Minocycline: Organs and Systems
Respiratory
Minocycline and nicotinamide therapy for bullous pemphigoid have been associated with severe pneumonitis.
The syndrome of pseudotumor cerebri consists of symptoms and signs of raised intracranial pressure in the absence of neuroimaging or cerebrospinal fluid abnormalities. Most cases are idiopathic, but several drugs have been implicated as causative or contributory.
The first description of minocycline-related pseudotumor cerebri was published in 1978. Further data have been published concerning 12 patients who developed pseudotumor cerebri after taking standard doses of minocycline for acne vulgaris. Nine developed symptoms within 8 weeks of starting minocycline therapy. Minocycline was withdrawn, and none of the patients developed recurrences for at least 1 year afterwards. However, three patients had substantial residual visual field loss.
It seems reasonable to assume that the mechanisms may be similar to that postulated for tetracyclines, which reduce cerebrospinal fluid absorption, possibly by an effect on cyclic adenosine monophosphate at the arachnoid villi. Minocycline crosses the blood-brain barrier more effectively than other tetracyclines, because of its greater lipid solubility. Therefore, a physician who prescribes minocycline should keep his eye on the patient’s eyes.
Mouth and teeth
Staining of permanent teeth by tetracyclines takes place during tooth development by well-documented mechanisms. Tetracycline forms a complex with calcium ortho-phosphate during calcification, which then darkens with exposure to light. With minocycline, however, the staining occurs after eruption in previously normal-colored, fully mineralized adult teeth. For example, adult-onset tooth discoloration coincident with minocycline administration occurred in four of 72 patients.
There are at least four theories about the mechanisms of this adverse effect.
- That minocycline attaches to the acquired pellicle glycoproteins (the “extrinsic theory”). This in turn etches the enamel, and cycles of demineralization and remineralization occur. It oxidizes on exposure to air or as a result of bacterial activity, and the final product is insoluble black quinine.
- That minocycline, bound to plasma proteins, is deposited in collagen-rich tissues, such as pulp, teeth, and bones (the “intrinsic” theory). Minocycline is then slowly oxidized over time with exposure to light.
- That a breakdown product of minocycline chelates with iron to form insoluble complexes.
- That minocycline is deposited in dentine during denti-nogenesis, accelerating or changing the process.
Whatever the mechanism(s) might be, staining of adult dentition occurs in 3-6% of patients who take long-term minocycline 100 mg/day. The onset of discoloration can occur at any time from 1 month to many years after the start of treatment.
The importance of avoiding permanent staining of the teeth cannot be over-emphasized, as many patients with acne are already prone to negative psychological effects. Minocycline should therefore be prescribed only with great care.
Liver
Hepatotoxicity associated with minocycline has been reviewed, covering data reported to the WHO Centre for International Drug Monitoring, which had recorded 8025 reactions to minocycline, of which 493 were reactions involving the liver. The authors stated that fields available to define indications for use, time of treatment, and outcome subsequent to the reactions were seldom completed.
They therefore concentrated on more complete records in patients known to have used minocycline for acne. Patients taking minocycline for reasons other than acne or those given intravenous minocycline were excluded. Altogether, 65 patients were then commented on; 58% were women and 94% were aged under 40 years. Briefly, two types of hepatic reactions were recognized: autoimmune hepatitis associated with lupuslike symptoms occurring after 1 year or more of exposure to minocycline, and hypersensitivity reactions associated with eosinophilia and exfoliative dermatitis occurring within 35 days of therapy.
The authors stated that they did not have any clear information about the absolute and relative risks of hepatitis, whether these were hypersensitivity reactions or autoimmune hepatitis, in patients taking minocycline for varying lengths of time, and that a study of the comparative rates of hepatitis in people exposed to minocycline compared with those not exposed is required. In the meantime, new reports of severe hepatic reactions to minocycline continue to appear, including one case of autoimmune hepatitis requiring liver transplantation in a woman who had used minocycline 50-200 mg/ day for 3 years. Another case of liver transplantation has previously been reported in patients with hepatic failure after minocycline therapy.
Some patients consider drugs to treat a common der-matological disease such as acne vulgaris to be cosmetics rather than medications. Safer alternatives than minocycline should be considered in the treatment of acne.
Pancreas
Minocycline has been associated with acute pancreatitis.
Skin
Long term minocycline often results in pigmentation of skin, nails, bones, thyroid, mouth, and eyes. The bones of the oral cavity are probably the most frequently affected sites of pigmentation. On the skin, the blue-black pigmentation develops most frequently on the shins, ankles, and arms. Other patterns include pigmentation that either is generalized and symmetrical or develops at sites of inflammation. The pigmentation is often permanent when sites other than the skin and oral mucosa are involved. The pigment is a product of an oxidation reaction. In an experimental rat study, pigmentation of the thyroid gland was prevented by ascorbic acid. Laser treatment was successfully used in two cases.
