not permitted.

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© 2018 EDIZIONI MINERVA MEDICA Giornale Italiano di Dermatologia e Venereologia 2018 April;153(2):243-55
Online version at http://www.minervamedica.it DOI: 10.23736/S0392-0488.18.05872-8

REVIEW
R H E U M AT O L O G I C D E R M AT O ( PAT H O ) L O G Y:
HOW THE MICROSCOPE CAN HELP THE CLINICIAN

Skin manifestations of rheumatoid arthritis

Viviana LORA  1, Lorenzo CERRONI  2, Carlo COTA  3  *

1Division of Dermatology, San Gallicano Dermatological Institute, Rome, Italy; 2Research Unit of Dermatopathology, Department of

Dermatology, Medical University of Graz, Graz, Austria; 3Unit of Dermatopathology, San Gallicano Dermatological Institute, Rome, Italy
*Corresponding author: Carlo Cota, Unit of Dermatopathology, San Gallicano Dermatological Institute, Via Elio Chianesi 53, 00144 Rome, Italy.
E-mail: carlocota@yahoo.it

A B S TRA C T
Rheumatoid arthritis is a chronic systemic disease that, in addition to articular involvement, may exhibit a variety of extraarticular manifesta-
tions. The skin is frequently involved mainly in the most severe forms of the disease. Rheumatoid nodules, accelerated rheumatoid nodulosis,
rheumatoid nodulosis, Felty syndrome, rheumatoid vasculitis, pyoderma gangrenosum, rheumatoid neutrophilic dermatosis, interstitial granu-
lomatous dermatitis, and palisaded neutrophilic granulomatous dermatitis are reviewed both clinically and histologically. Moreover, cutaneous
reactions related to treatments of rheumatoid arthritis, in particular to biologic agents, are described. Early recognition of these entities through
a clinical and histological correlation permit to optimize the management of patients.
(Cite this article as: Lora V, Cerroni L, Cota C. Skin manifestations of rheumatoid arthritis. G Ital Dermatol Venereol 2018;153:243-55. DOI:
10.23736/S0392-0488.18.05872-8)
Key words: Rheumatoid arthritis - Skin - Rheumatoid nodule - Felty Syndrome - Dermatitis - Biological factors.

R heumatoid arthritis (RA) is a chronic, inflammatory

disease related to immune function and character-
ized by destructive, disabling polyarthritis. It is increas-
ingly evident that RA does not only affect the joint but
can often present with extra-articular and systemic com-
plications.1 In RA any organ system can be potentially in-
volved, giving rise to the concept of rheumatoid disease.
Epidemiology
RA has an incidence of 0.5% to 1% in the total popu-
lation.1-3 It can occur in all races and ethnic groups al-
though it affects more frequently North American and
North European people.1-3 Women are three times more
likely to develop RA than men, and 80% of RA pa-
or other proprietary information of the Publisher.
hormonal factors in the pathogenesis of the disease.2, 5
Recently, a reduction of incidence in women has been
reported, probably related to the increased use of oral
contraceptives that appear to have a protective effect.6
A positive family history increases the risk of RA
about three to five times, and concordance rates are in-
creased in monozygotic compared to dizygotic twins.3, 7
An overview of epidemiological studies by Frisell et al.
showed that the heritability of RA is about 40%, a figure
lower than the often-cited 60% that was based on twin
studies.8 Heritability is not modified by sex, but evi-
dence suggests that seropositive RA, i.e. RA in which
either rheumatoid factor (RF) or antibodies against
citrullinated peptides (ACPA) are present, is more fa-
milial than seronegative RA.1, 8

tients develop the disease between the ages of 35-50.1, 4 Genome-wide association studies have identified
In women, the first peak of incidence occurs after the more than hundred susceptibility loci associated with
first childbirth, whereas the second one occurs in the the disease, most of which involved in immunological
perimenopausal age, suggesting an important role of mechanisms.1, 9, 10 The most relevant among these loci

Vol. 153 - No. 2 Giornale Italiano di Dermatologia e Venereologia 243

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LORA SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS

