Drug-induced lupus erythematosus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Drug-induced lupus erythematosus (DIL or DILE) is an autoimmune disorder, similar to systemic lupus erythematosus (SLE), which is induced by chronic use of certain drugs. These drugs cause an autoimmune response (the body attacks its own cells) producing symptoms similar to those of SLE. There are 38 known medications to cause DIL but there are three that report the highest number of cases: hydralazine, procainamide, and isoniazid.^[1] While the criteria for diagnosing DIL has not been thoroughly established, symptoms of DIL include fever, elevated blood pressure, skin lesions, and arthritis. Generally, the symptoms recede after discontinuing use of the drugs.^[2]

[Note the term “generally.” There are reported cases of DIL that do not go away completely after the offending drug is removed.]

While this may not be a prevailing illness in this age of heritable and non-transmittable diseases, research on drug-induced lupus could lead to a greater understanding on the immune system. This greater understanding of our immune systems could lead to breakthroughs in many other diseases such as HIV, influenza, and other communicable diseases. Research on this topic also has pharmaceutical implications as to avoid immune reactions from future drugs.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Hydralazine was the first agent to be associated with the development of lupus-like symptoms in 1954. Since then, more than 100 drugs have been identified as the cause of drug-induced lupus, with the list expanding with the development of newer biologic agents each year. https://www.ncbi.nlm.nih.gov/books/NBK441889/

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

• the exact pathophysiology of drug-induced lupus erythematosus is not fully understood.
• some genetic risk factors include HLA-DR4, HLA-DR0301, and complement C4 null allele.
• Drug-induced lupus is probably mediated by reactive drug metabolites, not the ingested medications, and susceptibility to neutrophil-mediated oxidative transformation is a property of ten lupus-inducing drugs reported so far.

• Three mechanisms are implicated in the causation of drug-induced lupus erythematosus:

1. Slow acetylation with genetic deficiency of N-acetyltransferase.
2. Inhibition of DNA methylation of CD4+ T-cells.
3. The metabolites of the offending drug are subjected to oxidative metabolism and serve as a substrate for myeloperoxidase; which is activated in polymorphonuclear neutrophils.

Three mechanisms are implicated in the causation of drug-induced lupus erythematosus:

• Slow acetylation with genetic deficiency of N-acetyltransferase. It is found that slow acetylators with genetic deficiency of N-acetyltransferase are at higher risk of DIL, especially from procainamide and hydralazine.

• Inhibition of DNA methylation of CD4+ T-cells. the demethylation of CD4+ T-cells makes them auto-reactive by over-expression of the LFA-1 adhesion molecule. These auto-reactive T-cells can then overstimulate autoantibody production by interaction with self class II MHC molecules on B-cells and induce apoptosis of macrophages by interacting with self class II MHC molecules on macrophages which release the highly antigenic apoptotic chromatin from the dying macrophages. This autoantibody production and release of antigenic macrophages chromatin is thought to contribute to the development of lupus-like autoimmunity.

• The metabolites of the offending drug are subjected to oxidative metabolism and serve as a substrate for myeloperoxidase; which is activated in polymorphonuclear neutrophils. This interaction results in the formation of reactive metabolites that directly affect lymphocyte function in the thymus making them auto-reactive. Virtually all lupus-inducing drugs undergo oxidative metabolism, whereas analogous non-lupus-inducing drugs do not. Also, both mouse and human studies implicate thymic activity in the pathophysiology of DILE.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Drug-induced lupus (DIL) is known to be caused by hundreds of different drugs.^[1] They are classified as high, moderate, low, or very low risk. While some drugs have good evidence of association with DIL, there are case reports implicating several other drugs as a possible cause of DIL. In addition, Several herbal medications have also been reported to cause a lupus-like syndrome. Procainamide and hydralazine have the highest incidence of causing DIL, with risks reported as high as 30% with procainamide and 5% to 10% with hydralazine. All anti-TNF agents have been associated with DIL, with the risk being higher with etanercept and infliximab. https://www.medsafe.govt.nz/profs/PUArticles/March2017/DrugInducedLupus.htm https://www.ncbi.nlm.nih.gov/books/NBK441889/

The processes that lead to drug-induced lupus erythematosus are not entirely understood. The exact processes that occur are not known even after 50 years since its discovery, but many studies present theories on the mechanisms of DIL.

