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Table 3 Options for management of patients with previous hypersensitivity reaction to RCM (adapted from Torres
etal. 2021, with permission)
Management Advantages Disadvantages Comment
Avoidance Safety Diagnosis unresolved For patients with other diagnostic
options (e.g., magnet resonance
tomography)
Premedication Easy Breakthrough reactions
False sense of security
No evidence for strong
benet
No standard regime
Risk of side effects
Use of a nonculprit
alternative only by
history
Alternative by ST
negativity
Alternative by DPT
negativity
Easy
Reduction of reaction rates
High negative predictive
value in patients with
positive ST to culprit
Exclusion of RCM highly
suspected not to be tolerated
Severe anaphylaxis unlikely
RCM application is better
controlled by experts in
DPT than by radiologists
RCM dose can be titrated
Weak evidence
Cross-sensitivity not
excluded
Time consuming
Expertise needed
Only few patients with
IHR have positive ST
Useful in NIHR
No benet for
nonallergic reactions
Time consuming
Hospitalization
necessary
Expertise needed also
for emergency
treatment
Probably not helpful for preventing
severe allergic HR
Considered increasingly
controversial
Generally not recommended for
allergic reactions, as there is not
enough evidence of its effectiveness
Use of different RCM more effective
compared with single-dose
premedication
Increasing evidence
Increasingly recommended by
experts
Risk stratication
needed
Increasing evidence that DPT is not
less safe than DPT to other drugs
K. Brockow
using a combination of H1-antihistamine (e.g.,
50mg diphenhydramine 1h before application)
and corticosteroids (e.g., 50mg prednisone 13,
7, and 1 h before application) is often cited
(Sánchez-Borges et al. 2019). The efciency
of premedication is likely to be low and one
should not rely on their efcacy. For high-risk
patients, the setting should be as safe as possible, e.g., taking place in hospitals with code
teams and under close observation (possibly
using pulse oxImetry).
In patients with severe anaphylaxis and urgent
need, RCM should be avoided before allergological workup. Sometimes a noncontrasted CT scan
or MR scan can be performed. If RCM is considered indispensable, after a risk-benet analysis
one may administer the nonculprit RCM after
premedication and with emergency preparedness
including anesthesia standby.
7.2 Management ofPatients After
Allergy Workup
For patients without the need for immediate contrasted imaging, an allergy workup is recommended (Fig.1). In those patients with IHR being
skin test-positive to the culprit RCM, a skin testnegative alternative can be administered without
premedication under emergency preparedness.
Applying premedication might be considered in
very severe IHRs. The positive culprit and other
skin test-positive RCMs should be avoided. If
available, BAT or LTT may supplement skin testing to select a RCM for future use. Whether DPT
is advisable is decided on an individual basis, e.g.,
depending on the severity of the reaction. In
patients with negative skin tests to the culprit and
alternatives, a nonculprit agent with premedication
and under emergency preparedness can be applied.
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281
Contraindications for the further use of RCM
may be those with very severe IHRs after riskbenet analysis and after severe bullous or systemic NIHR. However, in the vast majority of
patients, allergy testing in addition to changing
the RCM substantially helps to increase safety of
subsequent RCM exposures in patients with previous RCM hypersensitivity.
Conict of Interest No conict of interest.
Funding No funding.
References
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Cutaneous Adverse Reactions
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toBiologic Agents
KarenJ.L.Choo andYiWeiYeo
1 Introduction
The usage of targeted biologic agents in the form of
monoclonal antibodies (mAbs) is rapidly expanding in the treatment of neoplastic, autoimmune, and
inammatory conditions. In contrast to most other
drugs, which are small molecules, mAbs are proteins. Many of the mAbs contain variable amounts
of mouse (murine) origin, considered as chimeric,
rendering them more immunogenic. Fully human
mAbs are considered less immunogenic than chimeric mAbs (Isabwe etal. 2018). However, even
fully human proteins can cause adverse reactions.
The World Health Organization established guidelines for the nomenclature of these biologic agents
in 2017 based on the antibody target (molecule,
cell, and organ) (WHO 2017). It no longer required
that the source of different parts of the antibodies
be determined by its name (see Table1).
