Current Dermatology Reports (2021) 10:128–139

https://doi.org/10.1007/s13671-021-00346-1

CONTACT DERMATITIS (BRANDON ADLER AND VINCENT DELEO, SECTION EDITORS)

Patch Testing and Immunosuppression: a Comprehensive Review

Brandon Levian1 · Justin Chan1 · Vincent A. DeLeo2 · Brandon L. Adler2

Accepted: 9 September 2021 / Published online: 30 October 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review To provide an up-to-date synthesis of the literature on patch testing (PT) in patients undergoing immu-
nosuppressive therapy or experiencing certain immunosuppressive diseases.
Recent Findings With respect to immunosuppressive drugs, there is a risk of false-negative reactions if PT is conducted on
patients taking prednisone at a dose greater than 10 mg daily. Topical corticosteroids, particularly high-potency formulations,
could suppress positive reactions if applied to the test area in the days before PT. Other conventional systemic immunosup-
pressants have the potential to induce false-negative reactions in a dose-dependent manner, based on low-quality evidence.
Dupilumab may carry a risk of suppressing positive reactions depending on each allergen’s immunologic signature, but
existing studies show mixed results regarding this hypothesis. PT should be avoided following significant ultraviolet light
exposure, but the ideal waiting time is unknown.
For patients with HIV, sarcoidosis, or leprosy, there is a lack of research establishing the extent to which these disease states
could impact the accuracy of PT.
Summary For the most part, knowledge of the effects of immunosuppressive drugs and disease states on PT is based on
small, retrospective studies. Given the prevalence of allergic contact dermatitis and numerous causes of immunosuppression,
there is a need for high-quality studies investigating the impact of immunosuppression on PT in order to standardize practice
and allow clinicians and patients to make the best-informed decisions possible.

Keywords Immunosuppression · Immunosuppressive therapy · Patch testing · Corticosteroids · Calcineurin inhibitors ·

Cyclosporine · Tacrolimus · Azathioprine · Methotrexate · Mycophenolate mofetil · Biologic medications · Tumor necrosis
factor · Interleukin · Dupilumab · Apremilast · Janus kinase inhibitors · UV light

Introduction (APCs), including Langerhans cells and dermal dendritic

Allergic contact dermatitis (ACD) is a type IV (delayed-
type) hypersensitivity reaction that represents a T cell-
mediated immune response to specific allergens [1]. The
mechanism involves two distinct phases: sensitization and
elicitation. In the sensitization phase, which is clinically
asymptomatic, an allergen penetrates the skin and binds to
host proteins, forming a hapten [2]. Antigen-presenting cells
This article is part of Topical Collection on Contact Dermatitis
* Brandon L. Adler
brandon.adler@med.usc.edu
1
Keck School of Medicine, University of Southern California,
Los Angeles, CA, USA
2
Department of Dermatology, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA
cells, transport the hapten to regional lymph nodes, guided
by the release of keratinocyte-secreted pro-inflammatory
cytokines and chemokines including tumor necrosis factor
alpha (TNF-α), interleukin (IL)-1β, and IL-18 [1, 3, 4]. At
regional lymph nodes, naïve T cells are educated to recog-
nize the hapten and then enter the circulation [5]. Subse-
quently, elicitation occurs when, upon re-exposure to the
same or a chemically similar hapten, hapten-specific T cells
migrate to the skin and produce the clinical symptoms of
ACD.
Recent advances have highlighted the complexity of the
immunologic pathways involved in ACD beyond the clas-
sical paradigm. ACD is traditionally considered to primar-
ily be a T helper 1 (Th1) cell-mediated phenomenon. More
recent investigations demonstrate not only that additional T
cell subsets (e.g., Th2, Th17, Th22) are involved, but also
that allergens have their own molecular immunological
Current Dermatology Reports (2021) 10:128–139
signatures, displaying biased activation in their expression
of cytokines and inflammatory markers [6]. While this field
of inquiry is still in its infancy, it has been shown that nickel
primarily elicits a Th1/Th17- and Th22-skewed response,
whereas fragrance and less so rubber accelerators polar-
ize towards Th2 [6]. In addition, there has also been a shift
in understanding of the broader immunologic pathways
involved in ACD: the innate immune system, including mac-
rophages, innate lymphoid cells, and natural killer cells, may
play a significant role in the effector phase in particular [7].
Patch testing (PT) serves as the gold standard for the
diagnosis of ACD and relies on the ability to provoke posi-
tive reactions in previously sensitized patients, reproducing
the elicitation phase in a controlled fashion [8]. A major
factor that may influence both the development of ACD
and the diagnostic accuracy of PT is concomitant use of
immunosuppressive and immunomodulatory medications,
which may induce hyporeactivity through nonspecific anti-
inflammatory activity or targeted effects along the sensitiza-
tion and/or elicitation pathway. In addition, certain comorbid
conditions that impact immune regulation could potentially
modulate PT results. Herein, we first review the evidence on
the effects of medications and ultraviolet (UV) light on PT,
then discuss the influence of select disease states including
HIV, sarcoidosis, and Hansen’s disease (leprosy).
