International Journal of Clinical Medicine, 2013, 4, 20-30
Published Online December 2013 (http://www.scirp.org/journal/ijcm)
http://dx.doi.org/10.4236/ijcm.2013.412A2004
Open Access IJCM
Reactive Arthritis: From Clinical Features to Pathogenesis
Ethelina Cargnelutti1,2, María Silvia Di Genaro1,2*
1Division of Immunology, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, San Luis, Argentina;
2Laboratory of Immunopathology, Multidisciplinary Institute of Biological Investigations-San Luis (IMIBIO-SL), National Council
of Scientific and Technical Investigations (CONICET), San Luis, Argentina.
Received October 27th, 2013; revised November 20th, 2013; accepted December 10th, 2013
Copyright © 2013 Ethelina Cargnelutti, María Silvia Di Genaro. This is an open access article distributed under the Creative Com-
mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited. In accordance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the
owner of the intellectual property Ethelina Cargnelutti, María Silvia Di Genaro. All Copyright © 2013 are guarded by law and by
SCIRP as a guardian.
ABSTRACT
Reactive arthritis (ReA) is a sterile synovitis which occurs after a gastrointestinal or urogenital infection. ReA belongs
to Spondyloarthritis (SpA), a group of diseases that share several clinical and radiological features including familiar
clustering, absence of rheumatoid factor and association with HLA-B27. Clinically, ReA is characterized by an asym-
metric arthritis predominantly affecting the lower limbs, often associated with urethritis, conjunctiv itis and other extra-
articular symptoms. The ReA prevalen ce depends on the incidence of causative pathogen s. The ReA diagnosis is based
on clinical features and serological tests to evidence previous infection. Different treatment including antibiotics, dis-
ease modifying antirheumatic drugs (DMARs) and biologic agents has been recommended. Even though knowing that
infections trigger th e jo int inf lammation , th e ReA pathog enesis remains to be poo r ly understoo d. Sev eral ani mal models
and in vitro studies have been used to elucidate the mechanisms involved in ReA development. In this sense, HLA-B27
transgenic rat or mice have been used to explain the role of this molecule in SpA aetiopathogenesis. Moreover, the in-
fectious model of Yersinia-induced ReA in rodents has shed some lights on the relationship between host genetic sus-
ceptibility to infection and abnormal immune response in ReA development. Understanding the immune mediators
triggering ReA will contribute to find a specific treatment for this arthritis. In this review, we focus on clinical features,
epidemiology, treatment, and the different attempts to understand the pathogenesis of ReA.
Keywords: Reactive Arthritis; HLA-B27; Spondyloarthritis; Yersinia-Induced ReA; Therapy
1. Introduction
Reactive arthritis (ReA) is arthritis that arises following a
gastrointestinal or urogenital infection. It is a form of
Spondyloarthritis (SpA), a group of diseases with com-
mon features including inflammatory arthritis (generally
an asymmetrical oligoarthritis), absence of rheumatoid
factor and genetic association with the human leukocyte
antigen (HLA)-B27. In addition to ReA, SpA also in-
cludes ankylosing spondylitis (AS), psoriatic arthritis (PsA),
arthritis related to inflammatory bowel disease (IBD-SpA)
and undifferentiated SpA (U-SpA) [1]. Nevertheless, at
present it exist a discussion whether this classification
represent alternative presentatio ns of one entity with het-
erogeneous phenotype [2]. Currently, according to the
Assessment of Spondylo Arthritis International Society
(ASAS) classification criteria (2009-2011), the SpA is
classified as axial and peripheral arthritis [3].
The term “ReA” was introduced by Avohen et al. in
1969 to describe arthritis induced by Yersinia entero-
colitica [4]. Moreover, the clinical features of this dis-
ease were characterized and the diagnosis of the preced-
ing infection through serological methods was establish ed
[5]. The name ReA involves the immunological origin of
this arthritis in which microorganisms do not en ter in the
joint cavity and antibiotic treatment has no effect on its
development or outcome [6]. Even though none cultiva-
ble microorganism has been isolated from the joints of
patients with ReA, bacterial antigens have been demon-
strated in synovial fluid or tissue using different tech-
niques, indicating deficient clearance of the inducer bac-
teria [7-10]. In addition, Chlam ydi a trachomatis mRNA
has been detected in the joints of patients with post-ve-
*Corresponding author.