Familiarity with the adverse cutaneous reactions of these medications will enable clinicians to
better balance the potential risks and benets of
these biologic medications in the clinical management of patients. In this chapter, we aim to summarise the hypersensitivity mechanism,
Table 1 Nomenclature of monoclonal antibody (mAb)
biologic agents
Prex Substem Target class Stem
Random -ba-
-ami-
-ci-
-fung-
-gros-
-ki-
-li-
-ne-
-os-
-toxa-
-ta-
-vet-
-vi-
Bacterial
Serum amyloid protein
(SAP)/amyloidosis
(Pre-Sub-Stem)
Cardiovascular
Fungal
Skeletal muscle massrelated growth factors and
receptors
Interleukin
Immunomodulating
Neural
Bone
Toxin
Tumour
Veterinary use (Pre-Stem)
Viral
-mab
presentations, and management considerations of
mAb-related drug eruptions. Cutaneous infections
and malignancies due to the specic immune
blockade of biologic agents, another important
aspect of biologic use, are beyond the scope of this
chapter and are not specically covered.
K. J. L. Choo
Department of Dermatology and Allergy Centre,
Singapore General Hospital, Singapore, Singapore
e-mail: Karen.Choo.J.L@singhealth.com.sg
Y. W. Yeo (*)
Department of Dermatology, Singapore General
Hospital, Singapore, Singapore
e-mail: yeo.yi.wei@singhealth.com.sg
© Springer Nature Switzerland AG 2022
H. Y. Lee, D. Creamer (eds.), Drug Eruptions, Updates in Clinical Dermatology,
https://doi.org/10.1007/978-3-031-09388-3_24
2 General Principles/
Classication
Consensus denitions and classication of mAbs
hypersensitivity reactions are lacking. A practical
approach that classies these reactions based on
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K. J. L. Choo and Y. W. Yeo
their clinical presentation, underlying mechanism, and temporal presentation is suggested
(Jackson and Bahna 2020; Hong and Sloane
2019; Santos and Galvão 2017; Picard and
Galvão 2017).
2.1 Localised Injection Site
Reactions
Injection site reactions (ISRs) are common with
the use of subcutaneous biological agents with an
incidence of 0.5–40% (Thomaidou and Ramot
2019). ISRs present as swelling, erythema, pruri-
tis, and pain around the site of injection and can
be divided into two groups based on their mechanism of action—namely irritative reactions
(immediate) and allergic reactions (immediate or
delayed) to the excipient or the drug itself
(Thomaidou and Ramot 2019).
The reported incidence of ISRs with common
biologics was highest with Etanercept (2.97–
37%), Adalimumab (5–20%), and Omalizumab
(2.7–45%), while Ustekinumab, Secukinumab,
Brodalumab, and Guselkumab had the lowest
reported incidence of less than 5% (Thomaidou
and Ramot 2019).
2.2 Systemic Hypersensitivity
Reactions
Although overlapping mechanisms and clinical
presentation exist, generally, these reactions can
be divided into the following categories based on
the primary disease mechanism and tempo of
onset:
Immediate Hypersensitivity Reactions
sequent administrations. Distinctive features of
cytokine release syndrome (or sometimes
referred to as infusion reactions) are headache,
fever, chills, rigors, or chest/back pain. Often,
patients may also have non-specic symptoms
such as ushing, breathlessness, giddiness, nausea, and/or vomiting. Most of these symptoms
can be prevented or attenuated with premedication with paracetamol, glucocorticosteroids, and
a slower infusion rate. The majority of cytokine
release syndrome are mild. Yet, there is one infamous example (Suntharalingam etal. 2006) of a
severe cytokine release syndrome: TGN1412, an
anti-CD28 mAb. In its phase 1 clinical trial, six
healthy men were given a single iv bolus of
TGN1412 and after an hour, all of them developed severe headaches, low back pain, nausea,
vomiting, diarrhoea, fever, hypotension, and
bilateral pulmonary inltrates. Most went on to
develop multiorgan failure with two requiring
intubation and mechanical ventilation.
