Seminars in Arthritis and Rheumatism 63 (2023) 152272

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Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit

Cutaneous immune-related phenomena in patients with inflammatory

arthritides treated with biological therapies: Clinical and
pathophysiological considerations
Aliki I. Venetsanopoulou a, Konstantina Mavridou b, Paraskevi V. Voulgari a,
Alexandros A. Drosos a, *
a
Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece
b
Department of Dermatology, University Hospital of Ioannina, Ioannina, Greece

A R T I C L E I N F O A B S T R A C T

Keywords: In recent years, identifying the pathophysiologic mechanisms underlying autoimmune arthritides and systematic
Biologic drugs diseases has led to the use of biological drugs. The primary targets of those biological therapies are cytokines, B
Tumor necrosis factor inhibitors cells, and co-stimulation molecules. So far, these targeted therapies have shown good clinical improvement and
Skin lesions
an acceptable toxicity profile. However, by blocking components of an intact immune system, autoimmune
cutaneous adverse events
phenomena and paradoxical inflammation have emerged, and among them many cutaneous immune-related
adverse events (irAEs).
In this article, we review the current state of knowledge on the clinical features and mechanisms of specific
cutaneous irAEs observed during treatment with biological therapies. Among those, psoriatic skin lesions are the
most commonly observed. Herein, we also report new cases of cutaneous irAEs recently seen in our clinic to help
physicians treating inflammatory arthritides recognize cutaneous irAEs early and better manage patients
receiving biologic therapies.

Introduction IL-6 receptor inhibitors; ustekinumab (UST), an anti-IL-12/23 p40

Since the early 1990s, advances in understanding the mechanisms of
autoimmunity and inflammation have provided new therapeutic targets
for treating inflammatory arthritides. Following that, the introduction of
several biologic disease-modifying antirheumatic drugs (bDMARDs) and
their biosimilars was a turning point in treatment with significant ben­
efits for rheumatoid arthritis (RA), psoriatic arthritis (PsA), and anky­
losing spondylitis (AS) patients [1].
Biologics that are genetically engineered proteins target specific sites
of the inflammatory cascade, such as cytokines, cell surface molecules,
and adhesion molecules [2]. Five tumor necrosis factor α (TNFα) in­
hibitors (TNFi) have been developed so far: etanercept (ETN), infliximab
(IFX), adalimumab (ADA), certolizumab (CTZ), and golimumab (GOL)
[3–6]. Biologics acting on other targets include Anakinra, a recombinant
IL-1 receptor antagonist [7]; abatacept (ABA), a selective T cells
co-stimulation inhibitor [8]; secukinumab (SEC), a selective interleukin
(IL)-17A inhibitor [9]; tocilizumab (TCZ) and sarilumab (SAR), both
monoclonal antibody [10]; rituximab (RTX), an anti-CD20 monoclonal
antibody; and belimumab, a B cell growth factor inhibitor [11]. In
addition, targeted synthetic disease-modifying antirheumatic drugs
(tsDMARDs) have recently been applied, including apremilast, a phos­
phodiesterase 4-inhibitor, and tofacitinib, baricitinib, filgotinib, and
upatacitinib which are Janus kinase (JAK) inhibitors.
Treatment with these agents helps patients achieve clinical remis­
sion, prevents structural damage, and leads to a better functional
outcome [12–14]. They are usually used in combination with conven­
tional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or
for patients with an adequate response to csDMARDs [15–17]. Their
good efficacy and general safety are well established in many clinical
randomized controlled trials (RCT) [18].
However, the intervention of these drugs in the pathophysiological
mechanisms of the body can be accompanied by adverse effects (AE)
[19–21], and several autoimmune phenomena. These phenomena range
from an isolated expression in the patients’ sera of an autoantibody, such

* Corresponding author: Alexandros A. Drosos, Rheumatology Clinic, Department of Internal Medicine, Medical School, University of Ioannina, Ioannina 45110,
Greece. Tel: 302651007503; Fax: 302651007054
E-mail address: adroso@uoi.gr (A.A. Drosos).