Reactive Arthritis: From Clinical Features to Pathogenesis
Open Access IJCM
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nereal ReA, raising the possibility that viable forms of
this microorganism may be present [11,12].
A controversy exists in relation to the clinical find ings
to diagnose ReA [13]. According to the 4th International
Workshop on Reactive Arthritis (Berlin, 1999), the term
ReA must apply to a patient with typical clinical features
of this disease and in those whose preceding infection
was caused by the classic microorganisms involved in
their development. The minimum time interval between
the gastrointestinal/genitourinary infection symptoms and
arthritis should be of 1 - 7 days, maximum 4 weeks. It is
advisable for the investigation of microorganisms induc-
ers of ReA by culturing urine/feces or through serologi-
cal methods [14]. The current diagnosis of ReA is per-
formed considering clinical features, radiologic examina-
tion and laboratory tests. However, for diagnosis of ReA,
there is not a single laboratory test, and the radiological
images do not help much in diagnosing an acute episode.
The investigations performed to ReA diagnosis, and also
to make a differential diagnosis are based on hematologic,
microbiologic, serologic and radiologic findings, and on
synovial fluid studie s ( Table 1).
2. Epidemiology
The incidence and prevalence of ReA depends of geo-
graphic region and the prevalence of causative pathogens.
The ReA incidence is estimated to be 5 - 14/100,000 pa-
tients aged 18 - 60 years [15,16]. Most patients are aged
20 - 40 and it is more common in Caucasians affecting
equally men and women [16]. A population-based study
in Oregon and Minnesota (US) reported a ReA incidence
following documented enteric bacterial infections ranged
from 0.6 to 3.1 cases per 100,000, depending upon the
organism [17]. Two registry-based studies from Spain
reported that 1.2% to 1.4% of all patients with SpA was
diagnosed with ReA [18]. A recent epidemiological
study in Argentina informed that from 402 patients with
SpA aged 38.3 - 58 years, 25 (6.2%) had ReA [19]. In
outbreaks triggered by a single source of infection, 0% -
22% of infected subjects developed subsequent Re A [20].
The HLA-B27 antigen is found in 30% - 70% of pa-
tients with ReA, which is a lower frequency compare to
others SpA, such as AS with 90% of patients positive for
this antigen [21]. Patients with this molecule manifest a
more severe arthritis with a tendency to progress to a
chronic stage and also they have greater chance of de-
veloping extra-articular symptoms [22]. At present, there
are descript more than 100 isoforms of the HLA-B27
molecule (http://www.ebi.ac.uk/ipd/imgt/hla) that differ
in the aminoacidic sequence. Most HLA-B27 molecules
seem to be associated with SpA; however, there would
be a hierarchy of association between the different sub-
types of these molecules. Thus, HLA-B*2704 shows high-
er association with SpA, followed by HLA-B*2705,
HLA-B*2702 and HLA-B*2707, while HLA-B*2706
and HLA-B*2709 are less associated to these diseases
[23]. Furthermore, there is a geographical distribution of
these isoforms, with a prevalence of HLA-B*2704 and
HLA-B*2707 for Asians, and HLA-B*2705 and HLA-
B*2702 for Caucasians [24]. In regional studies in South
America, the most frequent HLA-B27 isoforms are HLA-
B*2705 and HLA-B*2702 [25-27]. In Argentina, it is
estimated a prevalence of 4% of HLA-B27 in the general
population [28]. A study in 11 Rheumatology Centers in
Argentina reported in 405 patients with SpA that 50% of
patients with ReA were positive for HLA-B27 [29].
Table 1. Methods and expected results for ReA diagnosis.
Hematology Erythrocyt e se di mentation rate (ESR): usually elevated.
C-reactive protein level (CRP): usually elevated.
