Characteristics of the patients having developed DI-LE following treatment with anti-PD(L)1 immunotherapy
| Gender, age, cancer histology | Previous cancer treatments | Drug | Causal relationship | Time to occurrence of DI-LE* (in weeks) | DI-LE form† | Severity grade | Histopathological characteristics of a skin biopsy | Direct immunofluorescence in skin biopsy | Autoimmune biology in serum‡ | Serum creatine kinase (normal value <145 IU/L) | Other irAEs | Treatment for cutaneous lupus, and outcome | Best overall antitumour response, and reintroduction of PD(L)1 (or reason for withdrawal) |
| Patient 1, woman, 48 years old, triple-negative breast carcinoma | Farmorubicine-endoxan-5-fluorouracil; eribulin, capecitabine; gemcitabine | Atezolizumab | Likely | 6 | SCLE Clinical aspect and location: erythematosus, neckline | 1 | Inflammatory monomorphic lymphocyte infiltrate in perivascular and periadnexal sites throughout the dermis. Alcian blue staining revealed mucin deposits in the dermis. | Positive for IgG, linear, moderate, epidermal dermal junction Negative for C3d | Negative Titre for ANA negative (<1/80), aDNA<10, ENA negative complement in normal range (C3=1.73; C4=0.26) | Normal (75 IU/L) | No | Topical steroids, resolution in 2 weeks | PR No interruption of atezolizumab |
| Patient 2, woman, 80 years old, diffuse large B-cell lymphoma | R-CHOP; R-GEMOX; R-lenalidomide | Nivolumab | Likely | 14 | SCLE Clinical aspect and location: papulosquamous erythematous in the lower limbs, symmetrical | 2 | Inflammatory perivascular lymphocytic infiltrate of the upper and middle dermis. Alcian blue staining revealed mucin deposits. | Negative | Negative Titre for ANA<1/80; aDNA<10; ENA negative Low complement C4 and CH50 but normal C3 (C3=1.53; C4<0.02; CH50<10) | Normal (28 IU/L) | Yes: hepatitis grade 2 | Topical steroids, resolution in 3 weeks | PD Temporary withdrawal of immunotherapy due to lupus, and then definitive withdrawal of nivolumab due to disease progression |
| Patient 3, woman, 66 years old, carcinoma epidermoid | Radiotherapy; carboplatin-cetuximab-5-fluorouracil; paclitaxel-cetuximab; methotrexate-carboplatine | Nivolumab | Likely | 4 | SCLE Clinical aspect and location: erythematosus on the trunk, back and face | 2 | Perivascular lymphocytic infiltrate of the upper dermis with discrete vacuolisation of the epidermal basal layer. Alcian blue staining revealed mucin deposits in the dermis. | Negative | Positive with ANA+ and SSA+ Titre for ANA=1/640; aDNA<10; ENA=1.5 weakly positive; SSA=94 U/mL, complement in normal range (C3=1.42; C4=0.2; CH50 not done) | Normal (30 IU/L) | No | Topical steroids, resolution in 2 weeks | SD Temporary withdrawal of immunotherapy due to lupus |
| Patient 4, man, 63 years old, melanoma | None | Pembrolizumab | Certain | 22 | SCLE Clinical aspect and location: generalised, clearly erythematosus, papular and macular aspects on the trunk, back, abdomen and thorax Systemic lupus erythematosus (SLICC criteria4 were SCLE+arthralgia+positive serum antibodies) | 3 | Lichenoid dermatosis with staged apoptotic bodies in the epidermis. Peripheral inflammatory mononuclear infiltrate in the upper dermis. Alcian blue staining did not reveal any mucin deposits in the dermis. | Positive for IgG: discontinuous low-intensity band and epidermal dermal junction. C3d positive: rough band | Positive with SSA+/SSB+ Titre for ANA>1/1280 (mottled aspect); aDNA<10; ENA>28 highly positive with SSA>241 U/mL and SSB=86 U/mL (n<7), complement in normal range (C3=1.07; C4=0.21; CH50>60) | Elevated: 238 IU/L when lupus appeared, then 181 IU/L 15 days later, then return to normal levels | Yes: vitiligo universalis, hepatitis grade 2 | Topical steroids, oral hydroxychloroquine, resolution in 4 weeks | CR Permanently discontinued due to the adverse event and the CR |
| Patient 5, man, 48 years old, melanoma | Dacarbazine-fotemustine; ipilimumab | Pembrolizumab | Certain | 10 | Chilblain lupus on the toes | 1 | Not performed | Not performed | Negative Titre for ANA<1/80; aDNA<10; ENA not done; complement in normal range (C3=1.17; C4=0.2; CH50=49.3) | Normal (58 IU/L) | Yes: vitiligo universalis | Topical steroids, resolution in 2 weeks | PR No discontinuation of pembrolizumab |
| Total: Median (range) age 63 (48–80) years | – | – | – | Median (range): 10 (4–22) weeks | – | – | – | Positive in two of four cases tested (50%) | ANA positive in two of five cases (40%) | – | – | – | – |
*Time between the first infusion of anti-PD(L)1 and the onset of symptoms of lupus erythematosus.
†Among Obermoser et al.7
‡Serum assays for autoimmune factors, with normal values indicated: ANA, serum titre, normal <1/80; aDNA, normal <10 IU/mL; ENA, ratio, normal <1.1 (ratio=sample absorption/standard absorption); SSA, normal <7 U/mL; SSB, normal <7 U/mL; C3, normal values=0.9–1.80 g/L; C4, normal values=0.10–0.40 g/L; CH50, normal value >31.6; creatine kinase (CK), normal values=0–145 IU/L.
aDNA, anti-DNA; ANA, antinuclear antibody; CH50, 50% complement haemolytic; CR, complete response; DI-LE, drug-induced lupus erythematosus; ENA, extractable nuclear antigen; irAE, immune-related adverse event; PD, progressive disease; PR, partial response; R-CHOP, rituximab-cyclophosphamide hydroxyadriamycine oncovin prednisone; R-GEMOX, rituximab-gemcitabine oxaliplatine; SCLE, subacute cutaneous lupus erythematosus; SD, stable disease; SLICC, Systemic Lupus International Collaborating Clinics4; SSA, Sjögren’s syndrome-related antigen A; SSB, Sjögren’s syndrome-related antigen B.