are genes encoding MHC class II molecules, especially evident synovitis.1, 10 Joint swelling in RA reflects sy-
HLA-DRB1*0401/*0404, which are implicated in T- novial membrane inflammation consequent to immune
cell recognition of autoreactive peptide.11 In particular,activation, and is characterized by abundant leucocyte
HLA-DRB1 locus is associated with a more aggressive infiltration. In particular, the cellular composition of sy-
disease and with higher mortality.12 HLA-DRw3 allele novitis in RA includes numerous innate immune cells
has been found associated with increased RF positivity, (e.g., monocytes, dendritic cells, mast cells, and in-
rheumatoid nodules, and severity of the disease, where- nate lymphoid cells) and adaptive immune cells (e.g.,
as HLA-DRw2 appears to be a less aggressive factor T-helper-1 and T-helper-17 cells, B cells, plasmablasts,
associated with lower RF titers and less rheumatoid and plasma cells).1, 10 Consequently, robust tissue re-
nodules present in the patients.13 Other RA-associated sponse consisting of increased chondrocyte catabolism
non-HLA genetic loci codify for proteins involved in with synovial osteoclastogenesis as well as of synovial
co-stimulatory pathways (CD28, CD40, the interleu- fibroblasts assuming an aggressive inflammatory, ma-
kin-6 receptor), in post-translational modification (eg, trix regulatory, and invasive phenotype, promotes the
PADI, which catalyses the post-translational modifica- articular destruction.16 This inflammatory milieu is reg-
tion of peptidylarginine to citrulline), and in intracel- ulated by a complex cytokine and chemokine network,
lular regulatory pathways (e.g., PTPN22, TNFAIP3, mainly orchestrated by TNF_α and IL-6.1, 10 In the pro-
STAT3), each of which might contribute to alter the cess, a cascade of inflammatory mediators is released,
balance between the activation and the shutdown of the contributing to the maintenance of the disease.
immune response.1, 10 Environmental risk factors include smoking, expo-
Emerging data show that epigenetic mechanisms (i.e. sure to silica dust or other pulmonary deleterious par-
DNA methylation), altered histone acetylation, and mi- ticles, infections, vitamin D deficiency, obesity and mi-
croRNAs could contribute to RA pathogenesis, prob- crobiome perturbations.1, 10 Smoking has been shown
ably connecting the environmental triggers to changes to increase the risk for seropositive RA by more than
in gene expression.1, 10, 12, 14 twofold, especially in individuals with HLADR01/04
alleles.17 Preliminary evidence suggests that cigarette
Pathophysiology of RA smoking can induce expression in the lungs of the en-
zymes responsible for citrullination of various proteins,
Stages of RA thus creating antigen targets of autoantibodies that are
Three stages of rheumatoid arthritis have been delin- tightly associated with RA.18 Periodontal disease has
eated by Holmdahl et al., characterized by autoimmune been associated with RA and particularly the Porphy-
priming, tissue attack, and chronic inflammation.15 In romonas gingivalis, a gram-negative bacterium, has
the pre-RA phase, autoantibodies (RF and ACPA) and been shown to possess enzymes which generate citrulli-
pro-inflammatory cytokines (tumor necrosis factor α, nated proteins; such RA autoantigens are indeed detect-
interleukin 6) can be detected, preceding the onset of ed in the gingival tissue of subjects with periodontitis.19
clinically evident articular disease during the early RA Other infectious agents (e.g., Proteus mirabilis, Esch-
phase. Established RA is characterized by chronic in- erichia coli, and Epstein-Barr virus) have been suggest-
flammation and cartilage and bone damage.1, 10 ed to trigger the disease, generally via molecular mim-
icry.1, 10 Lastly, emerging data from animal models of
Autoimmune response and inflammation arthritis suggest an essential role of the gut microbiome
in the development of the disease, probably related to
The earliest events in the autoimmune priming phase immune regulation and maintenance of host tolerance.20
include an altered innate immune reactivity and aber-
rant T- and B-cell activation, most probably in mucosal Diagnosis and classification of RA
or other proprietary information of the Publisher.

tissues, culminating in the production of autoantibodies

that recognize a range of post-translationally modified RA can be difficult to diagnose at onset because of
proteins with citrulline residues. This loss of tolerance overlapping symptoms with other arthritis such as
can lead to initially asymptomatic and then clinically osteoarthritis or reactive, psoriatic and infectious ar-