https://doi.org/10.1016/j.semarthrit.2023.152272

Available online 27 September 2023

0049-0172/© 2023 Elsevier Inc. All rights reserved.
A.I. Venetsanopoulou et al. Seminars in Arthritis and Rheumatism 63 (2023) 152272

as an antinuclear antibody (ANA), double-stranded DNA (dsDNA), or
antiphospholipid antibody (aPL), to a full-blown autoimmune
organ-specific or systemic disease, including drug-induced lupus (DIL)
[22,23]. Many AEs have been reported in the literature, mainly
regarding infections and musculoskeletal and cutaneous manifestations.
Most of AEs present within the first year after treatment initiation with a
biological agent; however, they may also occur years after treatment
suspension [24].
The cutaneous AEs reported in patients receiving biologics are
diverse; Eczema, skin infections, and drug-related eruptions are the most
common [25]. There are also specific immune-related cutaneous
adverse events (irAEs) observed with biological agents, including pso­
riasis, vitiligo, malar rash in the set of Acute Cutaneous Lupus Erythe­
matosus (ACLE), cutaneous vasculitis, erythema nodosum, alopecia
areata, granuloma annulare, and others [26]. Among those, psoriasis is
the most often reported [27]. Table 1 depicts the most commonly
described cutaneous manifestations related to the use of biological
agents.

Table 1
Summary of cutaneous Manifestations Associated with Biological Agents
Biological Main cutaneous Pathophysiological mechanisms Prevalence Treatment
agents manifestations

TNFi and • Injection site reactions • Local irritation or immune response to the • Common • Usually resolve on their own; cold compresses, topical
biosimilars injection corticosteroids, antihistamines for symptomatic relief
• Urticaria (hives) • Allergic reaction or hypersensitivity type • Rare • Discontinuation of TNFi, antihistamines, or corticosteroids
I, mast cell activation
• Cutaneous infections • Suppression of the immune system • Variable • Antifungal or antibiotic medications, topical care
heightens an individual’s susceptibility to • If needed discontinuation of TNFi
illnesses
• Psoriasis • Dysregulation of TNFα, production of • Common • Topical corticosteroids, systemic therapies (e.g., MTX)
IFNα
• Vitiligo • Cytokine dysregulation and cytotoxic • Rare • Topical corticosteroids, phototherapy, calcineurin inhibitors,
CD8+ T-cells activation depigmentation therapy
• Acute Cutaneous Lupus • Dysregulation of TNFα, IFN-type I • Rare • Discontinuation of TNFi, topical corticosteroids, systemic
Erythematosus Rashes apoptosis, autoimmunity corticosteroids, other immunomodulatory therapies
• Cutaneous vasculitis • Immune complex deposition, • Rare • Discontinuation of TNFi, systemic corticosteroids,
Dysregulation of TNFα immunosuppressive agents
• Erythema Nodosum • Immune dysregulation, granuloma • Common • Symptomatic treatment, NSAIDs, systemic corticosteroids,
formation discontinuation of TNFi if severe
• Alopecia Areata • Immune dysregulation, INFγ production, • Rare • Topical corticosteroids, systemic corticosteroids,
autoreactive CD8+ cells discontinuation of TNFi, systemic immunomodulatory
therapies
• Granuloma Annulare • Immune dysregulation, T-cell activation, • Rare • Topical corticosteroids, cryotherapy, systemic corticosteroids
granuloma formation
IL-17 • Candidiasis • Inhibition of IL-17 pathway • Common • Antifungal therapy for candidiasis
Inhibitors
• Psoriasis • Dysregulation of IL-17 pathway, IFNα • Common • Topical corticosteroids, systemic therapies (e.g., MTX)
production
• Vitiligo • Dysregulation of IL-17 pathway, cytotoxic • Rare • Topical corticosteroids, phototherapy, calcineurin inhibitors,
CD8+ activation depigmentation therapy
• Cutaneous vasculitis • Immune dysregulation, immune complex • Rare • Discontinuation of IL-17 inhibitors, systemic corticosteroids,
formation immunosuppressive agents
• Alopecia Areata • Dysregulation of IL-17 pathway, INFγ, • Rare • Topical corticosteroids, systemic immunomodulatory
CD8+ activation therapies
• Granuloma Annulare • Dysregulation of IL-17 pathway, T-cell • Rare • Topical corticosteroids, cryotherapy, systemic corticosteroids
activation
IL-12/IL-23 • Urticaria • Dysregulation of IL-12/IL-23 pathway, • Common • Antihistamines, topical corticosteroids, systemic
Inhibitors hypersensitivity type I corticosteroids
• Psoriasis • Dysregulation of IL-12/23 pathway, IFNα • Common • Topical corticosteroids, systemic therapies (e.g., MTX)
production
• Vitiligo • Dysregulation of IL-12/IL-23 pathway, • Rare • Topical corticosteroids, phototherapy, calcineurin inhibitors,
CD8+ activation depigmentation therapy
• Alopecia Areata • Dysregulation of IL-12/IL-23 pathway, • Rare • Topical corticosteroids, systemic immunomodulatory
IFNγ production therapies
• Granuloma Annulare • Dysregulation of IL-12/IL-23 pathway, T- • Rare • Topical corticosteroids, cryotherapy, systemic corticosteroids
cell activation
Rituximab • Pruritus, urticaria/rash • Depletion of B cells, Immune complex • Common • Symptomatic treatment, topical or systemic corticosteroids,
(RTX) formation, hypersensitivity type I discontinuation of RTX
• Psoriasis • Depletion and dysregulation of B cells and • Rare • Topical corticosteroids, systemic therapies (e.g., MTX)
IFNα production
• Cutaneous Vasculitis • Depletion of B Cells, Immune Complex • Rare • Topical or systemic corticosteroids, discontinuation of RTX,
Formation other immunomodulatory therapies (e.g., intravenous
immunoglobulin)
IL-6R • Pruritus, urticaria/ rash • Inhibition of IL-6 signaling, hypersensi­ • Common • Antihistamines, topical corticosteroids, systemic
Antagonists tivity type I corticosteroids
• Granuloma Annulare • Immune dysregulation, T-cell activation • Rare • Topical corticosteroids, systemic corticosteroids
JAK inhibitors • Herpes Zoster, Skin • Immune dysregulation, Viral reactivation • Common • Antiviral therapy, Antibiotics
Infections
• Urticaria • Immune dysregulation, hypersensitivity • Common • Antihistamines, Corticosteroids
type I
• Vitiligo • Immune dysregulation, IFNγ CD8+ T-cells • Rare • Topical corticosteroids, phototherapy, calcineurin inhibitors,
activation depigmentation therapy

