Abstract

Nivolumab is widely used to treat several late-stage malignancies such as melanoma and non-small-cell lung cancer by inhibiting the interaction between the programmed cell death protein-1 and its ligand. By stimulating an antitumor immune response,it also Embryo biopsy leads to immune adverse events. Here. we report two cases of subacute cutaneous lupus erythematosus (SCLE) induced by nivolumab. Case 1:a 72-year-old woman with a stage IV melanoma. Two months after nivolumab discontinuation because of autoimmune hepatitis,the patient was in complete remission and pruritic nummularerythematous plaques appeared on the back and arms. Case 2:a 43-year-old man put under nivolumab for a metastatic non-small-cell lung cancer. After two cycles,an annular erythematous eruption appeared on the hands,arms,and chest. The hypothesis of SCLE was confirmed by biopsies showing lymphoid perivascular inflammatory infiltrates,with scarce C3 deposits along the basal layer of the epidermis in patient 2. Both patients tested positive for antinuclear antibodies and anti-SSA antibodies. Lesions were regressive under topical corticosteroids and hydroxychloroquine for the first patient and oral prednisone for the second patient. No systemic involvement was observed. The occurrence of SCLE 2 months after nivolumab discontinuation is evidence that the drug effect is prolonged because of the maintenance of programmed cell death protein-1 reception saturation for months. A causal relationship between SCLE and nivolumab is suggested by (i) the occurrence of SCLE after at least two cycles,(ii) the regression of lesions following treatment with corticosteroids and hydroxychloroquine,and (iii) the fact that it appeared after remission in our first patient.

Keywords:adverse event,nivolumab,subacute cutaneous lupus erythematosus

Introduction

The programmed cell death protein-1 (PD-1) inhibitor nivolumab is used widely to treat several late-stage malignancies,including melanoma [1]. Inhibition of the PD-1–PD-1 ligand interaction stimulates an antitumor immune response [2]. Many of the adverse events (AEs) associated with PD-1 inhibitors are immune-mediated [3]. Here,we report on two cases of nivolumab-induced subacute cutaneous lupus erythematosus (SCLE).

Clinical cases

Patient 1:A 72-year-old woman with an unremarkable medical history presented with superficial spreading melanoma on the back (Breslow depth:1 mm;mitotic index:3/mm3;no ulceration). Broad local excision was performed. Thirteen months later,the woman underwent bilateral axillary lymph node dissection for bilateral recurrence. Eighteen months afterthe dissection,a computed tomography (CT) scan indicated metastases in the spleen,the lungs,and the left axillary lymph node. The melanoma was BRAF wild type,and first-line nivolumab immunotherapy was initiated. After 13cycles of 3 mg/kg nivolumab,the patient developed autoimmune hepatitis:alanine transaminase at five times the upper limit of normal (ULN),aspartate transaminase at three times the ULN,and γ-glutamyl transpeptidase and alkaline phosphatase at five times the ULN,and so thenivolumab treatment was discontinued. At that time,all the metastatic sites other than the spleen had been cleared;the patient then underwent splenectomy and achieved complete remission. Two months later,a CT scan confirmed the absence of progressive lesions;there was no recurrence of melanoma,but pruritic nummular erythematous plaques appeared on the patient’sback and arms (Fig. 1).

A histological examination showed lymphoid inflammatory infiltrates predominantly in perivascular areas,with focal lesions of the dermis and epidermis (corresponding to a diagnosis of cutaneous lupus),but no C3 or IgG deposits along the basal layer of the epidermis.

The patient was positive for anti-Ro/SS-A,anti-La/SS-B,and antinuclear antibodies (1/640),and negative for antiDNA antibodies. A standard lupus workup ruled out
extracutaneous involvement. A 3-month course of treatment with 400 mg/day hydroxychloroquine was initiated. After 4 months of follow-up,no relapse was noted and only residual scarring was present.

Patient 2:A 43-year-old male heavy smoker was diagnosed with non-small-cell lung cancer and massive mediastinal lymph node metastasis. The patient was started on combination chemotherapy with cisplatin and pemetrexed,but this had to be discontinued after two cycles because of renal toxicity. Next,treatment with nivolumab was initiated. After two cycles,an annular erythematous eruption appeared on the dorsal aspect of the hands,arms,and chest,and then progressed to the rest of the body (Fig. 2). At this point in time,a CT scan confirmed that the patient’s lung cancer was spreading. However,the metastases in the mediastinal and left hilar lymph nodes were stable,as was the left pleural and pericardial effusion. Micronodular pulmonary infiltrates appeared around the peribronchial and left lower lobe mass. There was an increase in the size of the subpleural nodule in the medial basal and anterior segments of the left lower lobe,with multiple mesenteric adenopathies and a 2.5 cm tumor mass.

A punch biopsy of a cutaneous lesion indicated discrete lymphoid perivascular inflammatory infiltrates,with scarce C3 deposits along the basal layer of the epidermis.
The patient tested positive for antinuclear antibodies (1/320) and anti-SSA antibodies (>600 IU/ml). The nivolumab was therefore withdrawn after two cycles,and treatment with 400 mg/day hydroxychloroquine and topical betamethasone dipropionate was initiated. The skin lesions did not respond to this treatment,and a severe flare-up was observed 2 weeks later. Additional treatment with 1 mg/kg/day oral prednisone led to clearance of the skin lesions in 3 days,leaving hypopigmented scars.

Both cases have been reported to the French pharmacovigilance network.

