Drugs as a cause of perforating dermatoses – a literature review

Introduction

Perforating dermatoses (PD) comprises a diverse group of skin disorders characterised by extrusion of dermal materials through the skin. Unfortunately, the classification is not consistent. For this article, we use the categorisation provided by Rapini in 1989 [1]. Primary PD encompasses clinicopathologic entities: reactive perforating collagenosis (RPC), elastosis perforans serpiginosa (EPS), perforating folliculitis (PF), and Kyrle’s disease (KD). The classification is based on the type of dermal materials eliminated by the skin: collagen, elastin, keratotic, and degenerated material removal, respectively (table 1). The secondary variation of PD is referred to as acquired perforating dermatoses (APD). Rapini proposed this term in 1989 to describe the entirety of perforating dermatoses observed in adults with systemic diseases [1]. While the categorisation provided by Rapini in 1989 has been widely adopted, it is important to note that the classification of PD remains a topic requiring further investigation and unification. PD comprises a rare group of diseases most often associated with kidney disease, diabetes, and metabolic syndrome in patients, but there are also reports of PD induced by drugs.
We are the first to perform a literature review to summarise PD caused by molecularly targeted therapy (MTT) drugs (sorafenib, nilotinib, dasatinib, erlotinib, gefitinib, vemurafenib, lenvatinib, sirolimus, bevacizumab, necitumumab, panitumumab, cetuximab, terepril, bendamustine-rituximab). MTT drugs are one of the major modalities of medical treatment for cancer, which block the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumour growth, rather than traditional chemotherapy by simply interfering with all rapidly dividing cells [2]. Furthermore, monoclonal antibodies such as infliximab, etanercept, ranibizumab, and natalizumab, as well as immunomodulatory imide drugs (lenalidomide, leflunomide), antiviral drugs (indinavir, telaprevir), and penicillamine, are described as PD-inducing drugs.
The significance of this review is due to the extensive range of medications that have the potential to induce perforating dermatoses. This study aims to fill a knowledge gap regarding cutaneous side effects, which can be induced by drugs, including perforating dermatoses. The collected data are novel and, to our knowledge, have not been previously described.

Kinase inhibitors

Sorafenib

Data from the literature have shown that one of the most common drugs that can cause PD is sorafenib. Sorafenib is a multikinase inhibitor (MKI) sanctioned for treating metastatic renal cell carcinoma (RCC) and hepatic cell carcinoma (HCC). It hinders RAF-1 kinase, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR 3, platelet-derived growth factor (PDGF) receptor, c-KIT, RAF kinases, and FMS-like tyrosine kinase 3. So far, 11 cases of PD caused by sorafenib have been reported (table 2) [3–36]. The smallest known dose was 200 mg a day. In all reported cases, sorafenib-induced PD occurred in men aged 49 to 83 years, with an average age of approximately 63 years (table 2). The time onset ranged from 2 to 273 weeks (median 8 weeks). Most often, patients received sorafenib for RCC (4 patients) or HCC (7 patients). In 5 cases the occurrence of PD resulted in the discontinuation of sorafenib. In the remaining patients, the treatment was continued and dermatological therapy with topical corticosteroids, oral antihistamines, or oral isotretinoin were applied. Noteworthy, the best results were obtained with cessation of the drug.
It should be noted that in 9 of 11 cases with sorafenib-induced PD, the diagnosis of perforating folliculitis was made. Vega Díez et al. described the only case diagnosed as RPC induced by sorafenib in a patient suffering from stage IV hepatocellular carcinoma [3]. Jerdan et al. described a patient who suffered from sorafenib-induced PF and HCC but was also infected with human immunodeficiency virus (HIV) [6]. This is the fourth case of a patient who developed perforating dermatoses while being infected with HIV [6, 35–37]. Sato-Sano et al. were the only ones to describe a male patient treated with sorafenib for HCC due to hepatitis C virus infection [5]. In turn, Severino-Freire et al. reported the largest number of sorafenib-induced PD (3 cases). All of them were men, 2 patients suffered from HCC and one from RCC; all developed PF and EPS induced by sorafenib [7].
It should be stressed that PD is not included in the typical cutaneous side effects caused by sorafenib. The most frequently reported cutaneous adverse reactions caused by sorafenib are drug-induced exanthem, alopecia, hand-foot syndrome (palmar-plantar erythrodysaesthesia syndrome), erythema, pruritus, dry skin, exfoliative dermatitis, acne, eczema, and erythema multiforme. In very rare cases, sorafenib can cause radiation recall dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, and toxic epidermal necrolysis [38].
There are several possible mechanisms that could explain the induction of sorafenib cutaneous adverse effects, including perforating dermatoses. c-RAF kinase, which is involved in epidermal proliferation, is paradoxically activated, leading to reduced differentiation. Metalloproteinase-9 is also decreased, leading to decreased elimination of elastic fibres. The hair follicle cycle and local skin inflammation are affected by the inhibition of PDGF [5, 8, 9].