Conventional Immunosuppressive
Medications
Corticosteroids
A. Systemic
Systemic corticosteroids exert broad immunomodulatory
and anti-inflammatory effects via the inhibition of a variety
of cytokines and proinflammatory mediators, including T
cells and APCs [9, 10]. The effects of systemic corticos-
teroids on patch testing have been studied extensively. In
perhaps the earliest study, Sulzberger et al. patch tested 5
patients with known contact allergy after starting oral cor-
tisone 150 mg daily [11]. While there was a trend toward
reduced reactivity to more dilute allergens, positive reactions
to standard allergen concentrations were maintained. Later,
O’Quinn and Isbell documented significantly suppressed
PT reactions among 6/20 (30%) known sensitized patients
taking prednisone 40 mg daily [12]. Similarly, in another
study, 18 known sensitized subjects were patch tested to
Rhus antigen 3 times: at baseline, 48 h after starting a 7-day
course of prednisone 40 mg daily, and again 4 weeks later.
While pre- and post-prednisone, 100% of subjects had posi-
tive PT results, nearly half showed significantly suppressed
129
reactions while on treatment [13]. At lower doses, Feuerman
and Levy observed dose-dependent suppression of positive
PT reactions in patients retested after 48 h on prednisone,
with complete suppression in 3/12 (25%) patients taking
40 mg daily, 2/15 (13%) taking 30 mg daily, and 1/16 (6%)
taking 20 mg daily [14]. While nearly all (15/16 [94%])
patients on prednisone 20 mg daily maintained positive PT
reactions, there was a slight reduction in reaction strength in
5/16 (31%). By contrast, a randomized, double-blind crosso-
ver study evaluated the effect of prednisone 20 mg daily
on PT reactions in a group of 24 nickel-allergic subjects.
Compared to placebo, prednisone significantly diminished
PT reactivity to a nickel dilution series (in 90% vs 10% of
subjects, P < 0.05) as well as to nickel 5% pet (in 53% vs 0%
of subjects, P < 0.05) [15••]. The authors concluded that
prednisone 20 mg daily is sufficient to suppress PT reactions
to nickel. Further studies have confirmed positive reactions
in patients taking 5–10 mg of prednisone per day [16, 17].
Much less research has been devoted to systemic corti-
costeroids other than prednisone. Verma et al. conducted PT
on 21 patients with Parthenium hysterophorus ACD before
and after betamethasone 2 mg daily for 6 months, observing
a significant reduction in positive reactions to P. hystero-
phorus extract, with 12/21 (57%) initially positive reactions
maintained and 9/21 (43%) lost (P = 0.0039) [18]. It was not
reported if there was any reduction in the strength of reac-
tions that remained positive.
Society-based guidelines on PT in patients receiving
systemic corticosteroids are in Table 1. Based on available
data, consensus opinion from the North American Contact
Dermatitis Group (NACDG) is that testing is acceptable on
prednisone up to 10 mg daily [19••]. At higher doses, the
withdrawal time should be 3–5 days. Per the European Soci-
ety of Contact Dermatitis (ESCD) [20••], if discontinuing
treatment is not feasible, the lowest possible dose of cor-
ticosteroids should be used (with no provision of a “safe”
dose), the possibility for false-negative reactions must be
strongly considered, and repeat PT is advised if the patient
discontinues treatment. More specifically, recent German
guidelines advise discontinuing prednisone ≥ 20 mg daily
7 days before PT when possible [21••]. With respect to
patients receiving intramuscular triamcinolone 40 mg, the
NACDG advises waiting at least 4 weeks prior to PT [19••].
Interestingly, the half-life of a systemic corticosteroid has
been shown to be a poor predictor of time to regaining
full immune function, so this is a potential area for further
research [22].
