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A review of bullous pemphigoid associated with PD‐1 and PD‐L1 inhibitors
Abstract
Background
Dermatologic toxicity represents a substantial portion of all immune‐related adverse events (irAEs) associated with PD‐1/PD‐L1 inhibitors. Bullous pemphigoid (BP) is a rare cutaneous side effect of these medications, which can initially be clinically indistinguishable from other, low‐grade cutaneous toxicity.
Objective
To better characterize the clinical features of BP associated with PD‐1/PD‐L1 inhibitors, evaluate the efficacy of various treatment regimens, determine the frequency of prodromal pruritus, and assess whether immunological diagnostic studies for BP are warranted in patients treated with checkpoint inhibitors who develop intractable pruritus.
Methods
A comprehensive review of the English‐language medical literature was performed using key terms. Papers published on any date and from all origins were considered. Fourteen publications, containing 21 patient cases, were selected independently by two reviewers and deemed relevant to the present publication.
Results
Pruritus was a prominent feature of the majority (12/21) of cases and preceded or occurred concurrently with BP development. Bullae developed within 6–8 months of initiation of PD‐1/PD‐L1 inhibitors; however, a smaller subset of patients did not develop bullae for 1–1.5 years following initiation of therapy. Mean time to pruritus was similar for pembrolizumab and nivolumab at 19 and 21 weeks, respectively. Development of BP required discontinuation of immunotherapy in 76% (16/21) of cases.
Conclusion
Prodromal or “non‐bullous” variants of BP must be considered in patients treated with checkpoint inhibitors who develop protracted or worsening pruritus. Early diagnostic immunological evaluation of the skin may lead to improved patient outcomes by facilitating timely initiation of treatment and prevent disruptions in cancer therapy.
... On the other hand, ICIs non-specifically activate the immune system, thereby inducing immune-related adverse events (irAEs), including severe ones [2]. Cutaneous toxicity is one of the most common irAEs, occurring in 30-40% [3] of patients treated with ICIs (according to other sources, 30-50% of patients [4]). The most common dermal irAEs include pruritus, rashes, vitiligo, and lichenoid reactions [3,4]. ...
... Cutaneous toxicity is one of the most common irAEs, occurring in 30-40% [3] of patients treated with ICIs (according to other sources, 30-50% of patients [4]). The most common dermal irAEs include pruritus, rashes, vitiligo, and lichenoid reactions [3,4]. The development of bullous pemphigoid (BP) has been reported in approximately 1% [4] or 0.6% [2] of patients treated with anti-PD-1/PD-L1 antibodies. ...
... Alternative treatment modalities include, among others, tetracyclines, niacinamide, methotrexate, dapsone, azathioprine, mycophenolate mofetil, plasma exchange, intravenous immunoglobulin, rituximab, infliximab, omalizumab, and dupilumab [2,8,9,11,12]. Most patients treated with PD-1/PD-L1 inhibitors who developed BP had to discontinue immunotherapy [2,3,8]. In reported cases, patients were treated with local therapy, and most of them required additional systemic treatment with corticosteroids. ...
Dermatological toxicity is one of the most common immune-related adverse events (irAEs) of treatment with immune checkpoint inhibitors (ICIs). Bullous pemphigoid (BP) is a rare and serious complication of these drugs that can be difficult to establish, as its initial symptoms may be indistinguishable from mild skin lesions. This paper presents the case of a 68-year-old patient who developed BP after receiving one of the ICI therapies, pembrolizumab, for advanced non-small cell lung cancer (NSCLC). After approximately 7 months of therapy, a grade 3 skin toxicity in the Common Terminology Criteria for Adverse Events (CTCAE) occurred in the form of rash and pruritus. Pembrolizumab was then held and prednisone and antihistamines were introduced. When dermal toxicity improved to grade 1, pembrolizumab was resumed and prednisone was kept at a dose of 10 mg. Immunotherapy was discontinued 3 months later, after the recurrence of grade 3 skin toxicity symptoms. When the patient developed blisters filled with clear fluid, dermatologists suspected pembrolizumab-induced bullous pemphigoid. Bullous pemphigoid was subsequently confirmed using a direct immunofluorescence test and histopathological examination. The patient’s skin condition improved after the use of steroid therapy and methotrexate, and the cancer process stabilized for over one year. Cancer progression and deterioration of the patient’s general condition were observed approximately 4 months after the termination of pembrolizumab therapy. The paper also discusses the key aspects of ICIs-induced BP, especially pembrolizumabinduced BP in the first-line treatment of metastatic NSCLC. Early diagnosis of skin lesions and the initiation of appropriate treatment may lead to better outcomes for patients and prevent disruptions in immunotherapy.
... ICI-BP is an uncommon and challenging specific D-irAE that is usually seen in the context of PD-1 or PD-L1 inhibition. 22 This disease process frequently results in discontinuation of ICI therapy, as well as the use of systemic immunosuppressants, 41 although early diagnosis and targeted management can allow for continued ICI therapy in appropriate cases. 42 ICI-BP cases tend to be more delayed in presentation than typical drug-induced BP, can manifest after a rash-free pruritic prodrome, may be 'non-bullous' with eczematous/urticarial plaques, or may present with bullae and other morphologies (eg, eczematous eruptions). ...
... 42 ICI-BP cases tend to be more delayed in presentation than typical drug-induced BP, can manifest after a rash-free pruritic prodrome, may be 'non-bullous' with eczematous/urticarial plaques, or may present with bullae and other morphologies (eg, eczematous eruptions). 41 These eruptions are important as they may have implications for tumor response and potentially survival. 24 The morphologic findings of bullous pemphigoid as presented below reached consensus by expert panel adjudication. ...
... ICI-BP usually presents with, and may be preceded by, significant pruritus, and may be associated with mucosal symptoms/erosions. 41 The disease can be further classified into four subtypes based on morphology: (1) classic BP, characterized by tense vesicles and bullae, open erosions with collarettes of scale, which may involve the oral mucosa in a minority of cases; some cases may be nonbullous with urticarial edematous plaques; (2) atypicaleczematous, which presents as scaly, moist plaques, with collarettes of scale and potential crust from dried serous drainage; (3) atypical-pruritus only, which does not have a clear rash but may have linear erosions from patient excoriation; (4) atypical-other, which could be any other type of skin eruption that may meet criteria based on biopsy and lab criteria. ...
With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.
The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.
Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover’s, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder’s description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).
These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.
... Cutaneous adverse reaction related with PD-1/ PD-L1 inhibitors are common and being increasingly reported. Lopez et al. further characterized immunotherapy-induced BP, stating that pruritus and non-bullous cutaneous findings may be the only symptoms, necessitating awareness and prompt immunofluorescence assays to establish the diagnosis (35). ...
... In the same report by Lopez at al., development of BP required discontinuation of immunotherapy in 76% (16/21) of cases, while the remaining five patients continued the immunotherapy with an additional designated BP treatment. In most cases SCS were the main component of the treatment regimen (35). Muntyanu et al. review the management strategies and recommendations for cutaneous immune-related adverse events of immune checkpoint inhibitors, suggesting starting with whole body application of topical potent corticosteroids twice daily, followed by SCS (0.5-1 mg/kg/day prednisone) intermittently for short periods as possible (36). ...
... A possible impairment of immunotherapy's efficiency by an 1-2-months antibiotic course prior to the treatment initiation was postulated (39). At Lopez et al. review five patients were treated with doxycycline with variable cancer outcome, without a causal connection that can be established between the antibiotics and disease progression (35). ...
Background
Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous disease. Topical or systemic corticosteroids are often used as the first-line treatment. However, long-term corticosteroid use may lead to significant side effects. Therefore, various adjuvant immunosuppressant therapies are used as steroid-sparing agents, with accumulating reports of biological treatments for severely recalcitrant BP.
Objective
To describe the clinical and immunological features of a series of patients with recalcitrant BP treated with immunobiological therapies. To assess the efficacy and safety of their therapies.
Methods
Patients receiving biological treatment for BP from two centers were assessed. Here, we described the clinical, immunopathological, and immunofluorescence findings of adult patients with BP and analyzed the clinical response and adverse events associated with various biological therapies.
Results
We identified nine eligible patients treated with rituximab (seven), omalizumab (three), or dupilumab (one). The mean age at diagnosis was 60.4 years, the average BP duration before biologic initiation was 1.9 years, and the average previous treatment failure was 2.11 therapies. The mean follow-up period from the first biological treatment to the last visit was 29.3 months. Satisfactory response, defined as clinical improvement, was achieved in 78% (7) of the patients, and total BP clearance was achieved in 55% (5) of the patients at the last follow-up visit. Additional rituximab courses improved the disease outcomes. No adverse events were reported.
Conclusions
Efficient and safe novel therapies can be considered in recalcitrant steroid-dependent BP non-responsive to conventional immunosuppressant therapies.
... Bullous pemphigoid (BP) is classically caused by autoantibodies to BP180 and BP230, two basement membrane hemidesmosome proteins, leading to the development of local-ized or generalized tense bullae, most commonly in the elderly [72]. The development of BP has been associated with primary cancers, including melanoma and non-small cell lung cancer most notably; however, BP has also been associated with ICI targeting PD1/PDL1 [34,73,74]. The incidence of BP in patients taking ICI (ICI-BP) is about 1%; BP is well established as the most common bullous eruption secondary to ICI (Figure 2) [3,34,35]. ...
