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Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome

^a Department of Rheumatology, Harrogate District Hospital, Harrogate HG2 7SX, ^b Department of Pharmacy, Policy and Practice, Keele University, Staffordshire ST5 5BG, ^c Drug Information Unit, Selly Oak Hospital, Birmingham B29 6JD, ^d Rheumatology and Rehabilitation Research Unit, Leeds University, Leeds LS2 9NZ, ^e Department of Hepatobiliary Medicine, Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TT

Correspondence to: Professor Emery.

At presentation another patient (case 1) was found to have hepatitis with a serum aspartate transaminase concentration of 385 IU/l. Viral hepatitis and liver autoantibody screens gave negative results. A liver biopsy confirmed chronic active hepatitis. The hepatitis resolved completely after minocycline was stopped. Furthermore, on review of the notes, the index patient was also noted to have had raised aspartate aminotransferase concentration of 98 IU/l at her first presentation. Again no cause was found, and these tests returned rapidly to normal after discontinuation of minocycline.

Having determined that minocycline could cause an autoimmune drug reaction leading to hepatitis, we looked for further cases prospectively in 1993 and found four more (table 1, cases 4-7). Three of these (cases 5, 6, and 7) were again young women taking minocycline who developed severe hepatitis and were positive for antinuclear antibody. The fourth (case 4) was a 37 year old man who had also been taking long term minocycline for acne. He initially became jaundiced in February 1993. He did not present to his doctor at this stage, but five months later, after the jaundice resolved, he became unwell again. He had severe hepatitis with an aspartate aminotransferase concentration of 2320 IU/l, with a strongly positive antinuclear antibody titre. Although he was still taking his minocycline at this stage, we do not know whether he took it continuously throughout. Cases 5 and 7 presented with jaundice and all three women experienced profound malaise and polyarthralgia in addition to their hepatitis. In all, liver biopsies showed moderately severe changes of acute or chronic active hepatitis. Apart from antinuclear antibody, hepatitis viral screens and other autoantibody tests gave negative results. All seven patients' symptoms and laboratory investigations returned to normal within three months of their discontinuing minocycline. Although their acne deteriorated, all seven have had no recurrence of symptoms or biochemical abnormalities to date, emphasising that these reactions were likely to be drug related.

We requested data from the Committee on Safety of Medicines regarding all minocycline reactions reported in the United Kingdom until April 1994. Table 2 summarises the available data on 11 cases of systemic lupus erythematosus and 16 cases of hepatitis. There is similarity between the cases we described and those reported to the Committee on Safety of Medicines, particularly the spontaneous recovery seen on drug withdrawal and the recurrence of symptoms on rechallenge. Nevertheless, two people died while taking this drug for acne--one after severe hepatitis and coma, and one from pancytopenia.