B. Topical
Topical corticosteroid formulations are widely used to
reduce inflammation for various skin conditions. Fol-
lowing application, the free steroid molecule binds to the
130 Current Dermatology Reports (2021) 10:128–139

Table 1  Society-based guidelines for patch testing on immunomodulatory agents

Agent Society Guideline

NACDG (2012) [19••] ESCD (2015) [20••] BAD (2017) [58] German S3 (2019) [21••]
Corticosteroids, systemic 10 mg; 3–5 days ND; 5 half-lives (rule of 10 mg; ND 20 mg; 7 days
(maximum dose; with- thumb)
drawal time)
Corticosteroids, topical 3–7 days 7 days 2 days (potent formula- 7 days
(withdrawal time) tions)
Calcineurin inhibitors, Dose-dependent inhibition False-negative reactions ND Discontinue prior to PT if
systemic may occur possible
Calcineurin inhibitors, ND ND ND ND
topical
Azathioprine Dose-dependent inhibition False-negative reactions ND Does not affect reactivity
may occur
Methotrexate Little to no effect ND ND ND
MMF Dose-dependent inhibition ND ND ND
TNF-α inhibitors Little to no effect ND ND ND
IL-17 and IL-12/23 Little to no effect (usteki- ND ND ND
inhibitors numab)
Dupilumab ND ND ND ND
Apremilast ND ND ND ND
Janus kinase inhibitors ND ND ND ND
UV exposure to test site, 1 week ND 6 weeks 4 weeks
avoidance time

BAD British Association of Dermatologists, ESCD European Society of Contact Dermatitis, IL interleukin, MMF mycophenolate mofetil,
NACDG North American Contact Dermatitis Group, ND not discussed, PT Patch testing, TNF tumor necrosis factor, UV ultraviolet.

cytoplasmic glucocorticoid (GC) receptor, which then
either translocates to the nucleus, where it binds to the GC
response element in the promoter region of target genes, or
remains in the cytoplasm to interact with cellular transcrip-
tion proteins [23, 24].
Some existing studies indicate that topical corticoster-
oids applied to the test site may negatively impact and even
totally suppress PT reactions. Among 8 patients patch tested
after a 24-h pre-treatment with triamcinolone acetonide
0.1% cream, compared to a vehicle control group, 3/8 (38%)
showed complete suppression of reactions and another 3/8
(38%) showed reduction in reaction size [25]. Similarly, pre-
treatment with betamethasone dipropionate 0.05% at either
full strength or at a 1:4 dilution for several consecutive days
partially or totally suppressed the majority of positive PT
reactions [26]. In another study, 3-week pretreatment with
clobetasol 0.05% cream strongly suppressed PT responses in
nearly all (18/20 [90%]) nickel-allergic subjects as evaluated
by clinical scoring as well as laser Doppler flowmetry and
transcutaneous ­PO2 measurement [27].
Other studies have reported more modest effects of topi-
cal corticosteroids on PT results. In patients pretreated with
triamcinolone acetonide 0.1% administered 3 times daily
for 7 days versus vehicle control, there was no difference
among 12/18 (67%) PT pairs, with reduction in reaction
strength on the triamcinolone-treated site in 4/18 (22%)
[28]. Dahl and Jordan compared PT reactions in 4 patients
tested in duplicate, with one side of the back pretreated with
betamethasone valerate 0.1% cream 3 times daily for 3 days
and the other left as an untreated control site. In 3/4 (75%)
patients, there was reduced reaction strength on the steroid-
treated site, but complete suppression only occurred for one
allergen, undecylenic acid [29]. Sukanto et al. studied PT
results in 14 subjects pre-treated with 4 topical steroids of
varying potencies, finding that the intensity and size of reac-
tions were markedly reduced, without significant differences
between groups. Complete suppression only occurred for
weaker (1+ and some 2+) reactions [30].
Experiments in which topical steroids were included
alongside standard allergens in PT chambers showed con-
flicting results. Across 15 patients with positive reactions
to nickel sulfate 5%, inclusion of triamcinolone acetonide
0.1% within the chamber hardly impacted the intensity of
PT reactions [25]. On the other hand, Rietschel found that
triamcinolone acetonide 0.1% and 0.025% ointment within
PT chambers suppressed nearly all reactions in subjects with
known thimerosal allergy [31]. In a real-life scenario, Fisher
reported negative PT to neomycin-nystatin-triamcinolone
formulations tested as-is, in contrast with strongly positive
reactions when ethylenediamine hydrochloride, included as
a stabilizer, was tested separately. However, paraben-allergic
patients reacted to a hydrocortisone 0.5% formulation that
Current Dermatology Reports (2021) 10:128–139
contained parabens, suggesting a lower risk of suppression
from weaker steroids [32].
Across a plethora of studies, the preponderance of evi-
dence suggests that topical corticosteroids can potentially
suppress and, in some instances, completely inhibit PT reac-
tions, with the strongest effect generally exerted by higher-
potency formulations. While the earliest time point at which
topical corticosteroid application could interfere with PT
results remains to be determined, guidelines call for avoid-
ance of topical corticosteroids prior to testing. Specifically,
the consensus opinion of the NACDG is evenly split between
3 and 7 days [19••]. The ESCD suggests taking topical ster-
oid use into consideration when planning PT [20••], and
German guidelines recommend discontinuation beforehand
[21••]. Both discuss waiting 7 days before proceeding with
PT while acknowledging the lack of solid supporting evi-
dence for this period.