Nilotinib

Nilotinib, an orally active second-generation tyrosine kinase inhibitor (TKI), is sanctioned for use as first-line therapy in the treatment of chronic myeloid leukaemia (CML). Nilotinib targets a specific amino acid residue in the breakpoint cluster region – Abelson oncogene (BCR-ABL1) protein – selectively and competitively [39]. There are 3 cases of CML patients in whom PD occurred after the initiation of nilotinib, and all were diagnosed with PF. Saraswat et al. reported 2 cases of PF induced by nilotinib [4]. The third patient with CML was described by Lamy Velasco et al. (table 2) [13].
As in the case of sorafenib, the induction of PF is not a typical skin complication following the use of nilotinib. Skin side effects such as foliculitis, pruritus, alopecia, eczema, urticaria, hyperhidrosis, acne, dry skin, and erythema are usually noted. Uncommonly, nilotinib can cause ecchymosis, swelling face, blisters, dermal cysts, erythema nodosum, hyperkeratosis, petechiae, photosensitivity, psoriasis, skin discoloration, and in very rare situations, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, or sebaceous hyperplasia [40].
The aetiology of the induction of skin manifestations by nilotinib is unknown; however, it is suggested that nilotinib may cause a PF as a result of its ability to inhibit the PDGF receptor, a kinase that is involved in the development of normal hair follicles [41].

Dasatinib

Dasatinib also belongs to second-generation TKI. It is commonly used for Philadelphia chromosome-positive (Ph+) acute lymphocytic leukaemia (ALL) with prior resistance or intolerance of other therapies, and Ph+ CML in chronic, accelerated, or myeloid or lymphoid blast phase [42]. Prabhakaran et al. identified a case of PF induced by dasatinib in a male patient after receiving a bone marrow transplant for CML [14].
Dasatinib has very similar cutaneous side effects to nilotinib and sorafenib and, like the other 2, has been reported to cause PF (table 2) [43]. PF perhaps in some way is associated with TKI, but the mechanism is not well-elucidated. It is hypothesised that this is due to a disturbance in keratinisation [44].

Erlotinib

Erlotinib is a drug that inhibits the activity of epidermal growth factor receptor (EGFR) tyrosine kinase. It exerts its therapeutic effects in the management of non-small cell lung cancer (NSCLC) and pancreatic cancer by inhibiting the proliferation, adhesion, migration, and apoptosis of EGFR-expressed tumour cells [45].
In the available literature, we found 2 cases of PD induced by erlotinib, both of which were diagnosed with RPC (table 2). Jiang et al. described a case of acquired RPC in a patient with lung adenocarcinoma treated with erlotinib [15]. Suzuki et al. reported a case of RPC induced by erlotinib administered for small-cell lung cancer (stage IV) with multiple metastases to the bones, brain, liver, and adrenal glands [16].
Erlotinib, as a TKI, causes similar skin side effects to dasatinib, nilotinib, or sorafenib. These side effects include drug exanthema, pruritus, alopecia, paronychia, folliculitis, acne/acneiform dermatitis, hirsutism, palmar-plantar erythrodysesthesia syndrome, or in very rare situations Stevens-Johnson syndrome [46].
Erlotinib inhibits the activity of EGFR tyrosine kinase in tumor cells. Since EGFR is also widely expressed at the basal layer of the epidermis, the outer root sheath of the hair follicles, and the sebaceous and sweat glands, EGFR inhibitors may disrupt the differentiation of keratinocytes, resulting in disruption of the epidermis and follicular epithelium, leading to cutaneous and sebofollicular units toxicities [15, 16].

