PD-1/PD-L1 inhibitors are monoclonal antibodies that amplify the immune response to counteract tumor immune-evasive mechanisms and are an increasingly administrated therapy for primary and metastatic malignancies. Although these immunomodulators have shown significant clinical efficacy in the treatment of several malignancies, upregulated immune response sometimes triggers immune-related adverse events (irAEs). A study reported 49% of patients treated with anti–PD-1 antibodies developed dermatologic toxicities, including vitiligo, maculopapular, lichenoid, and eczematous reactions.1 Over the past several years, immunobullous reactions and Steven–Johnson syndrome (SJS) have emerged as additional cutaneous irAEs.1–4
LPPemph is an immunobullous dermatosis histologically characterized by a combination of lichen planus (LP) and subepidermal bullae, which may resemble bullous pemphigoid (BP). However, the pathogenesis of LPPemph is due to circulating antibodies targeting an epitope (MCW-4) at the C-terminal NC16A domain of the BP180 kDa antigen, which is different from the targeted epitope of BP.5,6 The exact prevalence of LPPemph is unknown, however, using the available data of the ICD 10 code of LPPemph (L43.1), the estimated prevalence is approximately 1 in 1,000,000 patients.7 Although extremely rare, LPPemph has been reported in association with PD-1/PD-L1 inhibitors. It is proposed that the blockage of PD-1/PD-L1 signaling could induce the imbalance between T helper cells and T regulatory cells, which further leads to the production of autoantibodies against BP180.8,9 To the best of our knowledge, the subepidermal bullae in these cases has only been reported at the nonfollicular dermal–epidermal junction.10–19 Furthermore, positive serological tests for BP180 and/or BP230 antibodies have been reported in all tested cases.10–16 In this report, we present a case of a follicular immunobullous dermatosis with a negative serological test of BP180 and BP230 antibodies in a nivolumab-treated patient and further discuss the possible underlying pathogenesis.
A 60-year-old African American man with a medical history of transitional cell carcinoma of the bladder and hepatocellular carcinoma arising in the background of hepatitis C-induced liver cirrhosis presented to our clinic after being initiated on nivolumab therapy. The patient completed 13 cycles of immunotherapy over the course of 30 weeks with a positive treatment response indicated by decreased alpha fetal protein (AFP). However, for approximately 1 month, the patient had developed recurrent, targetoid plaques and erythematous to dusky cyanotic patches distributed on the right frontal scalp, arms, hands, and legs with progression to oral mucosal erosions and bullous lesions on the back, forearms, and bilateral palms. The oncologist discontinued nivolumab because of the possibility of immunotherapy-induced SJS. After 2 courses of steroids and 1 dose of infliximab, the rash disappeared, and the treatment with nivolumab was resumed.
The rash re-emerged 3 weeks later, nivolumab was again withheld, and the patient was referred to the dermatologist for further evaluation. The scalp showed raised, flaccid blisters and exfoliative skin with erythema, associated with a positive Nikolsky sign (Fig. 1). A punch biopsy of the right parietal scalp was performed. Histology revealed a lichenoid infiltrate with no clefting along the dermal–epidermal junction (Figs. 2A–D). There was, however, prominent multifocal perifollicular clefting associated with an intense inflammatory infiltrate and mild fibrosis (Figs. 3A–D). Direct immunofluorescence (DIF) revealed a linear pattern of IgG and C3 deposition at the dermal–epidermal junction and in a perifollicular distribution (Figs. 4A–D). The ELISA study of patient's serum was negative for autoimmune disease markers, including lupus erythematosus antibodies (ANA, RNP, anti-Sm, anti-DNA, antichromatin, anti-SSA/Ro and anti-SSB/La, and complement C4 and C3), pemphigus antibodies (desmoglein-1 and 3), and pemphigoid markers (BP 180 and BP 230 antibodies). The indirect immunofluorescence study was not performed.
At the 1-week follow-up, the patient reported significant improvement of the rash with 40 mg dose of prednisone in the morning and 20 mg in the evening. At the 1-month follow-up, there was complete resolution of the previously seen bullous reaction. However, the patient was no longer a candidate for additional immunotherapy due to the side effects of the medication.
In this report, we describe a histologically distinct variant of LPPemph, which is characterized by perifollicular bullae and unremarkable ELISA study of serum, and designate it PD-1/PD-L1 inhibitor–induced lichen planopilaris pemphigoides.