Type IReactions: IgE Mediated
IgE-mediated reactions require a sensitisation
phase before a reaction can develop. Reactions
typically occur after at least one uneventful
administration (with one notable exception:
cetuximab). Clinical presentation of IgEmediated reactions ranges from cutaneous only
reactions (urticaria or angioedema) to systemic
anaphylactic shock and often, overlaps with clinical features of cytokine release syndrome. An
elevated serum tryptase (indicative of mast cell
degranulation) at the time of the reaction suggests the possibility of IgE-mediated reaction.
Skin tests (skin prick and intradermal test) to culprit mAb could be performed 4–6weeks after the
reaction. A positive test on immediate reading
suggests IgE-mediated reactions.
Cytokine Release Syndrome
Cytokine release syndrome is a result of rapid
destruction of cells targeted by the mAbs through
complement-mediated or antibody- mediated cell
death, which leads to the release of IL6 and TNFα
pro-inammatory cytokines (Santos and Galvão
2017). These reactions usually occur on rst
administration of mAbs and may wane with sub-
IgG Mediated
The mechanism of IgG-mediated reactions
against mAbs is less well dened. In the case of
iniximab, IgG antibodies can be associated with
reduced efcacy (due to increased clearance or
by blocking the antibody binding site) and/or
hypersensitivity reactions. In mouse models,
IgG-dependent anaphylaxis occurred due to the
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binding of anti-mAbs IgG to Fc-gamma-receptors
on macrophages, basophils, and neutrophils
(Jönsson etal. 2019). Another postulated mechanism of IgG-dependent reaction is the formation
of large immune complexes that activates the
complement system, which in turn generates anaphylatoxins (C3a and C5a) (Finkelman et al.
2016). Based on these mechanisms, it is not sur-
prising that the clinical symptoms of IgGmediated reaction may mimic those of
IgE-mediated type I reactions. The difference
between the two may be apparent during skin
prick tests reading as these tend to be negative for
IgG-mediated reactions.
Non-immediate Hypersensitivity
Reactions
Type III Reactions: Serum Sickness like
Reactions (SSLR)
This is the commonest non-immediate hypersensitivity reaction to mAbs and can occur at rst
exposure although they most frequently develop
after at least one uneventful infusion. These reactions are thought to be due to the deposition of
immune complexes of mAb and anti-mAb IgGs
in capillaries of the skin, kidney, and other
organs. Onset is typically 5–7days post infusion.
Clinical manifestations include fever, malaise,
arthralgia/arthritis, jaw pain/tightness, erythematous/urticarial rash, purpura, or conjunctival
haemorrhage. In some cases, immediate-type
hypersensitivity reactions may precede or follow
SSLR.
Delayed Type IV Reactions
A wide range of reactions have been reported
ranging from maculopapular exanthema and
symmetrical drug-related intertriginous and exural exanthem (SDRIFE) (Yang et al. 2017) to
more severe phenotypes such as SJS/TEN
(Urosevic-Maiwald et al. 2012) (the latter are
rare and there are only a few case reports in the
literature).
Data on the frequency of hypersensitivity
reactions is limited due to differences in denition and classication of these reactions. The
prevalence of mAbs hypersensitivity reactions
has been reported to be 63%, 13%, 21%, and 3%
for type I, cytokine release, mixed type, and
delayed type IV reactions in her cohort (Isabwe
etal. 2018).
2.3 O-Target Inammatory
Cutaneous Eruptions
A wide range of inammatory dermatoses have
been reported in association with biological
agents (Murphy et al. 2022). Most well recognised are those of psoriasiform eruptions or psoriasis with the use of anti-tumour necrosis
factor-α (anti-TNF) agents. Commonly referred
to as “paradoxical eruptions” in the literature,
this term is best limited to the appearance or
exacerbation of a condition that usually responds
to the same class of drug (Toussirot and Aubin
2016). Various mechanisms have been proposed
for these off-target inammatory cutaneous eruptions. This includes:
1. Polarisation of T cell responses where inhibi-
tion of a cytokine associated with a particular Th subset may skew responses towards
another Th polarisation. For example, Th17
pathway blockade for the treatment of psoriasis may result in polarisation towards a
Th2 phenotype resulting in an eczematous
eruption (Mufti et al. 2021; Eyerich et al.
