Drug-induced lupus erythematosus M32.0

The discovery of drug-induced lupus erythematosus (DILE) is usually attributed to BJ Hoffman, who first reported lupus-like symptoms after treatment with sulfadiazine in 1945 (Hoffman BJ (1945). Later, in 1985, hydrochlorothiazide was reported to induce subacute cutaneous lupus erythematosus (SCLE), leading to the concept of "drug-induced SCLE" (Reed BR et al. 1985). To date, over 100 drugs from different drug categories have been associated with DILE. For a long time, only procainamide and hydralazine were considered high-risk drugs with a relevant risk (Yokogawa N et al. 2009) of developing DILE. These drugs no longer play a major role in clinical practice. However, cases of DILE caused by newer oncological drugs and biological modulators are increasing (Bukhari M 2012).

Drug-induced lupus erythematosus" or "drug-induced LE" describes a lupus-like syndrome that is associated with the use of medication and regresses after the drug is discontinued. Drug-induced lupus erythematosus (DILE) is a lupus-like autoimmune disease that usually occurs with chronic exposure to certain medications (months to years) and resolves after discontinuation of the triggering medication.

• Similar to idiopathic lupus, drug-induced LE can be divided into three main forms:
• Drug-induced systemic lupus erythematosus (DILE)
• Drug-induced subacute cutaneous lupus erythematosus (DISCLE)
• Drug-induced chronic cutaneous lupus erythematosus (DICLE).

The latter two forms could also be defined as drug-induced cutaneous lupus erythematosus (DICLE). Patients taking different medications may also develop different forms of DILE, whose clinical manifestations and serologic features may vary considerably.

Drug-induced lupus erythematosus accounts for 6 to 12% of all lupus cases, with an annual incidence of 15,000 to 30,000 new cases per year (US data). The epidemiology of DIL reflects the population taking the drug responsible for DIL. Minocycline-induced lupus is more common in younger women, while the now rare procainamide- or hydralazine-induced lupus is more common in older people.

The pathophysiology of DIL is unclear. Different mechanisms are responsible for the induction of autoimmunity by various lupus-inducing drugs. There are some genetic risk factors such as HLA-DR4, HLA-DR0301 and the complement C4 null allele, which vary depending on the drug. Slow acetylators with a genetic deficiency of N-acetyltransferase are at higher risk for DIL, especially from procainamide and hydralazine.

Drugs associated with DILE have different chemical structures, such as aromatic amines, hydrazine and sulfhydryl groups, suggesting that there is no single chemical configuration for DILE (Yung RL et al. 2011). Four categories of drugs can be distinguished:

Drugs that

• definitely
• probably
• possibly and
• recently

have been characterized as DILE-inducing (Chang C et al. 2010). Drugs can also be categorized by risk level into high, medium, low or very low risk categories. The most common drugs that cause systemic DILE are (see also Gronhagen CM et al.2012):

• Hydralazine (high risk)
• Procainamide (high risk)
• Isoniazid (medium risk)
• Minocycline (very low risk)
• Terbinafine
• Proton pump inhibitors (PPI)
• Tumor necrosis factor-alpha inhibitors (very low risk) (Aguirre Zamorano MA et al. 2010; He Y et al. 2018).
• Immunomodulators(leflunomide)
• Antiepileptic drugs
• Chemotherapeutic agents.

Proton pump inhibitor (PPI)-induced SCLE: These SCLE cases are becoming increasingly common (proton pump inhibitors (PPI) reduce gastric acid secretion by inhibiting the K+/H+ -ATPase pump in the parietal cells of the stomach. In a case-control study, 66 of 234 SCLE cases from Sweden were found to be associated with PPIs Gronhagen CM et al.2012). A recent retrospective review of 88 DISCLE cases found PPIs to be among the most common drug classes involved in causing LE (Michaelis TC et al. 2009; Laurinaviciene R et al. 2017)

The most common drugs that trigger chronic cutaneous DILE are:

• Fluorouracil compounds or their modern derivatives such as capecitabine(Merlin F et al. 2008).

Apparently, the inhibition of DNA methylation leads to the development of DIL. Demethylation of CD4+ T cells makes them autoreactive by overexpression of the LFA-1 adhesion molecule. These autoreactive T cells can then overstimulate autoantibody production by interacting with class II MHC molecules on B cells and induce apoptosis of macrophages by interacting with class II MHC molecules on macrophages, which release the highly antigenic apoptotic chromatin from the dying macrophages. This autoantibody production and release of antigenic macrophage chromatin is thought to contribute to the development of lupus-like autoimmunity

A genetic predisposition plays a role in the development of DILE. Drugs such as procainamide, hydralazine and isoniazid contain an aromatic amine or hydrazine structure and are mainly metabolized by acetylation using N-acetyltransferases (Yung RL et al. 2011). The majority of patients with procainamide- or hydralazine-induced lupus erythematosus are slow acetylators. They are more susceptible to autoantibody accumulation after exposure to procainamide or hydralazine compared to fast acetylators (Strandberg I et al. 1976). In contrast, isoniazid-mediated DILE appears to be less related to the acetylator phenotype, although isoniazid is also metabolized by acetylation.

HLA: An association between the occurrence of DILE and certain human leukocyte antigens (HLA) such as HLA-DR2, HLA-DR3, C4A and C4B class III zero complement alleles is suspected. The results require further confirmation (Russell GI et al. 1987).

Complement system: It is known that hydralazine, penicillamine, isoniazid and metabolites of procainamide are potent inhibitors of the covalent binding reaction of complement component C4, which could inhibit the activation of complement component C3 in the classical complement pathway and hinder the clearance of immune complexes.