Complete blood c ell count: in the acute phase may show l eukocytosis.
Rheumatoid factor: negative.
Antinuclear antibody: negative.
HLA-B27 testing: not diagnosis, but has prognostic value as positive results may indicate more serious disease.
Microbiology Urine culture: may be positive for Chlamydia at the beginning of the infection.
Stool culture: positive for Salmonella, Shigella or Yersinia whether obtained early.
Synovial fluid studies Cell count: at early time of ReA is high and dominated by polymorphonuclears.
Microscopy under polarized light: negative for urate crystals.
Synovial fluid culture: negative.
Serology Antibodies against Yersinia, Salmonella, Campylobacter, Chlamydia, Neisseria gonorrhoeae, Borrelia burgdorferi, and also
against β-hemolytic streptococci should be determined and followed: positive for Salmonella, Shigella, Yersinia or Chalmydia.
Radiological images Early disease: soft tissue swelling around affected joints that can represent large effusions; tendon swelling as in the calcaneal
region.
Chronic disease: bone and cartilage erosions with adjacent bone proliferation specially in the lower extremities; paravertebral
ossification.

Reactive Arthritis: From Clinical Features to Pathogenesis
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3. Clinical Features
The classic clinical characteristics of ReA involve an
axial joint arthritis, enthesitis and peripheral oligoarthritis
(less than 5 joint affected) usually asymmetrically ac-
companied by extra-articular symptoms [30]. The mus-
culoskeletal symptoms are commonly acute and at be-
ginning associated with systemic features such as malaise,
fever, fatigue and weight loss [31].
Urogenital infection precedes 1 - 6 weeks the muscu-
loskeletal symptoms. Their presentation varies from mild
to severe with prostatitis or cervicitis. Howev er, it can be
asymptomatic in both sex. It is often accompanied by
other signs such as penis discharge in males, pain with
urination, or hematuria [32]. On the other hand, acute
diarrhea appears approximately one month before articu-
lar manifestations in post-dysenteric ReA. Gastrointesti-
nal symptoms are absent or mild in ReA triggered by
Yersinia, unlike in patients with Sa lmonella and Campy-
lobacter infections where symptoms are more severe and
of longer du ration [33] .
Joint inflammation could be axial, involving the lum-
bar spine or sacroiliac joints, alternatively it is peripheral,
commonly affecting the large joints of lower extremities,
being knees, foot joints and ankles the most frequently
involved. However, affectation of upper extremities (el-
bow, shoulder) and polyarticular forms have been re-
ported in which the subtalar, metatarsophalangeal and toe
interphalangeal joints tend to be affected [34,35]. Some
patients suffer from dactylitis which is a diffus e swelling
of entire finger or toe, sometimes referred as “sauce digit”.
This feature is common in ReA, but also in PsA and it is
used to make a diagnosis of axial SpA using the ASAS
criteria [36] or PsA using the ClASsification criteria for
Psoriatic ARthritis (CASPAR) [37].
Enthesitis is an inflammation of the transitional zone
where tendons and ligaments insert into the bone and
sometimes it is the unique manifestation of this arthritis.
Achilles tendonitis and plantar fasciitis are the most com-
mon types of enthesitis in ReA, but another enthesis can
be involved [38].
Extra-articular symptoms are frequently observed in
ReA and include mucocutaneous, ocular and occasion-
ally cardiac manifestations. Mucocutaneous lesions are
very specific of ReA and more frequent in HLA-B27
positive patients. Circinate balanitis is the most common
skin manifestation of this arthritis following by kerato-
derma blennorrhagicum, occurring in almost 50% and
10% of the patients, respectively [39]. A well recognized
complication of Yersinia-infection is erythema nodosum
which is a painful rash predominantly on the extensor
surfaces of the arms and legs [40]. Nails changes (nail
dystrophy, subungual debris, and periungual pustules),
hyperkeratosis and oral lesions also may occur [38].
