Bullous Pemphigoid–like Skin Lesions and Overt Eosinophilia in a Patient With Melanoma Treated With Nivolumab: Case Report and Review of the Literature

Abstract

The widespread use of immune checkpoint inhibitors has shed light to several unusual immune-related adverse effects of the drugs. Severe cutaneous adverse reactions are generally rare with anti-PD1 agents. We present in this paper the case of a 48-year-old patient with melanoma who developed bullous pemphigoid-like skin lesions along with fever, arthralgia and overt eosinophilia following adjuvant treatment with nivolumab. The condition was successfully treated with corticosteroids and a rechallenge with another anti-PD1 agent did not lead to recurrence of the skin lesions. We also reviewed the literature on the epidemiologic, clinical, and histopathologic characteristics of bullous pemphigoid as well as on the treatment and prognosis of this dermatologic condition in patients with melanoma or other malignancies under treatment with immune checkpoint inhibitors.

Mucous Membrane Pemphigoid, Bullous Pemphigoid, and Anti-programmed Death-1/ Programmed Death-Ligand 1: A Case Report of an Elderly Woman With Mucous Membrane Pemphigoid Developing After Pembrolizumab Therapy for Metastatic Melanoma and Review of the Literature

“…Among the 27 cases of anti PD-1/PD-L1-associated BPs, four had a long delay (>60 weeks) between starting anti PD-1/PD-L1 therapy and onset of BP (patients 5, 11, 17, and 18) ( 34 , 36 , 41 , 42 ). Similarly to our patient, three patients developed a BP 4, 12, and 12 weeks after discontinuation of the anti PD-1 therapy (patients 1, 22, and 23, respectively) ( 32 , 46 , 47 ). This could be explained by the durable activity of anti PD-1/PD-L1 on immunity ( 70 , 71 ).…”

“…We examined the intrinsic accountability of pembrolizumab therapy on MMP induction in our patient with metastatic melanoma because of its extrinsic accountability based on the following reports: (i) MMP and BP have immunological similarities ( 7 ); (ii) intrinsic accountability of anti PD-1/PD-L1 treatments on BP induction: 27 BP have been reported as case reports or short series ( 32 – 49 ) and two BPs listed as adverse drug reaction in two large trials with anti PD-1 ( 50 , 51 ); (iii) recently, one pembrolizumab-associated MMP case report ( 52 ), and (iv) some of the anti PD-1/PD-L1-associated BPs had atypical clinical phenotypes ( 33 – 35 , 42 , 47 ).…”

“…The potential drug induction of AIBD has been known for decades ( 18 , 59 – 66 ). Recently, between 2015 and 2018, 18 case reports or small series described 27 patients who developed BP while receiving anti PD-1/PD-L1 therapy, including three with negative DIF ( 35 , 37 ) or without DIF confirmation ( 47 ) but with typical clinical presentations (Tables 1 , 2 ). Fourteen patients received anti PD-1 nivolumab therapy (patients 2, 4, 7, 9, 10, 13, 15, 18, 20, 22, 23, and 25–27) ( 33 , 35 , 38 , 42 , 44 , 46 , 47 , 49 ), 11 received anti PD-1 pembrolizumab therapy (patients 1, 5, 6, 8, 11, 12, 14,16, 19, 21, and 24) ( 32 , 34 – 37 , 39 , 40 , 43 , 45 , 48 ), one received anti-PD-L1 durvalumab therapy (patient 3) ( 33 ), and one received anti-PD-L1 atezolizumab therapy (patient 17) ( 41 ).…”

“…The comparison with the “usual” BPs ( 7 , 69 ) highlights particularities in these anti PD-1/PD-L1-associated BPs as follows: a predominance of males (female-to-male sex ratio, 0.4 vs. 1.5), younger age [mean, 69 years; median, 68 years (range, 35–90 years) vs. mean, 83 years], no evidence of neurological disorders, more extensive diseases (52 vs. 41%), and no circulating autoantibodies against BP230 except in one patient (8 vs. 60–70%), while 91% of the tested sera had circulating autoantibodies against BP180-NC16A (vs. 80–90%). Moreover, seven cases had atypical clinical phenotypes, as head and neck involvement or mucosal lesions ( 33 – 35 , 42 , 47 ), raising doubts about the diagnosis of BP ( 53 ).…”

Management of immune checkpoint inhibitor‐related adverse events: A review of case reports

“…Most patients required discontinuation of therapy completely for a short period of time as well as immunosuppressant treatment. (32) Vitiligo (1), granuloma annulare (2), bullous pemphigoid (3), psoriasis (22), erythema multiforme (1), lichenoid reaction (2), Grover's disease (1) Endocrinologic (52) Type 1 diabetes mellitus (38), hypophysitis (9), isolated adrenal insufficiency (1), thyroid storm (2), hypothyroidism (2) Gastrointestinal (47) Acute liver failure (1), hepatitis (8), bile duct obstruction (1), cholangitis (1), pancreatitis (1), hemorrhagic gastritis (1), ileitis (1), colitis (32), intestinal obstruction (1) Pulmonary (11) Organizing pneumonia (5), sarcoidosis (2), pneumonitis (4) Neurologic (20) Myasthenia gravis (5), Guillain-Barre syndrome (3), cerebral edema (1), necrotizing encephalopathy (1), encephalitis (2), mononeuropathy multiplex with rhabdomyolysis (1), necrotic myelopathy (1), Bell's palsy (1), inflammation enteric neuropathy (1), brachial plexus neuritis (2), peripheral neuropathy (2) Cardiac (7) Myocarditis (2), cardiomyopathy (1), coronary spasm (1), pericardial effusion (3) Rheumatologic (28) Remitting seronegative symmetrical synovitis with pitting edema (1), arthritis (12), dermatomyositis/myositis (4), Goodpasture's disease (1), scleroderma (2), polymyalgia rheumatic (3), sicca syndrome (5) Nephrotic (7) Cystitis (1), renal failure (1), nephrotic syndrome (4), acute glomerulonephritis (1) Hematologic (16) Pancytopenia (2), neutropenia (6), aplastic anemia (2), pure red cell aplasia (1), thrombocytopenia (3), acute thrombosis (1), hemophagocytic lymphohistiocytosis (1) Ophthalmologic (17) Uveitis (7), Vogt-Koyanagi-Harada disease-like uveitis (2), orbital inflammation (3), dry eye (2), ulcerative keratitis (1), ocular myositis (2) Otorhinolaryngologic (2) Sinusitis…”