244 Giornale Italiano di Dermatologia e Venereologia April 2018

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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©
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SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS LORA
Table I.—ACR/EULAR classification criteria for rheumatoid ar-
thritis (modified from Aletaha et al.).21
Criteria
A. Joint involvement
1 Large joint
2-10 Large joints
1-3 Small joints
4-10 Small joints
>10 joints (at least 1 small joint)
B. Serology
Negative RF and negative CCP
Low positive RF or low positive CCP
High positive RF or high positive CCP
C. Acute phase reactant
Normal CRP and ESR
Abnormal CRP or ESR
D. Duration of symptoms
<6 weeks
≥6 weeks
Score of ≥6 is diagnostic criteria for rheumatoid arthritis.
CCP: cyclic citrullinated peptide; CRP: C-reactive protein; ESR: erythrocyte
sedimentation rate; RF: rheumatoid factor.
thritis.1 Therefore, a diagnosis of exclusion should be
made. The combined American College of Rheuma-
tology (ACR) and European League Against Rheuma-
tism (EULAR) in 2010 presented new criteria for clas-
sification of RA, in order to include features of early
rather than chronic arthritis.21 In the new criteria set,
classification as “definite RA” is based on the confirmed
presence of synovitis in at least one joint, absence of
an alternative diagnosis better explaining the synovitis,
and achievement of a total score of 6 or greater (out of
10) from the individual scores in four domains: num-
ber and site of involved joints (range 0-5), serological
abnormality (range 0-3), elevated acute-phase response
(range 0-1) and symptom duration (range 0-1) (Table I).
Extra-articular manifestations of RA
RA may present a variety of extra-articular manifes-
tations (EAMs) which can develop at any time during
the course of the disease, even in the early stages.22 In a
multicenter Italian study conducted in 587 patients with
RA, EAMs were found in 40.9% of the patients, more
frequent males. Sicca syndrome (17.5%) and rheuma-
or other proprietary information of the Publisher.
toid nodules (16.7%) were the most common EAMs.23
History of smoking, early disability, presence of anti-
nuclear antibodies, and RF-positivity were found as the
principal predictor factors of systemic disease.24 Severe
Vol. 153 - No. 2 Giornale Italiano di Dermatologia e Venereologia 245
EAMs of RA include pericarditis, pleuritis, vasculitis,
peripheral neuropathy, Felty syndrome, glomerulone-
Points phritis and scleritis or episcleritis, and are associated
with greater comorbidity and premature death.25 Inter-
0 estingly, Turesson et al. described the presence of rheu-
1
2
matoid nodules (RNs) as a predisposing factor for de-
3 velopment of severe EAMs, especially in patients who
5 develop them within 2 years from diagnosis of RA.26
The skin is one of the most frequently affected ex-
0
2
tra-articular organ, and in what follows we will focus
3 on the main cutaneous conditions associated with RA
(Table II).
0 Cutaneous involvement is observed very often in RA,
1
mainly in patients with more severe disease.2, 24, 27-32
0 Skin manifestations appear to be induced by various
1 mechanisms such as activation of inflammatory cells
(neutrophils, lymphocytes, and macrophages), vascu-
lopathy, vasculitis, acral deformity, and drugs.27
Non-specific as well as specific cutaneous lesions
may be observed. Non-specific lesions seem to be more
numerous and frequent than specific one in some case
series.27 They include diffuse skin atrophy with edema
mainly on interphalangeal joints, palmar erythema and a
bluish shade over the fingertips. Raynaud phenomenon
can be observed in RA patients, although its estimated
prevalence seems to be decreased within the observa-
tion period (1977-2010) from 11.2% to 9.4%.30 Nail in-
volvement appear to be characteristic but not specific of
RA and consists of onycholysis, ridging, clubbing, yel-
low discoloration, red lunula and pterygium inversum.29
Many other skin abnormalities have been described in
the literature but some of them seem to be casual.
Specific cutaneous conditions commonly observed
in RA patients include rheumatoid nodules and neutro-
Table II.—Cutaneous manifestations of rheumatoid arthritis.
Neutrophilic dermatosis –– Pyoderma gangrenosum
–– Rheumatoid neutrophilic dermatosis
Palisading granuloma –– Rheumatoid nodule
–– Palisaded neutrophilic granulomatous
dermatitis
–– Interstitial granulomatous dermatitis
Vascular –– Small-, medium-, and large-vessel vasculitis
–– Bywater’s lesion
Drug reaction to therapy –– Psoriasiform dermatitis
–– Eczematous reactions
–– Vasculitis
–– Lichenoid eruptions
–– Granulomatous reactions
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©
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LORA SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS

philic dermatoses, whereas uncommon manifestation of

the disease are represented mainly by rheumatoid vas-
culitis, Felty Syndrome and Bywaters’ lesions.
Some of these entities are characterized by peculiar
histologic alterations that alone allow the correct di-
agnosis, whereas in many other a clinical-pathological
correlation is essential.

Rheumatoid nodules
Rheumatoid nodules (RN) are the most common
extra-articular manifestation of RA, occurring in about
35-40% of patients. RN generally are not related to se-
verity or progression of RA, and their appearance be-
fore arthritis has been observed.2, 33 On the other hand,
RN occurred more often in patients with long-standing
disease and positive for RF (90% of patients), and their
frequency correlates directly with RF titer. In some pa-
tients, RN may be the indicator of more severe systemic
extra-articular manifestations, which subsequently lead
to a clinically poorer outcome.29, 32 RN have been re-
ported more frequently in the Caucasian population
with a male predominance.34
Clinically, RNs are most commonly found at the
site of recurrent mechanical pressure or trauma such
as extensor surfaces of olecranon, forearm, fingers, oc-
cipitus, back, sacral prominences and heels 29, 35 (Fig-
ure 1A, B). Unusual reported sites are the foot, buccal
mucosa, vulva and penis. RN can also be observed at
several extracutaneous organs such as lungs, pleura,
pericardium, heart, pharynx, vocal cords, peritoneum,
dura, sclera, and liver.35, 36 In most of the patients, the
diagnosis of RN is based on clinical findings alone. In
cases with unusual location, or when they appear in the
absence of other signs of RA, histology is mandatory
for a correct classification.35 Histopathologically, RN
are characterized by the pattern of palisading necrobi-
otic granuloma, with a central red area due to fibrin de-
position.35 They are usually seated in the deep dermis
and subcutis ranging from multiple foci to a large area
of collagenolytic granuloma (Figure 1C). Three classi-
cal zones can be recognized: a central area of fibrinoid
necrosis with streaks and granules; a surrounding area
or other proprietary information of the Publisher.
A B
C D
Figure 1.—Rheumatoid nodules: A) skin-colored nodules on the right
elbow; B) skin-colored nodule at the intermediate phalanges of the left
hand; C) palisading granulomatous inflammation with an inner central
necrotic area, an intermediate area with palisading macrophages, and
a surrounding zone of perivascular granulation tissue with infiltrative
inflammatory cells (H&E stain, magnification ×10); D) higher magnifi-
cation (H&E stain, magnification ×200).
ure 1D).24, 27 The central area incorporates collagen,
fibrils, fibrin, proteins, and other cellular debris. It can
be rimmed by an intensely eosinophilic accumulation
of fibrin, (in Red granuloma) and may show clefts and
cystic degeneration. Mucin deposition with edematous
mucinous-appearing necrobiosis appears to be rare in
RN, and this represents histopathologically the most
useful criterion in the differential diagnosis with deep
granuloma annulare.37 In the peripheral palisade, the
histiocytic component may have an epithelioid ap-
pearance and may include foreign body giant cells. An
admixture of lymphocytes, neutrophils and mast cells
may be also observed. The surrounding stroma shows
vascular dermal tissue, occasionally with granulation

with palisading macrophages, displaying an increased tissue-like appearance, as well as perivascular infil-
expression of HLA-DR antigen; and a peripheral trate composed of lymphocytes, plasma cells and his-
area showing perivascular inflammation composed tiocytes. Eosinophils may be present. Foci of vasculitis
of lymphocytes, plasma cells and histiocytes (Fig- are rarely observed.