2011).
2. Disruption of negative feedback loops leading
to the overproduction of other cytokines.
Paradoxical psoriasis due to anti-TNF agents
is proposed to be due to increased production
of type I interferons by plasmacytoid dendritic cells which are normally downregulated
by TNFα (Murphy etal. 2022; Collamer and
Battafarano 2010).
3. Secondary effects related to the antidrug
immune responses (Murphy etal. 2022).
4. Non-specic interactions with Fc receptors
that may activate innate immunity (Murphy
etal. 2022).
5. Host factors and genetic predisposition may
play a role (Murphy etal. 2022; Bucalo etal.
2020).
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K. J. L. Choo and Y. W. Yeo
3 Classes ofBiologic Agents
andTheir Reactions
3.1 Anti-tumour Necrosis Factor-α
Agents (Anti-TNFs)
Five agents that are currently available include
Iniximab, Adalimumab, Etanercept, Certolizumab Pegol, and Golimumab and are approved
for use in the treatment of chronic plaque psoriasis, hidradenitis suppurativa, rheumatoid arthritis, spondylarthritis, and inammatory bowel
disease, among other indications.
Hypersensitivity Reactions
Local Injection Site Reactions (ISRs)
ISRs are frequent with anti-TNFs with a reported
incidence of 3–37% with Etanercept and 5–20%
with Adalimumab (Thomaidou and Ramot 2019).
ISRs to anti-TNFs are usually self-limiting
(Zeltser etal. 2001; Murdaca etal. 2013) although
there have been occasional reports of severe reactions. Bavbek etal. described an immediate ISR
with Etanercept in a 28-year-old man who presented with localised erythema, swelling, and
pruritis after the 22nd injection followed by generalised urticaria and pruritis (Bavbek 2011).
Skin prick testing with Etanercept 25mg/1ml,
13days post reaction, was negative but intradermal testing was positive at 1/100 dilution. Patient
was challenged with 2.5 mg of Etanercept and
reacted with generalised urticaria. He was eventually managed with a desensitisation protocol
with concurrent antihistamines and was able to
tolerate the medication with small local ISR reactions of less than 3 cm (Bavbek 2011). Recall
phenomenon has been reported with Etanercept
(Zeltser etal. 2001).
Acute Infusion Reactions andAnaphylaxis
Intravenous Iniximab administration has been
associated with a 20% risk of infusion reactions
(O’Meara etal. 2014; FDA 2018). A systematic
review on iniximab-related infusion reactions in
patients with inammatory bowel disease found
that 5–23% of IBD patients on Iniximab devel-
oped immediate infusion reactions while 1–3%
of patients developed late reactions, usually of
the serum sickness type (Lichtenstein etal. 2015).
Serious infusion reactions occurred in <1% of
patients and included anaphylaxis, convulsions,
erythematous rash, and hypotension (FDA 2018).
The presence of antidrug antibodies to
Iniximab has been correlated with the development of infusion reactions. A meta-analysis on
patients with IBD treated with Iniximab showed
that the presence of antidrug antibodies conferred
a 2.4-fold risk increase of acute infusion reactions and a 5.8-fold risk increase of serious infusion reactions (O’Meara etal. 2014). Conversely,
the concomitant use of immunosuppressive
agents such as methotrexate or low-dose glucocorticoids has been shown to reduce the formation of anti-Iniximab antibodies and the risk of
infusion reactions (Galvão and Castells 2015).
While acute infusion reactions to Iniximab
often show symptoms resembling anaphylaxis,
detection of IgE antibodies has only been rarely
demonstrated, suggesting that many may represent cytokine release syndrome. Further support
for this comes from the diminishing of some of
these reactions by reducing the infusion rate,
reports of normal tryptase levels in some cases,
and the development of anaphylactic type reactions during the rst infusion (Lecluse et al.
2008).