A predisposing factor to developing DIL is N-acetylation speed, or the rate at which the body can metabolize the drug. Acetylation speed is generally a genetic factor. A study showed that 29 of 30 patients with DIL were slow acetylators. In addition, these patients had more hydralazine metabolites in their urine than fast acetylators.^[2] These metabolites (byproducts of the interactions between the drug and constituents in the body) of hydralazine are said to have been created when leukocytes (white blood cells) have been activated, meaning they are stimulated to produce a respiratory burst.^[3] Respiratory burst in white blood cells induces an increased production of free radicals and oxidants such as hydrogen peroxide.^[4] These oxidants have been found to react with hydralazine to produce a reactive species that is able to bond to protein.^[5] Monocytes, one type of leukocyte, detect the antigen and relay the recognition to T helper cells, creating antinuclear antibodies leading to an immune response.^[6] Further studies on the interactions between oxidants and hydralazine are necessary to understand the processes involved in DIL.

Of the drugs that cause DIL, hydralazine has been found to cause a higher incidence. Hydralazine is a medication used to treat high blood pressure. Approximately 12% of the patients who have taken hydralazine over long periods of time and in high doses have shown DIL-like symptoms.^[7] Many of the other drugs have a low to very low risk to develop DIL. The following table shows the risk of development of DIL of some of these drugs on a very to high scale.

• High risk:
  • Procainamide (antiarrhythmic)
  • Hydralazine (antihypertensive)
  • Isoniazid (antibiotic)

• Moderate to low risk:
  • Infliximab anti (TNF-α)
  • Etanercept anti (TNF-α)
  • Minocycline (antibiotic)
  • Pyrazinamide (antibiotic)
  • Quinidine (antiarrhythmic)
  • D-Penicillamine (anti-inflammatory)
  • Carbamazepine (anticonvulsant)
  • Oxcarbazepine (anticonvulsant)
  • Phenytoin (anticonvulsant)
  • Propafenone (antiarrhythmic)
• Herbal medications have also been linked to more lupus flares. These include:
  • alfalfa sprouts.
  • echinacea.
  • melatonin.

https://www.ncbi.nlm.nih.gov/books/NBK441889/

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

As a reminder, rheumatologic conditions tend to declare themselves over time, as opposed to immediately displaying all the classic clinical manifestations of the disease.

There is an inherited difficulty in distinguishing true drug-induced autoimmunity from an exacerbation of pre-existing autoimmunity or unmasking of a second autoimmune disease. It will become even more important to recognize medication-induced lupus syndromes given the expanding list of medications associated with DIL.

Here are possible differentials to DIL:

• Idiopathic systemic lupus erythematosus
• Systemic sclerosis (scleroderma)
• Rheumatoid arthritis
• Connective tissue diseases
• Granulomatosis with polyangiitis
• Fibromyalgia
• Lichen planus
• Chronic radiation dermatitis
• Rosacea
• Psoriasis
• Dermatomyositis
• Granuloma annulare
• Actinic keratosis

https://www.visualdx.com/visualdx/diagnosis/drug-induced+lupus+erythematosus?diagnosisId=51883&moduleId=101 https://www.thepermanentejournal.org/issues/43-the-permanente-journal/original-research-and-contributions/7458-drug-induced-lupus,-a-one-time-hit-or-a-harbinger-of-future-autoimmunity-a-case-report.html

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

• In the U.S.: As many as 10% of the approximately 500,000 cases of SLE may be DIL.
• It is estimated that 6 to 12% of all SLE cases are of drug-induced lupus type. The incidence has been reported to be of 15,000 to 30,000 per year in the U.S..^[1]

• There is no information about case-fatality rate on drug-induced lupus, but it can be potentially fatal. 16466117 ^[2]

Patients with DILE tend to be older (50–70 years old) than those with SLE (average age 29 years at diagnosis). Elderly persons generally are more susceptible to DILE.

In DIL, no significant statistical difference is apparent in the prevalence for males versus females. In contrast, SLE affects women with considerably higher frequency than men (female-to-male ratio of 9:1).

More whites than blacks develop DIL; more blacks than whites present with SLE.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

• Infection
• Thrombocytopenia purpura — bleeding near the skin surface, resulting from a low number of platelets in the blood
• Hemolytic anemia
• Myocarditis
• Percarditis

Prognosis of drug-induced lupus erythematosus is better than systemic lupus erythemathosus. Symptoms usually disappear within several days to weeks after stopping the medication that caused the condition.

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