246 Giornale Italiano di Dermatologia e Venereologia April 2018

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SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS LORA
Well-formed necrobiotic granuloma represents the
third final stage of the histological progression of RN.
An initial phase of acute inflammation is characterized
by a scar-like area with newly formed proliferated cap-
illaries with surrounding monocytes, followed by a sec-
ond granulomatous phase with initial development of
palisading macrophages and central necrosis.36
From a clinical standpoint, a microscopic diagnosis
of RN may correspond to the classical form or refer to
more rare conditions such as accelerated rheumatoid
nodulosis, rheumatoid nodulosis or Felty Syndrome.
The pathogenesis of RNs is not clearly understood,
and a number of different theories have been proposed.
The most accepted view is that RNs are lesions medi-
ated by immune complexes.38 Kato et al. demonstrated
by immunohistochemical studies that their formation as
well as fibrin deposits are secondary to complement ac-
tivation due to aggregation of IgM-RF on the endothelial
cell surface after a vascular injury, resulting in immune
complexes (IC) formation.39 In addition, confined accu-
mulation of RF complexes at the site of injury seems to
stimulate local monocytes to produce interleukin-1 and
other angiogenetic factors (TNF-α and TGF-β), causing
fibrin deposition as procoagulant response to the angio-
neogenesis. An increased number of IL-23 and IL-17
positive cells has been also recently found in RNs, com-
pared to both the skin of healthy subjects and the non-
RN skin of RA patients, indicating that IL-23 and IL-17
may be also necessary for the onset of RN in RA.40
RN cytokine profiling suggests that they represent a
Th1 granuloma, as defined by Hessian et al.2, 41
Accelerated rheumatoid nodulosis
Accelerated rheumatoid nodulosis (ARN) has been
first described as a complication of methotrexate (MTX)
therapy in patients with RA. It is characterized by rapid
onset and worsening of nodules in chronic RA patients
during MTX therapy. When compared with classical
RN, the lesions are smaller with a different distribu-
tion, such as the metacarpophalangeal and proximal
interphalangeal joints of the hands and feet, and on the
ears.42 ARN has been observed in 8-11% of MTX-treat-
or other proprietary information of the Publisher.
ed RA patients. 24
The duration of MTX therapy before onset of ARN is
variable with a mean of 35.1±31.1 months.43
The pathogenetic mechanism of ARN is still unclear.
Vol. 153 - No. 2 Giornale Italiano di Dermatologia e Venereologia 247
Merrill identified an adenosine-1receptor-mediated
pathway as responsible for macrophage recruitment and
multinucleated giant cell promotion.44 Interestingly,
Shimoura et al. reported a case of MTX-induced ARN
where Epstein-Barr virus (EBV) was detected in RN and
lymph nodes of the patient, supporting the hypothesis
that MTX-associated immunosuppression could impair
immune surveillance of EBV-infected cells, leading to
the development of ARN.45
Increased frequency of HLA-DRB1*0401 and RF se-
ropositivity have been associated with ARN.43
Besides MTX, other medications as azathioprine,
leflunomide, infliximab, etanercept and aromatase in-
hibitors have been seen capable of inducing ARN.2, 46-48
The term “immunomodulatory agent-associated accel-
erated nodulosis” has been proposed to broaden this
concept to all immunomodulatory drugs.2 Histopatho-
logically, ARN is indistinguishable from classical RN.29
Rheumatoid nodulosis
Bywaters described rheumatoid nodulosis for the first
time in 1949.49 It is characterized by the presence of
numerous RN in patients with palindromic rheumatism
and mild or no systemic manifestations of RA. Male
patients aged 30 to 50 are most commonly affected. The
diagnosis of rheumatoid nodulosis is based on diagnos-
tic criteria suggested by Couret, including: 1) multiple
subcutaneous RN identified by biopsy; 2)  recurrent
joint symptoms with minimal clinical or radiologic in-
volvement; 3) benign clinical course; and d) no or mild
systemic manifestations of RA.50 Positivity for RF and
poor response to standard treatment have been subse-
quently added to the diagnostic criteria. Absence of ra-
diologic subchondral bone cysts as well as of positive
RF does not eliminate rule out the diagnosis of rheuma-
toid nodulosis, particularly at the onset of the disease.
Although rheumatoid nodulosis is considered as a
self-limited disease and usually is not associated with
the development of classical RA, about 40% of 16 pa-
tients developed classic erosive RA in one study.51
A variant of rheumatoid nodulosis not associated
with RA, known as pseudorheumatoid nodules or be-
nign rheumatoid nodules has been reported in healthy
children and more rarely in adult patients. Pseudorheu-
matoid nodules may mimic the histologic features of
RN, but they usually occur in different anatomic sites
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
LORA SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS

than conventional RN associated with RA. Typically,

pseudorheumatoid nodules are located on the prepa-
tellar and pretibial areas, feet, scalp, and malleoli. In
these patients there is no evidence of systemic disease
or RF positivity, nor of subsequent development of RA.
The pathogenesis of this entity is unclear, and repetitive
trauma may be a predisposing factor in some of these
lesions. According to many authors, pseudorheumatoid
nodules may represent a deep variant of granuloma an-
nulare in a late stage of evolution.29