Apart from iniximab, there are few reports of
true anaphylactic reactions to other anti-TNFs
(Sala-Cunill etal. 2019). A single centre Italian
study of 671 patients on anti-TNF agents
observed the highest frequency and severity of
hypersensitivity reactions to Iniximab (68%)
compared with 6% to Etanercept and 12% to
Adalimumab. 91% of anaphylactic events were
attributed to Iniximab. In contrast, anaphylaxis
was only seen in 2% of patients treated with
Etanercept and none on Adalimumab (Puxeddu
etal. 2012). Nonetheless, rare cases of anaphylaxis have been reported with adalimumab in
postmarking surveillance (Murdaca etal. 2013).
Several reports of successful desensitisation to
anti-TNF agents have been reported (Makowska
and Lewandowska-Polak 2020).
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O-Target Inammatory Cutaneous
Eruptions
Off-target inammatory cutaneous eruptions
have been most commonly reported with antiTNF agents (Murphy etal. 2022). A recent systematic review showed that the most commonly
reported inammatory cutaneous reaction with
anti-TNFs was psoriasis or psoriasiform eruptions (n=1051), followed by eczematous eruptions (n=267), lupus-like eruptions (n= 216),
sarcoidosis-like eruptions (n=91), and alopecia
areata (n=66) (Murphy etal. 2022). Other recognised but less common reactions include
hidradenitis suppurativa, lichenoid eruptions,
granuloma annulare, bullous pemphigoid, dermatomyositis, pyoderma gangrenosum, and cutaneous vasculitis (Murphy etal. 2022).
Psoriasis/Psoriasiform Eruptions
Paradoxical psoriasis in the form of palmoplantar
pustulosis was rst reported in a systematic
safety follow-up in a cohort of 107 patients with
spondyloarthropathy who received Iniximab in
2003 (Baeten etal. 2003). This was followed by
increasing reports of psoriasiform eruptions and
new onset psoriasis. Anti-TNFs have been
reported to induce and/or exacerbate psoriasis in
about 3.8–10.7% of patients (Murphy et al.
2022). Thought to be a class effect, paradoxical
psoriasis has been most reported with Iniximab
(56.6%), followed by Adalimumab (30%),
Etanercept (11%), Certolizumab pegol, and
Golimumab (Murphy et al. 2022). Latency is
variable, ranging from less than 1month to more
than 10years after drug initiation, with an average of 16.4 months (Murphy et al. 2022).
Infections have not been observed to be a triggering factor (Toussirot and Aubin 2016). However,
a recent case-control study found that a family
history of psoriasis, psychological stressors, and
tobacco use was signicantly associated with the
development of TNF-inhibitor-induced psoriasis
(Ya etal. 2020).
A systematic review by Collamer etal. showed
that the most common morphologies were pustular psoriasis (56%), plaque psoriasis (50%), and
guttate psoriasis (12%) (Collamer and Battafarano
2010). Of these, 15% of patients experienced
more than one type of reaction. In patients with
pre-existing psoriasis, paradoxical reactions may
exhibit different morphology to the original presentation such as guttate or pustular lesions in a
patient with pre-existing plaque psoriasis. The
most frequently affected areas include palmoplantar areas, the scalp and exures seen in more
than 50% of cases (Toussirot and Aubin 2016).
Indeed, palmoplantar pustulosis seems to be
over-represented in anti-TNF-induced psoriasis
with a report from the French Pharmacovigilance
Database showing that such eruptions were
mostly pustular lesions and occurred mainly on
the palms and/or soles (33.3% in the French
Pharmacovigilance Database and 42.9% in the
literature), while palmoplantar pustular psoriasis
represents only 1.7% of the psoriatic patients
(Joyau etal. 2012).
Histology may be indistinguishable from psoriasis or palmoplantar pustulosis unrelated to
anti-TNF therapy with features including epidermal hyperplasia, parakeratosis, epidermal lymphocytic inltrate, dilated capillaries, and
intraepidermal pustulosis. However, other reports
have suggested some subtle differences including
the presence of spongiosis, lichenoid inltrate,
and eosinophils (Navarro and Daudén 2014).
Various mechanisms have been proposed:
1. Increased production of type I interferons by
plasmacytoid dendritic cells which are normally downregulated by TNF-alpha (Collamer
and Battafarano 2010).