One-third of patients with ReA suffer of conjunctivitis
once it is established, being more common after a geni-
tourinary infection or enteric infection by Shigella, Sal-
monella and Campylobacter. The conjunctivitis is unilat-
eral or bilateral with a mucopurulent discharge and its
course is often mild and transient [41]. Acute anterior
uveitis (AAU) may be observed in about a 5% patients
with acute ReA and more than 50% patients with AAU
are HLA-B27 positive. Th is manifestation is very painful
and is characterized by sudden-onset, mostly unilateral
[42-44]. Others less frequent ocular symptoms are kerati-
tis [45], corneal ulceration, retrobulbar neutritis, scleritis
and hypema which appear in persistent or chronic ReA
[28]. The persistence of ocular inflammation may result
in complications such as posterior synechiae, glaucoma,
cystoids macular edema and cataract formation [46].
Cardiovascular manifestations in ReA and in other
members of the SpA family have long been recognized
and related to HLA-B27 positivity. Disturbances of the
cardiac conduction system are found early [47,48] and
cases with severe aortic insufficiency are found in late
disease [49].
4. Triggering Microbes
Different bacteria species are associated with ReA de-
velopment [15]. The classical enteric pathogens capable
of triggering this arthritis belong to the genders Salmo-
nella, Yersinia, Shigella and Campylobacter. On the other
hand, C. trachomatis is the most common urogenital
pathogen related to ReA [11,12]. Salmonella, Yersinia,
Shigella and Campylobacter are Gram-negative bacteria
with lipopolysaccharide (LPS) in their outer membrane.
Furthermore, they are facultative or obligate intracellular,
aerobic or microaerophilic bacteria. These characteristics
probably account for their relation with ReA [31]. Epi-
demiological studies support the high association be-
tween infection with these bacteria and ReA develop-
ment. Thus, in a study performed in different Rheuma-
tology clinics in Berlin, Germany, from 52 patients with
ReA a causative pathogen was identified in 29/52 (56%)
[50]. In 17 (52%) of the patients with enteric ReA one of
the enteric bacteria was identified: Salmonella in 11/33
(33%) and Yersinia in 6/33 (18%). C. trachomatis was
the causative pathogen in 12/19 (63%) of the patients
with urogenic ReA [50]. In 74 patients with the clinical
picture of U-SpA, a specific triggering bacterium was
also identified in 35/74 (47%) patients: Yersinia in 14/74
(19%), Salmonella in 9/74 (12%), and C. trachomatis in
12/74 (16%) [50]. Moreover, a 2-year epidemiological
study on ReA and possible ReA in Oslo (Norway) re-
ported an annual minimum incidence of Chlamydia-in-
duced ReA (n = 25) of 4.6/100,000, and of enteric ReA
(n = 27) of 5/100,000 individuals between 18 and 60
years [16]. In addition, a population-based cohort study
(n = 71) in Southern Sweden showed in patients with a

Reactive Arthritis: From Clinical Features to Pathogenesis
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23
new-onset arthritis that 45 % had had a prior infection, 27
(38%) had ReA and Campylobacter-induced ReA domi-
na te d the R eA group [51]. In addition, in a study perform-
ed in our laboratory in patients with musculoskeletal symp-
toms, we found immunoglobulin (Ig) A to Yersinia LPS in
13/124 (6%) sera and in 3/47 synovial fluids (6%). By West-
ern blot, IgA to Yersinia outer proteins (Yops) was found in
14/124 sera (11%) and 2/47 synovial fluids (4%) [52].
Among the less common triggering microorganisms
Clostridium difficile and pathogens strains of Escherichia
coli have been described cause ReA [17,53,54]. Other
microorganisms have been implicated as potential causes
of ReA, these include Chlam yd ia pneumoniae [55,56],
Ureaplasma urealyticum [57], Helicobacter pylori [58]
and multiple intestinal parasites [59-61]. Nevertheless,
most descriptions involving these microorganisms are
isolated cases and even in discussion [38].