... The incidence of BP in patients taking ICI (ICI-BP) is about 1%; BP is well established as the most common bullous eruption secondary to ICI (Figure 2) [3,34,35]. ICI-BP onset is classically delayed, occurring usually 4 months after ICI therapy initiation, with some cases developing after 1.5 years of therapy or even after ICI discontinuation [4,74,75]. Prodromal symptoms of ICI-BP may include generalized pruritus, followed by the formation of macular or urticarial lesions, and then followed by the development of tense bullae on the extremities and torso that are filled with either serous or hemorrhagic fluid. Oral mucosal involvement is reportedly present in up to 40% of ICI-BP, contrary to primary BP which has mucosal involvement in only 19% of patients [3,34,73,[76][77][78]. ...
... The most wellestablished theories include activation of antibody-secreting B cells, inhibition of immunosuppressive regulatory T-lymphocytes, cross-reaction between anti-BP180 antibodies since BP180 is expressed by many tumor cells, or the triggering of clinically undetectable emerging BP by ICI [3,8,[34][35][36][37]. Although patients with HLA-DQB 1*03:01, a major histocompatibility complex class-II allele, have been shown to be more likely to develop primary BP, it is unclear if such genetic predispositions hold true for ICI-BP [74,79]. It is also unknown if people who develop ICI-BP have BP180 antibodies prior to ICI initiation [35]. ...
The rapid evolution of anti-cancer therapy (including chemotherapy, targeted therapy, and immunotherapy) in recent years has led to a more favorable efficacy and safety profile for a growing cancer population, and the improvement of overall survival and reduction of morbidity for many cancers. Anti-cancer therapy improves outcomes for cancer patients; however, many classes of anti-cancer therapy have been implicated in the induction of bullous dermatologic adverse events (DAE), leading to reduced patient quality of life and in some cases discontinuation of life-prolonging or palliative therapy. Timely and effective management of adverse events is critical for reducing treatment interruptions and preserving an anti-tumor effect. Bullous DAE may be limited to the skin or have systemic involvement with greater risk of morbidity and mortality. We present the epidemiology, diagnosis, pathogenesis, and management of bullous DAE secondary to anti-cancer therapies to enable clinicians to optimize management for these patients.
... Anti-PD-1 nivolumab és pembrolizumab és anti-PD-L1 durvalumab és atezolizumab mellett nem ritka az immun-mediált bullosus pemphigoid (4., 5. ábra). Ipilimumab kezelés mellett fennálló bullosus pemphigoid súlyosbodását is leírták (3,23,(32)(33)(34). ...
... A szövettani vizsgálat jellemzően a teljes dermiszre kiterjedő granulomákat mutat, nem specifikus, szisztémás szarkoidózishoz kap-megkezdése után fél évvel induló bullosus pemphigoidot is (3). A bőrtünetek kezdetben viszkető, urticariform megjelenésűek lehetnek, a nyálkahártya érintettség ritka (3,23,33,34). Direkt immunfluoreszcens vizsgálat során lineáris IgG és komplement C3 depozit látható a bazálmembrán mentén, BP230 antitestet ritkábban, BP180 antitestet gyakrabban lehet kimutatni immunterápia mellett megjelenő bullosus pemphigoidban (3,25,32). ...
... Pemphigus vulgaris megjelenéséről eddig az irodalom nem számolt be, ugyanakkor néhány nivolumab kezelésben részesülő betegnél detektáltak anti-desmoglein és anti-plakin antitesteket klinikai tünetek nélkül (3,33,34). Ipilimumab kezelésnél egy eset kapcsán dermatitis herpetiformis került leírásra (3). ...
As the fifth pillar of antitumor treatment, immunotherapies have brought a significant breakthrough in oncology. Immune checkpoint inhibitors have been shown to be the most effective modality among immunotherapies by stimulating the antitumor activity of the patient’s immune system. Monoclonal antibodies such as inhibitors of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death protein ligand (PD-L1) as immune checkpoint blockers (ICIs) have been approved in many solid tumors. In addition to the introduction of immunotherapies, immunerelated side effects must also be expected. Skin reactions are one of the leading adverse immune-mediated adverse events. Below, we describe the typical immune-mediated adverse reactions affecting the skin during immunotherapy used in oncology.
... It is prudent to better understand such irAEs, and when possible, risk stratify patients accordingly to achieve a more precise decision at the point of care when continuation of immunotherapy is considered lifesaving (26). Though there is no current standard to predict toxicities, HLA typing has been proposed as a potential risk-stratifying parameter for irAE (26,27). We propose that the presented patients who developed bullous pemphigoid, pemphigus vulgaris, thyroiditis, vitiligo, and hepatitis may be associated with their genetic propensity toward such autoimmune conditions, which became unmasked by immunotherapy (Table 1). ...
... Bullous pemphigoid has been reported with almost all immunotherapies (1,27). There are HLA associations with BP among certain populations including DQB1 * 03:01 in Caucasians and Iranians, and DQB1 * 03:02, DRB1 * 11:01, and DRB1 04:03 in the Japanese (12). ...
Background
The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored.
Methods
The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient.
Results
Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population.
Conclusion
The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome.
... The oral mucosa is involved in less than one-third of cases. 36,37 Diagnostic evaluation is akin to classic disease, which includes identification of a subepidermal split and numerous eosinophils on histopathology, linear deposition of immunoglobulin G and C3 along the basement membrane on direct immunofluorescence, and peripheral detection of antibodies against hemidesmosomal proteins (BP180 and BP230). 13,25 A. Deutsch, M.Lacouture, A.Andriessen, et al these therapies for ICI-induced lichenoid eruptions is feasible and may be considered for refractory disease. ...
... Steroid-sparing agents include dupilumab, omalizumab, dapsone, methotrexate, and rituximab. 25,[36][37][38][39][40] Doxycycline and niacinamide may be used in mild presentations, but careful consideration should be taken with ICI-induced bullous pemphigoid given the association of systemic antibiotic use with dysregulation of the gut microbiome, which has been shown to potentially restrict the intended immune response of ICIs. 41 ...
Background:
In 2023, nearly 2 million patients will be diagnosed with cancer in the United States and at least 40% will be eligible for treatment with an immune checkpoint inhibitor (ICI). Cutaneous immune related adverse events (cirAEs) from ICIs are common and include pruritus as well as maculopapular, eczematous, bullous, lichenoid, and psoriasiform reactions. All clinicians interfacing with cancer patients must expedite proper evaluation and diagnosis, treatment, and/or consultation that supports the need for evidence-directed guidelines.
Materials and methods:
A panel of advisors was selected, and a systematic literature review generated foundational evidence to develop a treatment algorithm for cirAEs via a modified Delphi process. Iterations of the algorithm were performed until the group met consensus.
Results:
An algorithm that tailors the management of cirAEs was developed based on the CTCAE v.5 grading of skin disorders. Representative clinical images and suggested diagnostic measures, supplement the algorithm.
Conclusion:
Recognition and treatment of cirAEs guided through a multidisciplinary, physician-developed algorithm will limit disruption of immunotherapy, optimize quality of life, and enhance overall outcomes in patients treated with ICIs. J Drugs Dermatol. 2023;22:11(Suppl 1):s3-10.
... 1,2 Notably, anti-PD-1 and PD-L1 agents have emerged as a significant drug association with bullous pemphigoid (BP). [1][2][3] We report a case of drug-induced BP (DIBP) secondary to immunotherapy with pembrolizumab in combination with immunoglobulin-like transcript 4 (ILT4) MK-4830 in a patient with PD-L1-positive metastatic squamous cell carcinoma of the head and neck (SCCHN). ...
... Early recognition and diagnosis of DIBP in the setting of immunotherapy and advanced malignancies allows for the initiation of appropriate therapy and, as a result, helps to curtail disruption or discontinuation of anti-cancer regimens which are critical in this setting. Similar to our case, treatment discontinuation has been reported in at least 40% of cases of ICI-mediated BP. 3 Several other case studies have reported cancer progression and/or patient death shortly after BP diagnosis and discontinuation of immunotherapy. 4 Our patient had limited response to high-dose systemic corticosteroids but did demonstrate early clinical response to upadacitinib at 15 mg/day. JAKi has a rapid clinical onset between 1 and 4 weeks, which is favourable to achieve early control of disease. ...
Bullous pemphigoid is an acquired autoimmune subepidermal blistering disease that can arise following exposure to systemic medication, referred to as drug-induced bullous pemphigoid. Drug-induced bullous pemphigoid is a rare but potentially serious immune-related adverse event that should be considered in patients with advanced malignancies undergoing immunotherapy, with immune checkpoint inhibitors emerging in particular as a well-documented drug association in drug-induced bullous pemphigoid. We present a 74-year-old female with recurrent metastatic programmed cell death-ligand 1–positive squamous cell carcinoma of the head and neck area who developed drug-induced bullous pemphigoid in the setting of immunotherapy with a novel immunoglobulin-like transcript 4 inhibitor (MK-4830) in combination with pembrolizumab. Treatment with upadacitinib, a Janus-associated kinase-1 inhibitor, was pursued for significantly disabling disease that was recalcitrant to standard therapies and ultimately transition to palliative care. Follow-up at 4 weeks demonstrated good response. This is the first report describing the use of a Janus-associated kinase inhibitor for the treatment of bullous pemphigoid.