2. Blocking TNF-α may increase T helper 17
(Th17) cell production of pro-inammatory
cytokine IL-22 (Ma et al. 2010). Blocking
IL-23, a driver of Th17 differentiation, has
been reported to be effective in the treatment
of paradoxical psoriasiform lesions (Tillack
etal. 2014).
3. Anti-TNF inhibitors may predispose to infec-
tion (Li etal. 2019), which is a known trigger
of psoriasis, although in most cases of paradoxical reactions, no infectious triggers were
noted.
4. Patients with inammatory bowel disease and
chronic rheumatological conditions may have
a higher incidence of psoriasis (Li etal. 2019)
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K. J. L. Choo and Y. W. Yeo
with genetic polymorphisms possibly playing
a role in the predisposition to the development
of paradoxical reactions (Collamer and
Battafarano 2010).
Eczematous Reactions
Eczema as an adverse effect of anti-TNF therapy
has been reported to occur in approximately
5–20% of patients (Nakamura et al. 2017).
Personal history of atopy appears to increase this
risk. In a review by Nakamura etal., Iniximab
was most strongly associated with development
or exacerbation of pre-existing eczema
(Nakamura etal. 2017). The anti-TNF agent has
to be discontinued in 7 of 12 cases due to the
severity of the eczema with resolution following
cessation of therapy. In the other ve cases,
eczema was treated with topical or oral corticosteroids with continuation of the biologic agent.
Proposed mechanisms for the development of
eczematous eruptions with anti-TNFs include
tipping the balance in favour of Th2 pathway
inammatory conditions such as eczema due to
Th1 pathway blockade (Nakamura etal. 2017).
Granulomatous Reactions
Sarcoidosis or sarcoid-like granulomas occurring
in the setting of anti-TNF use are rare but have
been increasingly recognised, following a report
of 10 cases by Daïen etal. (2009). The estimated
incidence is about 0.04% with the most often
implicated biologic that of Etanercept (Murphy
et al. 2022) and other reports after use of
Iniximab and Adalimumab (Toussirot and
Aubin 2016). Clinical features reported did not
differ from de novo sarcoidosis with cutaneous
involvement estimated to occur in 24–50% of
patients and systemic involvement reported
(Murphy etal. 2022). Reported time to diagnosis
ranges from 1 to 84months with an average of
about 2years (Murphy etal. 2022). The anti-TNF
was discontinued in most cases with at least partial improvement, with some requiring systemic
steroids. Rechallenge was not performed and a
limited number of patients switched therapy
without relapse (Toussirot and Aubin 2016).
Other granulomatous diseases such as granu-
loma annulare and interstitial granulomatous
dermatitis have also been described (Murphy
etal. 2022). In a series of nine patient with gran-
uloma annulare, the mean onset was 6months
from drug initiation and adalimumab was the
most frequently implicated anti-TNF agent.
Rash resolved with topical corticosteroids in
seven out of nine cases despite continuation of
the anti-TNF (Voulgari etal. 2008). Interstitial
granulomatous drug reactions have been
reported with Adalimumab with at least two
cases in the literature (Martorell-Calatayud
2010).
Lupus-like Reactions
While uncommon, lupus-like reactions are recognised with the most common inciting biologic
being Iniximab (56%), followed by adalimumab (25%) and Etanercept (15.5%) (Murphy
etal. 2022). Presentations include isolated cutaneous lupus (45–56%) and lupus-like syndromes with systemic lupus erythematosus
occurring in 17–30% of lupus cases (Murphy
etal. 2022). Cases of cutaneous lupus were predominantly of the discoid lupus or subacute
cutaneous lupus subtype (Murphy etal. 2022;
Jani etal. 2017). While earlier reports suggest a
signicant association between anti-TNF use
and lupus (Moulis etal. 2014), this association
has been questioned in a prospective observational cohort study by Jani etal. which failed to
show a signicant increase in lupus-like events
with anti-TNF use after adjusting for differences in baseline characteristics (adjHR 1.86;
95% CI 0.52 to 6.58) compared to rheumatological patients on non-biologic DMARD (Jani
etal. 2017).