The AE was classified as a ‘probable adverse drug reaction’,according to the Naranjo algorithm,as follows:
(1) Previous conclusive reports on this reaction (+1),AEs appearing after the suspected drug was administered (+2),symptoms receding when the drug was discontinued (+1),no re-administration of the drug (0),no alternative causes that could on their own have caused the reaction (+2),placebo not been administered (0),drug levels in the blood or other fluids had not been determined (0),no change in the dose administered (0),no similar reaction in the past with the same drug (0),and confirmation of the AE by objective evidence (+1),yielding a total score of 7.

Discussion

Here,we reported on two cases of SCLE that emerged after the initiation of nivolumab treatment. There was no systemic involvement. To the best of our knowledge,only one other such case has been reported to date [4]. Interestingly,there are no other reports of drug-induced subacute cutaneous lupus erythematosus (DISCLE) with The cutaneous AEs known to be associated with nivolumab are maculopapular rash,vitiligo,pruritus,acneiform dermatitis,photosensitivity reaction [5],the occurrence or exacerbation of psoriasis [3,6],lichenoid reactions of the skin or the oral mucosa [7],eczema,Steven–Johnson syndrome,toxic epidermal necrolysis [8],cutaneous sarcoidosis [9],and bullous pemphigoid [10].
Depending on their severity,these AEs should prompt the discontinuation of treatment with nivolumab. According to the summary of product characteristics for nivolumab,the occurrence of a grade 3 cutaneous AE (graded according to the Common Terminology Criteria for Adverse Events,version 4.03) requires the temporary discontinuation of nivolumab treatment (i.e. until resolution),and a grade 4 AE requires the definitive cessation of treatment. In cases of DISCLE not considered as a grade 3 or Plerixafor ic50 4 AE,checkpoint inhibitor treatment can be continued;treatment of the AE is based on topical steroids and hydroxychloroquine. To avoid a loss of antitumor activity,immunosuppressive treatments should be avoided [11]. Furthermore,systemic involvement is only observed in 20% of cases of SCLE,meaning that immunosuppressive treatment is not immediately required in most instances [12].

The time to onset of cutaneous AEs after the initiation of nivolumab ranges from a day to a year (median for all grades:5 weeks),and the time to resolution ranges from a day to more than 68.3 weeks (median:18 weeks) [13]. Around 34% of nivolumab-treated patients develop a cutaneous AE. Only 0.7% of these are grade 3 or 4 events,and 75% occur before 16 weeks of treatment (i.e. eight cycles) [13],with a peak at 13 weeks.

In our first patient,the occurrence of DISCLE 2 months after the discontinuation of nivolumaband the prolonged remission confirm that AEs can occur several months after treatment discontinuation. Indeed,the drug effect can be prolonged from 16 weeks to more than 56 weeks after discontinuing therapy. This might be because of the maintenance of PD-1 receptor saturation for several months after the discontinuation of therapy [5,14].

Twenty percent of cases of cutaneous lupus erythematosus are drug induced,and most of these are subacute. However,SCLE in patients over the age of 50 years is occasionally associated with cancers such as lung,breast,and gastric cancers,non-Hodgkin lymphoma,laryngeal cancer,cancer of the uterus,esophageal adenocarcinoma in situ,cholangiocarcinoma,hepatocellular cancer,and melanoma [15]. The diagnostic criteria for paraneoplastic SCLE were described 30 years ago:the SCLE Soil microbiology must appear after the neoplasm,and the two conditions have to progress in the same manner [14];hence,if the SCLE is spreading,the tumor is likely to be resistant to the current treatment.

On average,paraneoplastic SCLE appears 6 months after the neoplasm (range:0–48 months),regresses during remission,and reappears if the cancer relapses [16].
In our first patient,SCLE appeared while she was cancer free,under complete remission,and it quickly responded to hydroxychloroquine and topical corticosteroid. As for patient 2,SCLE (a) appeared almost 2 months after cancer diagnosis and 1 month after the introduction of nivolumab,(b) worsened when the patient’s cancer was spreading,(c) resisted to hydroxycholoroquine and topical corticosteroids,and (d) persisted after cessation of nivolumab treatment,(e) but was regressive under oral corticosteroids eventhough his cancer was still spreading.

This is why (i) the occurrence of SCLE after 1 month of treatment in one case and 2 months after discontinuation in the other,(ii) the regression of lesions following treatment with topical/oral corticosteroids and hydroxychloroquine (especially in patient 2,who was not cancer-free),and (iii) the fact that the SCLE appeared after remission in our first patient suggested a diagnosis of nivolumab-induced SCLE and not a paraneoplastic SCLE.

Vitiligo is the only immune-mediated,nivolumabassociated AE to have been linked to improved overall survival and progression-free survival in patients with melanoma [17]. No other immune-mediated AEs (including SCLE) have been linked to longer survival or a higher response rate.

The fact that patients with autoimmune conditions were excluded from the pivotal phase III nivolumab trials makes it difficult to know how to treat these individuals. However,a growing body of literature shows that nivolumab treatment triggers a flare-up (albeit usually mild and easily manageable) in around 50% of patients with preexisting autoimmune disease.

However,nivolumab does not trigger a flare-up of previous ipilimumab-induced autoimmune toxicity [18]. Our two reports on a rare type of DISCLE emphasize that (i) the full spectrum of antiPD-1-associated AEs has not yet been characterized and (ii) DISCLE requires multidisciplinary management.