5. Pathogenesis
Despite knowing the initial event (gastrointestinal or
urogenital infection), the pathogenesis of ReA is not
completely understood. Environmental and genetic fac-
tors are involved and different aspects should be consid-
ered in the development of ReA including impaired
elimination of causative microbes, persistence of their
antigens in the joints, host immune response and g enetics
factors like the presence of the molecule HLA-B27 (Fig-
ure 1).
The classical bacteria triggering this arthritis are inva-
sive and cause primary infection in the gastrointestinal
(enteric pathogens) or genitourinary mucosa (C. thra-
chomatis), from there they disseminate to other organs
such as lymphoid tissue, spleen and liver [28]. As men-
tioned above, mRNA of C. thrachomatis and DNA from
other enteric pathogens or their products have been de-
Figure 1. Model of ReA pathogenesis. (1) Pathogenic bacteria attach and invade the intestinal epithelium. HLA-B27 in anti-
gen presenting cell (APC) such as macrophages may be responsible for bacterial persistence; (2) In mesenteric lymph node
(MLN), APC could present arthri togenic peptides through HLA-B27 to CD8+ T cells, or HLA-B27 itself could be recognized
through killer immunoglobulin receptor (KIR)3DL2 on CD4+ T cells. Moreover, HLA-B27 misfolding induces an unfolded
protein response (UPR); (3-4) APC with non-active bacteria or with bacterial antigens, and T cells disseminate within pe-
ripheral blood and eventually reach the joint; (5) In the target joint, gut derived APC and T cells induce immune response
with IFN-γ and IL-17 production, recruitment of other cells and induction of mesenchymal cells activation, which enhance
and sustain inflammation.

Reactive Arthritis: From Clinical Features to Pathogenesis
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tected in the synovial fluid or tissue of patients with ReA.
These facts demonstrate that the entire bacteria or their
products traffic from the initial site of infection to the
joint. On the other hand, persistence of Y. enterocolitica
has been informed in peripheral blood up to 4 year after
initial infection in patients with ReA [62], as well in dif-
ferent organs in ReA rat models [63]. Furthermore, per-
sistence of Salmonella enteritidis has been demonstrated
in human epithelial cells after 14 days of in vitro infec-
tion [64]. The impaired elimination of causative microbes
plus the traffic of their antigens to the joint could be re-
sponsible of pathological immune response in the joint
[28]. However, the detailed mechanisms by which those
antigens reach the joint and induce inflammation remain
to be fully elucidated.
An imbalance in the cytokine levels may be responsi-
ble for persistence of causative microbes and also reflect
the pathological immune response in the joint. In this
way, diminished levels of TNF produced by peripheral
blood mononuclear cells (PBMC) of patients with ReA
[65] and elevated amounts of IL-10 have been demon-
strated at the beginning of the disease [66]. However, in
patients at chronic stage of arthritis, elevated amounts of
TNF produced by PBMC and CD3+IFN-γ+ cells from
blood and synovial fluid have been reported [66]. An-
other authors observed in patients with ReA enriched
amounts of CD4+IL-17+ cells within synovial fluid sup-
porting the hypothesis that IL-17 could contribute to
pathogenesis of ReA [67]. In line with these results, we
detected higher IL-17 and IFN-γ levels in regional lymph
nodes of TNFRp55−/− mice with Y. enterocolitica -in-
du ced ReA and significantly increased number of CD4+IL-
17+ cells in these mice compared to their counterpart
wild-type [68]. In addition, in this animal model we ob-
served decreased amounts of IL-10 and Treg cells at ar-
thritis onset (day 14 after infection) in contrast with chro-
nic stage of arthritis [69]. These works and others advo-
cate the idea that in ReA, a specific cellular immune re-
sponse take place in the joint and chronic stimuli allows
to the cells maintain the inflammatory process for long
periods [70].
The first genetic factor described to be related to ReA
and SpA in general, is the molecule HLA-B27. The role
of HLA-B27 in SpA is not completely known and several
hypotheses try to explain it. Since HLA-B27 is a class I
histocompatibility molecule, it h as been postulated that it
presents arthritogenic bacterial peptides to CD8+T cells,
thus stimulating an autoimmune response (molecular
mimicry) [71-73]. However, in HLA-B27/human β2-mi-
croglobulin (hβ2-m) transgenic rats, two different ap-
proaches demonstrated that CD8+T cells are not neces-
sary for development of SpA-like phenotype. Further-
more, the depletion of CD8+T cells through antibodies
[74] or the elimination of CD8α protein expression by
chemical mutation of CD8α gene [75] does not prevent
disease in this SpA rodent model.