Drug biotransformation: Procainamide is oxidized by activated neutrophils, leading to the formation of the cytotoxic metabolite procainamide hydroxylamine (PAHA). PAHA interferes with the central tolerance of T cells, leading to the production of autoreactive T cells that may trigger autoimmunity. Similarly, hydralazine can disrupt B cell tolerance and contribute to the development of pathogenic autoreactivity by interfering with receptor editing through inhibition of the ERK signaling pathway (Mazari L et al. 2007). Quinidine and procainamide at therapeutic concentrations have been reported to inhibit the uptake of apoptotic thymocytes by macrophages, which could make these accumulated cells a source of uncontrolled uptake of self-antigens in certain situations (Mazari L et al. 2007).

Autoantibodies against myeloperoxidase have been found in the serum of DILE patients (Nassberger L et al. 1990). Other drugs, including hydralazine, quinidine, phenytoin, sulfone, penicillamine, chlorpromazine and isoniazid, undergo similar biotransformation as procainamide, resulting in reactive metabolites that can trigger DILE. In contrast, small molecule drugs can bind to proteins and stimulate immune reactions after binding (Chang C et al. 2010).

Epigenetic dysregulation in adaptive immune cells and other mechanisms of autoreactivity

Hydralazine and procainamide inhibit the DNA methylation of T cells (Cornacchia E et al. 1988). Demethylation of CD4+ T cells renders them autoreactive by overexpression of the LFA-1 adhesion molecule. Procainamide, for example, is a competitive DNA methyltransferase inhibitor, while hydralazine prevents the induction of DNA methyltransferase by inhibiting the ERK signaling pathway.

These autoreactive T cells can then overstimulate autoantibody production by interacting with class II MHC molecules on B cells and induce apoptosis of macrophages by interacting with class II MHC molecules on macrophages, which release the highly antigenic apoptotic chromatin from the dying macrophages. It is hypothesized that this autoantibody production and the release of antigenic macrophage chromatin contribute to the development of lupus-like autoimmunity.

Arthralgia is common and often the first symptom, occurring in up to 90% of patients. Constitutional symptoms such as myalgia, fever and weight loss are also common. Skin involvement is common and may include photosensitivity, purpura, erythema nodosum, and subacute cutaneous lupus erythematosus (SCLE) rash. Scarring alopecia, discoid lesions and mucosal ulcers occur less frequently in DIDIL than in DISLE. Serositis, especially pleuritis, is also common. Although pericarditis has been rarely reported in DIDIL as a consequence of some drugs, large pericardial effusions or cardiac tamponade rarely occur in DIL.

Hydralazine-induced lupus is often manifested by arthralgia, myalgia, fever, rash (a rash around the cheeks is common), hepatosplenomegaly, lymphadenopathy and pleuritis. Rare cases of glomerulonephritis, neuropsychiatric manifestations and pericarditis have been reported. While arthralgia, myalgia, fever and pleurisy are common in procainamide-induced lupus, rash and lymphadenopathy are less common and glomerulonephritis or CNS involvement are rare. Minocycline-induced lupus is usually characterized by fever, arthralgia, arthritis, rash and, rarely, pneumonitis and cutaneous vasculitis.

Positive autoantibodies have frequently been reported with anti-TNF agents. In patients treated with anti-TNF agents, positive autoantibodies such as ANA and anti-dsDNA occur frequently (up to 50 %). Only a few patients develop DILE (<1%). Skin rash, thrombocytopenia, leukopenia, hypocomplementemia and rarely hemolytic anemia are the manifestations of DIL as a result of anti-TNF agents. It is noteworthy that the development of DILE from one anti-TNF agent does not always lead to DILE from another anti-TNF agent. The symptoms of DILE resolve within a few weeks to months after discontinuation of the anti-TNF agent, but the autoantibodies may remain positive for several years.

Both interferon-alpha and interferon-beta have been associated with the development of DILE. As with anti-TNF agents, the development of autoantibodies, including ANA and anti-dsDNA, is common, while DIL occurs in less than 2% of cases. Arthralgia, arthritis and leukopenia are common symptoms.

Subacute cutaneous lupus erythematosus (SCLE) can be idiopathic, but is drug-induced in about one-third of cases. Hydrochlorothiazide is the classic drug associated with SCLE. Other medications that have been reported to cause SCLE include terbinafine, anti-TNF agents, antiepileptic drugs, proton pump inhibitors, nonsteroidal anti-inflammatory drugs, antiarrhythmic drugs, calcium channel blockers, and ACE inhibitors. The rash occurs in a photodistribution. Morphologically, SCLE presents as a papulosquamous psoriasiform to lichenoid skin appearance, but may also have a scaly annular morphology with central clearing. DISCLE is associated in more than 3/4 of cases with anti-Ro/SSA positivity, speckled ANA and 30% positivity with anti-La/SSB.

The guidelines for DILE developed by Xiao and Chang (Xiao X et al. 2014) can help confirm a diagnosis of DILE. In particular, the diagnosis of DILE must be made after a clinical examination, a review of medication and medical history, and a comprehensive assessment of the disease over time following exposure to the causative drug and withdrawal. Symptoms may include LE arthritis, serositis, antinuclear and anti-histone antibodies, in addition to various skin manifestations similar to those known to be non-drug induced.

Recognizing and discontinuing the suspected drug is the first and most important step in the treatment of DILE. As this is a self-limited disease, symptomatic treatment measures are preferable.

Drug-induced lupus can develop several weeks to several months after the start of medication, which can complicate the diagnosis. Furthermore, it is not possible to distinguish this clinical picture from SLE on clinical features alone, although DILE tends to be milder and renal or CNS involvement, vasculitis, leukopenia and pericarditis are rare.

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