large HCV-RNA load in the blood. In particular, the

means by which CYA is withdrawn in such cases must be

carefully studied in the future. Further studies of the long-

term effects of CYA (more than 5 years) and the long-term

outcome after discontinuation of CYA therapy are also

necessary.

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Tattoo art by Mike Malone, China

Sea Tattoo Company. From the

collection of Norman Goldstein, MD,

The World of Tattoos Museum,

Honolulu, Hawaii.

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