It was found that heavy chains of HLA-B27 have a
tendency to misfold forming homodimers and hetero d i me r s
due to aberrant disulfide bound formation by unpaired
Cys residues at position 67 [76]. HLA-B27 misfolding
causes a stress response in the endoplasmic reticulum
and the cell activates multiple signaling pathways that
orchestrate what is known as the unfolded protein re-
sponse (UPR). One consequence of UPR activation is the
polarization of cell to responding to patter recognition
receptors (PRR) agonists (TLR 4, 2 and 3) toward the
production of greater amount of IL-23 over IL-12, which
in turns provide a stimulus for Th17 survival and activa-
tion in individual with permissive IL-23R polymorphism
[77]. Additionally, the non-can onical forms of HLA-B27
antigen expressed on cell surface are plausible to be rec-
ognized by killer immunoglobulin receptors (KIR) such
as KIR3DL2 on CD4+ T cells, and then, trigger inflam-
mation [1,21,78].
Other genetic factors (e.g. IL-23R, IL-1R2, TNFRS1,
TRADD, etc.) has been associated with AS, PsA and
IBD-SpA [79]; therefore, it is possible that these factors
may also have significance in ReA since even individu-
als negative for HLA-B27 also develop ReA following
mucosal infection.
6. Treatment
Since infections trigger ReA, the use of antib iotic therapy
in this arthropathy has been proposed and it is possible
when the trigger bacterium has been isolated. However,
the use of antibiotics is controversial probably because
several studies have been conducted enrolling patients
with ReA caused by heterogeneous pathogens. Moreover,
other studies have often employed antibiotic monother-
apy that may be not effective in the aberrant forms of
bacteria causing ReA. In contrast, a clinical trial in 2010
enrolled only p atients with blood or synovial tissu e posi-
tive for Chlamydia detected by PCR [80]. In this study,
the patients were randomized to receive doxycycline +
rifampin, azithromycin + rifampin or placebo. After six
months, 63% of the patients with combination antibiotic
therapy versus 20% of placebo group had clinical im-
provement as measured by swollen joint count [80].
Therefore, this was the first trial that provide evidence
supporting antibiotic therapy efficacy in Chlamydia-in-
duced ReA.
The current treatment of ReA is based on rest, non-
steroidal anti-inflammatory drugs (NSAIDs) [81]. In case
of NSAID-resistance or active disease for more than 4
weeks, intra-articular injection of corticosteroids is rec-
ommended in patients with mono or oligoarthritis [82,83].
Topical corticosteroids are useful for ReA extra-articular
symptoms such as uveitis, circinate balanitis and kerato-

Reactive Arthritis: From Clinical Features to Pathogenesis
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25
derma blennorrhagicum [84].
In chronic and severe ReA, disease-modifying antir-
heumatic drugs (DMARDs) are recommended and the
most used is sulfasalazine (SSZ) [81] which shows lim-
ited effectiveness in patients with ReA acute episodes
[85]. Another DMARD is methotrexate, which may be
used as an alternativ e to SSZ in patients who are allergic
or intolerant to SSZ or who do not respond to this drug
[84]. The DMARDs treatment is an alternative to anti-
TNF therapy and may delay the swi tch to biol ogic agents.
The TNF antagonists such as infliximab, etanercept
and adalimumab showed impressive short-term improve-
ments in AS [86], however, data on the use of this anti-
TNF therapy in ReA are limited [87-92]. A largest recent
experience with TNF antagonists in ReA supported the
safety and efficacy of these agents in refractory ReA [89].
In this study, 10 patients with ReA previously refractory
to NSAIDs and DMARDs received anti-TNF therapy
within a median of 6 months (range 2 - 12 months) be-
tween the onset of ReA and the initiation of th e treatment.