... Dramatically, biologics-induced BP has also shown an unexpected treatment effect in some reports. Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, the mainstay of biologics causing BP, have been reported in many cases and reviews (3,4), but to our knowledge, there were no reports to illustrate their roles in the treatment of BP. Hence, in this paradoxical phenomenon, we mainly focused on biologics including tumor necrosis factor (TNF)-a, interleukin (IL)-17, and IL-12/IL-23 or IL-23 inhibitors that have effects of both inducing and treating BP. ...
... There were many cases and reviews relevant to BP cases caused by PD-1/PD-L1 inhibitors including pembrolizumab, nivolumab, and cemiplimab, but no reports about treating BP to date. Nonspecific activation of the immunity and the shared antigens between tumor cells and the BMZ have been involved in the development of PD-1/PD-L1 blockers-inducing BP (3,4,(68)(69)(70). In the treatment of BP, omalizumab, an antibody targeting IgE, and dupilumab, an antibody binding IL-4 receptor subunit a (IL-4Ra), are now increasingly utilized for the treatment of BP as novel therapeutic approaches (71)(72)(73). ...
Objective
This study aimed to investigate the clinical features of biologics-induced bullous pemphigoid (BP) and the therapeutic effects of those agents for BP, exploring the underlying pathophysiological mechanisms.
Methods
We searched PubMed, Web of Science, and Elsevier for studies involving pemphigoid patients treated with or induced by identical biologics published in English from January 2009 to April 2022.
Results
Seventeen cases of drug-induced BP associated with anti-tumor necrosis factor (aTNF)-α therapies, one with interleukin (IL)-17 inhibitors, and seven with IL-12/IL-23 or IL-23 inhibitors were enrolled. Time to cutaneous toxicity varied among different types of agents, and the characteristics of clinical examinations were similar to idiopathic BP. Discontinuation of the culprit drugs and initiation of topical or systemic corticosteroids were adequate in most cases. Several monoclonal antibodies above have also been reported for the treatment of refractory or recurrent BP, especially concurrent with psoriasis.
Conclusion
Biologics for immune-related diseases, including TNF-α, IL-17, and IL-12/IL-23 or IL-23 inhibitors, can both induce and treat BP, which might be associated with a helper T cells Th1/Th2 imbalance, complicated inflammatory networks, and a specific individual microenvironment, suggestive of a new perspective on the therapeutic algorithms of BP. There have been numerous reports about biologics inducing or treating BP. We have taken note of this phenomenon and focused on biologics with both pathogenetic and therapeutic effects on BP. Our review summarized the clinical characteristics of associated cases, trying to figure out the underlying mechanisms of this paradoxical phenomenon and to provide an integrated perspective and new therapeutic alternatives for BP.
... Our clinical differential diagnosis also included bullous pemphigoid secondary to pembrolizumab, which the patient received in conjunction with EV. Immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody directed against programmed death-1 receptor, are well documented to cause bullous pemphigoid [11]. However, the histopathology and immunofluorescence studies were not consistent with BP in our case. ...
... In addition, we recorded the PD-1 inhibitor, pembrolizumab, as a trigger in 2.9% of cases, inducing an intense course of bullous phenotype of BP. Checkpoint inhibitors were documented to induce both bullous and nonbullous BP phenotypes (37,38). In the present study, we did not identify other medications that might trigger BP flares in patients with multiple comorbidities. ...
Background:
Bullous pemphigoid (BP) is a rare autoimmune blistering disease predominantly affecting the elderly population.
Objectives:
The present study aims to identify clinical factors that may influence outcomes of BP, including skin phenotype, serology, mucosal involvement, pruritus, and triggers.
Methods:
A retrospective analysis was conducted on 70 cases with BP registered from January 2019 to December 2022. The Bullous Pemphigoid Disease Activity Index (BPDAI) score was used to assess disease intensity. The BPDAI-Pruritus score and a modified Brest questionnaire were used to document pruritus. Anti-BP180 and anti-BP230 autoantibodies were regularly recorded. Peripheral blood eosinophil counts were documented during flare-up and remission phases of BP.
Results:
Of the cases, 81.4% were identified with bullous BP, 12.9% with nonbullous BP and 5.7% with localized BP. Oral involvement was documented in 17.1% of cases. Increased peripheral eosinophilia was prominent in the nonbullous phenotype and returned to normal level during remission in both phenotypes.
Conclusion:
The outcomes of BP depended on the disease phenotype and trigger types. Bullous BP showed more intense disease activity, while nonbullous BP demonstrated more intense pruritus. BP associated with diabetes mellitus (DM) or psoriasis manifested as a more severe disease, predominantly with the bullous phenotype and pruritus, compared to cases without comorbidities. New triggers, including SARS-CoV-2 infection and vaccination, were documented (Tab. 6, Ref. 43). Text in PDF www.elis.sk Keywords: bullous pemphigoid, nonbullous pemphigoid, pruritus, comorbidity, eosinophilia, new triggers.
... An indirect support of the possible association between melanoma and BP is emerging evidence that treatment of melanoma with ICIs can be followed by BP onset (22). ICIs are monoclonal antibodies meant to interfere with tumor evasion mechanisms, such as the expression of inhibitory signals that prevent their detection and destruction from the immune system. ...
Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.
... These autoantigens cause priming of abnormal T cells that can lead to further tissue damage in peripheral tissue and to generation of aberrant B cells and subsequent autoantibodies such as BP180 in germinal centers. 4,10,11 Cyclosporine is a calcineurin inhibitor that reduces synthesis of IL-2, resulting in reduced cell activation. 12 Therefore, cyclosporine may alleviate BP in patients who are being treated, or were previously treated, with an immune checkpoint inhibitor by suppressing T cellmediated immune reaction and may be a rapid alternative for patients who cannot tolerate systemic steroids. ...
... A recent metanalysis highlighted that HLA-DQA1*0505 is associated with an increased odds of PB, while DQA1*0201 carries protection from this disease [47]. Drug-induced BP may be triggered following exposure to certain drug classes, principally inhibitors of dipeptidyl peptidase 4 (DPP-4i) for the treatment of diabetes mellitus and oncologic immunotherapy with inhibitors of the PD-1 immune checkpoint [48,49]. Japanese patients who presented BP during treatment with DPP-4i had the following risk alleles: DQB1*0301, DQA1*0505, DRB1*1101, and DRB1*1201. ...
HLA class II molecules are key factors determining susceptibility to autoimmune disorders, and their role in immune-mediated skin conditions such as psoriasis has been extensively investigated. However, there is currently little understanding of their role in antibody-mediated skin diseases such as autoimmune blistering disorders. We researched the available literature using PubMed to narratively review the current knowledge on HLA associations in antibody-mediated blistering skin pathologies. Our results summarized the risk alleles that are identified in the literature, together with certain known protective alleles: in the pemphigus group, alleles HLA-DQB1*0503 and HLA-DRB1*0402 are most commonly associated with disease; in the pemphigoid group, the most studied allele is HLA-DQB1*0301; in epidermolysis bullosa acquisita, few genetic studies are available; in dermatitis herpetiformis, the association with haplotypes HLA-DQ2 and HLA-DQ8 is strongly established; finally, in linear IgA bullous disease, specific HLA alleles may be responsible for pediatric presentations. Our current pathogenic understanding of this group of disorders assigns a key role to predisposing HLA class II alleles that are able to bind disease autoantigens and therefore stimulate antigen-specific autoreactive T cells. The latter engage B lymphocytes that will produce pathogenic autoantibodies. The distribution of HLA alleles and their disease associations are variable across demographics, and an in-depth pathogenetic understanding is needed to support associations between HLA alleles and disease phenotypes. Additionally, in a personalized medicine approach, the identification of HLA alleles associated with the risk of disease may become clinically relevant in identifying susceptible subjects that should avoid exposure to known triggers, such as medication, when possible.
... The most common autoimmune-related adverse reactions to nivolumab are gastrointestinal and cutaneous; other potentially rare side effects include pneumonia, endocrinopathy, and myocarditis [1]. Skin adverse reactions account for approximately 30-40% of the adverse reactions associated with nivolumab, including pruritus, macular papules and vitiligo [2]. ...
Background
Bullous pemphigoid (BP) is a serious and rare complication of nivolumab. This study aimed to explore the clinical characteristics of nivolumab-induced BP and provide a reference for prevention and treatment of BP.
Methods
Literature on nivolumab-induced BP was collected for retrospective analysis by searching both Chinese and English databases as of July 31, 2023.
Results
Sixty patients were included, with a median age of 71 years (range 30 to 85 years), and they were predominantly male (78.3%). The median time to onset of BP was 31 weeks (range 2.4, 216) after nivolumab administration. Tense bullae (93.3%), pruritus (55.0%), and urticarial plaques (31.7%) were the most common manifestations. Lesions were found on the limbs (50.0%), trunk (38.3%), palms and soles (15.0%). Skin biopsies mainly showed subepidermal bullous/blister (50.0%) and eosinophilic infiltration (46.7%). Direct immunofluorescence showed mainly linear deposition of C3 and IgG (46.7%) at the dermal-epidermal junction. The patients stopped taking nivolumab and received systemic steroids (73.3%), topical steroids (63.3%), monoclonal antibodies (21.7%), doxycycline/minocycline (30.0%) and other treatments. Symptoms improved or were relieved in 88.4% of patients but did not improve in 8.3% of patients.
