A Case of Belatacept-Induced Chilblains Lupus

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CASE REPORT
A case of belatacept-induced chilblain lupus
Neha Kinariwalla, MPhil,
a
Meera Tarazi, MD,
b
Jesse M. Lewin, MD,
c
Sameera Husain, MD,
b
Syed A. Husain, MD,
d
and Stephanie M. Gallitano, MD
b
New York, New York
Key words: belatacept; chilblains systemic lupus erythematous; immunosuppression; kidney transplant.
INTRODUCTION
Chilblain lupus erythematosus (CHLE) is a rare
form of chronic cutaneous lupus erythematosus
characterized by purple plaques/nodules and edem-
atous skin, mainly around the acral regions of the
body. The familial form is due to a heterozygous
mutation in the TREX1 gene, a widely expressed
gene that encodes 39to 59exonuclease to remove
unneeded fragments that may form during DNA
replication and has also been found to be implicated
in immune regulation and viral infection.
1
The spo-
radic form remains with unknown etiopathogenesis.
Drug-induced chilblain lupus is rare and has previ-
ously been reported predominantly in patients on
tumor necrosis factor inhibitors and abatacept.
2
We
herein report a case of a man with a recent renal
transplant who was started on belatacept and sub-
sequently developed CHLE. The rash resolved with
the discontinuation of the medication.
CASE REPORT
A 60-yeareold man with a history of Crohn’s
disease and end-stage renal disease due to enteric
oxalosis underwent uncomplicated living donor
kidney transplantation with thymoglobulin and
methylprednisolone induction. He was initially
treated with tacrolimus and mycophenolate mofetil
maintenance immunosuppression, but the myco-
phenolate mofetil was replaced with azathioprine
one week after the transplant due to persistent
diarrhea. Because of the worsening of the diarrhea,
induction dosing of belatacept 10 mg/kg was initi-
ated 2 months posttransplant, with reduced-dose
azathioprine and tacrolimus (he was previously
intolerant to maintenance corticosteroids).
One month after belatacept initiation, in the
autumn, he developed an eruption, which began
as a ‘‘blister’’ on the left second toe and continued to
spread to other toes. The patient noted a burning
sensation, especially at nighttime, when he was
unable to warm his feet despite the use of socks.
Other than his immunosuppression changes
mentioned earlier, he had had no other changes in
his medication regimen since the transplant. The
regimen included atovaquone, gabapentin, omepra-
zole, tamsulosin, nystatin, and valganciclovir.
On physical examination, he was noted to have
blanching red-purple erythematous toes with over-
lying scale (Fig 1). Serology showed negative anti-
nuclear antibodies, anti-RNA, and anti-Smith
antibodies. His C3 and C4 levels were within normal
limits. COVID-19 serologies were negative. A skin
biopsy performed on the right third toe revealed a
mild perivascular lymphocytic infiltrate, conspicu-
ous interface change with vacuolar alteration of the
basal layer, and singly scattered necrotic keratino-
cytes in the lower epidermis (Fig 2,Aand B). A
colloidal iron stain (Fig 2,C) highlighted the
increased amount of mucin in the interstitial dermis.
Abbreviations used:
CHLE: chilblain lupus erythematosus
CTLA-4: cytotoxic T-lymphocyteeassociated an-
tigen 4
SCLE: subacute cutaneous lupus erythematosus
From the Columbia University Vagelos College of Physicians and
Surgeons, New York
a
; Department of Dermatology, Columbia
University Vagelos College of Physicians and Surgeons, New
York
b
; The Kimberly and Eric J. Waldman Department of
Dermatology, Icahn School of Medicine at Mount Sinai, New
York
c
; Department of Medicine, Division of Nephrology,
Columbia University Vagelos College of Physicians and Sur-
geons, New York.
d
Funding sources: None.
IRB approval status: Not applicable.
Correspondence to: Neha Kinariwalla, MPhil, Columbia University
Vagelos College of Physicians and Surgeons, 161 Fort
Washington Avenue, Herbert Irving Pavilion, 12th Floor, New
York, NY 10032. E-mail: nk2674@cumc.columbia.edu.
JAAD Case Reports 2022;21:112-5.
2352-5126
Ó2022 by the American Academy of Dermatology, Inc. Published
by Elsevier, Inc. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
https://doi.org/10.1016/j.jdcr.2022.01.007
112