Table 2--Reports of minocycline induced systemic lupus erythematosus-like syndromes and hepatitis (data from the Committee of Safety on Medicines)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Case
 No     Sex       Age     Year         Dose                                    Reaction                                                      Outcome
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Systemic lupus erythematosus-like syndromes
  8    Data      Data     1986     100 mg daily            Rash, arthritis, hepatitis, antinuclear antibody          Recovered on drug withdrawal
      unknown   unknown
  9      M        26      1986   50 mg twice daily         Arthritis, antinuclear antibody                           Recovered on drug withdrawal. Rechallenge led to
                                    >7 months                                                                          recurrence with antinuclear antibody positive,
                                                                                                                       deoxyribonucleic acid antibody negative
 10      F       Data     Data   50 mg twice daily         Systemic lupus erythematosus                              Unknown
               unknown  unknown     >2 years
 11      F        22      1989   50 mg daily 5/12          Flare of known systemic lupus erythematosus               Unknown
 12      F        20      1990   50 mg twice daily         Arthritis, systemic lupus erythematosus                   Recovered on drug withdrawal
                                     3 years
 13      F        17      1990  50 mg daily 4 years        Disabling arthritis, myalgia, antinuclear antibody        Recovered on drug withdrawal (had been chair bound)
                                                             1/3200, deoxyribonucleic acid
                                                             antibody/extractable nuclear antibody/antinuclear
                                                             antibody negative
 14      F        15      1991   50 mg twice daily         Systemic lupus erythematosus                              Initially unable to hold a cup. Given corticosteroids.
                                       3/12                                                                            Outcome unknown
 15      F        28      1991   50 mg twice daily         Disabling arthritis, myalgia, fever, antinuclear          Recovered on drug withdrawal. Antinuclear antibody
                                     6 years                 antibody 1/400, erythrocyte sedimentation rate            remained 1/400
                                                             25 mm in 1 h, anticardiolipin antibody positive, smooth
                                                             muscle antibody
 16      F        18      1992   50 mg twice daily         Arthralgia, erythrocyte sedimentation rate 29 mm in       Recovered on drug withdrawal. Recurred on challenge
                                     2 years                 1 h, antinuclear antibody 1/20                            and settled again. Deoxyribonucleic acid antibody
                                                                                                                       negative
 17      F        17      1992   50 mg twice daily         Arthralgia, antinuclear antibody 1/6400, erythrocyte      Recovered with two weeks of drug withdrawal.
                                    22 months                sedimentation rate 23 mm in 1 h, anticardiolipin          Antinuclear antibody remains weakly positive,
                                                             antibody, extractable nuclear antibody/deoxyribonucleic   antinuclear antibody negative. Patient remains well
                                                             acid antibody negative
 Autoimmune hepatitis
 18      M        39      1984  100 mg daily 10 days       Hepatitis                                                 Recovered on drug withdrawal
 19      F       Data     1985  100 mg daily 3 years       Hepatitis                                                 Also on oral contraceptive pill. Recovered on drug
               unknown                                                                                                 withdrawal
 20      F       Data     1985     100 mg daily            Hepatitis                                                 Also on oral contraceptive pill. Recovered on withdrawal
               unknown              29 months                                                                          of drugs
 21      F        39      1988  200 mg daily 1/12          Hepatitis, dizziness, taste change, headache              Unknown
 22      F       Data     1989   50 mg twice daily         Exfoliative dermatitis, fever, anaemia, hepatitis         Hepatic cause led to death. Had also recently taken
               unknown                                                                                                 proguanil, chloroquine, "tanning" tablets, and recent
                                                                                                                       immunisations (cholera, typhoid, yellow fever)
 23      M        17      1990  100 mg daily 3/12          Hepatitis                                                 Recovered on drug withdrawal
 24      M        18      1990  100 mg daily 1/12          Hepatitis, jaundice (infection screen negative)           Also on cephalexin. Rechallenge with minocycline led to
                                                                                                                       recurrence of jaundice
 25      M        22      1990   50 mg twice daily         Hepatitis                                                 Recovered on drug withdrawal
                                    28 months
 26      F        22      1990   50 mg twice daily         Hepatitis, pancytopenia                                   Death as a consequence of pancytopenia
                                       5/12
 27      M        18      1991  100 mg daily 7/12          Hepatitis                                                 Recovered on drug withdrawal
 28      M        22      Data   50 mg twice daily         Hepatitis (infection screen negative)                     Recovered on drug withdrawal
                         unknown
 29      M        20      1992   50 mg twice daily         Hepatitis, arthritis (infection screen negative)          Brufen, naproxen, sulphasalazine, temazepam used to
                                      1 year                                                                           treat arthritis, which then completely resolved on
                                                                                                                       minocycline withdrawal
 30     Data     Data     1992     6 g overdose            Erythroderma, hepatitis, renal impairment                 Unknown
       unknown  unknown
 31      M        73      1992   50 mg daily 9 days        Hepatitis                                                 Had also taken paracetamol and (much earlier)
                                                                                                                       metoclopramide and astemizole
 32      M        23      Data   50 mg twice daily         Prolonged jaundice (maximum bilirubin 830),               Recovered on drug withdrawal
                         unknown   intermittent              hepatitis nuclear antibody and infection screen
                                                             negative, smooth muscle antibodies positive.
                                                             Caeruloplasmin normal
 33      F        23      1993  100 mg daily 9/12          Acute hepatitis                                           Also on oral contraceptive pill. Recovered on drug
                                                                                                                       withdrawal

