Drug induced cutaneous lupus erythematosus L93.1

The discovery of drug-induced cutaneous lupus erythematosus (DI-LE) is attributed to BJ Hoffman, who first reported "lupus-like symptoms" after treatment with sulfadiazine in 1945.

Drug-induced cutaneous lupus erythematosus (DI-CLE) is a drug-induced and driven, often photosensitive, reversible, autoimmunological abnormal reaction in which the intake of the drug leads to symptoms similar to lupus erythematosus after a latency period of varying length (a few weeks to years!). Photosensitivity is found in about 80% of patients (Black et al. 2002).

Based on the clinical symptoms, drug-induced cutaneous lupus erythematosus (DI-CLE), adapted to the classification of idiopathic lupus erythematosus, is divided into 3 skin groups, the:

• drug-induced acute cutaneous lupus erythematosus (DI-ACLE) as a cutaneous manifestation of drug-induced systemic lupus erythematosus
• drug-induced subacute cutaneous lupus erythematosus (DI-SCLE)
• drug-induced chronic cutaneous lupus erythematosus (DI-CCLE).

The independence of Di-SCLE and DI-CCLE has not yet been established. Di-CCLE occurs preferentially in the picture of drug-induced subacute cutaneous lupus erythematosus. Drug-induced chronic discoid lupus erythematosus (DI-CCLE) is a rather rare clinical manifestation.

Drug-induced lupus erythematosus affects 6% to 12% of the total clinically diagnosed pool of lupus erythematosus cases (based on all DI-LE variants). The annual incidence is 15,000 to 30,000 per year (figures for the US population / Chang C et al. 2011). It should be noted that, by definition, these incidences only reflect the population that has taken the medication in question. If the total collective of DI-LE patients is analyzed according to their clinical subgroups, the following distribution pattern emerges:

• 41.4% cases with systemic DI-LE (w= 75%; m=25%) - DI-ACLE.
• 37.9 % cases with DI-SCLE
• 20.7 % cases with DI-CLE without further clinical differentiation. This group also includes the rare drug-induced chronic LE (DI-CCLE /He Y et al. 2018). This shows that the subacute cutaneous lupus variant (DI-SCLE) is the most common clinical manifestation in the overall collective of drug-induced cutaneous lupus erythematosus (DI-CLE). Older female patients are preferentially affected (Lowe GC et al. 2011). The rare drug-induced chronic cutaneous LE (discoid or tumidus type = DI-CCLE) is often associated with the use of fluorouracil-containing drugs (Marzano AV et al. 2009).

The pathogenic mechanisms that could explain why different drugs with heterogeneous chemical structures and functions lead to autoimmunity are still only partially understood (Yung RL et al. 2011). Obviously, however, a complex immunobiological scenario is a prerequisite for this drug-induced, dysbalanced, pathological immune response. The symptoms of drug-induced lupus can begin a few weeks after the application of a new medication. However, periods of several months up to 10 years are also known (see classification below)

DI-LE and genetics:

• HLA: For many years, a connection between the occurrence of DI-LE and certain human leukocyte antigens (HLA) such as HLA-B8, HLA-DR2, HLA-DR3, HLA-DQw2, HLA-DRw5 has been suspected. The results of various studies are not congruent in this respect. The results of various studies are not congruent in this respect (Batchelor JR et al. 1980; Russell GI 1987).
• Complement system: The complement system could also play a role in the aetiopathology of DILE (Sim E et al. 1989). For example, hydralazine, penicillamine, isoniazid and procainamide are strong inhibitors of the covalent binding reaction of complement component C4, which inhibits the activation of complement component C3 in the classical complement pathway. The result is an obstruction in the elimination of immune complexes.
• Disruption of acetylation (polymorphisms in the NAT2 gene): Known lupus erythematosus-triggering drugs such as procainamide, hydralazine and isoniazid contain structures of aromatic amines or hydrazines. These are mainly metabolized by acetylation under the catalytic influence of the enzyme N-acetyltransferase 2 (Yung RL et al. 2011) and then excreted. Polymorphisms in the coding NAT2 gene are responsible for the different types of acetylation. In the human population, a distinction is made between phenotypes with rapid, intermediate and slow acetylation. Polymorphisms in the NAT2 gene can be associated with fundamental disorders of the detoxification process of pharmaceuticals, which is associated with higher drug toxicity. Since N-acetyltransferase-2 also plays an important role in the neutralization of reactive oxygen species, NAT2 polymorphisms can lead to an imbalance in the antioxidant systems and cause autoimmunological reactivity. It is suspected that this mechanism could also play a role in the pathogenesis of vitiligo (Srivastava DSL et al. 2020), as there is a significantly higher risk of vitiligo in various genotypes of slow acetylators (Bazid HAS et al. 2024).
• The majority of patients with procainamide or hydralazine-induced lupus erythematosus are also slow acetylators. They are more susceptible to the initiation and accumulation of autoantibodies after procainamide or hydralazine exposure compared to fast acetylators (Perry HM Jr et al. 1970; Strandberg I et al. 1976; Woosley RL et al. 1978).