Gefitinib

Gefitinib, like erlotinib, is a novel antineoplastic agent that inhibits EGFR tyrosine kinase and has demonstrated efficacy against a locally advanced or metastatic non-small cell lung cancer with activating mutations of EGFR-TK [47].
There is only one case report of gefitinib-induced perforating dermatoses, described by Fernández-Guarino et al., in a 46-year-old man who was treated by this drug due to lung squamous cell carcinoma for 2 months, and the treatment was based on discontinuation of gefitinib; the type of PD was not specified (table 2) [17].
The mechanism of action of gefitinib potentially impairs the normal functioning of the epidermis by affecting keratinisation and keratinocyte differentiation [48]. However, the primary modifications occur within the hair follicle because EGFR plays a key role in regulating the hair cycle, thereby facilitating the transition from anagen to catagen [49]. Gefitinib is also associated with skin toxicity, resulting in dry skin, allergic reactions, and pruritus [50]. The mechanism of skin toxicity has been studied in a mouse model, but there is no clear answer. Pathological examination indicated a decrease in tight junction-related markers in the skin and colon of mice, along with elevation of macrophages and neutrophils following the administration of gefitinib. In a mouse model, the negative effect of gefitinib on the skin and colon was successfully confirmed [51–53].

Vemurafenib

Vemurafenib is an oral B-Raf kinase inhibitor used for the treatment of unresectable, late-stage melanoma in adult patients with BRAF V600 mutation.
One case of PF was reported in a 62-year-old man treated with vemurafenib for metastatic melanoma (table 2). Due to the severe skin manifestations, it was decided to change the drug to nivolumab, despite the effectiveness of vemurafenib. PF lesions were very severe, especially on the trunk, but also occurred on the head and legs. During treatment of melanoma with nivolumab, PF began to improve rapidly, and one month after the cession of vemurafenib the skin lesions disappeared. The mechanism of PF induced by vemurafenib is unknown. The patient was suffering from chronic renal insufficiency, diabetes mellitus, and arterial hypertension. This background may have contributed to the development of PF by vemurafenib [18].
Vemurafenib, like sorafenib, is a Raf kinase inhibitor. As mentioned earlier, sorafenib turned out to be the most common drug from the MTT drug group causing perforating dermatoses. On the other hand, sorafenib, in addition to Raf kinase, also inhibits VEGFR2, VEGFR3, PDGF receptor, and c-KIT [3–11]. Whether the inhibition of Raf kinases is the cause of the development of these dermatoses is unclear.

Lenvatinib

Lenvatinib is a multi-kinase inhibitor that selectively inhibits the kinase activity of vascular endothelial growth factor receptors: VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), among other kinases tyrosine participating in pro-angiogenic and oncogenic pathways, including receptors for a fibroblast growth factor (FGF) FGFR1, 2, 3, and 4, or platelet-derived growth factor receptors (PDGF) PDGFRα, KIT, and RET. It is used to treat adult patients with progressive, localised advanced or metastatic, differentiated thyroid cancer resistant to radioactive iodine treatment [54, 55].
Lenvatinib induced EPS in one patient, a 60-year-old man (table 2). The skin lesions were not severe enough to discontinue the use of the drug and only a topical glucocorticosteroid was used. It is worth keeping in mind that drug-induced EPS was described only after lenvatinib among all MTT drugs. In the literature, most cases of EPS proven by drugs include descriptions of EPS induction by penicillamine, which is used to treat Wilson’s disease and heavy metal poisoning. This drug binds heavy metal cations from the gastrointestinal tract, which reduces their absorption into the bloodstream. There are reports that it also inhibits macrophages, reduces the level of interleukin-1, and reduces the number of T-lymphocytes, which is why it is also used in the treatment of rheumatoid arthritis. However, the mechanism of its action remains incompletely explicated [5, 56–65].