Interleukin, IL; Interferon, IFN; Janus Kinase, JAK; Methotrexate, MTX; Rituximab, RTX; Tumor necrosis factor-α, TNFα; TNF inhibitor, TNFi

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A.I. Venetsanopoulou et al.
This study was performed in accordance with the Helsinki Declara­
tion of 1964 and its later amendments. All presented material is pub­
lished after written informed consent obtained from the reported
patients, although sensitive data and personal details are not included in
the publication.
Psoriatic skin lesions
Paradoxical cases of induced and/or worsened psoriatic lesions have
been described after TNFi treatment [27–30]. The same paradoxical
inflammation of psoriasis has also been reported with TNFi biosimilar
drugs [31]. These lesions present in 0.6-5.3% of RA patients, around 4%
of PsA patients, and up to 10% of IBD patients using TNFi, with a pre­
dilection to female patients [26,27,32]. Palmoplantar pustular psoriasis
is the most common clinical form. Still, there are many reports of
plaque-type psoriasis, guttate, nail, and scalp psoriasis, while there are
patients who may present more than one type of lesions [33–36]
(Fig. 1a,b).
The histopathologic examination may demonstrate a psoriasis-like
pattern, eosinophilic hypersensitivity reactions, lichen planus–like
dermatitis, or sterile pustular folliculitis [37].
The mechanism for such cutaneous irAEs due to TNFi remains partly
understood. As the time between treatment initiation and the develop­
ment of lesions varies widely, certain environmental factors, including
psychological stressors, psoriasis family history, and smoking, may
provoke the occurrence of psoriatic lesions in patients with a genetic
predisposition [38–40]. Polymorphisms, such as the Interleukin 23 Re­
ceptor (IL23R) gene, have been proposed to be involved [35].
A possible pathogenic mechanism underlying paradoxical psoriasis
in such cases involves, contrary to classical psoriasis, type-I interferon
(IFN)-driven innate inflammation. More specifically, dermal plasmacy­
toid dendritic cells are known to produce a high amount of IFN-α, which
may be responsible for psoriasis development. TNFα prevents the gen­
eration of plasmacytoid dendritic cells, thus down-regulate the pro­
duction of IFN-α. On the other hand, the inhibition of TNFα by TNFi
favours the generation of plasmacytoid dendritic cells and the produc­
tion of IFN-α [41,42]. The interleukin (IL)-23/T-helper (TH)-17 axis has
also been implicated in the pathogenesis, with an increased number of
IFN-secreting Th-1 and IL-17-/IL-22- secreting Th17 cells (Fig. 2).
Moreover, psoriatic skin lesions have been described in RA and SLE
patients receiving Rituximab (RTX) [43–45]. In those cases, it is hy­
pothesized that B cell population depletion may provoke an upregula­
tion of T-cells and lead to the development of psoriasis [46] (Fig. 2).
The patient’s clinical picture determines the treatment of psoriasis
induced by biologics. Topical treatment is preferred in mild cases, while
more severe ones may require systematic treatment. Discontinuation of
the biological agent usually has a beneficial result on the lesions. At the
Fig. 1. a,b. A 56-year-old woman with seronegative RA refractory to MTX and
hydroxychloroquine was treated with ETN 50mg/week subcutaneously.
Initially, she responded very well to the new treatment regimen. However, 6
months later, she developed psoriasiform skin eruptions affecting the palms of
the hands (Fig. 1a). ETN was discontinued, she was treated with 15mg/day
prednisone, and 2 months later, she was free of her skin rashes (Fig. 1b). She
continued receiving MTX and hydroxychloroquine and we added CTZ 200mg
every two weeks subcutaneously.
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Seminars in Arthritis and Rheumatism 63 (2023) 152272
same time, another type of TNFi may be used, or in persistent or even
worsened cases, a switch to another biologic class may be required [36,