Rheumatoid vasculitis
Rheumatoid vasculitis (RV) is a potentially serious
complication of RA that affects approximately 2% to
5% of patients with long-standing disease (generally
>10 years in duration).2, 52 Male patients with multiple
RN, joint erosions, high titer of RF, or already treated
with drugs that modify the disease including biological
agents, are at higher risk of developing RV.2, 52 It has
been described rarely in the early phases of RA or at
onset of the disease.
RV represents a type III hypersensitivity reaction in
which immune complexes activate complement, trig-
gering chemotactic recruitment of neutrophils and caus-
ing damage of the endothelium.52
RV is a heterogeneous disorder that may show a va-
riety of clinical and histological features. The disease
can involve any organ. However, cutaneous involve-
ment is often the presenting sign of RV and is reported
in about 90% of patients. In about half of the cases a
peri and/or epineural arteritis can be observed, mani-
festing with peripheral nerve lesions as mononeuritis
multiplex or sensory symmetric neuropathy.53 Systemic
vasculitis is seen in less than 1% of patients with RV
and heart, lungs, central nervous system, eyes, gastroin-
testinal tract and kidneys may be involved.54 Prognosis
is dependent upon size of blood vessels involved and
severity of systemic manifestations.52 Cutaneous RV
without systemic complications has a relatively favor-
able course. On the contrary, when cutaneous lesions
are followed by peripheral nerve as well as bowel in-
volvement the prognosis may be poor.55
or other proprietary information of the Publisher.
Figure 2.—Cutaneous small vessel vasculitis. Leukocytoclastic vascu-
litis with a neutrophilic infiltrate, red blood extravasation, and fibrinoid
necrosis of blood vessel walls (H&E stain, magnification ×200).
simultaneously in the same biopsy or be observed in dif-
ferent lesions from the same patients. RV of small vessels
is generally a leukocytoclastic vasculitis characterized
by neutrophilic and eosinophilic infiltrates with leukocy-
toclasia, red blood extravasation, and fibrinoid necrosis
of blood vessel walls (Figure 2). The corresponding clin-
ical presentations are represented by petechiae, palpable
purpura, hemorrhagic vesicles, non-specific macula-
papular erythema and erythema elevatum diutinum-like
lesions. Patients may also develop urticarial vasculitis,
characterized by wheals that persist for more than 24
hours healing with hyperpigmentation.2, 29, 52 Deposition
of IgM as well as C3 in small and medium-sized vessels
has been detected by direct immunofluorescence.
The so-called Bywaters’ lesions represent a peculiar
clinical manifestation of RV of small vessels, first de-
scribed in 1957 by Bywaters.56 They are characterized
by small, 0.5-1 mm purpuric papules which appear on
the distal fingers, usually on the digital pulp, the nail
fold or the nail edge, in patients with RV. They may be
observed in up to 41% of patients, and typically are not
associated with systemic vasculitis.29, 52, 57 Originally,
Bywaters and Scott argued that these lesions could
precede more severe vascular involvement; however, a

Clinical suspicion of RV requires histological confir- subsequent study did not show association with a pro-
mation. In the skin, vasculitis may affect dermal small gression to systemic vasculitis.58, 59 Thus, Bywaters le-
capillaries and postcapillary venules as well as medium sions need no specific therapy because they are often
sized arteries. Diverse types of vasculitis may be present transient and painless.30

248 Giornale Italiano di Dermatologia e Venereologia April 2018

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS LORA

RV of medium-sized vessels at the dermal-subcuta-
neous junction can be histologically indistinguishable
from polyarteritis nodosa, characterized by segmental
and concentric necrotizing vasculitis of medium-sized
arteries with neutrophilic debris, fibrin and red blood
cells extravasation. Subcutaneous nodules, ulceration
mostly observed on the lateral malleolus or pretibial
region, livedo reticularis and atrophie blanche are the
corresponding clinical lesions.29, 30
In addition to vasculitis, other infrequent vasculo-
pathic histological patterns have been described by
Magro and Crowson in a series of 43 patients with RA.28
They include: pauci-inflammatory vascular thrombosis,
reactive angioendotheliomatosis with glomeruloid neo-
vascularization, non-follicular pustular vasculitis, peri-
follicular vasculitis with sterile neutrophilic folliculitis,
lymphocytic vasculitis, granulomatous vasculitis and
intravascular histiocytopathy. The corresponding clini-
cal pictures ranged from palpable purpura to vasculitis,
ulceration or urticarial dermatitis.
ceptibility to Epstein-Barr viral infection reported in pa-
tients with FS.64 In addition, neutropenia is also the cause
of an increase of the rate of infection in these subjects.61
Poor prognosis has been associated to Felty syn-
drome with a mortality rate of up to 25%, with deaths
often due to sepsis.63
Pyoderma gangrenosum
Pyoderma gangrenosum (PG) is a neutrophilic dis-
ease which is defined by a pathological abundance of
neutrophils in the dermis in absence of infection.65, 66
Clinically, it starts with a papule or pustule that evolves
in a necrotic ulcer with the typical well-defined viola-
ceous border and undermined edges, reaching up 5 to 10
cm in diameter in a few weeks.67 The disease can occur
on any skin surface (Figure 3A), but it is most common-