Most cases exhibited positive anti-nuclear
antibody (ANA) titres. However, the induction of
ANAs and anti-double stranded DNA (antidsDNA) antibodies has been recognised in clinical trials and post-marketing surveillance, even in
the absence of clinical lupus-like features (Sehgal
etal. 2015). Anti-histone, Anti-Ro, and Anti-La
antibodies are also not consistently positive
(Murphy et al. 2022). Most reported patients
achieved complete or partial resolution with
withdrawal of anti-TNF treatment (Jani et al.
2017; Moulis etal. 2014).
Cutaneous Adverse Reactions toBiologic Agents
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Cutaneous Vasculitis
There have been numerous reports on anti-TNF
induced cutaneous vasculitis (Toussirot and
Aubin 2016). Reported latency ranges from 9.6
to 34.5 months (Saint Marcoux and de Bandt
2006; Sokumbi etal. 2012). Most cases were lim-
ited to cutaneous small vessel vasculitis although
some cases involved medium to large vessels or
had systemic extra-cutaneous involvement
(Sokumbi et al. 2012). Clinical presentations
included purpura, ulceration, blisters, and erythematous macules. A case series of 39 patients
from a nationwide study in France found
Etanercept to be the most implicated biologic
(54%) (Saint Marcoux and de Bandt 2006).
However, similar to lupus-like reactions, the
study by Jani etal. failed to show a signicant
increase in vasculitis-like events after adjusting
for differences in baseline characteristics (adjHR
1.27; 95% CI 0.40 to 4.04) compared to rheumatological patients on non-biologic DMARDs
(Jani etal. 2017). In the French series, cessation
of medication resulted in resolution in most cases
without further treatment although some required
high-dose glucocorticoids with or without immunosuppressant therapy (Saint Marcoux and de
Bandt 2006).
Hidradenitis Suppurativa
Hidradenitis suppurativa (HS) is a chronic relapsing skin disease characterised by abscesses, nodules, and draining stulae often in the axilla and
groin of young adults. Adalimumab was FDA
approved for the management of moderate to
severe HS in 2015. Interestingly, HS has also
been reported as a paradoxical event with antiTNF treatment. Faivre etal. reported a series of
25 patients of paradoxical HS.Biologics implicated were TNF inhibitors in 22/25 cases including adalimumab (12/25), iniximab (6/25), and
etanercept (4/25) with the remaining three attributed to rituximab and tocilizumab (Faivre etal.
2016). Median duration of drug exposure to HS
onset was 12 (range 1–120) months. Patients
were mostly Hurley stage I (n=13) or II (n=11).
Complete improvement of HS was seen in 60%
of patients who were discontinued on the medication compared to only 7% in those that were
continued. Reintroduction of the same biologic
agent resulted in HS relapse in all three patients
(Faivre etal. 2016).
Other reported reactions include alopecia
areata, vitiligo, lichenoid eruptions, bullous pemphigoid, dermatomyositis, and pyoderma gangrenosum (Murphy etal. 2022).
3.2 Anti-CD-20 (Rituximab)
Rituximab is a chimeric mAb that binds to CD20
antigen present on all peripheral B Cells, rapidly
depleting their numbers. It is licensed for the
treatment of B Cell Lymphoma and many autoimmune diseases. Rituximab treatment results in
two main categories of adverse reactions: immunodeciency and hypersensitivity reactions.
Hypersensitivity Reactions
Among all mAbs reported here, Rituximab has
the highest rate of immediate hypersensitivity
reactions (Fouda and Bavbek 2020). These tend
to occur early in the infusions and the symptoms
are often an overlap of cytokine release syndrome
caused by B cell lysis and that of IgE-mediated
hypersensitivity. TNFα and IL-6 levels correlate
with symptom severity (Santos and Galvão
2017). The frequency and severity of these infu-
sion reactions may differ according to the B Cell
counts, the underlying disease for which
Rituximab is used for and whether premedication
with glucocorticosteroids were included as pretreatment (Fouda and Bavbek 2020). For example, the rate of infusion tends to be higher for
lymphoma patients with a high tumour burden
(77%) (Régnier Galvão etal. 2015) compared to
patients with autoimmune diseases (between 11
and 30%) (Picard and Galvão 2017). Most of
these reactions tend to be mild, with the frequency decreasing with each subsequent infusion. Severe reactions and late reactions that
occur after at least one uneventful administration
would benet from skin tests and if positive,
desensitisation.