Calcineurin Inhibitors
Calcineurin inhibitors are a group of medications that act
through various mechanisms to inhibit the phosphatase cal-
cineurin, consequently suppressing T cell proliferation [33].
The systemic calcineurin inhibitors are cyclosporine and tac-
rolimus; approved topical agents in this class are tacrolimus
and pimecrolimus.
A. Systemic
In a prospective study of patients patch tested while on
immunosuppressants, 5/12 (42%) patients taking cyclo-
sporine 2–3 mg/kg/day had positive PT reactions to a vari-
ety of allergens [34]. Likewise, Rosmarin et al. reported
strong positive reactions in all 3 patients patch tested on
cyclosporine [16]. While these reports demonstrate that
positive reactions may occur on cyclosporine, patients were
not patch tested pre-initiation, rendering it unclear whether
any reactions might have been suppressed by treatment.
One study showed that high-dose cyclosporine (5 mg/kg/
day) inhibited PT responses by increasing the threshold for
reactivity in 6 patients who were patch tested at baseline
and again 2 weeks after starting treatment [35]. This may
not be clinically meaningful, however, as the threshold for
reactivity in this study fell below standard allergen concen-
trations. Furthermore, inhibition may only occur in the case
of weak PT reactions, with strong reactions unaffected in
a series of 33 patients patch tested before and after treat-
ment initiation (dose not specified) [36]. Additional sup-
port for performing PT while on cyclosporine comes from
a unique study of 10 patients who developed “angry back”
(excited skin syndrome) during testing [37]. Upon repeat
PT after starting cyclosporine 5 mg/kg/day, it was found
131
that the drug suppressed irritant, but not allergic, reactions.
The distinction between irritant and allergic reactions was
confirmed through repeat sequential testing starting 1 month
after resolution of dermatitis, during which over half of the
initial reactions were lost.
Conducting PT on patients taking cyclosporine is not
explicitly discouraged by the NACDG or ESCD, but phy-
sicians should recognize the possibility of false-negative
results (particularly for weak positive reactions) and con-
sider repeating PT if cyclosporine is discontinued [19••,
20••]. German guidelines recommend considering discon-
tinuation of cyclosporine prior to PT, when possible [21••].
B. Topical
Several studies have evaluated the effects of topical cyclo-
sporine on PT [38–40]. Taken in aggregate, they showed
that suppression of PT reactions occurred in a small minor-
ity of patients. However, we can draw limited real-world
conclusions from these results, as topical cyclosporine is not
widely used outside of ophthalmic applications. Recently,
Mose et al. conducted a randomized clinical trial in 76
human subjects examining the effects of various topical
corticosteroids as well as topical tacrolimus and pimecroli-
mus on an experimental model of diphencyprone (DPCP)
ACD, as measured by visual inspection and skin ultrasound.
Among all the tested drugs, only tacrolimus 0.1% demon-
strated a significant pre-treatment anti-inflammatory effect
compared with control [41]. The implications of this finding
with regard to routine practice of PT are unclear.
Due to the paucity of data, it is not possible to formulate
a guideline describing the necessary delay between topical
calcineurin inhibitor application and patch testing. Out of
caution, some experts advise waiting between 5 and 14 days
after use of topical calcineurin inhibitors before performing
PT [42, 43].
Azathioprine
Azathioprine exerts its immunosuppressive effects via its
active metabolite 6-thioguanine, which is incorporated into
DNA and RNA and inhibits purine synthesis [44, 45], as
well as diminishing the endogenous population of mono-
cytes [46] and cutaneous Langerhans cells [47]. An early
case report by Pigatto et al. demonstrated a strong PT reac-
tion to nickel sulfate 5% in a patient taking azathioprine
100 mg daily for over 2 years; of note, azathioprine was
withheld for 2 days prior to testing [48]. In a prospective
series of patients patch tested while on immunosuppres-
sants, 1/5 (20%) patients taking azathioprine monotherapy
and 2/12 (17%) on azathioprine combined with other immu-
nosuppressants showed positive PT reactions; it is unknown
132
if suppression of positive reactions could have occurred, as
testing was not conducted off drug [34]. In the most com-
pelling study to date, investigators in India conducted PT
on 47 patients with confirmed Parthenium hysterophorus
dermatitis before and after starting azathioprine at a dose
of either 300 mg weekly or 100 mg daily. After 6 months of
therapy, a positive PT result to P. hysterophorus extract was
demonstrated in 45/47 (96%) patients, leading authors to
conclude that azathioprine does not significantly influence
PT [49••]. However, it is unclear if similar results would be
obtained using commercially available allergens.
Given the lack of conclusive evidence on the effects of
azathioprine on PT, the NACDG does not explicitly recom-
mend discontinuing treatment prior to testing, but advises
maintaining awareness of potential dose-dependent inhibi-
tion [19••]. The ESCD recommends that azathioprine treat-
ment be discontinued prior to PT, if possible [20••], while
German guidelines allow for PT on azathioprine [21••].