47].
Vitiligo
Nonsegmental vitiligo is considered a multifactorial immune-
mediated disease characterized by skin, mucosa, and hair depigmenta­
tion with acquired, progressive, and depigmented lesions. TNFi have
been related to vitiligo development or even the progression of pre-
existing lesions. Cases of vitiligo during anti-IL-12/23 and anti-IL-17
agents or ABA treatment have also been reported [48–51]. Interest­
ingly, new-onset vitiligo may improve with the maintenance of the
biological treatment, while pre-existing vitiligo may worsen. There is a
report of new-onset vitiligo in a patient receiving tofacitinib, a JAK in­
hibitor treatment that has been shown efficacy in cases of known vitiligo
disease [52,53].
According to all the above, the pathogenesis of vitiligo is rather
complex; External triggers such as UV light and trauma in genetically
predisposed individuals stimulate the production of Reactive oxygen
species (ROS) in skin keratinocytes. Accumulation of excessive ROS
damages cells may lead to the formation of DNA breaks, protein frag­
mentation, enzyme activation, and further release of chemokines, such
as CLCX9, CLCX10, and CXCL16 from keratinocytes [54–56]. Chemo­
kines inside the dermal venules activate melanocyte-specific cytotoxic T
cells, which infiltrate the skin and kill melanocytes, while autoreactive
CD8+ T cells release cytokines, such as TNFα or IFN-γ. These cytokines
provoke further chemokines production from the keratinocytes,
ensuring CD8+ T-cell migration and autoimmune destruction of mela­
nocytes. In patients receiving TNFi, it is hypothesized that TNFα is
suppressed, and IFN-γ seems to play the key role leading to an autoim­
mune loss of melanocytes from the involved areas by recruiting patho­
genetic CD8+ cells which destroy melanocytes [48,57,58].
Acute Cutaneous Lupus Erythematosus (ACLE)
Malar rash presents with erythema affecting the face in a butterfly
distribution and typically sparing the nasolabial folds. Other close re­
gions, such as the neck, may be affected. It may last from days to weeks
and is occasionally painful or pruritic. Acute cutaneous Lupus Erythe­
matosus (ACLE) rashes may be attributed to new lupus onset in patients
without the pre-existing disease (Fig. 3a,b). In these cases, lupus diag­
nosis requires a temporal association between the development of the
skin lesions and treatment administration [59].
TNFi have been frequently associated with positive autoantibodies in
patients, including ANA and anti-dsDNA, while in less than 1% of pa­
tients, they may lead to lupus occurrence [60]. The main manifestations
of anti-TNF-induced lupus include rash, leukopenia, thrombocytopenia,
and hypocomplementemia. Most reports on lupus have been related to
IFX use, with an estimated incidence of up to 0,22%, followed by ADA
and ETN [61].
So far, little is known about the specific molecular pathways asso­
ciated with malar rash and ACLE. It is hypothesized that in genetically
susceptible individuals’ different environmental factors, including UV
light, may impact keratinocytes to defective apoptosis and release of
nuclear and particle antigens. This process may activate innate immune
responses, where dendritic cells are stimulated and release type I IFNs,
including IFN-α and TNFa, which drives cell apoptosis. On the contrary,
TNFa inhibition could interfere with apoptosis by decreasing the
expression of adhesion molecules. This affects the clearance of apoptotic
material by phagocytic cells, and the overall induced antigenic envi­
ronment may cause the production of autoantibodies and the clinical
expression of lupus. Furthermore, TNFa inhibition favours the produc­
tion of IFN-α by plasmacytoid cells, suppresses the Th1, and further
facilitates the pathogenesis of lupus. DCs may present autoantigens to
naïve, potentially self-reactive T and B cells in the lymph nodes and lead
A.I. Venetsanopoulou et al. Seminars in Arthritis and Rheumatism 63 (2023) 152272