Conclusion
Clinicians should closely monitor symptoms of BP in those receiving and discontinuing nivolumab, especially in older men. Early diagnosis and timely initiation of treatment may improve patient outcomes.
... Despite the fact that immune-mediated cutaneous side effects can appear from the first weeks of treatment, the latency period of BP induced by anti-PD1/PD-L1 is usually longer compared to other cutaneous toxicities, ranging from 10 months [29][30][31] to 18 months [32]. Contrary to these typical cases, our patient presented a BP flare at 3 days after receiving treatment, which is an atypical presentation, and it could suggest the presence of some predisposing factors. ...
Cutaneous immune-related adverse events (cirAEs) are the most common side effects of immune checkpoint inhibitor (ICI) therapy (30–50% for all grades). The vast majority of them are low or mild and can be treated without ICI interruption. Autoimmune blistering disorders, such as immune-mediated bullous pemphigoid (IBP), are rare (<1%) but potentially serious conditions that must be early detected. The onset generally occurs within the first months of the treatment, and it appears to be more common with antiprogrammed death-1 or antiprogrammed ligand 1 (anti-PD1/PDL1) than with anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4). We present a case of a three-day severe IBP onset after receiving the first cycle of atezolizumab. This exceptional early presentation could suggest the presence of some predisposing condition and demonstrates the need to better understand predictive toxicity-related biomarkers in candidate patients for immunotherapy.
... ICI-induced BP may lead to hospitalization, if extensive, and presents similarly to classic BP with a prodromal or concurrent pruritus followed by localized or generalized tense bullae on the limbs and trunk with background normal or erythematous skin (Fig. 5) [73]. Of ICI-induced BP cases, 10 to 30% have oral mucosal involvement [73,77]. BP can present anywhere from 6 weeks to over 18 months following initiation of ICI therapy [78][79][80]. ...
Purpose of Review
Immune checkpoint inhibitors (ICIs) have become a mainstay of oncologic treatment over the past decade. There are currently 11 ICIs approved by the U.S. Food and Drug Administration in the treatment of over a dozen malignancies. ICIs are associated with immune-related adverse events that can affect virtually any organ system. In some instances, these toxicities may lead to inpatient hospitalization and/or discontinuation of the ICI. This review highlights the clinical features and management of cutaneous toxicities most relevant to the inpatient dermatologist, including morbilliform eruptions, severe mucocutaneous reactions including lichenoid eruptions and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)-like reactions, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, and autoimmune bullous disease. We also review other systemic toxicities that present with skin findings that are relevant to the inpatient dermatologist.
Recent Findings
A distinct ICI-induced mucocutaneous eruption mimicking SJS/TEN but with a delayed presentation and more favorable prognosis has been reported. Biologic therapy for ICI-induced bullous pemphigoid is effective and does not impair survival compared with other systemic regimens. Early exposure to and higher doses of systemic corticosteroids have been shown to result in reduced progression-free and overall survival among patients on immunotherapy.
Summary
Given the increasing number of patients receiving ICIs alone and in combination with other anti-cancer regimens, as well as the complicated and varied clinical appearance of immune related adverse events, it is vital to promptly diagnose and treat these toxicities to provide optimal patient care while minimizing interruptions in oncologic treatment.
... Alternatively, there are modifiable triggers that are known to also trigger the development of BP, such as exposure to certain drugs. For example, BP has been reported as an adverse effect following the prescription use of both dipeptidyl peptidase IV inhibitors and programmed cell death-1/programmed death ligand-1 checkpoint inhibitors [22,23]. ...
Bullous pemphigoid (BP) is an autoimmune blistering disease that mainly affects the elderly. The human leukocyte antigen (HLA) system is believed to be one of the genetic factors involved in the development of BP. The connection between major histocompatibility complex class II, specifically HLA-DQA1, and BP remains inconclusive. The objective of this review is to find potential associations between BP and HLA-DQA1 alleles, identify the HLA-DQA1 alleles associated with an increased or decreased risk of developing BP, and highlight literature gaps for future research. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to conduct a literature review. Databases used included PubMed/MEDLINE, Google Scholar, Embase, and Cochrane Library. Only studies written in English and conducted after 2000 that investigated the association between HLA-DQA1 and BP in human subjects were included. Odds ratios were calculated from the data provided in the studies, and a meta-analysis was conducted using Review Manager (The Cochrane Collaboration, London, United Kingdom) and MetaXL (EpiGear International Pty Ltd., Queensland, Australia) software. The systematic review found five eligible studies, and all were included in the meta-analysis. Results show an increased odds for BP in the HLA-DQA1*05:05 loci (odds ratio (OR) = 2.25; 95% confidence interval (CI) = 1.80, 2.80) and decreased odds for BP in the HLA-DQA1*02:01 loci (OR = 0.50; 95% CI = 0.36, 0.70). Further research is needed to confirm these findings and explore the potential clinical implications for personalized medicine approaches in BP patients.
... Anti-CTLA-4 antibodies are only rarely implicated in the development of BP or other bullous disorders. Time to disease onset can vary, but most data indicates that it has an overall greater latency of onset than other skin irAEs [56]. ...
Simple Summary
It is estimated that 30–50 percent of patients treated with Immune Checkpoint Blockers will eventually develop cutaneous immune-related adverse events. These toxicities are in, most of the time, low-grade reactions; however, they are characterized by a wide clinical spectrum. Clinicians who utilize these novel agents must have a thorough understanding of the pathogenesis, clinical characteristics, as well as the proper treatment of these toxicities. In this review, we analyze the treatment approaches as well as unique features observed in melanoma patients who develop cutaneous immune-related adverse events.
Abstract
Immune checkpoint blockers (ICBs) have been widely used during the last decade for the treatment of various tumors, including advanced and metastatic melanoma. While these agents have improved melanoma patients’ survival rates, they have also been associated with various autoimmune toxicities, with the skin being most commonly affected. The severity of cutaneous toxicity can not only negatively affect patients’ quality of life but can also limit the proper treatment of cancer. Thus, the role of the dermatologist is substantial in early detecting and promptly treating these adverse events. Maculopapular rash, psoriasiform, lichenoid dermatoses and bullous pemphigoid are the most frequent cutaneous adverse events that require immediate intervention. Other rare autoimmune toxicities, e.g., sarcoidosis, dermatomyositis or subacute lupus, have also been reported. In this review, we summarize the aspects of ICB-induced cutaneous toxicities in patients with melanoma, emphasizing their management and treatment options in clinical practice.
... In addition to IgG autoantibodies, BP patients also have IgE autoantibodies that are thought to be linked to the inflammatory features of BP. 10 Recent years have seen the emergence of Drug Induced BP (DIBP), an entity that shares most of the clinical, pathological, and immunological features of common BP. Up to 90 drugs have been to date implicated in the induction of BP. 2 Sufficient data support a role of certain ACE inhibitors (mainly enalapril), diuretics (spironolactone and furosemide), antibiotics (ciprofloxacin), and most recently new cancer therapies (anti PD-L1) 11 in the induction of BP. However, of all drugs families, gliptins seem to induce the highest risk of DIBP, 12 making it an important issue in the field. ...
Dipeptidyl peptidase-4 inhibitors (DPP-4i), or gliptins, are a widely used glucose-lowering agents. A growing amount of evidence pointed to a possible role of DPP-4i in the induction of bullous pemphigoid (BP), which is an auto-immune skin blistering disease that mainly affects the elderly. In this article we discuss a case of DPP-4i associated BP and we provide an updated review of the current knowledge regarding this emerging entity. Use of DPP-4i, particularly vildagliptin, was found to significantly increase the risk of BP. BP180 would be in the center of the aberrant immune response. DPP-4i induced BP is thought to be associated with male gender, mucosal involvement, and milder inflammatory phenotype especially in Asian population. Generally, patients may not remit fully after DPP-4i withdrawal only and require either topical or systemic glucocorticoid courses.
... AntieCTLA-4 treatment is often associated with a morbilliform rash within 3 to 6 weeks of treatment onset, whereas anti-PD(L)1 results in a more severe, eczematous skin rash after 4 months to a year. Bullous pemphigoid is more frequent after anti-PD1 therapy, often accompanied by bullous pemphigoid antibodies (Lopez et al., 2018). Skin rash treatment often includes steroids and a dose reduction or treatment cessation where necessary (Choi et al., 2020;Friedman et al., 2016). ...
Checkpoint inhibitors treat a variety of tumor types with significant benefits. Unfortunately, these therapies come with diverse adverse events. Skin rash is observed early into treatment and might serve as an indicator of downstream responses to therapy. We studied the cellular composition of cutaneous eruptions and whether their contribution varies with the treatment applied. Skin samples from 18 patients with cancer and 11 controls were evaluated by mono- and multiplex imaging, quantification, and statistical analysis. T cells were the prime contributors to skin rash, with T cells and macrophages interacting and proliferating on site. Among T cell subsets examined, type 1 and 17 T cells were relatively increased among inflammatory skin infiltrates. A combination of increased cytotoxic T cell content and decreased macrophage abundance was associated with dual checkpoint inhibition over PD1 inhibition alone. Importantly, responders significantly separated from nonresponders by greater CD68+ macrophage and either CD11c+ antigen-presenting cell or CD4+ T cell abundance in skin rash. The microenvironment promoted epidermal proliferation and thickening as well. The combination of checkpoint inhibitors used affects the development and composition of skin infiltrates, whereas the combined abundance of two cell types in cutaneous eruptions aligns with responses to checkpoint inhibitor therapy.