Direct immunofluorescence was declined by the
patient. Based on the above findings, the patient
was diagnosed with CHLE, possibly caused
by belatacept. The patient was started on hydroxy-
chloroquine 200 mg twice daily for 2 months and
0.05% betamethasone dipropionate ointment.
Furthermore, conservative measures were taken,
including keeping the toes warm with socks, with
initial improvement in the symptoms. However, the
rash returned after hydroxychloroquine discontinu-
ation 2 months later. Other therapies, such as
nifedipine, were contraindicated. Belatacept was,
therefore, discontinued, resulting in the total, sus-
tained resolution of symptoms (Fig 3,Ato B).
DISCUSSION
Belatacept, a second-generation fusion protein
that is composed of the fragment crystallizable
region of human IgG1, linked to the extracellular
domain of cytotoxic T-lymphocyteeassociated anti-
gen 4 (CTLA-4), and inhibits the CD28-CD80/86
pathway, is the first fusion protein approved by the
Food & Drug Administration for use in transplanta-
tion and the first biologic agent to be incorporated
into standard transplantation maintenance immuno-
suppression protocols.
3
This fusion protein inhibits
T-cell activation by blocking costimulatory signals
from antigen-presenting cells while avoiding both
the renal and nonrenal toxicities associated with
calcineurin inhibitors.
4
Belatacept was developed to
be a higher-avidity variant of abatacept through 2
amino acid substitutions, CD80 and CD86, because
abatacept does not sufficiently inhibit alloreactivity
in pancreatic and kidney transplants.
5
Herein, we present a case of belatacept-associated
CHLE. CHLE is a rare form of cutaneous lupus
erythematosus that is typically triggered by cold
exposure, leading to ulceration. A set of diagnostic
criteria have been proposed by the Mayo Clinic
6
and
include 2 major criteria of (1) skin lesions of the acral
sites induced by exposure to cold or a drop in
temperature and (2) evidence of lupus erythemato-
sus in the skin lesions as determined by histopath-
ologic examination or direct immunofluorescence.
The 3 minor criteria include the following: (1)
coexistence of systemic lupus erythematosus or
other skin lesions of discoid lupus erythematosus,
(2) response to antilupus therapy, and (3) negative
cryoglobulin and cold agglutinin studies. Both major
criteria and 1 minor criterion are needed to diagnose
CHLE. The reported patient fulfilled both major
criteria and showed a response to antilupus therapy,
with marked improvement in the skin lesions using a
regimen of hydroxychloroquine and topical steroids.
Further evidence of belatacept as the causative agent
include the onset of the rash approximately one
month after belatacept initiation, recurrence of the
rash until belatacept was discontinued, and perma-
nent resolution after belatacept cessation despite the
withdrawal of hydroxychloroquine. The onset and
resolution of drug-induced cutaneous lupus can vary
widely. The duration between drug exposure and
the onset of skin lesions ranges from 3 days to
10 years, and the resolution time after withdrawal of
medication ranges between 1 week and 1 year.
7
The pathogenesis of sporadic CHLE is not well
understood, but is thought to be due to vasocon-
striction or microvascular injury provoked by the
cold. A type 1 interferon response may be pro-
voked locally, leading to cutaneous findings.
8
Drug-
induced chilblain lupus is rare and predominantly
reported in patients on tumor necrosis factor in-
hibitors.
2
Although there have not been reports of
belatacept-induced lupus, there have been 3 prior
reports on abatacept, belatacept’s parent com-
pound, causing drug-induced subacute cutaneous
lupus erythematosus (SCLE) and 1 report on sys-
temic lupus erythematosus with membranous ne-
phropathy associated with abatacept.
9-12
In all of
these cases, as with our patient, a longstanding
history of autoimmune disease preceded the initi-
ation of the costimulatory blockade. Each case of
SCLE resolved after abatacept discontinuation,
though the case of systemic lupus erythematosus
did not. Although the putative mechanism of the
development of SCLE is not certain, a proposed
pathogenesis is the development of antibodies to
the CTLA-4 portion of the abatacept molecule,
which subsequently interfere with the CTLA-4 an-
tigen on T-regulatory cells, inducing SCLE or other
Fig 1. Erythematous patches of the toes with edema and
some overlying scale.
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Kinariwalla et al 113

autoimmune syndromes.
10
However, the resolution
of cutaneous lesions in our patient and prior cases
of abatacept-associated SCLE after the discontinua-
tion of costimulatory blockade call this proposed
mechanism into question, given that we may not
necessarily expect the rapid disappearance of
antieCTLA-4 antibodies. We hope this report en-
courages further investigation into these reactions
and the potential role of the CTLA-4/CD28-CD80/86
pathway in triggering de novo autoimmune disease.
Given that this complication may occur in an
existing autoimmune milieu, further studies are
needed to better identify the risk factors for CHLE
induced by belatacept.
Conflicts of interest
None disclosed.
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Fig 3. Resolution of lesions after discontinuation of belatacept on the (A) left foot and (B) right
foot.
Fig 2. Punch biopsy from dorsal right third toe. A, B, Hematoxylin-eosin stains (original
magnifications: A, 340; B, 3400) show a mild perivascular lymphocytic infiltrate and
prominent interface change with vacuolar alteration of the basal layer and singly scattered
necrotic keratinocytes. C, Colloidal iron stain (original magnification: 3200) highlights the
increased amount of dermal mucin.
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