Fixed drug eruptions are characterized by solitary or multiple, round or oval, erythematous patches of variable size; some of them develop into bullae or superficial erosions. Characteristically they appear in the same site eac time the responsible drug is given, usually 30 minutes to 8 hours after administration, and with itching or burning as the first symptoms. Over a period of 1-2 weeks they fade, often with crusting and scaling, followed by hyper-pigmentation, which can persist for months.
Antimicrobial drugs, especially co-trimoxazole, ampi-cillin, and tetracyclines, can cause fixed drug eruptions, and cases have been attributed to minocycline. There is usually no cross-reactivity. However, a case of fixed drug eruption has been reported after minocycline in a patient with a previous eruption due to doxy-cycline.
• A 48-year-old man with urethritis took doxycycline 100 mg bd and developed a fixed drug eruption on the glans penis. Doxycycline was withdrawn and the eruption healed with symptomatic treatment. Eight months later he took minocycline 100 mg/day for rosacea. A few hours after having taken the first tablet he became aware of oval erythematous patches on the glans, prepuce, and scrotum. The patches rapidly became violaceous and developed into superficial erosions. He stopped taking minocycline and the lesions faded.
According to the authors, this is the first report of a fixed drug eruption after minocycline in a patient with a previous eruption due to doxycycline. They advised clinicians to be aware of this potential cross-reactivity when prescribing these two drugs.
A generalized pustular eruption was reported in a patient with acne treated with minocycline. Skin prick tests with minocycline were positive at 48 hours.
Immunologic
Immunoallergic reactions have been reported with minocycline and include lupus-like syndrome, autoimmune hepatitis, eosinophilic pneumonia, hypersensitivity syndrome, a serum sickness-like illness, and Sweet’s syndrome. Over 60 minocycline-induced cases of lupus-like syndrome and 24 cases of minocycline-induced autoimmune hepatitis were found in a review of the literature. In 13 patients, both disorders co-existed. These patients had symmetrical polyarthralgia/polyarthritis, raised liver enzymes, and positive antinuclear antibodies; they were also generally antihistone-negative, and only two patients had p-ANCA antibodies. Minocycline-related lupus can also occur in adolescents.
Lupus-like syndrome
Drug-induced lupus is a well-known phenomenon, although the mechanisms are unclear. The diagnostic features should include no prior history of systemic lupus erythematosus (SLE) before the start of treatment, at least one clinical feature of SLE, a positive antinuclear antibody during sustained drug therapy, and dramatic symptomatic improvement after drug withdrawal. Since 1970, at least 49 drugs have been reported to be associated with drug-related lupus, of which hydralazine and procainamide have been claimed to the most commonly implicated. However, new reports on minocycline-induced lupus continue to appear and it is possible that minocycline is now the most common cause.
In a retrospective nested case-control study in 27 688 young patients with acne, 7136 had used minocycline, of whom 29 had the lupus-like syndrome. Minocycline was associated with an 8.5-fold risk of the lupus-like syndrome. The effect was greater in longer-term users, but the absolute risk of developing lupus-like syndrome seemed to be relatively low.
Minocycline-induced lupus usually occurs some months, or even years, after the start of therapy, and it usually resolves when the drug is withdrawn. The diagnosis can easily be overlooked, especially in patients with rheumatoid arthritis. It would always be wise to follow the recommendation that a patient’s antinuclear antibody be checked before starting minocycline and when drug-induced lupus is suspected.
In a retrospective review of drug safety databases, minocycline was the only tetracycline derivative that caused drug-induced lupus. The authors proposed that the propensity of minocycline to cause drug-induced lupus may be due to the presence of a functional group that is easily oxidized to a reactive metabolite. However, the chemically modified tetracycline CMT-3, which has also reportedly caused a lupus-like syndrome, lacks this group, so another theory is needed.
• A 16-year-old girl, who had taken minocycline for acne for more than 2 years, developed a severe cough with paroxysms. She had also a recent history of joint pain with swelling and stiffness, fever, general weakness, and weight loss of 9 kg. She had been treated as an outpatient for presumed pneumonia with multiple antibiotics, but developed progressive dyspnea. Pulmonary lupus was suspected, and minocycline was withdrawn. She was treated with an initial 3-day course of intravenous methylprednisolone 20 mg tds, and then predni-sone 40 mg bd for 2 weeks. She improved very rapidly, and the prednisone was gradually reduced over 7 weeks.
According to the authors, the patient fulfilled all the criteria for a diagnosis of drug-induced lupus-like syndrome, that is no history of lupus erythematosus before minocycline therapy, the presence of antinuclear antibodies, at least one clinical feature of lupus erythematosus, and prompt recovery after withdrawal of minocycline. She also had positive antihistone antibodies, compatible with drug-induced lupus-like syndrome.
