Possible Role of Chloroquine to Induce a Complete Remission in the Treatment of Autoimmune Hepatitis: a Randomized Trial
Possible Role of Chloroquine to Induce a Complete Remission in the Treatment of Autoimmune Hepatitis: a Randomized Trial
The gold-standard treatment of Autoimmune hepatitis (AIH), with prednisone alone or in
 conjunction with azathioprine can reach resolution of the disease in 70-80% of the cases in
 US. However, in Brazil the response to these treatments seems to be worse, approximately 35%
 in five years. Because of the side effects of the gold-standard treatment and the need for an
 alternative option for the no responsive patients, news drugs must be evaluated for this
 proposal. Chloroquine diphosphate is an antimalarial drug that has been used for the
 treatment of rheumatological diseases for at the least five decades. Chloroquine was used as
 a single drug for up to two years for the maintenance of AIH remission in an open study.
 There was a 6.49 greater chance of relapse in the historical controls when compared with
 patients treated with chloroquine (72.2% x 23.5%; p = 0.031). The aim of this study was to
 investigate whether chloroquine in conjunction with prednisone can be used as an alternative
 treatment of AIH in a randomized study, and to evaluate its side effects.
Autoimmune hepatitis (AIH) is a chronic disease with a progressive destruction of hepatic
 parenchyma, leading to cirrhosis and high mortality in the absence of specific treatment. It
 has been demonstrated that the treatment with corticosteroids and azathioprine provides
 clinical and laboratory improvement, reduction of histological inflammatory activity on liver
 biopsy and an increased survival.

 Because of the side effects of the gold-standard treatment and the need for an alternative
 option for the no responsive patients, news drugs must be evaluated for this proposal.

 Chloroquine is a drug of the group of 4-aminoquinolines, synthetic derivatives of quinine and
 constituent of the bark of the Cinchona tree. Chloroquine accumulates in tissues in
 considerable amounts. In animals, from 200 to 700 times the plasma concentration can be found
 in liver, spleen, kidneys and lungs. As a weak base, it accumulates intracellularly,
 particularly in lysosomes with a consequent increase in pH within these organelles, which
 could contribute to its toxicity. Lysosomal lamellar bodies are observed in tissues affected
 by chloroquine, such as retina and neuromuscular system. Chloroquine inhibits the absorption
 and the binding of mitochondrial calcium, alters the membrane permeability and the transport
 of enzymes to the lysosomes. Apparently there are other mechanisms to explain its
 anti-inflammatory action; such as the interference with the release of TNF from mononuclear
 phagocytes by inhibiting gene expression and the down-regulation of TNF receptors, by
 delaying their transport to the cellular surface. Due to these mechanisms of action,
 chloroquine has anti-inflammatory activities and therefore is used in diseases such as
 rheumatoid arthritis and systemic lupus erythematosus. In liver diseases, chloroquine was
 used in patients with hepatitis B with normalization of the levels of aminotransferases and
 of the prothrombin time during treatment and relapse after drug discontinuation. Chloroquine
 was also evaluated in patients with porphyria cutanea tarda and despite the clinical and
 biochemical improvement, liver biopsies remained unchanged after one year of treatment.

 A previous pilot study was performed in our institution, and published in 2005, with
 chloroquine diphosphate for the maintenance treatment of AIH. In this study, 14 patients with
 a biochemical and histological remission were treated with chloroquine diphosphate 250 mg/day
 for at least 12 months or until disease recurrence, and compared with 18 historical controls,
 which was held in discontinuation of treatment after remission. The chance of relapse was
 6.49 times higher in the historical controls when compared with patients in the group treated
 with chloroquine (72.2% versus 23.5%, p = 0.031). The use of chloroquine was safe in patients
 with liver cirrhosis without decompensation, and there were no serious adverse events within
 two years of use.

 The most common adverse effects of chloroquine are mild and transient such as
 gastrointestinal symptoms, headache, dizziness, blurry vision and fatigue. The more severe
 reactions described are itching, cardiovascular manifestations, dyskinesias, eye injuries,
 neuromuscular disorders and hearing loss. Among the most feared adverse effects of
 chloroquine, are the eye injuries, usually associated with chronic treatment. They may
 consist of changes in the retina, lens, cornea and optic nerve. Usually they remain stable
 after drug withdrawal, if the drug is discontinued in early stages. However, the retinal
 damage can increase when found in advanced stages, and may progress even years after
 cessation of chloroquine. It is believed that the chloroquine retinopathy can be prevented or
 recognized in an early reversible stage with judicious use, appropriate doses and regular
 ophthalmologic follow-up. It is recommended that the daily dose does not exceed 250 mg of
 chloroquine diphosphate or 400 mg of hydroxychloroquine, and ophthalmologic evaluations are
 carried out every 4 to 6 months. Despite the adverse effects and toxic reactions described
 above, there is a consensus in most studies with chloroquine that it is a well tolerated
 drug, provided that the appropriate dosage guidelines and regular eye examinations are
 followed. With these cautions in mind, its use rarely causes serious side or irreversible
 effects.

 The aim of this study was to investigate whether chloroquine in conjunction with prednisone
 can be used as an alternative treatment of AIH in a randomized study, and to evaluate its
 side effects.

 To be included patients had to satisfy the following criteria simultaneously: a diagnosis of
 probable / definite AIH and the indication of treatment (according to the International AIH
 Group), normal liver function and absence of clinical signs of decompensated liver disease
 (ascites, hepatic encephalopathy, gastrointestinal bleeding and hepatocellular carcinoma).
 For their enrollment, it is necessary that the patients are in accordance with the proposed
 study, following the precepts of the Declaration of Helsinki. If patients refuse to
 participate in the study, they will be treated following the traditional guidelines of our
 service. Treatment will be discontinued in case of pregnancy, patient's desire, side-effects
 or relapse of AIH.

 Patients were randomized to receive azathioprine and prednisone or chloroquine and
 prednisone. The alternative treatment, with chloroquine, was maintained unless it caused
 major side-effects, no biochemical response or treatment failure. In this case, azathioprine
 was introduced in association with prednisone. All patients had visits every 30 days during
 the first six months with routine blood tests performed. After then, consultations were every
 two months. All complaints were recorded. Every patient were treated by the doctors
 responsible for the study, laboratory tests were performed in the Central Laboratory of the
 hospital. All patients underwent to initial ophthalmologic evaluation followed by six-monthly
 evaluations. The drug was withdrawal, if changes suggestive of retinopathy were observed.
Inclusion Criteria:

 -  Diagnosis of autoimmune hepatitis according to Autoimmune Hepatitis International
 Group with indication for treatment

 -  No evidence of decompensated liver cirrhosis

 -  Non-pregnant women and women with no intention to become pregnant

 -  Willing to participate in the study

 Exclusion Criteria:

 -  Discrete biochemical changes and histological inflammatory activity absent / minimal
 (periportal / peri-septal: 0/1 +) or decompensated cirrhosis

 -  Cases of loss of follow up