Serological BP180 antibody is consistently positive in all 14 reported cases of PD-1/PD-L1 inhibitor–induced LPPemph.10–16 There are 3 plausible explanations to account for the absence of detectable BP180 antibodies in this case. First, negative ELISA studies may be due to the prior and ongoing steroid therapy at the time of serology testing, resulting in fluctuating titers with subsiding disease severity leading to systematically undetectable levels of circulating antibodies. An additional explanation is that the patient's relatively limited cutaneous reaction may correlate with a diluted systemic effect (equilibrate the antibody within the patient's extracellular space) and thus have resulted in negative ELISA studies. A third possible explanation raising the possibility of a “novel antibody” in the current case. We hypothesize that the “novel antibody” primarily favors the perifollicular basement membrane and triggers a lichenoid reaction. This “novel antibody” is responsible for the distinct pathogenesis of lichen planopilaris pemphigoides and explains hair follicles as the primary location of clefting in this entity; in contrast to the clefting at the nonfollicular dermal–epidermal junction in LPPemph. Given the rarity of this entity, the ability to investigate different phases of the lesions, which could better elucidate the pathogenesis of lichen planopilaris pemphigoides, remains challenging.
A case–control study found 12 of 22 patients (55%) with LP had anti-HCV antibodies, considerably higher than the 25% of 40 psoriatic patients or the 0.17% of blood donors who tested positive.20 Chronic hepatitis C in our patient may have served as a contributing factor toward rash development. Because LPPemph may occur in longstanding LP, it is conceivable that if hepatitis C increases the risk of developing LP, it could also increase the risk of LPPemph. Nevertheless, our patient was diagnosed with hepatitis C more than 11 years ago and had no history of a similar rash before starting nivolumab therapy. In addition, the classic shaggy band pattern of fibrinogen in LP does not present in the current case.
Paraneoplastic autoimmune multiorgan syndrome (PAMS) or paraneoplastic pemphigus (PNP) is clinically defined as a polymorphous cutaneous eruption.21 DIF of PAMS usually shows intraepidermal and linear basement membrane zone patterns with IgG antibody. These IgG autoantibodies target the members of plakin family and desmogleins. However, the ELISA study of this patient's serum for desmoglein 1 and 3 was negative. Furthermore, treatment of the tumor in PAMS typically leads to a clinical improvement of the rash whereas in the current case development of LPPemph shortly followed by nivolumab therapy, with rash resolution after drug discontinuation and rash reemergence after drug rechallenge. This proposes causal relationship to the medication and a meaningful difference between PAMS and LPPemph and consequently favors our diagnosis of a drug-induced LPPemph.7
Lichen planopilaris (LPP), also known as follicular LP, is primarily a cicatricial alopecia and histologically presents with perifollicular fibroplasia, lichenoid perifollicular infiltrate, and vacuolar interface changes involving the follicular infundibulum and isthmus of hair follicles.22 Although this case shows similar histological finding as LPP on H&E imaging, the DIF findings is not consistent with LPP. DIF of LPP demonstrates nonspecific grouped globular deposits, usually IgM, adjacent to the follicular epithelium, indicating colloid bodies.23,24 PD-1/PD-L1 inhibitor has been reported to induce LPP.25–29 However, limited immunogenic evidence was provided in these reports. Therefore, the histological and DIF findings in this case is unlikely to be explained solely by LPP.
Reports of PD-1/PD-L1 inhibitor–associated LPPemph are extremely rare, with 15 reported case studies, including ours. Of these, only 5 were induced by nivolumab. We believe this case has striking features and represents a previously undescribed unique presentation. We termed it PD-1 inhibitor–induced lichen planopilaris pemphigoides. Furthermore, the distinct histopathology suggests a novel follicular-centric pathogenesis for this entity. Here, we highlight the importance of a multidisciplinary approach in managing the dermatologic toxicities of immune checkpoint inhibitors and emphasize the significance of perifollicular changes in the differential diagnosis of bullous dermatoses.
1. Hwang SJ, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455–461.
2. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017;44:158–176.
3. Coleman E, Ko C, Dai F, et al. Inflammatory eruptions associated with immune checkpoint inhibitor therapy: a single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. J Am Acad Dermatol. 2019;80:990–997.
4. Tetzlaff MT, Nagarajan P, Chon S, et al. Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features. Am J Dermatopathol. 2017;39:121–129.
5. Zillikens D, Caux F, Mascaro JM, et al. Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180. J Invest Dermatol. 1999;113:117–121.
6. Bouloc A, Vignon-Pennamen MD, Caux F, et al. Lichen planus pemphigoides is a heterogeneous disease: a report of five cases studied by immunoelectron microscopy. Br J Dermatol. 1998;138:972–980.