Fig. 2. Mechanisms related to paradoxical psoriasis in patients receiving biological agents.

Specific gene mutations may contribute to psoriasis development. This condition is triggered by mechanical events that cause an overgrowth and abnormal dif­
ferentiation of keratinocytes. Immature dendritic cells recognize foreign substances and move to other organs to present them to T cells. However, patients treated
with TNFi may experience an uncontrolled production of interferon INFα by plasmacytoid dendritic cells (pDCs), which can worsen psoriasiform lesions. This results
in overexpression of type I interferon, causing the skin phenotype of paradoxical psoriasis, which differs from classical psoriasis because it is not dependent on T cells.
TNF-α inhibition can also stimulate the Th17 axis, which promotes the binding of IL-17A and IL-23 to specific receptors, increasing their expression.
Rituximab, a medication that depletes B cell function, may also provoke paradoxical psoriasis and disrupt the immune cell and cytokine balance involved in psoriasis
development. This imbalance may lead to psoriasis-like skin lesions and the production of pro-inflammatory cytokines.

cutaneous lupus have been reported, such as an aggravation of discoid

lupus erythematosus (DLE) after SEC treatment for psoriasis [64].

Cutaneous vasculitis

Cutaneous vasculitis (CV) may present as palpable purpura, nodular

Fig. 3. a,b. A 50-year-old woman with seropositive RA was treated with MTX
plus a small prednisone dose. Initially, she responded well to the treatment, but
one year later, she had a flare-up of the disease. Therefore, ADA was started at
40mg/14 days subcutaneously with clinical and laboratory improvement. After
8 months, she developed erythematosus skin eruptions affecting her face in a
butterfly distribution and the V area of the neck (Fig. 3a). She also had positive
ANA (1:320 speckled pattern) and positive anti-Ro (SSA antibodies). ADA was
discontinued, and she started receiving prednisone 20mg/day. Two months
later, she significantly improvement her skin lesions (Fig. 3b). She continued
receiving MTX and small doses of prednisone and TCZ was added, 162mg every
week subcutaneously.
cytotoxic T cells to be directed against the epidermis [59]. Autoreactive
B cells also have a primary role as they are activated by IFN-α and
further provoke the release of autoantibodies (Fig. 4).
These skin lesions can be distinguished from other types of cutaneous
lupus erythematosus as they exhibit reduced numbers of CD4+ tissue-
resident memory T cells [62,63]. Interestingly, other forms of
erythema, ulcer, or even livedo racemosa. It has been associated with
several disorders, as well as with the use of certain drugs. It is charac­
terized by inflammation, immune complex deposition, tissue damage of
blood vessel walls, and associated skin lesions.
A French nationwide survey by Saint Marcoux et al. identified 39
cases of vasculitis during TNFi treatment, of which 32 had skin
involvement [65]. The precise mechanism is poorly understood,
although the short time from TNFi initiation to vasculitis onset and the
good response when TNFi is withdrawn suggest a causal link between
TNFi and cutaneous vasculitis [66]. However, it is hypothesized that the
condition may be related to a direct drug impact on the vessel wall, type
3 hypersensitivity reaction within the capillaries with the deposition of
TNFi/TNFα immune complexes, and possibly autoantibody production
[67].
There are reports of Henoch-Schönlein purpura (HSP), a small vessel
vasculitis, in patients with autoimmune diseases receiving IFX, ETN, and
ADA [68–72]. CTZ has been associated with leukocytoclastic vasculitis
and hypocomplementemic urticarial vasculitis [73,74]. SEC, an inhibi­
tor of interleukin IL-17A, has been related to cutaneous vasculitis, with
patients showing a good resolution of the lesions after withdrawal of the
drug [75,76]. Interestingly, these cases were previously reported to have
TNFi treatment, which was switched due to inefficiency.
Finally, RTX-induced cutaneous vasculitis has rarely been reported
in the literature, mainly in patients with lymphoma treated with RTX. In
each case, discontinuation of RTX leads to the resolution of the cuta­
neous lesion [77–79].

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A.I. Venetsanopoulou et al. Seminars in Arthritis and Rheumatism 63 (2023) 152272

Fig. 4. Hypothesis for the TNFi-mediated mechanisms of lupus skin lesions; The pathogenetic model encompasses both adaptive and innate mechanisms. The
increased number of plasmacytoid dendritic cells and decreased levels of TNFα may influence autoimmunity, leading to defective clearance of apoptotic antigenic
material and the release of IFN-α. A further influx of cells provokes skin lesions; CD8+ T cells, macrophages, neutrophils, B cells, and pDCs.

Erythema nodosum
Erythema nodosum (EN) is the most common form of panniculitis. It
is characterized by a sudden onset of multiple tender, cutaneous and
subcutaneous red nodules, most frequently located over the anterior and
lateral surfaces of the lower limbs. EN is considered a late-type hyper­
sensitivity reaction to several antigenic stimuli. “Biological” therapeutic
agents, ADA and IFX, have been reported to induce EN [80,81]. A case of
drug-induced EN after the administration of CTZ in Crohn’s Disease has
also been described [82]. Still, new lesions resembling EN in a patient
under treatment with TNFi should always raise a ‘red flag’ as there are
cases related to tuberculous adenitis [83].
Alopecia areata
other inflammatory cells around the hair follicle resulting in hair loss
[97,98].
Granuloma annulare
Granuloma annulare (GA) is a benign, asymptomatic, self-limited
papular eruption in the skin that develops in the skin of patients of all
ages. It is characterized by grouped papules in an annular shape with
erythematous colour. There are reports of GA in patients suffering from
RA, (Spondyloarthropathies) SpA and, psoriasis who are under treat­
ment with TNFi, including ADA, ETN and IFX drugs [99,100] (Fig. 5a,
b). In a series of 199 cases, GA was reported to develop after a mean of 6
months under TNFi treatment and ADA was the most frequently