Sirolimus

Sirolimus is a novel immunosuppressive macrolide that was isolated from a soil sample of Rapa Nui (Easter Island) by a strain of Streptomyces hygroscopicus, hence the designation rapamycin [66]. Sirolimus forms a complex with the cytoplasmic FK-506-binding protein, resulting in the inhibition of the mammalian target of rapamycin (mTOR), a protein kinase [67]. Posttransplant immunosuppression with sirolimus is a common practice, and its antiangiogenic and antineoplastic properties have been demonstrated [68]. Recent studies have demonstrated that sirolimus is frequently associated with cutaneous adverse effects that frequently affect the facial skin, specifically acneiform papulopustular eruption, and angioedema [66, 69, 70].
Lübbe et al. described a case of acquired RPC (ARPC) caused by sirolimus as an immunosuppressive treatment for liver transplant (table 2) [19]. Among the side effects of sirolimus in the setting of posttransplant immunosuppression, cutaneous signs and symptoms are a frequent problem that often leads to the discontinuation of treatment [71]. ARPC is an uncommon condition that is characterised by the transepidermal elimination of altered collagen. ARPC has been linked to diabetes, chronic renal disease, and malignancy [72, 73]. The phenomenon corresponds to a transepidermal elimination of necrotic collagen during a peculiar pattern of epidermal regeneration [74]. The pathogenesis of ARPC has been implicated by the overexpression of transforming growth factor-β3 (TGF-β3) [75]. Sirolimus is widely acknowledged to inhibit wound healing, which potentially facilitates the occurrence of APRC [76, 77]. The pathophysiology behind sirolimus-induced cutaneous side effects is unknown. A clue may come from the fact that it interferes with EGFR and inhibits tyrosine kinase activation [78]. The target of sirolimus, mTor, is a downstream effector of EGFR-mediated signalling. Because epidermal growth factor (EGF) plays a pivotal role in the differentiation of hair follicles, this common target may reflect the clinically comparable adverse effects of various medications [79, 80].