7. Hübner F, Langan EA, Recke A. Lichen planus pemphigoides: from lichenoid inflammation to autoantibody-mediated blistering. Front Immunol. 2019;10:1389.
8. Naidoo J, Schindler K, Querfeld C, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4:383–389.
9. Sage PT, Sharpe AH. T follicular regulatory cells in the regulation of B cell responses Trends Immunol. 2015;36:410–418.
10. Schmidgen MI, Butsch F, Schadmand-Fischer S, et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. J Dtsch Dermatol Ges. 2017;15:742–745.
11. Sato Y, Fujimura T, Mizuashi M, et al. Lichen planus pemphigoides developing from patient with non-small-cell lung cancer treated with nivolumab. J Dermatol. 2019;46:e374–e375.
12. Okada H, Kamiya K, Murata S, et al. Case of lichen planus pemphigoides after pembrolizumab therapy for advanced urothelial carcinoma. J Dermatol. 2020;47:e321–e322.
13. Senoo H, Kawakami Y, Yokoyama E, et al. Atezolizumab-induced lichen planus pemphigoides in a patient with metastatic non-small-cell lung cancer. J Dermatol. 2020;47:e121–e122.
14. Kwon CW, Murthy RK, Kudchadkar R, et al. Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic Merkel cell carcinoma. JAAD Case Rep. 2020;6:1045–1047.
15. Boyle MM, Ashi S, Puiu T, et al. Lichen planus pemphigoides associated with PD-1 and PD-L1 inhibitors: a case series and review of the literature. Am J Dermatopathol. 2022;44:360–367.
16. Wat M, Mollanazar NK, Ellebrecht CT, et al. Lichen planus pemphigoides-like reaction to PD-1 checkpoint blockade. J Cutan Pathol. 2022.
17. Strickley JD, Vence LM, Burton SK, et al. Nivolumab-induced lichen planus pemphigoides. Cutis. 2019;103:224–226.
18. Kerkemeyer KLS, Lai FYX, Mar A. Lichen planus pemphigoides during therapy with tislelizumab and sitravatinib in a patient with metastatic lung cancer. Australas J Dermatol. 2020;61:180–182.
19. Shah RR, Bhate C, Hernandez A, et al. Lichen planus pemphigoides: a unique form of bullous and lichenoid eruptions secondary to nivolumab. Dermatol Ther. 2022;35:e15432.
20. Chuang TY, Stitle L, Brashear R, et al. Hepatitis C virus and lichen planus: a case-control study of 340 patients. J Am Acad Dermatol. 1999;41:787–789.
21. Czernik A, Camilleri M, Pittelkow MR, et al. Paraneoplastic autoimmune multiorgan syndrome: 20 years after. Int J Dermatol. 2011;50:905–914.
22. Shiohara T, Mizukawa Y. Lichen planus and lichenoid dermatoses. In: Bolognia JL, Schaffer JV, Cerroni L, et al., eds Dermatology. 4th ed. Amsterdam, Netherlands: Elsevier; 2018:188–200.
23. Ioannides D, Bystryn JC. Immunofluorescence abnormalities in lichen planopilaris. Arch Dermatol. 1992;128:214–216.
24. Smith WB, Grabski WJ, McCollough ML, et al. Immunofluorescence findings in lichen planopilaris: a contrasting experience. Arch Dermatol. 1992;128:1405–1406.
25. Cogen AL, Parekh V, Gangadhar T, et al. Lichen planopilaris associated with pembrolizumab in a patient with metastatic melanoma. JAAD Case Rep. 2018;4:132–134.
26. Rossi A, Magri F, Caro G, et al. Eosinophilic folliculitis of the scalp associated with PD-1/PDL1 inhibitors. J Cosmet Dermatol. 2020;19:3367–3370.
27. Dominguez-Santas M, Fernandez-Nieto D, Diaz-Guimaraens B, et al. Avelumab-induced lichen planopilaris, a novel association. Int J Dermatol. 2021;60:e414–e416.
28. Uthayakumar AK, Rudd E, Noy M, et al. Severe progressive scarring pembrolizumab-induced lichen planopilaris in a patient with metastatic melanoma. Australas J Dermatol. 2021;62:403–406.
29. Garcia-Melendo C, Morales-Munera CE, Dalmau J, et al. Extensive lichen planopilaris as exclusive lichenoid reaction secondary to pembrolizumab in a patient with metastatic melanoma. Dermatol Ther. 2022;35:e15388.