drug-induced bullous pemphigoid L12.0

Drug-associated bullous pemphigoid (DABP) refers to cases of bullous pemphigoid that have clinical, histologic or immunopathologic features identical or analogous to those of the idiopathic form of bullous pemphigoid and that are associated with the systemic application or topical use of certain drugs. There are >170 publications in this context.

An association between BP and certain major histocompatibility complex(MHC) class II alleles is hypothesized. In particular, a significant association was found with the human leukocyte antigen DQβ1*0301 allele in populations of European ancestry (Zakka LR et al. 2011).It has been shown that although these results apply to populations of European ancestry, other alleles may also play a role in other populations (Sun Y et al. 2018). In the Japanese population, a significant association was found with the alleles HLA-DRβ1*04, HLA-DRβ1*1101 and HLA-BDB1*0302 (Okazaki A et al. 2000). These HLA alleles are associated with the recognition of conserved epitopes of BMZ antigens in patients with BP, which may contribute to the induction of autoimmunity (Thoma-Uszynski S et al. 2006). Furthermore, BP180-specific Th1 and Th2 cells have been shown to be restricted to the HLA-DQB1*0301 allele, with the Th1 phenotype also present in individuals without clinical signs of the disease. Whether the predisposing alleles are identical in idiopathic and drug-associated bullous pemphigoid (DABP) is still unclear (Fan WL et al. 2017).

The pathogenesis of the drug reaction in DABP is based on the assumption that drugs act as triggers in people with an underlying genetic predisposition and lead either to an intensification of the immune reaction or to a change in the antigenic properties of the epidermal BMZ. Drugs can alter these antigenic properties by binding to molecules in the lamina lucida of the BMZ, thereby acting as neoantigens and inducing the formation of anti-BMZ antibodies. Alternatively, they can structurally modify molecules and expose previously hidden epitopes, thereby stimulating the immune response. A "two-step" theory has been proposed that two different drugs can induce the disease, which has been observed in BP and other related bullous dermatoses (Shachar E et al. 1998).

Thiol-based drugs. It is known that the vast majority of thiol drugs contain or release sulfhydryl groups, either in the precursors or in the degraded metabolite (Walsh SR et al. 2005).Thiol drugs are capable of structurally altering the molecule to either act as haptens or expose epitopes, leading to the formation of anti-BMZ antibodies.

Alternatively, metabolism of these thiol drugs via an independent, non-immunologic mechanism may disrupt the integrity of the dermo-epidermal junction in the BMZ, which is achieved by interaction with the sulfhydryl groups in desmosomes. Certain thiol drugs, e.g. penicillamine, are able to reduce the activity of regulatory T cells (Treg), allowing the hyperproduction of autoantibodies against the antigens of the BMZ (Durdu M et al. 2011). These mechanisms synergistically favor the onset and progression of

DABP was originally considered a separate disease when Bean et al. observed a bullous skin eruption in an 11-year-old boy after administration of salicylazosulfapyridine in 1970.

Since that first case, just over 90 drugs have been linked to causing BP. While these case reports often describe tentative associations with drug administration based on temporal relationship or analogies to previously reported cases, a causal relationship often remains unclear. These clinical assessments are naturally subjective, especially since monomedication is rare.

Anti-inflammatory medication. Non-steroidal anti-inflammatory drugs (NSAIDs) were one of the first substances to be associated with the development of BP. There are now 13 cases described in the literature involving 8 different NSAIDs that differ in their structural composition and suspected mechanism of BP initiation. Celecoxib contains a sulfonamide group that is considered a hapten due to covalent bonds between macromolecules and reactive sulfonamide intermediates (Yang D et al. 2006). Aspirin is also thought to act as an autoimmune hapten, which other authors dispute (Lloyd-Lavery A et al. 2013). Sulfasalazine contains a sulfhydryl group, which is thought to be responsible for triggering an autoimmune response by acting as a hapten on basement membrane structures, and may have some cross-reactivity with the commonly used treatment dapsone.

Diuretics. Several classes of diuretics have been associated with DABP in 22 case reports, including loop diuretics, thiazide diuretics and aldosterone antagonists (Lloyd-Lavery A et al. 2013).

Loop diuretics, in particular furosemide, are sheer indicator drugs (Bene J et al. 2016). Loop diuretics are thiol-based drugs. Similarly, thiazide diuretics and aldosterone antagonists are also sulfur-containing diuretics that lead to similar pathogenetic mechanisms. A strong association with aldosterone antagonists was found in several case-control studies (Bastuji-Garin S et al. 2011).

Cardiovascular drugs (antihypertensives, antiarrhythmics, anticoagulants and statins). Antihypertensives have been identified as potential contributory factors in numerous cases of BP, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor II antagonists and calcium channel blockers (CCBs). ACE inhibitors containing sulfhydryl groups, in particular captopril, are suspected, although a plausible hypothesis on the underlying pathogenesis with a similar molecule, D-penicillamine, supports this assumption (Mallet L et al. 1989).

Antiarrhythmic drugs have also been described in a limited number of case reports. The corresponding data situation is rather modest.

Antibiotics. Antibiotics are relatively rarely mentioned in connection with DABP. A British case-control study showed that patients with BP took antibiotics significantly more frequently than the control group (Lloyd-Lavery A et al. 2013). Possible drugs: penicillins, cephalosporins, quinolones, nitroimidazoles, actinomycin and annamycin. During metabolization, penicillins release a sulfhydryl group, which is probably involved in the pathogenesis of the drug reaction.