Methotrexate
Methotrexate is an immunosuppressive antimetabolite that
competitively inhibits dihydrofolate reductase, inhibiting
DNA synthesis [50–52]. In a prospective study of patients
patch tested while on immunosuppressants, 2/3 (67%)
patients taking methotrexate monotherapy and all 3 taking
methotrexate combined with other immunosuppressants
demonstrated positive PT reactions [34]. Wentworth and
Davis also found that 4/7 (57%) patients patch tested on
methotrexate had positive reactions [53••]. Notably, most
(4/7) of the patients held the dose of methotrexate during
the week of testing. More recent case reports support the
ability to elicit strong positive PT reactions in patients taking
methotrexate [54].
While it appears that methotrexate minimally impacts PT
results, the existing evidence is of low quality. The NACDG
consensus holds that methotrexate has little to no effect on
PT [19••]. Other experts suggest using the lowest possible
dose of methotrexate or withholding treatment the week of
PT [43, 55].
Mycophenolate Mofetil
Mycophenolate mofetil (MMF), an immunosuppressive
pro-drug, disrupts de novo purine synthesis by inhibiting
inosine monophosphate dehydrogenase [56, 57]. In a pro-
spective series of patients undergoing PT while on immu-
nosuppressants, among 2 patients taking MMF 2 g daily,
and another 3 taking MMF combined with other immuno-
suppressants, Wee et al. observed positive reactions in 2/5
(40%) patients [34]. In another series, a patient demonstrated
mildly positive (1 +) reactions to cobalt, gold, and trieth-
anolamine while on MMF 2 g daily, but did not improve
Current Dermatology Reports (2021) 10:128–139
despite allergen avoidance. The patient underwent repeat
PT 1 year later off MMF and demonstrated new reactions to
several common preservatives, improving with subsequent
avoidance measures. However, the lengthy interval between
the two rounds of testing made it difficult to attribute the
initial negative PT result to the effects of MMF versus sub-
sequent sensitization [16]. In their series, Wentworth and
Davis reported negative PT results in a single patient taking
MMF [53••].
There is little evidence to either support or discourage
the use of MMF during PT. The NACDG cautions about
possible dose-dependent inhibition [19••], and European
guidelines likewise do not offer specific advice [20••, 21••,
58]; it may be prudent to test on the lowest dose possible
[19••, 59].
Biologic Medications and Other Novel
Immunomodulators
1. TNF‑inhibitors
TNF-α is a cytokine that plays essential roles in both the
sensitization and elicitation phases of ACD [60, 61]. Follow-
ing single reports showing development of ACD and posi-
tive PT reactions in patients taking TNF-α inhibitors, Wee
et al. reported in a prospective series of patients patch tested
on immunosuppressants that 4/6 (67%) on TNF-α inhibitors
(with or without other agents) displayed positive reactions
[34]. Later, a case–control study in psoriasis patients on bio-
logic therapies, including 8 taking TNF-α inhibitors (4 on
etanercept, 3 on adalimumab, 1 on infliximab), demonstrated
positive reactions in 80% of participants compared to 81% of
controls, with no significant differences in reaction strengths
between groups [62••].
Based on limited data, there is currently no evidence that
TNF-α inhibition suppresses PT reactions to any degree.
Furthermore, members of the NACDG have agreed that
TNF-α inhibitors likely have little to no effect on PT results
[19••].
2. IL‑17 and IL‑12/23 inhibitors
Th17 cells and their effector cytokines, including IL-17 and
IL-22, are increasingly targeted by psoriasis biologics due
to the central roles they play in its etiopathogenesis [63].
Discovery of the involvement of IL-17 in the mechanism of
ACD raises the question of whether its suppression could
affect PT results [64, 65]. Isolated case reports demonstrate
positive PT reactions in psoriasis patients taking secuki-
numab and ixekizumab [66, 67]. Conversely, in a partially
blinded trial, among 10 known nickel-allergic patients patch
tested at baseline and then 1 week after a single dose of
secukinumab 300 mg, there was a slight but significant
Current Dermatology Reports (2021) 10:128–139
reduction in reaction strength at the 72-h reading (P = 0.034)
but not at 48 h, with no differences in skinfold thickness or
histologic scoring [68••]. At our center, we recently saw a
patient with psoriasis on ixekizumab therapy who presented
with a chronic photodistributed dermatitis. Photopatch test-
ing performed according to NACDG guidelines [69] dem-
onstrated a mild (1 +) reaction to methylisothiazolinone on
the covered control side, compared to a strong (2 +) reaction
on the side irradiated with UVA, consistent with photoag-
gravated ACD (Adler et al., unpublished data).
