Rituximab-Induced Leukocytoclastic Vasculitis

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© 2022 Neurological Sciences and Neurophysiology | Published by Wolters Kluwer - Medknow
Rituximab‑Induced Leukocytoclastic Vasculitis
examination revealed no abnormalities. Laboratory tests
performed to assess any organ involvement or related
systemic diseases were all normal. A skin biopsy was
performed, and the histopathologic ndings revealed
LCV [Figure 2a and b].
Based on the temporal association between the rituximab
infusion and skin lesions and the clinicohistopathologic
ndings, a diagnosis of rituximab‑induced LCV was
made. Rituximab therapy was discontinued. Due to severe
arthralgia accompanying purpuric lesions, a short‑term
oral steroid regimen was planned in addition to topical
corticosteroids. In 2 weeks, both her skin lesions and
arthralgia showed regression, and no recurrence was
observed during a 3‑month follow‑up period [Figure 1b].
Discussion
LCV encompasses a wide and heterogeneous group of
small‑vessel vasculitis. Half of all cases of LCV are
single‑organ skin‑limited presentations characterized by
self‑limiting petechial lesions or palpable purpura, as well
as urticarial and necrotic‑ulcerative lesions. They most
commonly develop on gravity‑dependent areas, such as
the lower legs or sometimes up to the buttocks, the inferior
part of the trunk, and upper arms.[2,10] Distinguishing
medication‑related vasculitis from other etiologies of LCV,
such as systemic diseases, infection, and malignancy,
can be challenging. If LCV is suspected, a punch biopsy
should be performed for histopathologic correlation.[10] In
our case, the temporal correlation between the exposure to
the oending medication and the onset of the skin lesions
with a typical pattern helped in establishing the diagnosis.
The skin biopsy conrmed our diagnosis.
The majority of LCV cases are self‑limited and resolve
within weeks to months of onset; therefore, symptomatic
relief is the only focus in this group. In systemic
forms, the prognosis depends on the severity of internal
organ involvement and may require corticosteroids,
immunosuppressive agents, rituximab, and plasma
exchange to some degree.[2,3]
The pathogenesis of medication‑induced vasculitis
is unclear and is speculated to be multifactorial.
Studies suggest that as an environmental trigger, the
oending drug may act as a hapten and stimulate
immune responses that drive a cascade of inammation
involving small vessels in an individual with a genetic
predisposition.[4]
Letter to Editor
Leukocytoclastic vasculitis (LCV) is small‑vessel
vasculitis involving arterioles, capillaries, and
postcapillary venules. It is histopathologically
characterized by an inammatory inltrate consisting
of neutrophils with brinoid necrosis and nuclear debris
referred to as “leukocytoclasia.”[1] The microscopic
changes seen in LCV are not specic to any disease
entity; thus, this kind of histopathologic picture may
occur in various types of small‑vessel vasculitis aecting
the skin and internal organs. However, because of the
dominancy of single‑organ skin‑limited presentations,
the name LCV is more commonly used synonymously
for cutaneous small‑vessel vasculitis and cutaneous
leukocytoclastic angiitis.[2]
LCV usually presents as palpable purpura, symmetrically
distributed on the lower extremities, with or without
systemic involvement.[2,3] It may be either idiopathic
or associated with an underlying pathology such
as systemic diseases, medications, infections, or
malignancy. In medication‑induced LCV, antibiotics
and nonsteroidal anti‑inammatory drugs are the most
common triggers.[3] In recent years, however, with
increased use, biologic agents have taken their place in
the literature as new suspects in the etiology of LCV.[4]
Among these publications, very few rituximab‑induced
LCV cases stand out.[5‑9]
Here, we report the case of a 28‑year‑old woman with
a 3‑year history of generalized myasthenia gravis (MG)
presenting with LCV developing shortly after rituximab
infusion.