Monoclonal antibodies

Tumour necrosis factor inhibitors

In the realm of managing various inflammatory conditions such as rheumatoid arthritis (RA), spondyloarthritis, psoriasis, and inflammatory bowel disease (IBD), inhibitors targeting tumour necrosis factor-α (TNF-α) play a crucial role. These inhibitors represent a targeted therapeutic approach that differs from the broad, non-specific immunosuppressive agents typically used in the treatment of many inflammatory diseases [58]. Common adverse reactions of TNF inhibitors are dermatologic complications. For etanercept, uncommon and rare adverse reactions include the development or worsening of psoriasis (including pustular and palmoplantar), angioedema, skin cancer, cutaneous lupus erythematosus, lichenoid reactions, cutaneous vasculitis (including leukocytoclastic vasculitis), erythema multiforme, and Stevens-Johnson syndrome. Toxic epidermal necrolysis occurs very rarely (≥ 1/10,000 to < 1/1000) [81]. Overall, cutaneous adverse effects of infliximab are very rare, and these include increased sweating and lupus-like syndrome [82]. PD are not listed as complications of etanercept and infliximab. However, there are reports that they may cause PD [83, 84]. Infliximab has been reported to induce acquired PD (APD) in 5 cases (table 2). Only one patient was diagnosed with RPC, and the remaining 4 were diagnosed with APD diagnosis. In all cases, no hair follicle involvement was observed. Patients received infliximab for various reasons: 2 for RA, 2 for ankylosing spondylitis, and one for ulcerative colitis. The most common therapy used for APD was topical glucocorticosteroids and oral antihistamines [20]. Infliximab and etanercept, both separately induced PF in a 61-year-old man (table 2). The patient was treated with TNF-α inhibitors for RA. The first therapy was infliximab therapy. Skin lesions of PF appeared after 5 months of infliximab use. Then infliximab was discontinued. After 4 months of infliximab therapy discontinuation, etanercept therapy was initiated. Two months after starting etanercept therapy, skin manifestations in the course of PF developed again [22].
Research indicates that TNF-α preferentially induces programmed cell death in highly proliferating hair follicle keratinocytes. Blocking these inflammatory cytokines may disrupt the physiological apoptosis pathway of the hair follicle, potentially leading to follicular degeneration and transepidermal elimination. This, in turn, could contribute to the pathogenesis of PF in affected individuals. In addition, an alternative factor considering perforating disorders is fibronectin accumulating in the sera and skin, facilitating epithelial migration and proliferation, ultimately causing transepithelial elimination. TNF-α inhibits fibronectin production and enhances degradation via metalloproteinases. Blocking TNF-α may induce fibronectin accumulation, potentially favouring the perforating phenomenon [21]. Additionally, these inhibitors are thought to perturb the normal apoptotic processes in hair follicles. However, some studies suggest that TNF-α inhibitors can be used in the treatment of APD [85, 86].

Vascular endothelial growth factor inhibitors

Ranibizumab

Ranibizumab is a monoclonal antibody against VEGF and is indicated for ophthalmic intravitreal injection in the treatment of neovascular age-related macular degeneration (AMD), visual impairment due to diabetic macular oedema (DME), proliferative diabetic retinopathy (PDR), visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), and choroidal neovascularisation (CNV). It is not used for the treatment of skin lesions, but it can cause skin side effects, most often allergic reactions such as urticaria, pruritus, and erythema. PD is not listed as a side effect of this drug [87].
ARPC induced by intravitreal ranibizumab injections as a treatment for occult CNV has been reported (table 2). Ranibizumab was changed to aflibercept, and the skin lesions disappeared. It is worth bearing in mind that the patient had diabetes, kidney disease, liver dysfunction, and thyroid disease, which gives us a background that is also conducive to the development of PD. Intraocular injections of VEGF inhibitors do not cause a significant decrease in this factor in plasma and therefore do not significantly affect the general systemic circulation. On the other hand, lower systemic VEGF-A levels may elevate the risk of systemic complications, given VEGF’s crucial role in maintaining sufficient perfusion throughout the body [23].

Bevacizumab

Bevacizumab is a recombinant humanised monoclonal antibody directed against VEGF, used in combination with other antineoplastic agents in the treatment of metastatic carcinoma of the colon or rectum, metastatic breast cancer, non-small cell lung cancer, metastatic renal cell cancer, epithelial ovarian, fallopian tube, and primary peritoneal cancer, and cervical cancer [88].
In studies, the most common cutaneous adverse events, occurring in more than 10% of patients, were dryness and exfoliative dermatitis. A higher incidence of palmar-plantar erythrodysesthesia was documented with the drug in combination with chemotherapy than with chemotherapy alone (11% versus 5%). Additionally, a higher incidence of nail disorders was also documented in patients who received bevacizumab with chemotherapy than in those who received chemotherapy alone (10% versus 2%, respectively). The incidence of wound healing complications, including serious and fatal complications, is increased in patients treated with bevacizumab. Bevacizumab administration resulted in a reduction in wound tensile strength, decreased granulation and re-epithelialisation, and delayed time to wound closure in rabbits [89].
We found 2 cases where it can cause PD [23, 24]. Vano-Galvan et al. documented a case of a man with PD induced by bevacizumab used for colorectal cancer with liver metastases (table 2). Bevacizumab was not discontinued due to adequate tumour response and patient tolerability of skin manifestations [23]. PF was caused by the use of bevacizumab in a 59-year-old woman due to bladder cancer; the drug was discontinued, and the skin lesions disappeared [24].
VEGF blockade directly inhibits endothelial proliferation, showing a swift antivascular effect. Hypoxia is implicated in PD pathogenesis, with elevated matrix-degrading metalloproteins under hypoxic conditions potentially contributing to transepithelial channel formation. This may involve loosening inter-keratinocyte bonds, disrupting the basement membrane, and detaching collagen fibres, hypothetically leading to PD [23, 24].

