Subacute cutaneous lupus erythematosus (SCLE) lacks consensus diagnostic criteria and the pathogenesis is poorly understood. There are increasing reports of SCLE induced by monoclonal antibodies (mAbs), but there are limited data on the aetiology, clinical characteristics and natural course of this disease.
We devised a set of diagnostic criteria for SCLE in collaboration with a multinational, multispecialty panel. This systematic review employed a two-layered search strategy of five databases for cases of mAb-induced SCLE (PROSPERO registered protocol CRD42019116521). To explore the relationship between relative mAb use and the number of SCLE cases reported, the estimated number of mAb users was modelled from 2013 to 2018 global commercial data and estimated annual therapy costs.
From 40 papers, we identified 52 cases of mAb-induced SCLE, occurring in a cohort that was 73% female and with a median age of 61 years. Fifty percent of cases were induced by anti-tumour necrosis factor (TNF)-ɑ agents. A median of three drug doses preceded SCLE onset and the lesions lasted a median of 7 weeks after drug cessation. Oral and topical corticosteroids were most frequently used. Of the licensed mAbs, adalimumab, denosumab, rituximab, etanercept and infliximab were calculated to have the highest relative number of yearly users based on global sales data. Comparing the number of mAb-induced SCLE cases with estimated yearly users, the checkpoint inhibitors pembrolizumab and nivolumab showed strikingly high rates of SCLE relative to their global use, but ipilimumab did not.
We present the first systematic review characterising mAb-induced SCLE with respect to triggers, clinical signs, laboratory findings, prognosis and treatment approaches. We identify elevated rates associated with the use of checkpoint inhibitors and anti-TNFɑ agents.
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Monoclonal antibody (mAb)-induced subacute cutaneous lupus erythematosus (SCLE) has been reported in 52 patients across a range of 17 mAbs. Adalimumab, denosumab and rituximab were estimated to have the greatest number of annual users. Checkpoint inhibitors and anti-tumour necrosis factor-ɑ agents are associated with high rates of SCLE relative to the estimated global yearly use and other mAbs.
In an era of genomic medicine, the clear distinction of disease phenotypes is as critical as ever [
Lupus erythematosus (LE) exemplifies this classification challenge, in comprising a spectrum of autoimmune pathology, where aberrant inflammatory processes lead to cell injury with diverse patterns of disease. Cutaneous lesions may arise in isolation or as a feature of systemic lupus erythematosus (SLE), with a prevalence of around 70 in 100,000 [
Subacute cutaneous lupus erythematosus (SCLE) is a phenotypic subset of CLE, first described in 1979 as an intermediary between transient, acute CLE, and chronic, scarring CLE [
Numerous medications have been implicated in triggering the development of SCLE [
This review was conducted according to the PROSPERO registered protocol (CRD42019116521, accessible at
A lack of formalised consensus for the classification criteria of SCLE [ Inclusion and exclusion criteria used for monoclonal antibody-induced SCLE Features Inclusion Morphology Definite: Annular, polycylic Erythema multiforme-like Papulosquamous, plaques or papules with scale or desquamation, psoriasiform ‘SCLE’ without exclusion terms Possible: Plaques or papules Erythema with scale or desquamation Serology ANA-positive, anti-Ro antibody-positive OR ENA-positive Photosensitivity Lesions in sun-exposed areas: Face, neck OR arms Histology Prespecified: –IF dermatitis –Study synonyms: IF change, IF reaction, IF infiltrate, lichenoid reaction –‘Consistent with SCLE/lupus’ Supportive details included in cases: –Lymphocytic infiltrate of perivascular/dermoepidermal regions/junction/perifollicular/superficial/deep/dermis/epidermis –Parakeratosis, orthokeratosis, dyskeratosis, hyperkeratosis, necrotic/apoptotic keratinocytes –Mucin in dermis, colloid bodies, colloidal iron staining Morphology Nonspecific/contradictory CLE terms in the absence of inclusion terms Chronic, discoid, tumidus, panniculitis, profundus, chilblain, atrophic, scarring Acute, malar, macular, butterfly Stevens–Johnson syndrome Palpable purpura, nodules, bullous
Five databases were searched without any time limitations, with final searches conducted on 22 August 2019 (Fig. Study profile of the systematic review for monoclonal antibody-induced subacute cutaneous lupus erythematosus
Following duplicate removal, screening of abstracts, and critical appraisal, data extraction was performed by two reviewers independently using the same Microsoft Excel template (Microsoft Corporation, Redmond, WA, USA). Studies were eligible if they described human patients of any age and included individual-level primary data where sufficient patient characteristics could be extracted (electronic supplementary Table S1). English and non-English-language papers were included, with translation supplied by Google Translate for the initial screening. Variables extracted are specified in electronic supplementary Appendix S1. Verification of data extraction for German and Spanish papers was undertaken by bilingual doctors who were native speakers or had medical language qualifications in the language. Abstract screening disparities were resolved by a third reviewer, while appraisal and extraction disparities were resolved by discussion.