Serum sickness-like reactions have been
reported, with patients receiving Rituximab for
the treatment of autoimmune conditions (Bayer
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et al. 2019). Re-exposure has been attempted
with at least one in seven patients suffering a
recurrence in this French cohort (Bayer et al.
2019).
Other notable non-cutaneous adverse reac-
tions associated with Rituximab are increased
risk of infection including the reactivation of
hepatitis B virus, progressive multifocal leukoencephalopathy associated with JC virus, tumour
lysis syndrome, cardiac arrhythmias, acute renal
impairment, bowel obstruction and perforation
(Bayer etal. 2019; Iaccarino etal. 2015).
O-Target Inammatory Cutaneous
Eruptions
Cutaneous, pulmonary, neurological, gastrointestinal, and joint autoimmune and/or inammatory
reactions to Rituximab are uncommon but have
been reported (Thomas etal. 2012). Psoriasiform
dermatoses have been reported in patients receiving rituximab for Rheumatoid Arthritis and
Lupus Erythematosus (Thomas et al. 2012). It
can affect patients of any age and occur as early
as 6weeks to as late as 2years into the treatment
of Rituximab. Interestingly, the underlying disease responds well to Rituximab.
3.3 Anti-IL 1 (Anakinra,
Canakinumab)
Anakinra is a recombinant human IL-1 receptor
antagonist with indications in rheumatoid arthritis, cryopyrin-associated periodic syndrome, and
Still’s disease. The most common and consistently reported treatment-related adverse event
associated is injection site reactions, reported in
up to 71% of patients and typically within the
rst month of therapy (Mertens and Singh 2009).
The majority were mild to moderate, typically
lasting 2–4 weeks, and were characterised by
erythema, ecchymosis, inammation, and/or pain
(Kaiser et al. 2012). Rare cases of anaphylaxis
exist, with reports of successful desensitisation
protocols for anakinra hypersensitivity (Emmi
et al. 2017; Yilmaz et al. 2018). A paediatric
patient with anakinra-induced anaphylaxis was
also successfully treated with canakinumab, an
alternative IL-1 blocking agent (Aguiar et al.
2015).
Canakinumab is a human mAb against IL-1
beta and is indicated in periodic fever syndromes,
cryopyrin-associated periodic syndrome, familial
Mediterranean fever, and Still’s disease among
other indications.
No cases of anaphylactoid or anaphylactic
reactions were reported during clinical development (Gülsen et al. 2020) and patients with
anakinra anaphylaxis may tolerate canakinumab
(Aguiar et al. 2015). However, Sanan et al.
reported a patient with anakinra anaphylaxis who
developed anaphylactic symptoms during intradermal testing to canakinumab. The patient subsequently underwent successful desensitisation
to canakinumab (Sanan etal. 2020).
3.4 Anti-IL 4/13 (Dupilumab)
Dupilumab targets IL4α receptors which inhibits
both IL4 and IL13 signalling pathways. It has
been approved for patients with severe atopic
dermatitis, eosinophilic asthma, and nasal polyposis (Halling etal. 2021; Fargnoli etal. 2019).
Hypersensitivity reactions, mainly generalised
urticaria, occurred in <1% of trial patients
(Jackson and Bahna 2020).
The most common adverse reactions were
ocular in nature, conjunctivitis being the most
common, affecting up to a third of patients on
dupilumab, especially if there are pre-existing
allergic conjunctivitis. Apart from conjunctivitis,
blepharitis and keratitis have also been reported
(Fargnoli et al. 2019; Halling et al. 2021; Ou
etal. 2018).
O-Target Inammatory Cutaneous
Eruptions
Psoriasiform dermatitis has been one of the more
commonly reported inammatory cutaneous
reactions with an incidence of 3.3%; the onset is
usually within 1 year of starting dupilumab
(Murphy etal. 2022). Most of these patients who
developed psoriasiform paradoxical reactions
were given dupilumab for their atopic dermatitis
but at least 1 was treated for asthma. The
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