Alopecia areata (AA) is an autoimmune condition caused by the

overactivity of the immune system, which turns against and destroys the
hair follicles. Characteristic of this condition is the uneven thinning of
the hairs resulting in partial or complete hair loss from the head and/or
body in more severe cases. It can appear at any age, with a median age at
diagnosis of 33years-old. It may coexist with various autoimmune dis­
eases such as vitiligo, and psoriasis [84]. Heredity, endocrinological,
neuropsychological disorders, and environmental factors are all related
to AA occurrence [85]. AA-induced by biologics has been reported and
linked with the use of TNFi [86], especially with ADA [87,88] IFX [89,
90], ETN [91,92] and their biosimilar [93]. The incidence of AA after
TNFi has not been determined yet, while AA onset may present up to 89
months after TNFi exposure. Still, there is growing evidence of the Fig. 5. a,b. A 60year-old man with seropositive RA refractory to MTX plus ETN
occurrence of AA in patients receiving other biologics used in psoriasis was treated with TCZ 162mg/week subcutaneously. He responded to the
and PsA, such as Ixekizumab [94], brodalumab, SEC [95], and UST [96]. treatment regimen very well, but 10 months later, he manifested polycyclic skin
lesions affecting the lower extremities (Fig. 5a). The histopathological exami­
The underlying mechanism of AA pathogenesis in patients receiving
nation was compatible with granuloma annulare. Treatment with TCZ was
TNFi is still elusive. It hypothesized that TNFi might induce a collapse of
discontinued, and he received prednisone 10mg/day; 2 months later, he had
the hair’s follicle immune zone, leading to increased IFN-γ. This alter­
complete clinical resolution of the skin eruptions (Fig. 5b). He continued
ation in cytokine balance may induce infiltration of CD8+ T cells and receiving MTX and upadacitinib 15mg once daily, per os was added.