Positive PT reactions have also been observed in patients
taking ustekinumab, a monoclonal antibody that indirectly
inhibits the formation of IL-17A through its effects on
IL-12/23. A case report by Nosbaum et al. showed mainte-
nance of a strong PT reaction following initiation of usteki-
numab [70]. In Kim et al.’s series of psoriasis patients on
biologic therapies, 7 of whom were taking ustekinumab,
there were no differences in rates of positive reactions or
reaction strength in cases versus controls [62••].
In 2012, the NACDG suggested there was likely little to
no effect of ustekinumab on PT results [19••]. Apart from
the few small studies detailed above, little guidance is availa-
ble on patch testing on newer biologic agents. With regard to
anti-IL-17/23 therapy, some experts suggest delaying patch
testing until just before a patient’s next dose [59].
3. Dupilumab
Dupilumab is a human monoclonal antibody against IL-4Rα
approved for the treatment of moderate-to-severe atopic der-
matitis (AD) [71]. Conducting PT in patients with AD is
of great clinical relevance, as they may have an increased
incidence of ACD or at least susceptibility to sensitization
to certain allergens [72]. Dupilumab may have the potential
to unmask underlying ACD [73]. By blocking the Th2-medi-
ated humoral response, it has been postulated that patients
taking dupilumab may present with false-negative PT
responses to Th2-based haptens while maintaining positive
reactions to Th1-based haptens [74]. However, Raffi [75] and
Hoot [76] reported positive PT responses to Th2-based hap-
tens such as fragrances and rubber accelerators in patients
on dupilumab, contradicting this hypothesis. Likewise, in
our contact dermatitis clinic, we recently saw a massage
therapist suffering from severe chronic hand dermatitis only
partially controlled with methotrexate and dupilumab. PT
revealed multiple positive reactions to essential oils and fra-
grances, formaldehyde-releasing preservatives, and thiuram
mix relating to glove use (Adler et al., unpublished data).
A systematic review found that in 28 patients, the same
allergen was tested before and during dupilumab treatment,
comprising 144 test pairs [77••]. Of these pairs, follow-
ing dupilumab initiation, 71 (49%) remained positive, 17
(12%) were lost, 8 (6%) were newly positive, and 48 (33%)
133
were unknown. A recent retrospective series of 20 patients
undergoing PT before and after starting dupilumab showed
that 37/56 (66%) initial positive reactions became negative
on treatment, raising concern that the risk of false negative
reactions may be greater than supposed [78••]. The authors
did not note differing rates of reactions between presumed
Th1/Th17- and Th2-polar allergens.
Clearly, the impact of dupilumab on PT is an area of
active inquiry with major implications for diagnosis and
management of ACD, particularly in patients with con-
comitant AD. Due to the potential for suppression of PT
reactions, whenever possible, patients should be tested at
baseline prior to dupilumab initiation, or else retested should
treatment be discontinued.
4. Apremilast
Apremilast is an oral phosphodiesterase-4 (PDE-4) inhibi-
tor that is approved for the treatment of moderate-to-severe
psoriasis and psoriatic arthritis [51]. By decreasing forma-
tion of certain inflammatory mediators involved in ACD,
apremilast could theoretically exert a negative impact on PT
findings. West and Fowler observed several strong positive
PT reactions, including relevant reactions to glucosides, in
a patient with erythroderma that had cleared with 3 months
of apremilast 30 mg twice daily [79]. Other than this report,
there have been no studies of the possible impact of apremi-
last on PT results, and thus no formal guidelines on how to
proceed with testing in patients on this drug.
5. Janus kinase inhibitors
Janus kinase inhibitors are approved for treatment of condi-
tions including rheumatoid arthritis, psoriatic arthritis, and
ulcerative colitis and are actively being investigated for use
in AD and other inflammatory skin disorders [80, 81]. The
Janus kinase-signal transducer and activator of transcrip-
tion (JAK-STAT) pathway is activated by many cytokines
that are integral to the development of ACD [82], but to our
knowledge, there are no published studies on PT reactions in
patients on JAK inhibitors at the time of writing. We expect
this question will be addressed in the near future with the
increasing use of these agents for dermatologic and other
disease states.
Flynn et al. recently performed a retrospective cross-
sectional analysis of PT results in patients enrolled in a
randomized study of corticosteroid allergy in inflammatory
bowel disease [83••]. Thirty-eight of 184 patients (21%)
were on one or more systemic immunosuppressants (6-mer-
captopurine (n = 20), prednisolone 5–20 mg daily (n = 9),
infliximab (n = 7), adalimumab (n = 2), azathioprine (n = 2),
methotrexate (n = 1), MMF (n = 1), cyclosporine (n = 1)) at
134
time of PT. Thirty-four percent of patients taking immu-
nosuppressants and 48% of patients not receiving immu-
nosuppressants had at least one positive reaction, without
significant differences between groups (P = 0.13). There
was a non-significant difference in reactions to fragrance
mix and balsam of Peru (6% and 4% of immunocompetent
patients, respectively, versus none in the immunocompro-
mised group). The authors concluded that conducting PT
on immunosuppressed patients is feasible.