... The use of immune checkpoint inhibitors (ICIs) has been associated with various cutaneous immune-related adverse events (irAEs), including eczematous, psoriasiform, lichenoid, and bullous dermatoses. 1,2 Here, we evaluated reports of lichen sclerosus (LS) and morphea associated with ICIs. ...
... Within them, 75% of the studies were evaluating the interaction between specific medication use and the influence of pemphigoid disease incidence or other associated adverse outcomes. Within the term 2001-2018, it was mentioned that dipeptidyl peptidase 4 inhibitors (DPP4i), anti-PD1 or PD-L1 and loop diuretics were mentioned to be associated with a higher risk of newonset pemphigoid diseases (66,68). Furthermore, according to a real-world study in Germany, the use of glucocorticoids was reported to increase mortality in patients with bullous pemphigoid (77). ...
Background
In the field of autoimmune and inflammatory disorders, different approaches were applied to provide information regarding disease activity, comorbidities, epidemiological reports and risk factors. However, no previous studies had thoroughly analyzed the research trend in the field, and the bibliometric analysis focusing on pemphigoid diseases was available. The objective of the current study was to evaluate the current research trend in the field.
Methods
A search has been conducted for the Web of Science database based on various subcategories of pemphigoid diseases. Detailed information including articles’ publication types, Author information, citation, and publication information was attained for further analysis.
Results
Within the 6,995 studies, the top 100 most-cited articles were extracted for analysis. Among the top 100 studies, 70% of the studies focused on bullous pemphigoid. More than 60% of the top 100 studies were studies with original data. Furthermore, 30% of the studies were guidelines and narrative reviews. For the issues primarily focused on, most of the high-impact studies described the molecular mechanism of pemphigoid diseases (26%), managements (19%), risk factors of pemphigoid diseases (17%). Additionally, some other studies provided general review or discussed about the issue of epidemiology, diagnosis/definition, comorbidities and clinical characteristics of pemphigoid diseases.
Conclusion
This comprehensive bibliographic study of pemphigoid diseases provided an overview of current research focuses in the field. Topics such as disease management, molecular mechanism of pathogenesis, and drug-inducing pemphigoid diseases were highly mentioned in the most-cited studies. For researchers and clinicians, the researching trend and study focus in the top-100 cited studies could serve as a potential reference for future investigation and patient management.
... The latency of bullous disorders due to immunotherapy is generally longer than that of other cutaneous toxicities. In most cases, BP onset is noted concurrently with medication use within 6-8 months of drug initiation (8)(9)(10). In this case, however, the bullae first appeared earlier, approximately 3 weeks after the patient's last infusion. ...
The widespread use of immune checkpoint inhibitors in several malignancies has revealed new immune-related adverse events. Bullous pemphigoid (BP) is an antibody-driven autoimmune disease characterized by skin inflammation and fluid-filled bullae. Herein, a 69-year-old man with lung squamous cell carcinoma developed multiple vesicles and tense bullae 3 weeks after the initiation of a programmed death-1 (PD-1) inhibitor, pembrolizumab, and chemotherapy. Biopsy revealed a subepidermal bulla with lymphocytic and eosinophil infiltration, and immunohistochemical studies predominantly showed CD4⁺ cells, a few CD8⁺ cells, and the occasional CD20⁺ lymphocyte. The serum anti-BP180 antibody level, as well as the interleukin-6 and interleukin-10 levels, were elevated compared to the lower levels of tumor necrosis factor-α. Eosinophil levels were high and consistent with the development of blisters. A diagnosis of BP associated with PD-1 inhibitor therapy was made, and the Common Terminology Criteria for Adverse Events classification was grade 3. Immunotherapy was permanently discontinued, and the patient’s bullous lesions failed to react to high-dose systemic corticosteroids combined with minocycline and niacinamide. Intermittent blister recurrence occurred in 2 months, eventually improving with the administration of two courses of intravenous immunoglobulin. At 5 weeks of follow-up, the patient’s tumor was reduced on a computed tomographic scan. Despite stable BP treatment, however, he repeatedly developed complications due to the complexity of his underlying disease and could not be treated with anti-tumor therapy. Early recognition and management of serious immune-related bullous dermatologic toxicity are essential for patient safety.
... 7 Hence, there is clearly a need for intensified prevention efforts including raising awareness among exposed workers and intensive training in correct use of personal protective equipment, as well as development and usage of epoxy resin systems with a lower sensitization potential. 8 Prevention of sensitizations to epoxy components, and thus preserving the occupational health of the workforce in the wind turbine industry, is of particular importance considering the pursuit of renewable energies in light of climate change and the current European energy crisis. The last two decades have witnessed a substantial increase in the incidence of bullous pemphigoid (BP) worldwide. ...
Linked Article: Kawsar et al. Br J Dermatol 2022; 187:981–987.
... 23 Reported steroid-sparing immunosuppressive agents include mycophenolate mofetil, azathioprine, methotrexate, dapsone, nicotinamide, rituximab, intravenous IgG, omalizumab and dupilumab. 24,25 Only two of our patients required three lines of treatment. ...
Background:
Checkpoint inhibitor therapy (CPI) has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPI are commonly observed, however autoimmune blistering disorders such as bullous pemphigoid (BP) are rare.
Objectives:
To review the prevalence, incidence risk, clinicopathological features and management of bullous cutaneous irAEs toxicity associated to CPI therapy.
Methods:
A multicentre, retrospective, observational study of CPI associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006-2019.
Results:
7391 patients were identified. CPI associated bullous irAEs including BP (n=16) occurred in 0.3% (n=22). Median age of onset was 76 years old with male preponderance. Most patients had cutaneous melanoma (73%, n=16) of which 81% (13/16) were BRAF wildtype. Grade 1,2,3,4 skin toxicity occurred in 9% ,45%, 41%,4% respectively. The mucosae were involved in 27% and 25% of confirmed BP cases did not present with bullae. Median time to onset of bullous irAEs was 12 months, with median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms compared with combination therapy (median 12 months versus 7 months, respectively). 91%, 64%, 9% of patients required one, two or three lines of treatment respectively. Two cases occurred after completion of CPI (1 and 3 months). Of the 20 cases which presented whilst on CPI this was permanently discontinued in 55% (11/20) and temporarily held in 20% (4/20). In the four held CPI cases, bullous eruption re-flared in 50%.
Conclusions:
CPI associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0.3% over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared to other cutaneous irAEs, with a median time of 12 months and it can occur after cessation of therapy. Discontinuation of CPI's may be required. Recognising bullous irAEs promptly and referral to dermatology is essential to optimise management and improve patient outcomes and tumour responses.
Immune checkpoint inhibitors are a class of drugs used in cancer treatment that promote the immune system’s response by blocking the inhibitor signals from tumour cells, such as PD-1/PD-L1 and CTLA-4. Despite their clinical benefit, these monoclonal antibodies unspecifically activate the immune system and can lead to the development of ‘immune-related adverse events’. Cutaneous toxicities are the most frequent immune-related adverse events, reported in approximately 30–50% of patients treated with immunotherapy; the most common dermatologic toxicities are represented by rash, vitiligo, pruritus and lichenoid reactions. Usually these reactions are mild and it is not necessary to suspend immunotherapy. Potentially life-threatening skin toxicities, such as immunobullous eruption, are rare and may appear in approximately 1% of patients. In this report we describe a case of bullous pemphigoid, the most frequent bullous disease, that developed after treatment with pembrolizumab for a metastatic melanoma. The diagnosis, first suspected by the referring clinic, was confirmed by performing serology and biopsy with direct immunofluorescence. At the beginning, the patient was treated with high doses of systemic corticosteroids, without suspending the immunotherapy treatment. Subsequently, due to the continuous relapses, we decided to suspend pembrolizumab and systemic corticosteroid and to begin an off-label treatment with dupilumab. The following case gives cause for reflection about the management of a drug-induced disease in a immunocompromised patient, while exploring his therapeutic options.
This study aimed to describe bullous pemphigoid (BP) associated with immune checkpoint inhibitors (ICIs) reported in the United States Food and Drug Administration adverse event reporting system (FAERS). We obtained reports of ICI‐associated BP from the first quarter of 2011 to the first quarter of 2024 in the FAERS database. The reporting odds ratio (ROR) method of the disproportionality analysis was performed to assess the potential risk for ICI‐associated BP. We also described the clinical characteristics of ICI‐associated BP and evaluated the time to onset (TTO) of BP developed after treatment with ICIs. Eight hundred and six cases of ICI‐associated BP were gathered, in which 56.58% of the patients were aged 65 years or older. The majority of patients were male, accounting for 68.49% of all cases. The prevalent potential cancer type was skin cancer (31.64%). The results of the disproportionality analysis showed that males (ROR = 2.10 [1.78–2.49]), patients aged 65 or older (ROR = 2.13 [1.79–2.55]), and patients with skin cancer (ROR = 2.08 [1.80–2.43]) were more likely to develop ICI‐associated BP. In comparison to cytotoxic T‐lymphocyte‐associated antigen 4 inhibitor and programmed cell death ligand 1 inhibitor, programmed cell death 1 inhibitor‐associated BP has a higher risk of development (ROR = 24.45 [22.52–26.56]). ICI‐associated BP had a median TTO of 204 days (interquartile range 57–426 days). ICI‐associated BP is a rare but important immune‐related adverse event. Our study provided helpful information to help medical professionals further understand ICI‐associated BP.