Felty syndrome
Felty syndrome (FS) is characterized by the triad of
arthritis, leukopenia, and splenomegaly.60 It occurs in
1% of patients with RA, usually after long-standing dis-
ease, and affects almost exclusively the white popula-
tion.29, 61, 62 Felty patients tend to have more frequent RF
positivity (high titers), circulating immune complexes,
RN, and destructive arthritis, although they present less
or inactive synovitis than RA patients.29, 61, 62 Further-
more, extra-articular manifestations are more frequent
in Felty patients than in non Felty-RA patients.29, 61-63 A B
FS is genetically much more homogeneous than
RA.61 More than 85% of FS patients are DR4-positive
compared with 6070% of patients with rheumatoid ar-
thritis and 30% of Caucasian controls.61, 63
Skin manifestations of Felty syndrome include RN,
occurring in 76% of patients, and secondary leg ulcers
in vasculitis associated with venous insufficiency and
resulting hyperpigmentation.
Notably, Gridley et al. noted that patients with FS have
an increased risk of melanoma during the first year of di-
or other proprietary information of the Publisher.

agnosis, and as with RA patients, they are also at increased C

risk of lymphomas and leukemias.64 This association has Figure 3.—Pyoderma gangrenosum: A) erythematous ulcerated plaques
with well-defined edges to the right arm; B) diffuse neutrophilic dermal
been ascribed to neutropenia, splenic dysfunction, rela- infiltrate with abscess formation (H&E stain, magnification ×10); C) a
tively aggressive rheumatoid disease, and increased sus- detail of neutrophilic abscess (H&E stain, magnification ×200).