Discussion

The first report suggesting that systemic lupus erythematosus was exacerbated by tetracyclines was in 1959.⁴ This report of three cases suggested that tetracyclines might exacerbate pre-existing systemic lupus erythematosus rather than induce it. However, there are now 11 suspected cases of minocycline induced systemic lupus erythematosus. One report described a 22 year old Japanese woman who had taken 100-150 mg minocycline daily for two years.⁵ She presented with a symmetrical small joint polyarthritis, fever, malaise, cough, and pulmonary infiltrates. Antinuclear antibody was present in a diffuse pattern and DNA antibodies were not detected. She recovered one month after stopping the drug. Furthermore, this is not the only report of pulmonary infiltrates associated with minocycline.⁶ There are also other cases suggesting a more allergic type reaction with fever, lymphadenopathy, and eosinophilia.^{7 8 9} In one of these cases, rechallenging the patient led to a rapid recurrence of symptoms, with complete resolution on withdrawal of the drug.⁸ A recent report of five cases of drug induced systemic lupus erythematosus with minocycline adds further weight to this evidence that minocycline can induce autoimmune disease.¹⁰

The ability of tetracyclines to cause liver disease became apparent soon after their introduction.¹¹ Early reports described fatal microvesicular fatty liver degeneration occurring in pregnant women given high doses of tetracycline intravenously.¹² However, similar reactions were soon reported in non-pregnant women¹³ and men.¹⁴ The first report of this type of liver injury with minocycline again followed high dosages given intravenously.¹⁵ Liver transplantation after giving minocycline to a 17 year old girl has now been described.¹⁶ This cumulative evidence suggests a direct, dose related, hepatotoxic effect common to all tetracyclines. Part of this direct hepatotoxic effect may be due to metabolites of minocycline, as has been shown in animals.¹⁷ Although the principal metabolites of minocycline have been reported,¹⁸ the complete details of its breakdown may still be unknown.¹⁹

A second form of fulminant hepatitis with minocycline can occur as part of an allergic, idiosyncratic reaction.²⁰ A 39 year old woman developed fever, malaise, lymphadenopathy, and eosinophilia four weeks after starting oral minocycline. She subsequently developed severe hepatitis with stage II hepatic encephalopathy before making a full recovery after minocycline was withdrawn.²⁰ No other cause was identified, although no immunological tests were reported. In another similar case a 17 year old woman developed a fatal hepatitis after a one month course of minocycline.⁹ Again there were allergic features with rapid onset, fever, and eosinophilia. In this case exfoliative dermatitis and a streptococcal infection were additional complicating factors. However, liver failure was thought to be the cause of death, which occurred despite liver transplantation.

The cases we have identified with liver disease may represent a third type of hepatic injury. All these patients had chronic active hepatitis on biopsy, with no fatty change, eosinophilia, or allergic features. All occurred after prolonged oral treatment, had polyarthralgia or polyarthritis as a presenting feature, and were positive for antinuclear antibodies. This autoimmune type reaction has not previously been described. The four most recent cases all had severe hepatitis, requiring hospital admission, and may represent the more severe end of a spectrum. They were tertiary referrals from centres that had been unable to identify the underlying cause of these patients' hepatitis. Minocycline may be responsible for a number of such cases, particularly among younger women, owing to their increased exposure to this drug. The incidence of abnormal liver function results on this drug has not been established prospectively. However, in a small study of the use of minocycline in rheumatoid arthritis two of the 30 cases developed an unexplained hepatitis which resolved on withdrawal of treatment (M Farr, personal communication).