Drug biotransformations: Procainamide is oxidized by activated neutrophils, resulting in the formation of a toxic metabolite (procainamide hydroxylamine/PAHA). PAHA contributes to cytotoxicity together with myeloperoxidase (MPO) and reactive oxygen species. In addition, autoantibodies against myeloperoxidase have been found in the serum of DILE patients, indirectly supporting the role of myeloperoxidase-mediated metabolism in the development of DI-LE (Nassberger L et al. 1990). Other drugs, including hydralazine, quinidine, phenytoin, penicillamine, chlorpromazine and isoniazid, undergo similar biotransformation as procainamide, resulting in reactive metabolites that can trigger autoreactivity with DI-LE symptoms (Chang C et al. 2010).

Epigenetic dysregulation/epigenetic dysregulation in adaptive immune cells and other mechanisms of autoreactivity: It is known that LE-inducing drugs or their metabolites alter the epigenetic properties of immune cells. It has been shown that hydralazine and procainamide inhibit the DNA methylation of T cells (Cornacchia E et al. 1988). DNA hypomethylation in T cells leads to increased expression of LFA-1 (lymphocyte function-associated antigen 1), a cytokine (integrin) that is expressed by lymphocytes and other leukocytes. This signaling can in turn induce autoreactivity (Quddus J et al. 1993).

Other studies suggest that toxic metabolites, such as the "procainamide hydroxylamine/PAHA" metabolite, interfere with the central tolerance of T cells, which in turn leads to the production of autoreactive T cells. Similarly, hydralazine can undermine B cell tolerance and contribute to the development of pathogenic autoreactivity by interfering with receptor editing through inhibition of the ERK signaling pathway (Kretz-Rommel A et al. 1997). Furthermore, it is known that quinidine (no longer commercially available) and procainamide in therapeutic concentrations inhibit the uptake of apoptotic thymocytes by macrophages. Under certain circumstances, such accumulated apoptotic cells could in turn lead to uncontrolled autoantigenic symptoms.

Photosensitivity: Photosensitivity exists in the different DI-LE variants. It is also possible that drugs that have a photosensitizing effect per se can trigger immunological misreactions in perceptive organisms. In this constellation, increases in local type I interferon production and downstream molecules such as chemokine (C-X-C motif) ligand 9 (CXCL9) are known.

NETosis: The process of NETosis may also play a role in DI-LE pathogenesis. NETosis refers to a unique mechanism of neutrophil cell death. The core element of netosis are "neutrophil extracellular traps", or NETs for short, networks of cell-free DNA and proteins that are shed by activated neutrophil granulocytes. The process of NETosis is primarily designed to capture pathogens and attack these pathogenic microorganisms with antimicrobial proteins such as elastase and cathepsin G, while at the same time activating the immune system. During the process of NETosis, autoantigenic nuclear material and granular proteins can be released extracellularly, a process that potentially induces autoimmunity (Grayson PC et al. 2016). Since 2018, the LE-inducing drugs procainamide and hydralazine have been known to promote NET formation (Irizarry-Caro JA et al. 2018). However, other drugs such as minocycline and clozapine, both of which are also potentially DI-LE-inducing, do not trigger NETosis. Further studies are therefore needed to better understand the mechanism of drug-induced NETosis in DI-LE (He Y et al. 2019).

The age of manifestation of DI-CLE varies and depends on the time of exposure to the triggering drug. For example, minocycline-induced lupus erythematosus occurs more frequently in younger women, while procainamide- or hydralazine-induced lupus erythematosus occurs more frequently in an older population. Di-LE can also occur in children. Ethosuximide (antiepileptic drug) and minocycline (antibiotic) are the most common triggering drugs.

Areas exposed to light: face (whereby the center of the face and the periorbicular region tend to be left out), upper thorax, arms.

Acute or chronically active, few or numerous, disseminated, sharply or blurredly defined, 0.2-5.0 cm (rarely > 10.0 cm), disc-shaped, annular or gyrated, red or red-brown spots or plaques with a smooth or crusty surface. Blistering is possible. Erythema multiforme-like skin lesions are also possible. In these cases, it can be difficult to differentiate from Rowell syndrome. Rowell's syndrome is a clinical variant of acute or subacute cutaneous lupus erythematosus, which is characterized by the occurrence of annular or multiforme plaques.