Vol. 153 - No. 2 Giornale Italiano di Dermatologia e Venereologia 249

not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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©
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LORA SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS
ly seen on the legs. Typical of PG is the pathergy phe-
nomenon, characterized by the development of lesions
at the site of minor trauma.67, 68 PG can occur at any
age and most commonly affects women between 20 to
50 years of age,2, 30 and is not associated uniquely with
RA but can present in many different settings. In a re-
view by DeFilippis et al., PG was found associated with
inflammatory bowel disease (IBD) in 65.2% of cases,
with polyarthritis in 16.1% and with hematological dis-
orders in 12.5%.69 Among the four clinical variants of
PG i.e. ulcerative, pustular, bullous and vegetative, ul-
cerative form is the most associated with RA and other
seronegative polyarthritis.2, 30, 66
The pathogenesis of PG is multifactorial and seems
to involve neutrophilic dysfunction, pro-inflammatory
mediators, and genetic predisposition.70 Alterations in
chemotaxis, migration, phagocytosis, and bactericidal
ability of neutrophils have been reported in patients
with PG, although it is unclear whether the neutrophil
dysfunction is the primary reason for the development
of PG, or if neutrophils are the effector cells of an ab-
errant immune system. Comprehension step forward in
the understanding of the pathogenesis of PG is repre-
sented by the detection of genes responsible for some
autoinflammatory syndromes in which PG is present,
such as PAPA or PAPASH.70-72 The identified mutations
concern the proline-serine-threonine-phosphatase inter-
active protein (PSTPIP)-1 gene that encodes for CD2-
binding protein 1.73 Typically, CD2-binding protein 1
binds pyrin, causing inhibition over the inflammasome
complex and prevention of cytokine formation. Mu-
tated PSTPIP-1 leads to decreased inhibition of the
inflammasome, activation of caspase 1, and increased
production of IL-1b and IL-18.70 Other cytokines found
overexpressed are IL-8; tumor necrosis factor-alfa, IL-
17, IL-23, chemokines 1, 2, 3, and 16; and matrix me-
talloproteinase (MMP) 2 and 9.74 Interestingly, RA and
PG share a similar pro-inflammatory cytokine expres-
sion profile, and target therapy against cytokines such
as TNF alpha have been shown to be effective in both
RA and PG.74, 75
As with other neutrophilic diseases, the histological
features of PG are not specific and clinical-pathological
or other proprietary information of the Publisher.
correlation as well as negativity of culture are manda-
tory to confirm the diagnosis.66 Histopathologically,
PG shows variable features depending on the type (ul-
cerative, vegetative) and the evolution of the lesion, as
250 Giornale Italiano di Dermatologia e Venereologia April 2018
well as the exact location where the biopsy sample is
obtained. The center of the ulcer is characterized by a
dermal cellular infiltrate, predominantly neutrophilic,
which can evolve into an abscess formation, whereas at
the periphery the infiltrate is perivascular and predomi-
nantly lymphocytic 66 (Figure 3B, C).
Rheumatoid neutrophilic dermatosis
Rheumatoid neutrophilic dermatosis (RND) is a rare
cutaneous manifestation of RA first described by Acker-
man in 1978.76 It has a female predominance (ratio 2:1),
and is usually observed in patients with a severe, long
standing, seropositive RA (although one case associated
with a seronegative RA has been described).76 Clini-
cally, RND presents with symmetrical, fixed urticarial-
like papules, plaques, and nodules and rarely with vesi-
cobullous lesions, typically localized on the extensor
surfaces of the forearms and hands.2, 30, 78, 79 RND can
resolve spontaneously or with the improvement of RA.
Histopathologically, it is characterized by a dense
dermal neutrophilic infiltrate with endothelial swelling
and leukocytoclasia without vasculitis.80, 81 Collection
of neutrophils forming microabscesses in the papillary
dermis have been observed. Spongiosis may be present
and can evolve into intraepidermal vesiculation.
The pathogenetic mechanism remains to be clarified.
An immune complex activation with involvement of
cytokines such as IL-6 and IL-8 has been suggested.82
Interstitial granulomatous dermatitis and
palisaded neutrophilic granulomatous dermatitis
Interstitial granulomatous dermatitis (IGD) was first
reported in 1965 by Dickman et al. as “linear subcu-
taneous bands in rheumatoid arthritis.”83 Subsequently,
it has been described with several names including
“interstitial granulomatous dermatitis with cutaneous
cords and arthritis,” “rope sign,” “linear granuloma an-
nulare,” “linear rheumatoid nodule,” “interstitial granu-
lomatous dermatitis with plaques,” and “railway track
dermatitis.” 2, 30, 83-85 IGD is associated mainly with RA,
and rarely with other autoimmune disorders including
systemic lupus erythematosus. It predominantly affects
middle-aged women, although a pediatric case of a one-
week-old child with a neonatal lupus erythematosus has
been reported.86-88 Clinically, lesions involve symmetri-
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
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SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS LORA
A C
cally the axillae, the lateral part of the trunk, and inner
portions of the thighs.86-88 The distinctive sign of IGD
was initially described as skin-colored linear indura-
tions (“rope sign”) (Figure 4A) on the lateral part of the
trunk,83 but Tomasini et al. subsequently demonstrated
that the predominant clinical features of IGD are repre-
sented by erythemaotus to skin- coloured plaques and/
or papules rather than cords.83, 86 Histologically, IGD is
characterized by the presence of CD-68 positive epithe-
lioid histiocytes arranged interstitially in the reticular
dermis and frequently surrounding foci of degenerated
collagen (Figure 4B).84, 86, 87 Histiocytes can be arranged
in the dermis to form particular histological images,
suggestive but not specific for IGD, such as the “pseu-
dorosette” and the “floating sign” (Figure  4C).86, 87 A
reactive perivascular and interstitial lymphocytic infil-
trate with few neutrophils and/or eosinophils may be
observed, whereas vasculitis is absent.86, 87
Another RA-associated granulomatous dermatitis
is the palisaded neutrophilic granulomatous dermati-
tis (PNGD).89, 90 A debate is still ongoing as to wheth-
er IGD and PNGD represent two separate entities, or
two variants of the same disease.87-90 IGD and PNGD
or other proprietary information of the Publisher.
share some clinical and histological features, and both
are associated with RA and systemic lupus erythema-
tosus.87-91 Many authors report the coexistence in the
same patient of both types of lesions, supporting the
Vol. 153 - No. 2 Giornale Italiano di Dermatologia e Venereologia 251
Figure 4.—Interstitial granulomatous der-
matitis: A)  linear bands on the right axilla;
B)  inflammatory infiltrate interstitially dis-
tributed in the superficial and mid-dermis,
with formation of granulomatous rosettes
and discrete perivascular lymphocytic infil-
trate. (H&E stain, magnification ×200); C) a
detail of pseudorosette.
concept that IGD and PNGD are part of a unique clini-
cal-pathological spectrum.87-91 In these patients early le-
sions show leukocytoclastic vasculitis with dense neu-
trophilic infiltrates and focal degeneration of collagen,
fully developed lesions present with palisading granu-
