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Page 6 of 9 Wu et al. J Cancer Metastasis Treat 2020;6:40 I http://dx.doi.org/10.20517/2394-4722.2020.77

44 Nivolumab Melanoma Cutaneous BP Topical/oral steroids and dapsone [13]
45 Nivolumab Melanoma MMP Topical steroids [45]
46 Pembrolizumab Ovarian Ca. Severe MMP 3 Topical and oral steroids [46]
47 Nivolumab Lung Oral and cutaneous BP Oral steroid [8]
48 Atezolizumab Penile SCC Photodistributed BP Oral steroids [47]
49 Atezolizumab Urothelial cell Cutaneous BP 77 Topical steroids, doxycycline and [15]
Ca. niacinamide
50 Nivolumab Renal cell Ca. Cutaneous BP 52 IV and oral steroids [48]
51 Durvalumab and NSCLC BP 42 Oral steroids [49]
tremelimumab
52 Cemiplimab Cutaneous BP Oral steroids and rituximab [50]
SCC

SCC: squamous cell cancer; Ca.: carcinoma; NSCLC: non-small cell lung cancer; MMP: mucous membrane pemphigoid; BP: bullous
pemphigoid

may develop in the presence of anti-LAD-1 IgG antibodies alone but absence of anti-BP180 or anti-BP230
[13]
autoantibodies .
Treatment regimens generally include steroids (oral or topical or combination), often in conjunction with
discontinuation of immunotherapy. As steroids can potentially diminish immunomodulatory actions,
topical steroids are first-line treatment for BP and are largely safe due to their limited systemic absorption.
Meanwhile, oral nicotinamide and tetracycline (doxycycline or minocycline) have demonstrated a good
effect in mild or moderate cases whilst completely avoiding systemic steroids [14,15] . The role of nicotinamide
in treating BP is modulating inflammatory cytokines and acting as poly adenosine diphosphate ribose
[16]
polymerase inhibitor . However, severe cases have frequently required intravenous methylprednisolone
(1-2 mg/kg). Refractory immunotherapy-induced BP shows response to rituximab or omalizumab [12,17] ,
which are started after immunotherapy discontinuation and lead to resolution of BP. Future studies are
warranted to explore targeted immunosuppressant agents for severe steroid-refractory BP.

The question of resuming immunotherapy after resolution of BP remains under discussion. In the
situations where immunotherapy is ineffective, discontinuation is clearly warranted. While in the context of
a clinical response to immunotherapy, the discontinuation of immunotherapy is challenging, and the risks
of continued treatment must be carefully weighed against its benefits. As such, the decision of resuming
immunotherapy should be made as a part of multidisciplinary team and on an individual basis. In one
case report BP developed after the patient was transitioned to a higher dose of nivolumab. Another case
[18]
report showed improvement in BP after switching from nivolumab to pembrolizumab . Consequently,
immunotherapy should not be permanently discontinued without the trial of the previously tolerated dose
or frequency or different immunotherapy.

Understanding the correlation between the incidence rate of skin irAEs and oncology benefit or
immunotherapy resistance is critical for clinical practice. There is some evidence showing potential
positive association between development of cutaneous irAEs and improved survival in patients on
immunotherapy, particularly vitiligo [19,20] . In addition, a systematic review and meta-analysis suggested that
the skin, gastrointestinal and endocrine irAEs might be positively associated with clinical benefit, while
the pulmonary irAEs might be associated with immunotherapy resistance . However, the development of
[21]
severe BP in our case is not a marker of good response to immunotherapy, as the patient failed to respond
to nivolumab despite the extensive, refractory, severe BP. Immunotherapy resistance can be classified
[22]
as primary, such as in never-responders, or acquired, which emerges after a period of response . Our
patient had continuously slow disease progression in his metastatic left adrenal and left kidney mass since
nivolumab, which could be primary immunotherapy resistance. However, we could not totally exclude the
possibility of pseudo-progression, as his other metastatic diseases were largely stable. In a later phase, the