Risk of bias was considered to be inherently low given the observational nature of case reports. The publication quality was appraised according to the accuracy of descriptions and figures, the consistency of values, and appropriate application of statistical tests (electronic supplementary Appendix S1).
To determine whether large-scale use of anti-tumour necrosis factor (TNF)-ɑ agents accounted for high rates of SCLE, the relative global use of mAb products was estimated by modelling yearly global sales data (2013–2018) and dividing by the mean annual therapy cost taken from a truncated normal distribution of costs across different settings and indications. The 20 mAb products with the highest global sales in 2013 (licenced in the US and Europe as of November 2013 [
A truncated normal distribution was used to estimate the average annual therapy costs with the upper bound based on US data, as the US is reported as having exceptionally high biologic costs [
For the lower bound UK values, average costs were estimated for the treatment received by a single patient over 1 year, for adult indications, including induction and maintenance regimens. Yearly therapy prices were calculated for a range of oncological, musculoskeletal, respiratory and rheumatological indications of each drug as shown (electronic supplementary Table S3). Doses were calculated for a 70 kg adult with a body surface area of 1.75 m2. For drug treatments requiring a course duration of < 1 year, the average duration of treatment was taken from NICE guidance where provided, or the median course of treatment from available clinical trials (electronic supplementary Table S3). UK treatment costs were derived from September 2015 vial prices (British National Formulary 70th edition), unless stated. UK costs in 2013–2018 Great British Pounds (GBP) were converted to 2018 US$ using implied standard conversion rates based on purchasing power parities from the International Monetary Fund.
Descriptive statistics are provided according to information available in reports without adjustment. Regarding missing data, confidence intervals in Fig.
Overall, 1788 unique abstracts from database searches and conference abstracts were screened for inclusion (Fig.
The median age of onset for mAb-induced SCLE was 61 years (interquartile range [IQR] 51–66) and 73% of patients were female (38/52). The majority of patients had White European ancestry (94%, 27/33). Inflammatory arthritis was the most common indication for mAb therapy at the time of the SCLE eruption (40%, 20/50). The next most common indications for therapy leading to SCLE included advanced melanoma (12%, 6/50), psoriasis/psoriatic arthritis (10%, 5/50) and metastatic lung cancer (8%, 4/50).
mAbs implicated in inducing SCLE are shown in Table Summary of patient characteristics experiencing monoclonal antibody-induced subacute cutaneous lupus erythematosus Trait Percentage Further detail Monoclonal antibody No. of SCLE cases Age, years ( Median 61 Mean 58.9 IQR 51–66 Range 28–82 Etanercept Adalimumab Infliximab Nivolumab Pembrolizumab Golimumab Bevacizumab Abatacept Rituximab Denosumab Efalizumab Natalizumab Ranibizumab Secukinumab Ixekizumab Atezolizumab Ustekinumab 10 6 6 6 6 4 2 2 2 1 1 1 1 1 1 1 1 Sex 73% female 38/52 Ethnicity 94% White 3% Omani 3% Brazilian 27/33 1/3 1/33 Onset time, weeks ( Median 9 Mean 13.8 IQR 3–17 Range 1–100 Cessation time, weeks ( Median 8 Mean 14 IQR 3–17 Range 2–52 Lesion distribution ( 68% trunk 64% arms 41% face 30% neck 30% legs 30% back 18% hands 14% head 30/44 trunk 28/44 arms 18/44 face 13/44 neck 13/44 legs 13/44 back 8/44 hands 6/44 head First-line treatment ( Serology 85% ANA + 62% anti-Ro + 27% anti-dsDNA 42% anti-histone 39/46 24/39 9/33 5/12 Monotherapy: Biologic cessation TOP corticosteroid only PO corticosteroid only DMARD only 16% (8/49) 31% (15/49) 10% (5/49) 8% (4/49) Haematological Pancytopenia Lymphopenia Leukopenia Low complement 2/52 3/52 4/52 4/52 Polytherapy: TOP + PO corticosteroid DMARD + PO corticosteroid DMARD + TOP corticosteroid DMARD + PO + TOP corticosteroid Other 6% (3/49) 8% (4/49) 2% (1/49) 10% (5/49) 8% (4/49)
Lesions were most frequently distributed over the trunk and arms (68% and 64%, 30/44 and 28/44, respectively) [Fig.