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A.I. Venetsanopoulou et al.
involved drug. All lesions were resolved with topical corticosteroids,
while in 7 cases treatment with TNFi remained [100]. Similar reports
have been published regarding other biological therapies, including SEC
and TCZ [101,102].
Granuloma development in such cases is initiated with the uptake of
antigens by macrophages, which in turn present it to the CD4+ helper T-
cells. Interleukin 2 (IL-2) secretion further induces T-cell proliferation,
while IFN-ɣ secretion activates macrophages. TNFi prevents the role of
released TNFα by macrophages and T-cells. However, under unknown
mechanisms, in some cases treated with TNFi, the inflammatory process
continues, and macrophages develop large cytoplasms often surrounded
by lymphocytes and, occasionally, plasma cells. Many macrophages may
combine and form multinucleated cells, also called granulomas (Fig. 6).
These patients may benefit with topical and systematic treatments
including low dose steroids. Still, lesions can recur with rechallenge and
may follow a relapsing and remitting course [103].
Discussion
Biological therapies have emerged in the last two decades for treat­
ing autoimmune rheumatic diseases and inflammatory arthropathies.
These agents have been demonstrated to be efficacious with an accept­
able toxicity and tolerability profile [15–17]. However, their use may
cause some alterations in the function of the immune system with the
development of several adverse reactions. Among them, the most com­
mon are infections (common, viral, opportunistic), as well as the
development of autoimmune phenomena manifested as the presence of
autoantibodies and/or clinical features. TNFi are the most commonly
used biological agents. They can induce several cutaneous autoimmune
reactions like psoriasiform skin rashes, erythematosus lesions affecting
the face, skin vasculitis, EN, GA, and many others [2]. All of the above
are major diagnostic and therapeutic challenges for physicians. For this
reason, prior to initiating a biological agent, the diagnosis of the un­
derline disease must be clear. Furthermore, a screening test to exclude
occult infections like hepatitis B and C and tuberculosis and immuno­
logical tests, including ANA, should be performed [22,23].
Diagnosis of any type of skin reaction can be based on the patients’
minute and careful medical history, the temporal relationship between
clinical manifestations, the suspected biological agent administered, and
the presence of autoantibodies and skin biopsy. For example, in a case of
a patient with RA who received TNFi and developed erythematous skin
rash affecting the face in a butterfly distribution, the diagnosis of lupus
requires the identification of the temporal association between TNFi
administrated and the development of the skin rash in a patient without
pre-existing lupus, and also the presence of positive ANA or/and other
autoantibodies diagnostic of lupus [22,23].
Fig. 6. Mechanism relating TNFi agents to granulomas development. The upregulation of T-cells with subsequent macrophage activation leads to the granuloma
development in such patients.
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Seminars in Arthritis and Rheumatism 63 (2023) 152272
In the case of a patient who received a biological agent and devel­
oped skin vasculitis, or EN or GA, the diagnosis can be considered if
there is a temporal relationship between the offended drug, the clinical
manifestation development, and skin biopsy and/or the presence of
autoantibodies, in case of vasculitis.
Finally, in the case of a patient with PsA who received a biological
agent and developed a new psoriatic skin lesion, deciding if this skin
reaction is a disease flare or an adverse drug reaction is challenging. The
patient’s medical history will determine if there was clinical improve­
ment of psoriasis and synovitis, as well as a decrease in acute phase
reactants after starting the suspected biological agent. In the case of an
adverse drug reaction, the regions involved are mostly the scalp and
palmoplantar areas, and there is a relationship between the suspected