• A 54-year-old woman with a 2-week history of low-grade fever, dry cough, and dyspnea was given levoflox-acin for a presumed community-acquired pneumonia. Five days later she developed severe respiratory failure and was mechanically ventilated and given antibiotics (imipenem and clarithromycin). Microbiological examination of tracheobronchial aspirates was negative for pathogenic organisms, as were serological tests for common agents of atypical pneumonia. She progressively improved and was taken off the ventilator after 6 days and discharged about 10 days later, but 14 days later was readmitted with rapidly progressive pulmonary failure requiring mechanical ventilation. It then transpired that 2 weeks before the first episode of respiratory failure, she had started to take oral minocycline for acne vulgaris and had started to take it agai 24 hours before the second episode. The minocycline was stopped and she was given intravenous methylprednisolone. She improved rapidly, and for 12 months after minocycline withdrawal she remained free of respiratory symptoms.
It is a good rule of thumb that patients who develop minocycline-induced lupus should never be rechallenged with minocycline, as symptoms tend to recur. If minocycline is used to treat rheumatoid arthritis, the patient should be followed very carefully, as worsening arthritis may be erroneously attributed to the underlying disease. It should also be emphasized that in the search for a cause of joint pains, minocycline should always be considered.
Autoimmune hepatitis
In a review of relevant American and European literature, hepatitis and drug-induced lupus were reported in 66 cases after minocycline therapy, mostly after long-term treatment for acne.
- Minocycline-induced hepatitis with antinuclear, anti-mitochondrial, and antismooth muscle antibodies has been reported in a 19-year-old black West Indian woman who had been treated for acne for two years with oral minocycline (50 mg/day) and topical benzoyl peroxide (5%).
- Seven patients (17-22 years old) developed symptoms of arthralgia and arthritis after having taken minocycline 50-100 mg bd for 6-36 months for acne vulgaris. Increased titers of perinuclear ANCA were detected in all seven, five had fluorescent antinuclear antibodies, two had antihistone autoantibodies, and one had anticardiolipin antibodies. Symptoms resolved in five patients on withdrawal; the other two were treated with corticosteroids and also achieved remissions.
Autoimmune hepatitis has also been reported.
Three adolescents taking therapeutic doses of minocycline for 12-20 months met the 1993 International Autoimmune Hepatitis Group criteria for autoimmune hepatitis. All had hypogammaglobulinemia and positive antinuclear antibody and antismooth muscle antibody titers. Two underwent liver biopsy that showed severe chronic lymphoplasmocytic inflammation, necrosis, and fibrosis. All other causes of liver disease were excluded. One patient had resolution of symptoms after withdrawal of the drug, while two required immu-nosuppressive therapy.
Necrotizing vasculitis of the skin and uterine cervix has been reported in a patient taking minocycline.
A 35-year-old woman developed an asymptomatic, erythematous, subcutaneous nodule on the anterior aspect of her left leg. She had been taking minocycline 50-100 mg bd for acne for 2 years, and her only other medication was an oral contraceptive. A presumptive diagnosis of erythema nodosum was made. The nodule was injected twice with triamcinolone acetonide and she was given indometacin 50 mg tds but continued to take minocycline. Some weeks later, after a routine gynecological examination, pathological examination of a cervical biopsy showed necrotizing arteritis of the cervix. A biopsy of the pretibial nodule showed a necrotizing vasculitis with fibrinoid necrosis of the vessel walls and thrombosis. Her serum transaminase activities were increased, and an antinuclear antibody test was positive at 1:60 with a nucleolar pattern. Minocycline was withdrawn, and over the next 3 months her liver function tests normalized, the antinuclear antibody became negative, and the pretibial nodule and uterine cervix vasculitis resolved. There was no recurrence over the next 2 years.
Serum sickness
A serum sickness-like reaction clinically similar to classical serum sickness can result from the administration of a number of non-protein drugs, such as tetracyclines, penicillins, cephalosporins. Minocycline has been reported to cause serum sickness.
- A 16-year-old girl taking minocycline for acne developed typical symptoms of serum sickness after 14 days. Minocycline was withdrawn and her symptoms resolved after a short course of systemic steroids for 5 days.
- An 18-year-old woman developed typical symptoms of serum sickness after taking minocycline 50 mg/day for 10 days for acne. Her symptoms resolved gradually after minocycline was withdrawn.
The authors reviewed some other cases of serum sickness after the use of minocycline. They suggested that the syndrome is under-reported, either because of unaware -ness that it can be an adverse effect or lack of willingness of physicians to document the event.
Polyarteritis nodosa
Two cases of biopsy-proven cutaneous polyarteritis nodosa with positive perinuclear antineutrophilic cytoplasmic antibodies have been reported with long-term use of minocycline for acne vulgaris (50-100 mg/day for 44 months and 100 mg/day for 65 months). In one of the cases, involvement was not restricted to medium-size vessels alone. In both cases the vasculitis disappeared after a short course of prednisone (40 mg/day) and withdrawal of minocycline. Rechallenge was not performed. P-ANCA is usually found in microscopic polyangiitis, a vasculitis of smaller arteries, and its significance in polyarteritis nodosa is not clear.