Numerous treatment approaches to mAb-induced SCLE were recorded (
The most common medications applied were oral and/or topical corticosteroids. Thirty-one percent of patients were treated with topical corticosteroids alone (15/49), with triamcinolone 0.1% ointment being the most frequently used topical corticosteroid. Thirty-seven percent of patients were treated with oral corticosteroids (18/49), either alone (
Eighty-nine percent of patients were reported to respond partially or fully to first-line therapy (30/45). One patient experienced a flare when corticosteroids were weaned, and again when hydroxychloroquine was introduced as a corticosteroid-sparing agent [
In 2013, the mAbs with the highest sales were adalimumab, infliximab, etanercept, rituximab and bevacizumab. By 2018, the highest sales were attributed to adalimumab, etanercept, pembrolizumab, trastuzumab and bevacizumab. From modelling 2013–2018 global sales against estimated yearly therapy costs, the mAbs with the estimated highest yearly number of users were adalimumab, denosumab, rituximab, etanercept and infliximab (Table Estimated monoclonal antibody use according to total global sales and average global cost mAb Total global sales in 2018 (US$, $m)a Mean global mAb cost [US$ (min–max)]b Average estimated mAb yearly users across the years 2013–2018 [in thousands (min–max)] Adalimumab 19,952 34,870 (14,141–55,614) 615 (331–1524) Etanercept 7611 30,105 (11,085–49,142) 276 (149–713) Pembrolizumab 7171 107,625 (80,214–135,072) 68 (40–109) Trastuzumab 7053 47,119 (19,869–74,389) 160 (90–367) Bevacizumab 6919 86,810 (36,383–137,278) 84 (49–193) Rituximab 6821 23,559 (6323–38,153) 305 (172–1102) Aflibercept 6746 38,425 (9378–67,491) 187 (77–818) Nivolumab 6735 102,425 (40,614–164,291) 70 (37–179) Infliximab 6593 22,790 (15,730–29,854) 297 (209–440) Ustekinumab 5156 28,586 (15,280–42,415) 190 (86–435) Denosumab 4077 13,069 (3804–22,341) 325 (131–1286) Ranibizumab 3722 32,341 (10,187–54,514) 125 (63–396) Eculizumab 3563 547,771 (509,185–586,412) 7 (3–10) Golimumab 2977 33,712 (15,244–52,192) 94 (51–216) Omalizumab 2970 26,148 (12,696–39,619) 121 (61–277) Abatacept 2710 28,158 (18,677–37,653) 99 (63–162) Tocilizumab 2182 28,920 (15,782–42,081) 79 (34–187) Natalizumab 1864 47,775 (22,463–73,110) 41 (23–89) Cetuximab 1451 80,792 (15,351–146,256) 19 (9–103) Certolizumab pegol 1446 34,460 (11,632–50,322) 45 (17–163) Palivizumab 1381 22,914 (9139–36,697) 63 (34–167) Iplimumab 1330 123,321 (114,373–132,282) 11 (8–14) a2013–2018 global sales were used to calculate the estimated monoclonal antibody yearly users. 2018 data are shown here bMaximum value is based on electronic supplementary Table S2, while minimum value is based on electronic supplementary Table S3, with 1 GBP converted to 1.524 US$
With a high average therapy cost, pembrolizumab had 68,000 estimated yearly users, compared with adalimumab with an estimated 615,000 yearly users. The number of SCLE cases attributable to checkpoint inhibitors such as pembrolizumab and nivolumab showed an especially high ratio of SCLE relative to the estimated yearly users (Fig. Ratio of total cases (monoclonal antibody-induced SCLE) against the annual estimated monoclonal antibody users as a percentage. Therapies utilising anti-tumour necrosis factor-ɑ mechanisms are highlighted in yellow and anti-PD-1 drugs are shown in orange.