With regard to systemic involvement, arthralgias are common and often indicative of DI-LE. They occur in up to 90 % of patients. Constitutional symptoms such as myalgia, fever and weight loss as well as skin involvement are also common. Photosensitivity, hemorrhagic exanthema, erythema nodosum, cicatricial alopecia, disc-shaped lesions and mucosal ulcers occur less frequently in DIL than in SLE. Serositis, especially pleuritis, is frequently observed. Hydralazine-induced lupus often manifests itself in the form of arthralgias, myalgias, fever, facial exanthema, hepatosplenomegaly, lymphadenopathy and pleuritis. Other systemic complications such as glomerulonephritis, neuropsychiatric manifestations and pericarditis are rare. Procainamide-induced lupus erythematosus manifests itself primarily in the form of arthralgias, myalgias, fever and pleuritides. Exanthema and lymphadenopathies are rarer. Glomerulonephritis or CNS involvement are equally rare. Minocycline-induced lupus erythematosus is mainly characterized by fever, arthralgia, arthritides, exanthema; less frequently by pneumonitis or cutaneous vasculitis. The autoimmunity triggered by TNF-alpha antagonists is often conspicuous by the occurrence of positive autoantibodies, including ANA and anti-dsDNA (up to 50 %). Only a few patients develop DI-LE (<1%) with exanthema, thrombocytopenia, leukopenia, hypocomplementemia and, less frequently, hemolytic anemia. The symptoms of DI-LE subside within a few weeks to months after discontinuation of the anti-TNF drug, but the autoantibodies can remain positive for several years.

Laboratory values, especially antibody profiles, are inconsistent. It is noteworthy that the autoantibodies can remain positive for several months to years regardless of clinical symptoms. They must then continue to be interpreted as an expression of the immunological imbalance.

In 75% of cases, higher titers of ANA antibodies, more rarely anti-DNA antibodies. Particularly characteristic is the detection of anti-SSA/Ro antibodies (about 50% of cases) and anti-SSB/La antibodies. Possibly leukopenia (cytopenia), hypergammaglobulinemia.

Light-stressed exanthema is the most common clinical manifestation of drug-induced lupus erythematosus. The histopathology is similar to that of idiopathic SLE. It is not suitable for differentiating between the two clinical pictures. Subacute cutaneous lupus erythematosus (SCLE) is characterized by a vacuolar interface dermatitis with perivascular lymphohistiocytic infiltrates in the upper dermis, epidermal atrophy with apoptotic keratinocytes. Skin biopsies do not lead to significant differences between DI-LE and SLE. They should be performed on suspicious skin lesions to rule out other causes.

Recognizing and strictly avoiding the potentially triggering and damaging medication is the first and most important step in the treatment of DI-LE and Di-CLE. In everyday practice, the connections between clinical symptoms and medication are easily overlooked. The reasons for this are the often delayed manifestation between taking medication and the onset of symptoms. This distinguishes Di-CLE from most other known ADRs in which the connection between clinical symptoms and the medication administered is usually evident from the chronological sequence.

NSAIDs or low-dose corticosteroids can be used systemically for mild symptoms. High-dose corticosteroids should be reserved for systemic symptoms such as severe arthralgia or pericardial effusions.

External therapy: External mild glucocorticoids may be administered. They are only moderately helpful. Solar protection in both the UVB and UVA spectrum is important!

In principle, it can be stated that drug-induced lupus is generally less severe than its idiopathic non-drug-induced counterpart and that its symptoms subside after weeks to months following discontinuation of the drug in question.

More than a hundred medications are mentioned in connection with lupus erythemAtodes. While for some medications there is good evidence of an association with DI-LE, for others there are case reports that consider several other concomitant medications as a possible cause of DIL. In principle, drugs known to cause DI-LE can be categorized by risk level as high, medium, low or very low risk (Sarzi-Puttini P et al. 2005; Pretel M et al. 2014). This is useful from a clinical point of view for quicker orientation. Well-known high-risk drugs are hydralazine and procainamide. Isoniazid is a medium-risk drug, minocycline is a very low-risk drug. In addition, there are numerous chemotherapeutic agents and, more recently, various biologics such as TNF-α inhibitors (He Y et al. 2018; Shovman O et al. 2018). Reports of DI-LE due to antihypertensive and antifungal drugs (e.g. griseofulvin) are decreasing again due to their lower consumption (Michaelis TC et al. 2009). In this context, drugs that preferentially trigger other autoimmunological symptoms such as systemic sclerosis of the pulmonary vessels should also be considered. These include hydrochlorothiazide, calcium channel blockers and ACE inhibitors.