Patients receiving immune checkpoint inhibitor (ICI) therapy should be carefully monitored for the occurrence of immune-related adverse events (irAEs). We report the case of an 87-year-old woman with primary mucosal malignant melanoma (T4aN0M0) of the nasal cavity who developed bullous pemphigoid (BP), a rare irAE, after treatment with pembrolizumab. The patient received definitive heavy ion therapy followed by monotherapy with pembrolizumab. After 6 courses of pembrolizumab, she developed grade 2 oral mucositis, and pembrolizumab was discontinued. Since the oral mucositis improved with a topical steroid spray, and computed tomography revealed shrinkage of the nasal tumor, we followed up the patient after discontinuation of pembrolizumab. However, on day 237 after the first dose of pembrolizumab, she developed bullous dermatitis on the skin of the hands and face. A dermatologist was consulted and biopsy led to the diagnosis of BP. Accordingly, we initiated the patient on oral steroid therapy, which led to resolution of the BP, and the condition has not relapsed since. Meanwhile, the nasal tumor continues to remain shrunk, and the patient has been followed up without treatment, including pembrolizumab administration. Prompt diagnosis and treatment are necessary in patients developing irAEs during/after ICI therapy, and collaboration with specialist physicians could be important.
Cutaneous immune-related adverse events encompass a spectrum of dermatological manifestations, including lichenoid reactions, psoriasiform eruptions, eczematous dermatitis, immunobullous disorders, granulomatous reactions, pruritus, vitiligo, and severe cutaneous adverse reactions such as Stevens–Johnson syndrome. The conventional approach to treating high-grade or refractory cutaneous immune-related adverse events has involved high-dose systemic corticosteroids. However, their use is limited owing to the potential disruption of antitumor responses and associated complications. To address this, corticosteroid-sparing targeted immunomodulators have been explored as therapeutic alternatives. Biologic agents, commonly employed for non-cutaneous immune-related adverse events such as colitis, are increasingly recognized for their efficacy in treating various patterns of cutaneous immune-related adverse events, including psoriasiform, immunobullous, and Stevens–Johnson syndrome-like reactions. This review consolidates findings from the English-language literature, highlighting the use of biologic agents in managing diverse cutaneous immune-related adverse event patterns, also encompassing maculopapular, eczematous, and lichenoid eruptions, pruritus, and transient acantholytic dermatosis (Grover disease). Despite the established efficacy of these agents, further research is necessary to explore their long-term effects on antitumor responses.
Zusammenfassung
Moderne Immuntherapeutika wie Nivolumab, Pembrolizumab oder Ipilimumab, die sogenannte Immun-Checkpoints blockieren, haben die onkologische Therapie in den letzten Jahren revolutioniert. Mit dem neuen Wirkmechanismus der Blockade wichtiger Kontrollpunkte im Immunsystem zeigen sich jedoch auch eine Vielzahl an unterschiedlichen Nebenwirkungen. Diese treten nicht selten an der Haut auf. Zu den häufigsten dermalen Reaktionen unter Immuntherapie zählen die Vitiligo, Exantheme, blasenbildende Reaktionen oder der Lichen planus. Ausgeprägter Juckreiz kann Patienten stark beeinträchtigen. Der Verlauf bei auf die Haut beschränkten Nebenwirkungen ist häufig mild und gut zu behandeln oder selbstlimitierend. Hauterscheinungen können jedoch auch als Symptom systemischer Reaktionen auftreten. Eine frühe Diagnosestellung, die Einleitung einer adäquaten Therapie sowie eine interdisziplinäre Betreuung bei komplexen Erkrankungen sind entscheidend, um dauerhafte Einschränkungen für die Patienten zu verhindern und eine sichere Behandlung der zugrundeliegenden Tumorerkrankung gewährleisten zu können.
Bullous pemphigoid (BP) is one of the most common autoimmune bullous diseases and mainly affects an elderly population with multi-morbidity. Due to the frailty of many BP patients, existing treatment options are limited. The blisters associated with BP result from IgG and IgE autoantibodies binding to the central components of hemidesmosome, BP180, and BP230, stimulating a destructive inflammatory process. The known characteristic features of BP, such as intense pruritus, urticarial prodrome, peripheral eosinophilia, elevated IgE, as well as recent expanding evidence from in vitro and in vivo studies implicate type 2 inflammation as an important driver of BP pathogenesis. Type 2 inflammation is an inflammatory pathway involving a subset of CD4+ T cells that secrete IL-4, IL-5, and IL-13, IgE-secreting B cells, and granulocytes, such as eosinophils, mast cells, and basophils. It is believed that effectors in type 2 inflammation may serve as novel and effective treatment targets for BP. This review focuses on recent understandings of BP pathogenesis with a particular emphasis on the role of type 2 inflammation. We summarize current clinical evidence of using rituximab (B-cell depletion), omalizumab (anti-IgE antibody), and dupilumab (anti-IL-4/13 antibody) in the treatment of BP. The latest advances in emerging targeted therapeutic approaches for BP treatment are also discussed.
Bullous pemphigoid is the most common autoimmune blistering disease in industrialized countries and particularly affects the elderly. In this patient population, comorbid diseases are frequent and may complicate management and treatment of bullous pemphigoid. A better understanding why distinct diseases are more frequent in bullous pemphigoid patients may lead to new pathophysiological insights and - as a consequence - result in better patient care. The association of bullous pemphigoid with neurological and psychiatric diseases is well known and confirmed by several case-control studies. Association with further diseases such as malignancy and metabolic diseases are still discussed controversially. In recent years new relationships between bullous pemphigoid and autoimmune as well as inflammatory skin diseases have been reported. This review provides a systematic overview on studies addressing comorbidity in bullous pemphigoid patients. Increasing the awareness of both, common and rare comorbid diseases, may enable clinicians to optimize patient support and individualized treatment of bullous pemphigoid.
Background
Pembrolizumab, a programmed cell death protein 1 checkpoint inhibitor, is a novel drug used to treat a variety of advanced malignancies. However, it can also result in many immune-related adverse events, with cutaneous toxicities being the most frequent. Regarding pembrolizumab-induced skin adverse reactions, bullous pemphigoid (BP) has the worst effects on quality of life. Recently, there have been more and more reports of BP incidents resulting from pembrolizumab therapy in patients with cancer. This study aimed to define the clinical characteristics, diagnosis and management of pembrolizumab-induced BP and identify potential differences between classical BP and pembrolizumab-induced BP.
Methods
Case reports, case series, and case analyses of pembrolizumab-induced BP up to 10 December 2022 were collected for retrospective analysis.
Results
Our study included 47 patients (33 males and 14 females) from 40 studies. The median age was 72 years (range 42-86 years). The median time to cutaneous toxicity was 4 months (range 0.7-28 months), and the median time to bullae formation was 7.35 months (range 0.7-32 months). The most common clinical features were tense bullae and blisters (85.11%), pruritus (72.34%), and erythema (63.83%) on the limbs and trunk. In 20 of the 22 cases tested, the serum anti-BP180 autoantibodies were positive. However, in 10 cases (91.90%, 10/11) the circulating autoantibodies of anti-BP230 were negative. 40 patients had skin biopsies and the skin biopsy revealed subepidermal bullae or blister eosinophil infiltration in 75.00% of patients with pembrolizumab-induced BP, 10.00% of patients with lymphocyte infiltration and 20.00% of patients with neutrophil infiltration. There were 20 patients (50%) with eosinophilic infiltration around the superficial dermis vessels, 8 patients (20.00%) with lymphocyte infiltration around the superficial dermis vessels, and 4 patients (10.00%) with neutrophil infiltration around the superficial dermis vessels. Direct immunofluorescence detected linear immunoglobulin G (IgG) IgG and/or complement C3 along the dermo-epidermal junction in 36 patients (94.74%) with BP. IgG positivity was detected by indirect immunofluorescence in 81.82% of patients with BP. All patients were in complete remission (95.65%,44/46) or partial remission (4.35%, 2/46) of BP, whereas 9/46 patients had a relapse or refractory. The majority of patients achieved BP remission after discontinuation of pembrolizumab with a combination of topically and systemically administered steroid treatments, or other medications. The median duration of BP remission was 2 months (range 0.3-15 months).
Conclusion
A thorough diagnosis of pembrolizumab-induced BP should be made using clinical signs, biochemical markers, histopathological and immunopathological tests. Pembrolizumab-induced BP had similar clinical characteristics to classic BP. Temporary or permanent discontinuation of pembrolizumab therapy may be required in patients with perbolizumab-induced BP depending on the severity of BP and the response to medication. Pembrolizumab-induced BP may be effectively treated using topical and systemic steroid treatments in combination with other medications (e.g., doxycycline, niacinamide, dapsone, rituximab, intravenous immunoglobulins, dupilumab, cyclophosphamide, methotrexate, mycophenolate mofetil, and infliximab). Clinicians should provide better management to patients with BP receiving pembrolizumab to prevent progression and ensure continuous cancer treatment.