While many clinical suggestions have been set forth
regarding PT in the setting of immunosuppressive agents,
for most medications, it is not possible to determine effects
on testing with a high degree of confidence based on existing
studies, which tend to be small and retrospective in nature.
There is a need for large prospective studies of PT in patients
exposed to immunosuppressive agents. Until that time, con-
sensus opinions of experts in the field will continue to guide
practice.
UV Light
There is a concern that UV-induced immunosuppression
could affect the accuracy of PT. The generation of T regu-
latory cells and the failure of Langerhans cells to properly
present antigens to T lymphocytes form the mechanistic
foundation for immunotolerance after UV exposure [84].
Erythemogenic doses of UVB and UVA II were found to
reduce sensitization and induce tolerance to DNCB, which
was associated with a reduction in Langerhans cells [85, 86].
However, there is a lack of directly relevant studies on the
impact of UV-induced immunosuppression on the elicitation
phase of ACD in practice.
Kalimo et al. found that among 13 patients with known
contact allergy to a variety of common allergens, a single
exposure to UVB or psoralen plus ultraviolet A (PUVA)
4 days before PT reduced test reactivity at the irradiated
site in the majority of subjects. In the UVB group, marked
reduction of reaction strength only occurred when there
were strong erythemal reactions, whereas for PUVA,
this occurred with mild erythemal reactions or even in
the absence of perceptible erythema. For both UVB and
PUVA, suppression of PT reactivity did not correlate with
Langerhans cell density [87]. Among 9 nickel-allergic
patients who underwent PT before and immediately after
receiving 3 weeks of UVB phototherapy, there was a sig-
nificant reduction in the number and strength of reactions
at both exposed and unexposed sites, suggesting local as
well as systemic suppressive effects of UVB [88]. A simi-
lar effect was not observed with UVA phototherapy [88],
although a different study showed suppression of PT reac-
tions in 3 patients who had repeat testing after receiving
7–9 weeks of PUVA [89].
Current Dermatology Reports (2021) 10:128–139
A recent case–control study found no significant effect
on the number or strength of PT reactions in 22 patients
receiving narrowband UVB phototherapy within the previ-
ous 6 weeks (8/22 completing treatment 2–4 weeks prior,
and 14/22 in the 4–6 weeks prior). The pilot study was small
and potentially underpowered [90••].
Consensus opinions on delaying patch testing after UV
exposure to the test site vary widely from 1 week (NACDG)
[19••] to 4 weeks (German guidelines) [21••] to 6 weeks
(British guidelines) [58], with a lack of firm evidence in
support of the latter prolonged waiting period. Further well-
conducted studies are needed to confidently define the neces-
sary delay for PT following UV exposure.
Disease States
HIV
At the end of 2018, HIV had infected approximately 1.2
million people aged 13 and older in the USA [91]. Due to
impaired cell-mediated immunity in HIV/AIDS [92], includ-
ing reduced CD4 + T cells and thereby limited interactions
with APCs, it has been suggested that the development of
ACD may be inhibited [93].
There are only limited reports on the immunomodulatory
impact of HIV infection on the development of ACD and
accuracy of PT. Case reports and series describe HIV-posi-
tive patients, including those with low CD4+ counts, becom-
ing sensitized to DNCB and testing positive to a number of
common contact allergens [94–101]. We recently diagnosed
occupational ACD to nail cosmetics in a manicurist with
well-controlled HIV who demonstrated strong positive reac-
tions to multiple acrylates. In addition, the patient reacted
to linalool, found in an over-the-counter remedy being used
(Adler et al., unpublished data). All of which is consistent
with the knowledge that CD8+ T cells play a key effector
role in ACD, rather than the CD4+ T cells that define HIV
staging [101–103]. HIV status may in fact play a negligible
part in the sensitivity of PT.
Sarcoidosis
Sarcoidosis is a systemic disease of unclear etiology, char-
acterized by non-caseating granulomas most commonly
involving the lungs, lymph nodes, skin, and eyes. These
granulomas are non-necrotizing and are surrounded by
CD4+ and a smaller proportion of CD8+ T cells [104]. For
decades, it has been recognized that the active phase of sar-
coidosis limits antigen sensitization without disrupting the
ability to elicit an immune response from previous sensitiza-
tion [105]. In the non-lesional skin of sarcoidosis patients,
Current Dermatology Reports (2021) 10:128–139
particularly those with multisystem involvement, there were
significantly fewer Langerhans cells compared to controls
[106]. An early study showed similar rates of sensitization to
the potent sensitizer pentadecyl catechol in patients with sar-
coidosis compared to controls, with significantly lower rates
of sensitization for weaker sensitizers (DNCB and parani-
trosodimethyl amine) [107]. Subsequent studies confirmed
that DNCB sensitization and reactivity were diminished in
patients with sarcoidosis, and also associated with decreased
lymphocyte transformation [108, 109]. These findings open
up several avenues for future inquiry, but we are not aware
of any routine clinical studies of PT in sarcoidosis patients
to guide practice. Another consideration is that sarcoidosis
patients with organ dysfunction necessitating treatment com-
monly receive certain of the immunosuppressive medica-
tions discussed above.