Epidermal growth factor receptor inhibitors

Necitumumab

Necitumumab is a recombinant human IgG1 monoclonal antibody against EGFR. In combination with gemcitabine and cisplatin chemotherapy it is indicated for the treatment of locally advanced or metastatic EGFR expressing squamous non-small cell lung cancer [90].
Dermatologic symptoms are a significant problem for patients treated with necitumumab, as shown by their high incidence, affecting approximately 79% of patients [91]. These skin lesions include a wide range of conditions including acneiform eruptions, pruritus, dry skin, skin fissures, paronychia and palmar-plantar erythrodysaesthesia syndrome. It is disturbing that 8% of patients had skin symptoms that were considered severe, which highlights the importance of these side effects. Notably, skin toxicity usually manifests early in the course of therapy, typically within the first
2 weeks, emphasising the need for vigilant monitoring during this critical period. However, observations indicate that cutaneous side effects generally disappear within 17 weeks of onset [90]. So far, there has been one case report regarding the induction of PD by necitumumab, which induced APD in a male patient treated for lung cancer (table 2) [25].

Panitumumab

Panitumumab is an anti-EGFR monoclonal antibody that is indicated for the treatment of adult patients with wild-type RAS metastatic colorectal cancer [92].
Dermatological problems occurred in 90% of patients receiving the drug and were severe in 15% of cases. Clinical manifestations included acneiform dermatitis, pruritus, erythema, hypersensivity reactions, peeling, paronychia, dry skin, and skin fissures. Life-threatening, and fatal drug complications, including necrotising fasciitis, severe abscesses, and bullous mucocutaneous and erosive lesions, have also been observed in patients treated with panitumumab [93]. There are no data on the occurrence of panitumumab-induced PD. One case of ARPC induction by panitumumab has been reported. Tsutsui et al. described a case of acquired RPC caused by panitumumab in a woman treated for colon cancer (table 2) [26].

Cetuximab

Cetuximab is a monoclonal antibody against EGFR and is indicated for the treatment of patients with EGFR-expressing, RAS wild-type metastatic colorectal cancer and for the treatment of patients with squamous cell cancer of the head and neck region [94]. Cetuximab also causes a spectrum of skin lesions requiring careful monitoring and management. The most common adverse reactions include acneiform eruption, dry skin, paronychia, and various skin infections. These can include serious conditions such as S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, and keratitis/ulcerative keratitis, potentially leading to reduced visual acuity, as well as cheilitis. In a clinical trial involving 1373 patients treated with cetuximab, acneiform eruption was the most common skin disease, occurring in approximately 82% of patients. Importantly, this dermatological condition typically appeared within the first 2 weeks of therapy and persisted for more than 4 weeks [95].
The only report of cetuximab causing APD was the induction of APD in a 56-year-old woman treated with cetuximab due to spindle cell carcinoma of the left tongue. Discontinuation of cetuximab resulted in the resolution of skin lesions [27].
After EGFR inhibitor administration, mitogen-activated protein kinase expression diminishes, impacting keratinocyte proliferation, and differentiation, and inducing epidermal apoptosis. The EGFR signalling pathway, crucial for vascular homeostasis, suggests that EGFR inhibitor-induced keratinocyte necrosis and vascular imbalance may trigger transepidermal elimination and collagen fibers degeneration [26].
Panitumumab, necitumumab, and cetuximab are monoclonal antibodies blocking EGFR that provoke the occurrence of perforating dermatoses. These are monoclonal antibodies, but EGFR kinase inhibitors such as gefitinib and erlotinib, which inhibit the tyrosine kinase in the EGFR signalling pathway, which gives us an insight into the common pathogenesis of PD and interference in the EGFR signalling pathway.