Half the patients with autoimmune chronic active hepatitis present in their second decade and three quarters are women. Eighty per cent demonstrate antinuclear antibodies of homogeneous (diffuse) type and in 70% anti-actin smooth muscle antibodies are found. A high serum (gamma) globulin concentration is characteristic. Given this profile of classical autoimmune chronic active hepatitis it would be easy to have categorised the hepatic illness in each of our patients as autoimmune chronic active hepatitis (six of our seven patients were women aged 16-26 years). Spontaneous and rapid resolution of liver function test abnormalities is, however, most uncommon in autoimmune chronic active hepatitis. Most patients require long term treatment with prednisolone or azathioprine and have a 50% chance of relapse on stopping treatment. One of our patients was treated with steroids and made a dramatic recovery, but in the other cases rapid resolution followed discontinuation of minocycline alone. Patients should, however, be followed for at least a year after normalisation of their tests to exclude autoimmune chronic active hepatitis.²¹ Another form of autoimmune chronic active hepatitis is associated with liver kidney microsomal antibodies. These antibodies are targeted against P450 enzymes. In some of those patients a precipitating drug was recognised, and the hepatitis resolved on removal of the responsible agent (tienylic acid). However, in most forms of autoimmune chronic active hepatitis associated with liver kidney microsomal antibodies no causative xenobiotic has been recognised.

Acne itself could explain our findings, as it can induce arthritis,²² and is often seen in association with autoimmune liver disease. However, the clinical and biochemical resolution after withdrawal of the drug, despite deterioration of the acne, weighs against this. Furthermore, in two of our cases, and in three of the Committee on Safety of Medicines reports, reexposure to minocycline led to recurrence. If this does represent a drug induced systemic lupus erythematosus-like syndrome the finding of antinuclear antibodies with no antibodies to DNA is expected.²³ There have been reports of antibodies to histones being associated with drug induced systemic lupus erythematosus, but we were unable to show these in our first three cases (R Thomson, personal communication). The finding of two case reports from the Committee on Safety of Medicines of positive anticardiolipin antibodies is of interest. No clinically relevant sequelae to these antibodies were reported and both became negative at follow up.

Minocycline is understandably popular with general practitioners as compliance is likely to be better with a once or twice daily regimen. In 1993 there were 63998 prescriptions for minocycline in the West Midlands region at a cost of pounds sterling1.7m. The national figures for the same period were over 800000 prescriptions at a cost of nearly pounds sterling23.3m. This represents a considerable portion of the NHS drug budget, particularly because it is a relatively expensive drug compared with other treatments for acne. A cost-benefit analysis of its use would be appropriate.

By reporting these cases we hope to raise awareness of this type of drug reaction with minocycline, particularly among general practitioners, dermatologists, rheumatologists, and gastroenterologists. Reactions can be severe, so their recognition at an early stage may be important not only to aid recovery but also to avoid invasive investigations such as liver biopsy and treatments such as corticosteroids and immunosuppressants. In view of the severity of some reactions, including two deaths and one liver transplant, the use of minocycline for acne should be considered carefully. Monitoring of liver function tests may be necessary, although the true incidence of these autoimmune reactions to minocycline remains unknown and merits further study. Should routine monitoring of liver function tests be necessary, this would make the use of minocycline prohibitively expensive and inconvenient for patients. Safer and less expensive alternatives might therefore be more appropriate.

We thank Drs H C Mitchison, J Saunders, D M Hill, and J M Patient for allowing us to see and report on their patients. We also thank the Committee on Safety of Medicines for giving us access to their records on minocycline reactions, and the Department of Health for releasing the national prescribing figures; and Heather Smith for her expert help with typing this manuscript.

Funding: None.

Conflict of interest: None.

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Minocycline induced autoimmune hepatitis and arthritis

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