LUPUS: A GP Guide to Diagnosis
Drug Induced Lupus - New Research
Introduction
The cause of most autoimmune diseases is unknown. It is likely that a combination of genetic factors together with certain environmental agents contribute to autoimmune development. This is very clearly illustrated by the clinical syndrome of drug-induced lupus (DIL). DIL is a syndrome in which agents like procainamide, hydralazine, chlorpromazine, a-methyldopa, isoniazid and penicillamine cause a lupus-like illness in genetically-predisposed individuals. More than 70 drugs have been found to induce lupus-like disease. An understanding of the mechanism of action of DIL may serve to provide fundamental knowledge about disease initiation and progression which may be applied to the development of idiopathic lupus. Common clinical features of DIL are myalgia, arthralgia, fever and pleuritis, although renal and CNS involvement are usually absent. Approximately 85% of patients with hydralazine-induced lupus complain of arthralgia while 50% have myalgia. Pleuro-pulmonary involvement is common particularly in patients with procainamide-induced lupus. Mild haematuria or proteinuria in the absence of abnormal serum creatinine occurs in approximately 13% of patients with hydralazine-induced lupus but is found in 50-65% of those with idiopathic disease.
Of particular significance in DIL is the serological profile of the patient. The serological profile is similar in idiopathic lupus. Both conditions are characterised by anti-nuclear antibodies, however, only in idiopathic lupus do we detect autoantibodies specific for double stranded DNA.
Table 1 - Major drugs and chemicals associated with adverse effects in humans
|
||||||||||
Diagnostic criteria have not been fully established for DIL. The American College of Rheumatology criteria requires that 4 of 11 symptoms be met for the diagnosis of lupus. Patients diagnosed with DIL will only manifest 1 or 2 symptoms. A most important criteria is the temporal association between administration of a drug and the induction of a positive indirect fluorescent anti-nuclear antibody test. Complete remission always follows withdrawal of the drug. This is regarded as the most important criteria for diagnosis.
Incidence
The world-wide incidence of DIL is unknown. However, 500,000 individuals in the USA have lupus and it is believed that as many as 10% are drug related. The prevalence of DIL is not coincidental with prevalence of lupus (9: 1 in favour of females). However, women do seem to display a higher probability of developing the disease. It often manifests in males because procainamide is an antiarrhythmic and as males have a higher incidence of cardiac disease DIL is more likely to be diagnosed in this group. The age of patients presenting with DIL reflects the age of the population at risk for both underlying disease and therapeutic agents involved. The occurrence of DIL is, therefore, not necessarily influenced by the effects of chronological age of the immune system but by the underlying disease process and genetic predisposition of the patient. Most recent reports include cases of minocycline-induced lupus which were communicated to the Committee on Safety of Medicines in April 1994. Minocycline, sold as minocin MR, is one of the most widely prescribed antibiotics used for acne. In 1993 there were more than 800,000 prescriptions written for the drug which is cause of major concern as, unlike other drugs which may cause DIL, minocycline is used to treat an essentially benign condition.
Genetic Damage
A number of mechanisms have been proposed to explain how certain drugs such as procainamide and hydralazine cause DIL. Anti-nuclear antibodies are characteristically induced in DIL. It has, therefore, been suggested that these compounds may have effects on nuclear components of the cell and cause them to become recognised as non-self as if they were foreign bacteria. The modified DNA and, particularly, the histone or protein component of DNA is believed to drive this immune response.
The enzyme poly AOP polymerase is involved in preparing the DNA for repair and serum autoantibodies to this protein are also characteristic of DIL.
Some very recent studies have focused on the ability of neutrophils to metabolise lupus-inducing drugs to products which are toxic to the cell. For instance, procainamide can be metabolised by neutrophils to procainamide hydroxylamine. Studies on cells incubated in vitro with these two drugs, which are often used as model compounds for DIL, can stimulate oxidative damage to the genetic material of the cell through the production of oxygen-free radicals. These chemical species are highly toxic and may cause damage to the DNA and protein component of the nucleus giving rise to what appears to be foreign material to the immune system.
T-Cell Auto-reactivity
Treating human T-cells in vitro with therapeutic concentrations of procainamide causes a 30-50% decrease in total genomic deoxy-methylcytosine content, probably through enzyme inhibition. Similarly, UV radiation also induces this type of T-ceIl auto-reactivity. The results of such experiments suggest that certain environmental agents may inhibit T-cell enzymic activity, thereby altering the gene expression and function of the T-cell. The hypo-methylation of DNA has been examined in cells taken from lupus patients. Patients with active disease had less demethylated cytosine compared to age-matched controls. T-cells from lupus patients were found to be particularly depleted in methylated cytosine and the methylating enzyme. It has been suggested that T-cell DNA hypo-methylation may be caused as a result of genetic or environmental reasons and impairment of DNA methyl transferase activity could well induce a lupus-like disease.
Oestrogens and the immune response
Oestrogens may stimulate B-cell and T-cell activity in vitro. Studies have been carried out on the effects of oestrogen on lymphocytes taken from lupus patients and normal individuals. Oestrogens decrease the inflammatory mediator tumour necrosis factor (TNF). Depletion of this cytokine prolongs the survival of autoimmune cells in lupus. Oestrogens also undergo cytochrome P450 mediated detoxification reactions producing highly oxidising compounds called oxygen-free radicals. Chromosomal damage may occur to proteins involved in transcription and gene expression. Genetic mutations could also occur through these reactions and it has been suggested that lupus patients may have an inability to repair such damage resulting in cells which accumulate DNA damage and die by a programmed cell death mechanism, termed apoptosis. The resultant release of damaged DNA could give rise to anto-antigen formation and, subsequently, immune complex damage, a common consequence being renal impairment and vasculitis.
Summary
This review summarises present knowledge about how certain chemical and environmental agents act in a similar manner to each other in inducing lupus-like changes in T lymphocytes in vitro and in vivo. The results provide a new approach to potential mechanisms which are likely to be relevant for idiopathic lupus (see Figure). They would explain to some extent the clinical and anecdotal information known about this disorder, i.e. UV radiation, toxic fumes from paints, preservatives and tissue implants are often linked with clinical onset.
Legend to Figure
Mechanism for the role of exogenous toxins in the aetiopathogenesis of DIL.
Prof. Joe Lunec
Division of Chemical Pathology
Robert Kilpatrick Building
Clinical Sciences Building
Level 0
PO Box 65
Leicester Royal Infirmary
Leicester, LE2 7LX