Hansen’s Disease (Leprosy)
Leprosy is a chronic granulomatous disease caused by infec-
tion with Mycobacterium leprae or M. lepromatosis. The
disease is staged on a spectrum from polar tuberculoid (pri-
marily Th1 profile) to polar lepromatous (primarily Th2)
according to histopathological findings, increasing bacte-
rial load and immune status [110]. Early research found
that patients with lepromatous leprosy (LL) had signifi-
cantly lower rates of sensitization to DNCB than controls.
The effect was limited to patients without leprosy reactional
states; the presence of reactional states was associated with
sensitization rates comparable to those of controls [111,
112]. This was an early indication along with other works
that primarily uncomplicated LL, as opposed to tuberculoid
leprosy, is associated with abnormal delayed hypersensitiv-
ity [113, 114], yet others have found that all types of leprosy
can impair immune reactivity [115, 116].
In practice, the association between leprosy and ACD is
infrequently reported. A report of occupational ACD from
potassium dichromate in cement in an LL patient demon-
strated a similar strong PT reaction pre- and post-leprosy
treatment, implying a normal cellular immune response
throughout the course of disease [117]. There is another case
of ACD from triethanolamine in a moisturizing cream that
was applied to a dried out tuberculoid lesion in a patient with
relapsed leprosy [118]. Despite the rare association, it is
important to recognize that ACD overlying an existing lesion
could mask and delay the diagnosis of leprosy. We have
a general understanding that lepromatous leprosy reduces
immune reactivity, yet the amount of evidence as pertains to
different allergens and sensitization versus elicitation phases
of ACD are extremely thin.
135
Conclusion
Patch testing serves as the gold standard to detect ACD,
yet exogenous and endogenous immunosuppressive fac-
tors, including medications and disease states, may affect
its accuracy. As a result, there is a great need to understand
the interplay between immunosuppressive states and PT in
order to effectively diagnose and alleviate the symptoms of
ACD. A significant amount of research has been dedicated
to this topic, but many questions remain unanswered.
With respect to systemic corticosteroids, 10 mg/day of
prednisone or equivalent appears to be the cutoff beyond
which suppression of PT reactions may be expected. The
impact of topical corticosteroids on PT may be greater with
high-potency formulations, with a general consensus that PT
should be delayed for several days to a week after applica-
tion to the test site [19••, 20••, 21••]. Other conventional
immunosuppressants have demonstrated variable effects on
PT including potential dose-dependent suppression of reac-
tions, but the current body of evidence is generally of low
quality [19••, 20••, 21••, 34–36, 49••, 53••].
With regard to biologic agents, TNF-α inhibitors and
IL-17 and IL-12/23 inhibitors appear to have little to no
effect on PT [19••]. The impact of dupilumab on PT and
risk of false-negative reactions is a subject of active inquiry
that will evolve with increasing understanding of allergens’
immunologic profiles [78••]. Whenever possible, PT should
be conducted prior to dupilumab initiation. No studies of
PT in patients taking Janus kinase inhibitors have been
published to date, but we expect them shortly, given their
increasing use and potential to treat a variety of dermato-
logic conditions.
The exact avoidance time following UV exposure to the
test site is uncertain but 1 week should be allowed at mini-
mum [19••, 21••, 58].
Development of ACD and positive PT reactions in
patients with HIV, sarcoidosis, and leprosy have been
reported, yet the paucity of high-quality data and the com-
plex spectrum of immunosuppression involved in each dis-
ease limits our ability to make any generalizations about
their potential impact on PT findings.
While it is generally recommended to delay PT until after
immunosuppressive medication use or adequate management
of a relevant disease, we recognize that this is not always fea-
sible. It is important that patch-test clinicians recognize the
possibility for false-negative reactions due to a wide variety
of immunosuppressive states that may be outside direct con-
trol. If testing is negative despite high suspicion for ACD, it is
reasonable to consider empiric allergen avoidance and repeat
PT in the future should circumstances change.
136
Compliance with Ethical Standards
Conflict of Interest BLA has served as a research investigator and/or
scientific advisor to AbbVie and Skin Research Institute, LLC.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any
of the authors.
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