Anti-a4 integrin inhibitor

Natalizumab

Natalizumab is a monoclonal anti-α4-integrin antibody that, by binding to the α4 subunit of the α4β1 integrin expressed by lymphocytes, interferes with the migration of immune cells into the central nervous system [28]. Natalizumab has an indication for treatment as a single disease-modifying therapy in adults with highly active relapsing-remitting multiple sclerosis (RRMS) [96].
Patients receiving the therapy reported druginduced exanthem, which was the most common cutaneous adverse event, with an incidence of more than 10%. Other clinical manifestations included dermatitis, pruritus, night sweats, and dry skin [97]. The literature reports 2 cases of natalizumab causing PD. In both cases, an unspecified type of APD was diagnosed, and the drug was used to treat RRMS. Piqué-Duran et al. described a case of APD induced by natalizumab used for RRMS in a male patient (table 2). Therapy was continued because of the good tolerability of cutaneous lesions [28]. Fisher et al. reported a case of APD by natalizumab in a 55-year-old man used for his RRMS, which was treated with narrowband ultraviolet B therapy with significant results [29].
It is noteworthy that natalizumab does not appear to influence epidermal proliferation or induce an increase in matrix-degrading metalloproteins, aligning with findings observed in other discussed articles [28, 29].

Immune checkpoint inhibitor

Terepril

Terepril is a an anti-PD-1 monoclonal antibody. Skin adverse reactions reported in the worldwide post-marketing experience included skin necrosis and gangrene. Their incidence and causal relationship with exposure to terepril cannot always be reliably estimated [98]. Liu et al. documented a case of APD induced by terepril used for sigmoid colon adenocarcinoma with liver metastases and retroperitoneal lymphadenopathy (table 2). Common side effects of the therapy include immune-related adverse events, notably affecting the gastrointestinal tract, liver, and skin. Dermatologic reactions, primarily drug-induced exanthems, pruritus, and vitiligo, manifest in diverse forms such as maculopapular, morbilliform, follicular, pustular, vesicular, acneiform, and exfoliation. Histopathologically, variable morphologies like lichenoid, spongiotic, psoriasiform, urticarial, interstitial granulomatous, and vesiculobullous patterns have been reported. However, there are no other reports caused by terepril PD [30].
Another anticancer agent bendamustine-rituximab used in haematological malignancies is also mentioned in the literature (table 2). However, bendamustine, is a nitrogen mustard drug indicated for use in the treatment of chronic lymphocytic leukaemia (CLL) and indolent B-cell non-Hodgkin lymphoma (NHL), and rituximab is an anti-CD20 monoclonal antibody. These 2 drugs were used in combined therapy; therefore, it is difficult to conclude whether the skin lesions in PF belonging to PD are caused by the monoclonal antibody or the nitrogen mustard [31, 99].
Immunomodulatory imide drugs have also been described as drugs causing PD such as PF (table 2). This has been described for lenalidomide and leflunomide [33, 100]. Antiviral medications have been reported to induce PD, such as in HIV-positive patients who developed ARPC during indinavir therapy [36]. Telaprevir also induced APD in a patient infected with hepatitis C virus (HCV) [35]. In patients infected with HIV and hepatitis B virus (HBV) who received combined therapy with antiviral drugs, emtricitabine/tenofovir and atazanavir/ritonavir developed acquired EPS [34].

Conclusions

The mechanisms responsible for the induction of perforating dermatoses by drugs remain unclear, and further research is required. We hope that our literature review will supply further knowledge about the possible cutaneous side effects. This will provide a comprehensive understanding of the possibility of perforating dermatoses being caused by drugs, including molecularly targeted therapy drugs.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References