Quinolones are described in three case reports of DABP. Levofloxacin does not contain a sulfhydryl group, yet it is suspected that levofloxacin acts as a hapten, as antibodies against BP180 were detected in the serum of affected patients. A similar pathogenesis hypothesis has been described for ciprofloxacin.

Antimycotics, in particular griseofulvin and terbinafine, have been documented as triggers of BP. These agents have no similarities in their mechanism of action or molecular structure and, most importantly, neither agent contains a sulfhydryl or phenyl group.

Gliptins. There is ample evidence of an association between dipeptidyl peptidase 4 inhibitors (DPP4i), oral antidiabetic agents often used with metformin for the treatment of type 2 diabetes mellitus, and the development of BP. Several case reports refer to vildagliptin, sitagliptin, linagliptin, anagliptin and alogliptin as triggering agents.

The exact pathogenesis underlying the link between DPP4i and BP remains unclear. DPP4 is a plasminogen receptor expressed on the surface of cells that can activate plasminogen, resulting in the production of plasmin, a basic serine protease. Plasmin is known to cleave the immunodominant domain NC16A of BP180, which can subsequently be detected in the skin of the lesion and in the fluid that accumulates in the associated blisters. Numerous cell types in the dermis and epidermis, including keratinocytes, are known to express DPP4, which, when inhibited by DPP-4, can enhance the recruitment of eosinophils into the dermis by the chemokine eotaxin (CCL11) and other proinflammatory cytokines.

Anti-inflammatory drugs. D-penicillamine and its analog tiobutaritol have been linked in several case reports of DABP. D-penicillamine contains a characteristic sulfhydryl group that is thought to be responsible for the underlying pathogenesis of the drug reaction. These thiol drugs are thought to reduce the activity of Treg, allowing the overproduction of autoantibodies against the antigens of BMZ. Penicillamine-associated BP occurs late in treatment and in a non-dose-dependent manner. Interestingly, penicillamine-associated bullous dermatoses with combined features of pemphigus and pemphigoid have also been described (Rasmussen HB et al. 1989).

Biologics. Numerous case reports and case series in the literature increasingly report biologics as triggers of BP.

Tumor necrosis factor-α (TNFα) is a multifunctional proinflammatory cytokine that is involved in a variety of systemic diseases. In this context, antagonists of TNFα have emerged as an essential treatment in several autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease and psoriasis. BP has been linked to TNFα inhibitors in several case reports. Suspected agents include the recombinant fusion protein (etanercept) and the monoclonal antibodies (adalimumab, efalizumab and infliximab) (Ricci M et al. 2014). One theory to explain this apparent correlation could be that the ability of these agents to induce or even treat autoimmune diseases is related to the immunological profile, in particular the levels of IL-4 and IFN-γ. It is hypothesized that TNFα inhibitors may suppress both Th1 and Th2 responses in certain diseases. However, TNFα inhibitors have also been shown to increase the production of autoantibodies. Whether this is involved in the pathogenesis of DABP is unclear, although analogous autoimmune diseases have been induced and exacerbated during treatment with TNFα inhibitors (Mongey A-B et al. 2008). The IL-2 receptor is known to be expressed at significantly higher levels in BP and correlates with disease activity.

PD1 inhibitors targeting the programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) signaling pathways are able to enhance intrinsic inhibitory control of the immune system, particularly T-cell suppression. While this leads to an enhanced anti-tumor response, the non-specific activation of the immune system causes numerous immune-related adverse events (irAEs). PD-1/PD-L1 inhibitor-associated dermatologic toxicity accounts for a significant proportion of all irAEs, with a reported incidence of 30-40%. These adverse events are often mild, however, over 21 cases of DABP due to nivolumab, pembrolizumab, atezolizumab and durvalumab have been reported (Kumar V et al. 2017).

It is hypothesized that BP associated with epidermal growth factor receptor (EGFR) inhibitors may be explained by the expression of EGFR in basal keratinocytes. The exact mechanism is not known, but is thought to occur by altering the antigenic properties of molecules in the lamina lucida or by reducing the activity of Tregs, allowing overproduction of autoantibodies against these antigens.

In two cases of BP in kidney transplant recipients, mTOR inhibitors (sirolimus, everolimus) were identified as causative agents (Atzori L et al. 2015).

BP has previously been described in renal transplant patients due to a transplant-related cross-reaction with the skin or immune system dysregulation that non-specifically induces autoantibody production.

Vaccines. Vaccines associated with DABP include influenza, swine flu, tetanus toxoid and tetracoq, herpes zoster virus, rotavirus, and the various components of the hexavalent combination vaccines. None of the suspected vaccines show recognizable similarities between the structure of the vaccine components and the relevant basement membrane proteins, so an antibody-mediated response by the components themselves is unlikely (Walmsley N et al. 2011). The enhancement of the immune response could be triggered by the vaccination process itself, which initiates an inflammatory cascade leading to disruption of BMZ integrity with formation of basement membrane-specific antibodies. Although it is a rare event, there are about 110 reports of infantile BP in the literature, including 21 after childhood vaccination. In each case, a short latency period between vaccination and the onset of clinical symptoms has been described, with most cases occurring within a week (range: 5 hours to 4 weeks).

Neuroleptics and neurological disorders. The extent to which neuroleptics are a cause of BP remains to be clarified. There are 10 case reports in the literature linking amantadine, doxepin, escitalopram, fluoxetine, flupenthixol, gabapentin, galantamine, levetiracetam and risperidone.

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