agents and the development of psoriasis. On the other hand, if the
psoriatic lesion development is a disease flare, we expect a disease
relapse involving the joints, followed by an increase of the acute phase
reactants [22,23].
Regarding treatment, withdrawal of the suspected biological agent
may be sufficient in mild cases. In some cases, topical therapy with
calcineurin inhibitors and small doses of prednisone may be required to
achieve clinical resolution. When it comes to treating the underlying
disease, switching to a different type of biological agent is often the next
course of action. However, switching to a different biological agent
within the same class may be possible in some cases.
The prevalence of irAEs in patients treated with biological agents is
not well-known. Psoriatic skin manifestations with the use of TNFαi
were reported in 0,6-5, and 3% in RA patients and about 4% in PsA
patients [26,27,71]. The results are scarce regarding the prevalence of
lupus treatment with TNFi. However, the occurrence of ANA or dsDNA
antibodies is approximately 1%. Most reports are related to the use of
IFX, with an estimated incidence of lupus at 0,22% [61]. As far as the GA
development is concerned, in a large cohort of patients with RA and SpA,
from our group treated with TNFi, we identified 9 cases of GA among
199 RA patients, while no patients among 127 with SpA developed such
skin lesions. Of those patients who developed GA, 6 received ADA, 2 IFX,
and one ETN [100]. In another large cohort study from our group, we
described 32 cases of irAEs in RA, AS, and PsA patients treated with
TNFi. More specifically, we evaluated 252 patients with RA, 93 with AS,
and 90 with PsA. Of the 252 RA patients, 146 received IFX, 72 ADA, and
34 ETN. Twenty-two patients developed irAEs, 11 psoriatic lesions, 5
cutaneous vasculitis, 2 AA, 2 discoid lupus, one lichen planus, and one
vitiligo. Of the 93 patients with AS, 88 received IFN, 3 ADA, and 2 ETN.
A total of 9 patients developed irAEs (6 psoriatic lesions, one GA, one
AA, and one lichen planus). Finally, of the 90 PsA patients, 50 received
IFX, 5 ADA, and 35 ETN, and only one patient developed skin vasculitis.
Fifteen cases of irAEs were attributed to IFX, 13 to ADA, and 4 to ETN.
A.I. Venetsanopoulou et al.
The prevalence of psoriatic skin lesions in our cohorts was 4,4% of the
RA and 3,3% in SpA patients. The occurrence of irAEs ranged between
3-36 months with a median of 20 months. All patients responded well to
the topical treatment with steroids, or using small doses of prednisone in
some cases [26]. Recently two cases of AA were described by our group.
A 32-year-old woman with AS and a 48-year-old man with RA, who were
both treated with SB4 (Benepali), an ETN biosimilar. The two patients
developed AA, one after 6 months and the other after 12 months,
following the use of the TNFi biosimilar. The medication was dis­
continued. Prednisone 40mg per day was started, and 2 months later
steroid was discontinued and stopped, while the patients received ADA
40mg every 2 weeks subcutaneously without no new adverse drug re­
actions [93].
Conclusion
Nowadays, biological therapies targeting specific immune system
components, like cytokines or T and B cells, have revolutionized the
treatment of many inflammatory arthropathies and certain autoimmune
diseases. They have demonstrated efficacious in long-term clinical trials
with an acceptable toxicity profile. However, by inhibiting immune
system components, many autoimmune phenomena and paradoxical
inflammation have emerged, including lupus-like disease, psoriatic skin
rashes, GA, AA, and many others. By understanding the immunological
phenomena occurring during biological treatment, physicians can
establish a better approach for their patients. Thus, close monitoring and
early recognition of these autoimmune phenomena are important for
physicians to ensure they have an accurate diagnosis and treatment.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgement
The authors would like to thank Mrs. Chrysa Arvaniti for her excel­
lent secretarial assistance.
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