DI-SCLE (overview of triggering drugs)

DI-SCLE: In a population-based case-control study, the association between certain suspected drugs and SCLE was determined, with:

• Terbinafine (OR 52.9)
• TNF-α inhibitors (OR 8.0)
• Antiepileptic drugs (OR 3.4) and
• proton pump inhibitors (PPIs/OR 2.9) were found to have significantly increased odds ratios (ORs). PPIs-associated DI-SCLE has only been observed more frequently in recent years. In a large Swedish SCLE collective (n= 234 SCLE cases), around 30% showed an association with PPIs (Gronhagen CM et al. 2012). This trend is also evident in other large LE collectives (Sandholdt LH et al. 2014; Michaelis TC et al. 2009).

Fluorouracil compounds, capecitabine, NSAIDs, TNF-alpha antagonists and voriconazole are associated with the rare drug-induced chronic cutaneous LE (DI-CCLE) (Yoshimasu T et al. 2001; Merlin F et al. 2008).

Di-CLE-inducing drugs in detail (the preparations listed are documented by individual casuistics; no further clinical assignment to the individual CLE subtypes has been made). Thus, the list of DI-CLE-triggering drugs does not provide a constant overall clinical pattern as is the case with the well-described subtypes of idiopathic CLE.

Drugs that are highly likely to be associated with DI-CLE (in alphabetical order):

• Carbamazepine
• quinidine
• chlorpromazine
• ethosuximide
• Interferon-alpha
• isoniazid
• methyldopa
• minocycline
• penicillamine
• phenytoin
• Propylthiouracil
• Quinidine (antiarrhythmic drug)
• rifampicin
• Sulfasalazine.
• Drugs likely to be associated with DI-CLE include (in alphabetical order):
• ACE inhibitors
• Antiarrhythmics
• Proton pump inhibitors (PPIs)
• gold salts
• non-steroidal anti-inflammatory drugs (NSAIDs)
• oral contraceptives

Drugs that are likely to be associated with DI-SCLE include (in alphabetical order)

• antibiotics
  • Minocycline (200 mg/day- 2 years)
  • Trimethoprim/sulfamethoxazole (1 week)
• Antidiabetics:
  • Sulfonylureas
• Antihypertensives
  • Captopril
  • Cilazapril
  • Hydrochlorothiazide (light sensitization with increased carcinoma rate of the skin
  • Hydralazine (anthypertensive/50mg) (1-18 months), antimycotics
    • Griseofulvin
    • Terbinafine (also with topical application >36 months)
• Chemotherapeutics: The highest class of drugs associated with DI-SCLE were:
  • Anastrozole (aromatase inhibitor/16 months)
  • Capecitabine (chemotherapeutic agent/ 1.5 months
  • carboplatin
  • docetaxel
  • Doxorubicin (topoisomerase II inhibitors)
  • Gemcitabine (1 month)
  • Hydroxyurea (chemotherapeutic agent/1500 mg/day/ 36 months)
  • Mitotane (cytostatic/300 mg/1 month)
  • Palbociclib (chemotherapeutic agent, 2 months)
  • Pirfenidone (antifibrotic therapeutic agent, 8 weeks)
  • Tislelizumab (PD-1 inhibitor)
• Immunoglobulins/IVIG (0.8-1.3 g/kgKG/month/ 0.5-22 months)
• Interferons
  • Interferon alpha-2a (5 months/ exanthematic "lupus-like-disease" was described)
  • Interferon beta
• Proton pump inhibitors (PPIs):
  • Omeprazole (photosensitivity, multiforme exanthema, TEN, Stevens-Johnson syndrome);
  • pantoprazole
• TNF-alpha inhibitors (all anti-TNF agents are associated with DI-LE, although the risk is higher with etanercept and infliximab than with adalimumab.
  • Etanercept
  • Infliximab (3-36 months)
  • Adalimumab (24 months)
• Other:
  • Cinnarizine (calcium channel blocker)
  • Clozapine (neuroleptic/25 mg/day/8 days)
  • Emtricitabine/Rilpivirine/Tenofovir/ Disoproxil fumarate (combination drug/antiretroviral therapy/ 36 months)
  • Leflunomide (dihydroorotate dehydrogenase inhibitor/20 mg/day/ 36 months)
  • Piroxicam (non-steroidal anti-inflammatory drug)
  • Procainamide (antiarrhythmic drug)
  • Prifenidone (antifibrotic medication)
  • Ranitidine (H2 receptor antagonist)
  • Spironolactone (mineral corticoid receptor antagonist)
• Drugs that can induce chronic lupus erythematosus include (Solhjoo M et al. 2024):
  • Fluorouracil derivatives
  • Non-steroidal anti-inflammatory drugs
  • TNF-alpha inhibitors
  • Voriconazole

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