A 28‑year‑old woman, with a history of uctuating
weakness and diplopia following the postpartum period,
was diagnosed as having anti‑acetylcholine receptor
antibody‑positive MG at the age of 25 years. Her past
disease‑modifying treatment record included prednisolone
(PLN), intravenous immunoglobulins (IVIG), and
mycophenolate mofetil (MMF). In the early period,
treatment response to PLN was good, but she soon
developed marked iatrogenic Cushing’s syndrome. IVIG
failed to improve her condition without PLN. Recently,
MMF was stopped after 15 months due to a lack of
benets. Rituximab therapy was considered after all these
treatment attempts. Ten days after the rst i.v. infusion of
1000‑mg rituximab, skin lesions suddenly appeared on
the lower extremities of her body, which were compatible
with nonblanching purpuric lesions [Figure 1a]. Her vital
parameters were within normal range, and systemic
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Letter to Editor
162 Neurological Sciences and Neurophysiology ¦ Volume 39 | Issue 3 | July-September 2022
Rituximab is a chimeric mouse/human monoclonal
antibody directed to the CD20 B‑cell surface antigen.
Targeting CD20 B cells with rituximab provided
promising results for several autoimmune diseases
including refractory or severe MG.[11] The majority of
adverse events involving rituximab therapy are usually
mild and infusion‑related.[12] Vasculitis is not a commonly
reported toxicity for rituximab therapy. On the contrary,
rituximab has a well‑established role in the treatment
of systemic diseases associated with LCV, such as
anti‑neutrophil cytoplasmic antibody‑associated vasculitis,
cryoglobulinemic vasculitis, and hypocomplementemic
urticarial vasculitis.[2] There are some suggested
etiopathogenetic theories for this paradoxical reaction.
The development of an immune complex‑mediated
hypersensitivity vasculitis with the development of
antibodies to rituximab itself or its metabolites following
infusion is one of these theories. The second is thought to
be related to cytokine release syndrome. Cytokines released
after rituximab infusion may have a role in altering vessel
walls, as well as triggering a cascade of reactions leading
to the development of genuine vasculitis.[6,8]
In conclusion, it should be noted that although rituximab
is a treatment option in patients with systemic vasculitic
manifestations, it is itself a rare but true trigger for
LCV in skin‑limited forms. Further studies are needed
to determine the underlying pathophysiology for
rituximab‑induced vasculitis.
Declaration of patient consent
The authors certify that they have obtained all
appropriate patient consent forms. In the form, the
patient has given her consent for her images and other
clinical information to be reported in the journal. The
patient understands that name and initials will not be
published, and due efforts will be made to conceal
the identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conicts of interest.
Damla Cetinkaya Tezer, Ipek Gungor Dogan,
Cigdem Dicle Arican1, Serkan Demir, Melih Tutuncu2
Department of Neurology, Sancaktepe Sehit Prof. Dr. Ilhan Varank
Training and Research Hospital, 1Department of Pathology,
Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research
Hospital, 2Department of Neurology, Istanbul University‑
Cerrahpasa, Cerrahpasa School of Medicine, Istanbul, Turkey
Address for correspondence: Dr. Ipek Gungor Dogan,
Department of Neurology, Sancaktepe Sehit Prof. Dr. Ilhan Varank
Training and Research Hospital, Istanbul, Turkey.
E‑mail: dripekgngr@gmail.com
Submitted: 15‑Aug‑2021
Revised: 03‑Mar‑2022
Accepted: 07‑Mar‑2022
Published: 30‑Sep‑2022
References
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Figure 1: (a) Nonblanching purpuric skin lesions 10 days after
infusion (b) Improved skin lesions after 2 weeks
ab
Figure 2: (a) Mild acanthosis in the epidermis, dense neutrophils
in the upper and middle dermis, perivascular inflammatory cell
inltration consisting of fewer eosinophils and lymphocytes, prominent
leukocytoclasia, swelling of the vascular endothelium, brinoid material
in the vessel wall, abundant extravasated erythrocytes (b) Fibrinoid
material in the vessel wall with elastin stain
ab
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Letter to Editor
163
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How to cite this article: Tezer DC, Dogan IG, Arican CD, Demir S,
Tutuncu M. Rituximab-induced leukocytoclastic vasculitis. Neurol Sci
Neurophysiol 2022;39:161-3.
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Kluwer - Medknow
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treatment of myasthenia gravis: A systematic review. Muscle
Nerve 2017;56:185‑96.
12. Kimby E. Tolerability and safety of rituximab (MabThera).
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