lomas surrounding leukocytoclastic debris, fibrin and
altered collagen, and late lesions demonstrate palisaded
granulomas with dermal fibrosis and scant neutrophilic
debris.89, 90
On the other hand, other authors favor a distinction
between these dermatoses, highlighting differences in
clinical and histopathological presentation.87 Unlike
IGD, PNGD tends to present clinically with erythema-
tous papules, nodules or plaques with central ulceration
and crusting, most often located at the limbs.87 In addi-
tion, histology of PNGD shows an inflammatory infil-
trate richer in neutrophils and nuclear dust within the
areas of collagen degeneration, with foci of leukocy-
toclastic vasculitis, absent in IGD.87, 89 Finally, PNGD
seems to show a dynamic histological picture whereas
IGD is characterized by a more constant presentation.
The pathogenesis of these two reactive granuloma-
tous dermatoses may be related to immune-mediated
hypersensitivity processes. An immunocomplex-me-
diated or macrophagic delayed-type hypersensitivity
mechanisms have been hypothesized.87-91 An accurate
clinical-pathological correlation is necessary to get the
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means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
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LORA SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS
correct diagnosis. On histology, the main differential
diagnoses include interstitial granuloma annulare, pali-
saded neutrophilic granulomatous dermatitis (PNGD),
histiocytoid Sweet syndrome, Churg-Strauss granulo-
matosis, and granulomatous reactions to drugs including
interstitial granulomatous drug reaction (IGDR).28, 87
The prognosis of IGD/PNGD is favorable with reso-
lution in most cases, either spontaneously or following
treatment of the underlying disease.87, 88, 92
Drug-induced dermatoses
The therapy of RA has rapidly evolved over the last
two decades and is still evolving with numerous new
available drugs.1 The major therapeutic target is to sub-
side inflammation, which drives and influences clinical
symptoms, joint damage and comorbidities. Thus, sev-
eral conventional synthetic, biological or targeted syn-
thetic disease modifying antirheumatic drugs (DMARD)
may be used. Among these, anti-TNF drugs have revolu-
tionized the therapeutic approach and are widely used in
active RA that does not respond to conventional drugs.
While adverse reactions from conventional drugs such
as MTX, cyclosporine or chloroquine are well known,
biological target therapies may be related with unusual
and less known adverse events. Through an accurate re-
view of the literature, Moustou et al. included in the ad-
verse reactions to anti TNF drugs infusion and injection
site reactions, psoriasiform eruptions, lupus-like disor-
ders, vasculitis and granulomatous reactions.93
Psoriasis in all its clinical variants (i.e. plaque-type,
guttate, palmoplantar, ungueal and of the scalp) has
been described in the context of anti-TNF treatment.93, 94
Among psoriasiform dermatitis, the most characteristic
pattern is a localized pustular eruption occurring sym-
metrically on the palms and soles, resembling palmoplan-
tar pustulosis, which has been reported in approximately
one third of all reported cases.94 Histopathologically,
reported cases of psoriasis-like lesions developing un-
der anti-TNF treatment have the typical features of the
disease, including epidermal hyperplasia, parakeratosis,
elongation of the rete ridges, dilated capillaries in the
dermis and, in the case of pustular eruptions, an intraepi-
or other proprietary information of the Publisher.
dermal collection of neutrophils. In other cases, psoria-
siform eruptions may show on histology a lichenoid pat-
tern accompanied by focal necrotic keratinocytes and an
infiltration by lymphocytes and histiocytes.95, 96
252 Giornale Italiano di Dermatologia e Venereologia April 2018
Eczematous reactions including dyshidrotic eczema,
contact dermatitis, nummular eczema, atopic dermatitis
(AD) or AD-like reactions have been reported. In addi-
tion, patients receiving anti-TNF therapy often develop
antinuclear antibodies (ANAs), antibodies against dou-
ble-stranded DNA (anti-dsDNA) and against single-
stranded DNA, but rarely manifest clinical symptoms of
drug-induced lupus erythematosus (DILE).97 Similarly
to idiopathic lupus erythematosus, DILE can present as
systemic, subacute and chronic cutaneous lupus erythe-
matosus. It is very similar to the corresponding idio-
pathic form in terms of clinical, histologic and serologic
features although it is usually milder and resolves upon
drug discontinuation.
Several reports of leukocytoclastic vasculitis associ-
ated with anti-TNF-α have been reported.98 Despite the
possible coexistence of vasculitis in patients with RA,
the close temporal association of LCV with the initia-
tion of anti TNF-α therapy, the appearance of vasculitis
lesions at the site of etanercept injections, and the reso-
lution of vasculitis in most of the patient after treatment
discontinuation and re-appearance upon re-treatment
support a direct relation between LCV and anti-TNF
therapy.
Lichenoid eruptions are unusual cutaneous adverse
event of anti-TNF drugs.93 Histopathologically, they
share the common features of a lichenoid reaction, but
may present with three different clinical patterns: 1) li-
chen planus-like (LPLE); 2)  nonspecific maculopapu-
lar; and 3) the above-mentioned psoriasis-like.99 Rarely,
TNF inhibitors may induce lichenoid reactions follow-
ing Blaschko lines of the skin as we published in a fe-
male patient treated with etanercept for RA.100
(Figure 5A, B). Finally, noninfectious cutaneous
granulomatous reactions, including cutaneous sarcoid-
osis-like lesions, interstitial granulomatous dermatitis
and disseminated granuloma annulare associated with
TNF blockers have been described. 93 The mechanisms
by which anti-TNF-α therapy induces cutaneous ad-
verse event remain unclear. However, an interference
with the adaptive immune response by TNF inhibitors
in a genetically susceptible host is hypothesized.93 The
possibility of a drug-induction dermatitis should always
be considered in all patients with RA in order to provide
an accurate patient management that in severe cases re-
quire the drug discontinuation.
not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, log
means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use i
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(either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other
©
COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
SKIN MANIFESTATIONS OF RHEUMATOID ARTHRITIS LORA
 
 
 
 
 
A B
 
Figure 5.—Lichen striatus: A) erythematous, scaly, papular eruption fol-
lowing the lines of Blaschko on the right leg; B) lichenoid lymphocytic
interface dermatitis associated with perieccrine infiltrate (H&E stain;  
magnification ×10).
 
Conclusions
Rheumatoid arthritis is frequently associated with a
number of cutaneous manifestations that can represent  
a warning of disease severity. Rheumatoid nodules are
the most common. Rheumatoid vasculitis, neutrophilic  
dermatoses and DIG/PNGD are further skin manifesta-  
tions. Early recognition of these entities through a clini-
cal and histological evaluation permit to optimize the
management of patients.  
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
Article first published online: January 24, 2018. - Manuscript accepted: January 4, 2018. - Manuscript received: November 29, 2017.
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