To the best of our knowledge, this systematic review is the first to explicitly define clinical criteria for SCLE to robustly determine the inclusion of patients. With increasing mAb use and rising rates of drug-induced SCLE (DI-SCLE) [
The devised scoring criteria combined multiple clinical factors to reflect the diagnostic approach to SCLE [
Previous reviews on the patient demographics of DI-SCLE and non-DI-SCLE cases found comparable characteristics as those identified in this review [
For the variables considered, we did not find compelling evidence to suggest a distinct difference between the mAb-induced SCLE phenotype and DI-SCLE more generally. Compared with recent DI-SCLE studies [
Patients with systemic features in association with mAb-induced SCLE exhibited a similarly mild course to that reported in DI-SCLE [
Treatment modalities for CLE lack expert consensus or licencing [
Topical corticosteroids are considered to be the mainstay for limited cutaneous disease in CLE [
Given the rarity of SCLE, if there is a specific genetic, epigenetic, or pharmacokinetic context that predisposes a patient to mAb-induced SCLE, then greater use of a drug will heighten the likelihood of a predisposed patient receiving the triggering drug. However, we wanted to determine if the difference in case numbers reported for different mAbs simply reflected the differing number of yearly users. Following modelling of yearly users, we identified that anti-TNFɑ agents and checkpoint inhibitors were associated with a propensity for mAb-SCLE relative to their use. Given the recent licencing of nivolumab and pembrolizumab, their high relative rates of SCLE are particularly stark.
Immune checkpoint inhibitors blocking PD-1 or CTLA-4 pathways are utilised to reduce immune tolerance of malignancy and T-cell anergy [
We considered whether the relatively high rate of SCLE associated with anti-TNFɑ agents could reflect a publication bias, with rheumatologists more likely to diagnose and publish cases attributable to drugs they frequently use. However, we found more cases were reported by dermatologists than rheumatologists, and such a trend was not consistent across other rheumatological therapies of rituximab, ustekinumab or tocilizumab (Fig.
A multispecialty panel devised our inclusion criteria for the purpose of this review, therefore external validation is required. As most papers we included reported retrospective case series, this review was limited by incomplete data from reported cases. Some tests were not performed, however this is reflective of routine clinical care. Eight of the included sources came from conference abstracts, suggesting that grey literature was incorporated in the review; however, further hand searching would reduce publication bias further. The methodology has a language bias, with search strategies performed in the English language; we were unable to include non-European language papers in the screening process.
Annual mAb use was intended to provide a relative estimate of global use, however due to limited available prescription data of this kind, it is difficult to validate against existing data. The approximate annual costs utilised averages across two countries and cannot fully reflect the broad array of regimens used by physicians. Some mAb therapies have been licenced for many more years than others; for example, rituximab was licenced in 1997. Therefore, using estimated patient users across 1 year underestimates exposure of patients to the older drugs, as it does not incorporate the decades of use. Given this, the relationship between checkpoint inhibitors and mAb-induced SCLE is more striking as they have been licenced in the last decade.
Within the disease subtype of mAb-induced SCLE, there is great variability in serological findings, lesion distribution, treatment approach, and even the range of synonyms used for diagnostic terms. As the sheer complexity of the mechanisms governing tolerance and autoimmunity are further uncovered, clear phenotypic distinction and clarity of terms are vital to furthering understanding. To this end, we present the first systematic review of mAb-induced SCLE.
The authors are grateful for the support of Katharina Nucken in providing German translation assistance of the article. JS is supported by the National Institute for Health Research Biomedical Research Centre at the University of Oxford (NIHR-BRC-1215-20008).
CB is the overall guarantor for this work. EH and CB developed the search strategy. CB, YC, JS and IS contributed to the study design. SH, BM, CB, SE and AC contributed to the development of the selection criteria. YC, IS, CB and RH performed abstract screening, with CB adjudicating any disparities. CB, RH and HW performed the critical appraisal. CB, RH, YC and IS undertook data extraction. CB, JS and YC drafted the manuscript. JS and CB calculated the annual estimated mAb use. All authors read and provided feedback on the final manuscript.
None.
Christine Bolton, Yifan Chen, Ianthe R.M Schepel, Elinor Harriss, Silke C. Hofmann, Spencer Ellis, Alexander Clarke, Rachel Hawthorne, Helena Wace, Blanca Martin, Joel Smith declare there are no conflicts of interest.
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Below is the link to the electronic supplementary material. Supplementary file1 (DOCX 103 kb) Supplementary file2 (DOC 63 kb)