After a follow-up of 20.6 months, no severe adverse
events, including severe infection, were observed. Anti-
TNF therapy was rapidly effective in 9 patients (90%), as
shown by the rapid effect on a visual analog scale pain
score, tender joint count, swollen joint count, and ex-
tra-articular manifestations. Only mild infections were
documented, none of which were associated with the
triggering infection [89].
Our findings in Yersinia-induced ReA in TNFRp55−/−
mice demonstrated that, in the absence of TNF signaling,
redundant pathways, particularly Th17 and Th1 effec-
tor cells, may act in concert to sustain inflammation in
bacterial induced ReA [68]. Recently, we reported that
TNFRp55 modulates macrophage functions in response
to Yersinia LPS stimulation suggesting an essential r egu la-
tory role of TNF via TNFRp55 signaling [93]. Further-
more, we have reported that this pathway controlled the
induction and function of Treg cells through differential
regulation of cytokine production [69]. Our data support
the concept that TNFRp55 signaling may participate in
the modulation of immune response in ReA, suggesting
caution in the use of TNF blockers in cases of chronic
ReA.
Treatment switch to a second anti-TNF agent can be
an effective strategy in AS. There is a need for more
long-term studies to examine the longitudinal efficacy in
SpA of the newer biological therapies such as golimu-
mab, a fully human antib od y anti-TNF, an d ritux imab, an
antibody that induces B cell d epletion [86]. Ustekinumab,
an anti-p40 antibody blocking both IL-23 and IL-12 has
demonstrated clinical efficacy in PsA [94]. Secukinumab,
an anti-IL-17A antibody, has been used in a randomized
controlled trial with short duration of follow-up for AS
treatment showing good efficacy [86]. A trend towards
improvement was also demonstrated for secukinumab in
PsA [95]. Until now, these newer biological agents have
not been used in patie nts with Re A.
7. ReA Prognosis
ReA usually has a self-limiting course since the most
patients recover fully in 2 to 6 months. However, 15% -
30% of patients may develop chronic disease (>6 months
with clinical symptoms) [15]. The prognosis of enteric
ReA is best known being frequ ent recurrent acute attacks
in patients with ReA triggered by Salmonella, Shigella
and Yersinia [1,15]. In a Finnish study at mean of 11
years after Salmonella-induced ReA, 8/50 (16%) devel-
oped chronic SpA and 5 (12%) of these patients fulfilled
the criteria of AS [96]. In a similar study in 85 patients
with acute Yersinia-induced ReA, half to the patients
showed peripheral joint symptoms and on e-third of them
had radiologic evidence of sacroiliitis [97]. A 20-year
follow up study found that 32/100 of patients with Shig-
ella-induced ReA had AS [98]. Only HLA-B27 positive
patients ReA developed recurrent or chronic symptoms
[96]. Therefore, the prognosis is less favorable in patients
who are HLA-B27 positive [28].
8. Conclusion
A gastrointestinal or urogenital infection may trigger
ReA and genetic factors such as HLA-B27 which are
associated with chronic and more severe arthritis. How-
ever, the pathogenesis of this arthropathy is not com-
pletely known. Therefore, there are no specific treatment
for this disease. Anti-TNF therapy in ReA has been rec-
ommended for refractory ReA suggesting an association
with cytokine response and ReA development. Our ex-
perimental evidence indicates caution in the use of TNF
blockers in bacterial-triggered chronic arthritis. We be-
lieve that further investigation in animal models should
delineate the immunopathogenic mechanisms involved in
ReA and contribute to more specific therapeutic inter-
vention.
9. Sources of Funding
This work was supported by grants from Agencia Na-
cional de Promoción Científica y Tecnológica (PICT
2008-763; PICT 2011-0732), Universidad Nacional de
San Luis (Project 0401), M.S.D.G. is member of the
Scientific Career of National Council of Scientific and
Technical Investigations; E. C. is National Council of
Scientific and Technical Investigations fellow.
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