Background and aims:
Bullous pemphigoid is an autoimmune blistering disease that affects the elderly mostly. First-line treatment of systemic corticosteroids may cause significant adverse effects, especially in patients with multiple co-morbidities. Dupilumab shows certain effectiveness in treating BP. We aim to profile our experience with dupilumab in a series of patients with BP and review the articles published to date.
Methods:
Medical records of 9 patients with moderate-to-severe BP were retrospectively reviewed. All patients were administered dupilumab. Response to dupilumab was evaluated by NRS scores, number of lesions, and the systemic corticosteroids' dosage. The PubMed, Embase, and Web of Science databases were searched to identify eligible studies.
Results:
The 9 patients were identified in this case series with a median age of 68 years (range 42-89) and the median duration of disease before being treated with dupilumab was 6 months (range 1-144). Complete remission was achieved in 6 patients while partial response was achieved in one patient. The NRS score had decreased to varying degrees at week 2 in all patients, and skin lesions improved within 2 to 6 weeks. Fifteen publications were included: 3 retrospective studies and 12 case series or reports, with a total of 63 patients. The overall complete response and partial response rates were 74.6 % and 11.1 %, respectively.
Conclusion:
Dupilumab appears to be a safe alternative for the treatment of patients with refractory BP.
Immune checkpoint inhibitors (CPIs) are highly effective in the treatment of various cancers. Immunotherapy enhances antitumor activity by relieving inhibition of T cells responsible for immune surveillance. However, overactivation of T cells leads to immune-related adverse events (irAE), of which cutaneous adverse events are the most common. Examples include pruritus and maculopapular eruption most commonly, psoriasis and bullous dermatoses less commonly, and, rarely, severe, life-threatening eruptions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Many of these are autoimmune in nature, and these may present de novo or as recurrence of pre-existing disease. In order to maximize the therapeutic potential of CPIs, it is essential to recognize and effectively manage cutaneous irAE, which can otherwise lead to treatment interruption or discontinuation. This review summarizes the presentation and management of dermatologic adverse events secondary to immune dysregulation as a result of immune checkpoint inhibitor therapy, including the most common (maculopapular eruption, pruritus, lichenoid dermatitis, and vitiligo), less common (psoriasis, bullous pemphigoid, erythema multiforme, eczematous dermatitis, alopecia areata, and granulo-matous and neutrophilic dermatoses), and severe (acute generalized exanthematous pustulosis [AGEP], drug reaction with eosinophilia and systemic symptoms [DRESS], and Stevens-Johnson syndrome or toxic epidermal necrolysis [SJS/TEN]), as well as exacerbation of pre-existing cutaneous autoimmune disease (subacute cutaneous lupus erythematosus, dermatomyositis, eosinophilic fasciitis, leukocytoclastic vasculitis, and scleroderma-like reaction).
Bullous pemphigoid is a rare and severe adverse reaction to immune-checkpoint inhibitors that can be life-threatening. Here, we present two cases of bullous pemphigoid secondary to nivolumab and ipilimumab+nivolumab therapy, respectively. Both cases presented months after discontinuation of immunotherapy. Our first case highlights the life-threatening nature of bullous pemphigoid due to its potential to cause laryngeal oedema. Our second case illustrates that cytotoxic T-lymphocyte-associated protein-4 inhibitors can rarely lead to bullous pemphigoid, in addition to programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors. Both cases emphasise the importance of skin examinations and dermatological follow-up for patients during and even after discontinuation of immunotherapy.
The authors report a case of bullous pemphigoid (BP) that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma. Following regression of BP blisters, they reintroduced anti-PD-1 treatment. Due to the flare-up of BP, immunotherapy was discontinued again and corticosteroid was restarted. As the BP lesions regressed, interestingly, new skin metastases developed, exactly where the blisters were. One year after discontinuation of anti-PD-1 treatment, considering the significant tumor progression, pembrolizumab was restarted. This induced tumor remission, while the added low-dose corticosteroid was able to prevent the recurrence of BP. The patient carries the BP-predisposing HLA-DQB1*03:01 allele. In conclusion, anti-PD-1 rechallenge may be considered in metastatic melanoma, even if restarting anti-PD-1 has previously caused the flare-up of BP symptoms.
Resumen
Las dermatosis ampollosas autoinmunitarias subepidérmicas tienen como características comunes un despegamiento ampolloso dermoepidérmico y depósitos de inmunoglobulinas (Ig) y complemento a lo largo de la membrana basal epidérmica demostrados por inmunofluorescencia cutánea directa. Se han identificado seis enfermedades. El penfigoide ampolloso es la afección más frecuente en las personas ancianas. La corticoterapia tópica fuerte con dermocorticoides de clase 4 es eficaz y ha mejorado el pronóstico al reducir la mortalidad y la morbilidad. El penfigoide del embarazo se produce en el tercer trimestre o en el posparto y, por lo general, tiene un buen pronóstico. El penfigoide cicatricial sigue siendo a menudo desconocido y se diagnostica de forma tardía, con el riesgo de que se produzcan graves secuelas sensoriales; afecta principalmente a las mucosas externas y su tratamiento está aún poco codificado. La dermatosis por IgA lineal se presenta en adultos, donde puede ser inducida por medicamentos, y en niños; se caracteriza por depósitos de IgA y suele responder bien a la dapsona. La epidermólisis ampollosa adquirida es una enfermedad excepcional, que puede simular clínicamente una epidermólisis ampollosa distrófica hereditaria, un penfigoide ampolloso o incluso un penfigoide cicatricial. Suele ser grave y resistente al tratamiento.
Blistering eruptions range the gamut from an acute, self-limiting dermatitis such as poison ivy to the chronic, life-altering disorder epidermolysis bullosa. Some blistering ailments are discussed elsewhere including bullous impetigo, herpes zoster, and erythema multiforme. Blistering disorders are characterized by thin-walled, fluid-filled skin lesions. A small blister is referred to as a vesicle, whereas larger lesions (generally greater than 5 mm) are termed bullae.KeywordsBullous pemphigoidDermatitis herpetiformisEpidermolysis bullosa acquisitaAcropustulosis of infancy
Immune checkpoint inhibitors (ICIs) are increasingly used in cancer therapy and can have unintended side effects affecting several organ systems. Immune-related cutaneous adverse events (irCAEs) are the most frequent and earliest toxicities to arise. The most common irCAEs include maculopapular/morbilliform rash, pruritus, eczematous dermatoses, urticaria, lichenoid reactions, psoriasiform eruptions, and vitiligo. Interestingly, irCAEs are associated with an improved tumor response rate and positive prognosis in melanoma patients. Most irCAEs are mild and reversible, but when severe, they can drastically affect quality of life and cancer treatment course. Treatment is still an active area of research and depends on the rash severity. Management options include observation, topical and systemic corticosteroids, and various biologic and immunomodulatory therapies. This chapter outlines the epidemiology, clinical characteristics, evaluation, and management of irCAEs following ICI treatment.KeywordsCutaneous adverse eventsDermatologic toxicitiesImmune checkpoint inhibitorsImmune-related cutaneous adverse eventsPD-1 inhibitorPD-L1 inhibitorCTLA-4 inhibitor
[This corrects the article on p. 49 in vol. 8, PMID: 28228726.].
The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners.
Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) may confer durable disease control in several malignancies. In some patients, immune checkpoint mAb cause cutaneous immune-related adverse events. Although the most commonly reported cutaneous toxicities are mild, a subset may persist despite therapy and can lead to severe or life-threatening toxicity. Autoimmune blistering disorders are not commonly associated with immune checkpoint mAb therapy. We report a case series of patients who developed bullous pemphigoid (BP), an autoimmune process classically attributed to pathologic autoantibody formation and complement deposition. Three patients were identified. Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of each patient and rash, and corresponding radiologic findings at the development of the rash and after its treatment, are described. Patients receiving anti-PD-1/PD-L1 mAb may develop immune-related bullous pemphigoid. This may be related to both T-cell and B-cell mediated responses. Referral to dermatology for accurate diagnosis and management is recommended.
Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response, which has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD-1) receptor, nivolumab and pembrolizumab, have now been approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non-small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of approximately 25-40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard-of-care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD-1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD-1 inhibitors are associated with adverse events that have immune etiologies, with grade >3 adverse events typically reported in ≤16% of patients. However, the majority of immune-mediated adverse events (including grade 3-4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD-1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD-1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations. This article is protected by copyright. All rights reserved.
Immune checkpoint antibodies that augment the PD-1/PD-L1 pathway have demonstrated anti-tumor activity across multiple malignancies,
and gained recent regulatory approval as single agent therapy for the treatment of metastatic malignant melanoma and non-small
cell lung cancer. Knowledge of toxicities associated with PD-1/PD-L1 blockade, as well as effective management algorithms
for these toxicities, is pivotal in order to optimize clinical efficacy and safety. Herein, we review selected published and
presented clinical studies investigating single agent anti-PD-1/PD-L1 therapy and trials of combination approaches with other
standard anti-cancer therapies, in multiple tumor types. We summarize the key adverse events reported in these studies, and
their management algorithms.
Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.
We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.
A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).
Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease seen primarily in elderly persons. It is characterized clinically by the development of tense bullae and by the presence of an antibasement membrane antibody. In BP, the antigens involved in the autoimmunity are epidermal basement membrane peptides BPAg1 and BPAg2. We have compared high resolution typing of major histocompatibility complex class II loci (HLA-DRB1, DQB1) in 21 patients with BP, 17 with ocular cicatricial pemphigoid (OCP), and 22 with oral pemphigoid (OP) to a panel of 218 haplotypes of normal individuals. We found that the three diseases (BP, OCP, and OP) have significant association with DQB1*0301 (P = 0.005, P < 0.0001, and P = 0.001, respectively). The frequencies of alleles DQB1*0302, 0303, and 06, which share a specific amino acid sequence from position 71 to 77 (Thr-Arg-Ala-Glu-Leu-Val-Thr) were also increased (P = 0.01). We suggest that an identical major histocompatibility complex class II allele (DQB1*0301) is a common marker for enhanced susceptibility and that the same amino acid residues in positions 71-77 (DQB1*0301, -0302, -0305, -0602, -0603 alleles) are found in patients with BP, OCP and OP. Our findings propose that the autoimmune response in the three different clinical variants of pemphigoid, involves the recognition by T cells of a class II region of DQB1, bound to a peptide from the basement membrane of conjunctiva, oral mucosa, and skin.
Immune checkpoint inhibitors have dramatically improved patient outcomes across a variety of cancers. Recently, reports of bullous skin eruptions clinically consistent with bullous pemphigoid (BP) secondary to programmed cell death 1 (PD-1) inhibition have emerged.¹ We report a case of nivolumab-induced BP with complete response to rituximab therapy.
Programmed cell death protein 1 (PD-1) inhibitors (pembrolizumab, nivolumab) are novel immunotherapies revolutionizing the management of advanced malignancy with an improved adverse effect profile, yet the immune-related side effects are still being characterized.(1,2) We report the unique concurrence of bullous pemphigoid-like disease (BP) with keratoacanthomas and squamous cell carcinomas in two patients receiving anti-PD-1 immunotherapy for metastatic melanoma. This article is protected by copyright. All rights reserved.
Bullous pemphigoid (BP) is considered to be a humorally mediated autoimmune disease, but autoreactive T-cells and T-regulatory cells (Tregs) have also been implicated in this disease. Tregs and the programmed death-1 (PD-1) : programmed death ligand (PD-L) pathway are both critical in terminating immune response, and elimination of either can result in breakdown of tolerance and development of autoimmunity. We report a patient with metastatic malignant melanoma (MM), who underwent pembrolizumab (anti-PD-1) therapy following unsuccessful treatment with ipilimumab [anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4]. The patient developed BP with increasing serum titres of anti-BP180 IgG autoantibodies and increasing disease severity during pembrolizumab therapy. High doses of corticosteroids and methotrexate were needed to control the BP. Following the termination of pembrolizumab therapy, imaging showed complete regression of all metastatic sites. This result may indicate a crucial role for T-cell suppressive activity in controlling and preventing BP.
Checkpoint inhibitors, such as nivolumab, are revolutionary new drugs in cancer therapy. Mild dermatologic toxicities are commonly reported adverse events. Herein, we highlight the development of the autoimmune blistering condition, bullous pemphigoid (BP) in a patient undergoing treatment with nivolumab. A 60-year-old man, who was being treated with nivolumab (3mg/kg intravenously every 2 weeks) after failing chemotherapy for metastatic renal cell carcinoma, presented acutely with a blistering rash. This article is protected by copyright. All rights reserved.
Bullous pemphigoid (BP) is the most common autoimmune blistering disease and is linked to IgG recognition of 2 hemidesmosomal antigens, that is, BP230 (BP antigen 1) and BP180 (BP antigen 2, collagen XVII). The association of BP with other systemic diseases, particularly neurocognitive diseases, provides a potential clue in the underlying pathogenesis of BP. The role of HLA-DQB1*03:01 binding to the immunogenic portion of BP180 provides a potential mechanism by which exposure to neuronal collagen BP180 may lead to cutaneous disease. In our proposed multi-hit hypothesis, patients with underlying neuronal disease are exposed to previously sequestered self-antigen, most importantly BP180. Patients with the HLA-DQB1*03:01 allele show an increased T-cell avidity to several epitopes of BP180, particularly the BP180-NC16a domain. Thus, they have a genetic susceptibility to developing BP upon exposure to the target antigen. In a patient with dysregulation of Th1/Th2 balance, anergy is lost and T-cells are subsequently primed resulting in the development of functional autoimmunity against the BP180-NC16a domain leading to clinically overt disease.
Dermatological toxicity is one of the most commonly reported immune-related adverse events in patients receiving checkpoint inhibitor immunotherapy. We report the gradual development of a widespread bullous pemphigoid-like reaction in a metastatic melanoma patient 8 months after commencing treatment with the programmed-death-1 (PD-1) inhibitor pembrolizumab, requiring prolonged corticosteroid therapy. This case highlights the potential for insidious and late development of severe cutaneous toxicity following PD-1 inhibitor therapy and suggests that even prolonged immunosuppression may not necessarily compromise the efficacy of PD-1 inhibition in advanced melanoma.
Therapeutic immune checkpoint blockade for metastatic melanoma has been associated with vitiligo, pruritus, and morbilliform eruptions. Reports of other autoimmune skin disease in this setting are rare. We sought to expand the spectrum of cutaneous immune-mediated effects related to immune checkpoint inhibitor therapy. In this report, we describe two unusual cutaneous reactions related to checkpoint inhibitor therapy, namely bullous pemphigoid and dermatitis herpetiformis. The development of bullous pemphigoid and dermatitis herpetiformis in the context of checkpoint inhibitor therapy is consistent with previous investigations supporting the importance of effector and regulatory T-cells in the pathogenesis of these diseases.
Monoclonal antibodies against the immune checkpoint programmed cell death receptor 1 (PD-1) improve the hosts' antitumor immune response and have demonstrated tremendous promise in the treatment of advanced solid tumors and hematologic malignancies. Reports of serious autoimmune dermatologic toxicities from immune checkpoint blockade therapy, however, are emerging. We report our experience with five patients who presented with pruritic vesicles and blisters on the skin while treated with anti-PD-1 antibody immunotherapy with either nivolumab or pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae with immunohistochemical study for type IV collagen labeling the floor of the blister cavity and direct immunofluorescence studies (in three of the four patients tested) decorated linear IgG and C3 immune deposits on the blister roof, diagnostic of bullous pemphigoid. One patient developed bullous erythema multiforme. All patients had partial or complete resolution of skin lesions following treatment with systemic corticosteroid and cessation of checkpoint blockade. Recognition and treatment of rare immune-related bullous dermatologic toxicities will become increasingly important as more patients are treated with effective and newer immune checkpoint blockade therapy.
Background:
Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.
Methods and findings:
In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.
Conclusion:
Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have shown improved progression-free and overall survival in patients with advanced melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November 2015, treated with pembrolizumab for advanced melanoma, we encountered three cases of bullous pemphigoid (BP). We have previously reported a case of BP. In two recent cases, BP was diagnosed early and treated promptly with potent topical or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of developing cutaneous immune-related adverse events such as lichenoid reactions, eczema and vitiligo. No cases of BP were encountered in the previously published cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP appears to be another immune-related adverse event, and clinicians should have a low threshold for performing cutaneous biopsies and immunofluorescence studies in patients on anti-PD1 therapies.
In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma.
The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed cell death-1, is pioneering the treatment for advanced melanoma. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immune-related nature. Reported dermatological side effects mostly comprise nonspecific rash and pruritus. This is a report of a 75-year-old man with metastatic melanoma who was initially administered pembrolizumab at 10 mg/kg every 3 weeks. He developed spongiotic dermatitis that was partially treated with topical steroids after cycle 3. Pembrolizumab cycles were stopped because of disease progression after cycle 6. On the 30-day follow-up, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows. Both punch skin biopsies (haematoxylin and eosin and direct immunofluorescence studies) confirmed a bullous pemphigoid diagnosis. He was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment, which was switched to dexamethasone following the diagnosis of new brain metastases.
Bullous Pemphigoid may occur in extremely variegated manners, misleading even experienced dermatologists. Indeed the type and/or distribution of lesions may be unusual. Furthermore, there may be an atypical demographic profile of patients, a different clinical course and a different responsiveness to therapy. Up to 20% of cases the onset is characterized by a non-bullous phase, lasting weeks, months or in particular cases remaining the only manifestation of the disease. During this early phase lesions are generally pruritc erythematous, eczematous or urticarial; however, lesions ma also resemble polycyclic, targetoid, nodular or lichenoid lesions. These atypical lesions may also coexist with typical bullae. Other atypical presentations include a vesicular eruption and erythroderma. Manifestations in children differ from adult forms, presenting an exclusive genital involvement in 50% of cases or a preponderant involvement of the face, the palms and soles. Rarely bullous pemphiogid is confined to certain body areas, due to particular triggering factors or to a lower disease activity. Therefore, the need to formulate universally recognized diagnostic criteria is increasingly evident, especially for atypical bullous pemphigoid. Direct immunofluorescence of perilesional skin and detection of circulating autoantibodies are mandatory in the diagnosis, especially when the clinical presentation is doubtful.
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