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17
Reactive arthritis: can’t see,
can’t pee, can’t climb a tree…
SONIA SZAMOCKI, CLARISSA MARTYN-HEMPHILL, JAMES S.A. GREEN
Reiter’s disease, also known as reactive arthritis, is a
seronegative HLA-B27-associated autoimmune disease,
characterised by oligoarthritis of large joints with additional
ophthalmic and urological manifestations. Many will recall
the aide-mémoire ‘can’t see, can’t pee, can’t climb a tree’
from their medical school days. This article describes the
history and aetiology of Reiter’s disease, along with its
treatment and prognosis, and reminds readers to be vigilant
for its characteristic signs and symptoms.
H
ans Conrad Julius Reiter, born 1881,
was an eminent physician and a
contemporary of Hitler. His work while
Honorary Professor of Social Hygiene
included a book on racial hygiene:
Deutsches gold, gesundes leben – frohes
schaffen (German gold, healthy life – glad
work). He was subsequently convicted of
war crimes. It is unsurprising, therefore,
that there is mounting pressure to strip
Reiter of the honour of carrying the title
of this disease.
Discrediting his politics is easy; discrediting
his scientific rigour and talent is
more difficult. The triad of urethritis,
conjunctivitis and arthritis was described
by several people, including Benjamin
Brodie in 1818. But it was not until 1916,
when Reiter described a case of nongonococcal urethritis, conjunctivitis and
arthritis suffered by a young officer with
bloody diarrhoea, that this distinct arthritis
came to the attention of the scientific
community. He also discovered a nonpathogenic form of Treponema pallidum
(the causative agent of syphilis) enabling
his development of the ‘Reiter Complement
TRENDS IN UROLOGY & MEN’S HEALTH
Figure 1. Anterior uveitis is seen in 12–37%
of patients with reactive arthritis
Fixation Test’ for its detection. He went
on to describe the spirochaete responsible
for Weil’s disease. Furthermore, Reiter
also implemented strict anti-smoking
laws in Germany, which were extremely
progressive for the time. Charming and
loved amongst his students, he was a
corresponding member of the Royal
Society of Medicine in London. He lectured
in rheumatology until his 80s and died
aged 88.
Eponyms are gradually drifting out of
favour in medicine. This, coupled with
Reiter’s past, has led to the disease
being categorised more simply as
‘reactive arthritis’.1
AETIOLOGY AND EPIDEMIOLOGY
Reactive arthritis classically presents with
the triad of asymmetrical joint pain and
swelling, urological and ophthalmic
(Figure 1) manifestations two to four
weeks after infection, with specific
viruses or bacteria. Contrary to traditional
teaching, studies have shown that only one
third of reactive arthritis patients present
with the full triad of symptoms.2
JANUARY/FEBRUARY 2016
Sonia Szamocki, foundation year doctor,
Barts Health NHS Hospital Trust, London;
Clarissa Martyn-Hemphill, core surgical
trainee, Barts Health NHS Hospital Trust,
London; James S.A. Green, Consultant
Urological Surgeon, Barts Health NHS
Hospital Trust, London and Visiting
Professor, London South Bank University www.trendsinmenshealth.com
RHEUMATOLOGY
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Epidemiological data for reactive arthritis
are lacking due to the heterogeneity of
disease manifestation, and prevalence
studies are few in the absence of definitive
diagnostic criteria. The incidence has
been estimated to be in the region of
0.6–27:100 000 in Scandinavia, where most
of the studies on reactive arthritis have
been carried out.3 Similar to the aetiology
of other spondyloarthropathies, 75% of
patients are HLA-B27 positive.4 There is a
preponderance towards the male sex and
those of Caucasian origin, between the
ages of 20–40 years old.
The aetiology of reactive arthritis
is classically divided into enteric and
venereal subgroups to reflect the
causative micro-organisms:
• Commonest enteric agents: Shigella,
Salmonella, Yersinia, Escherichia coli
• Commonest venereal agents: Chlamydia,
Gonorrhoeae
More recently, groups in Finland, India
and France have found that some cases
of reactive arthritis appear to have been
precipitated by urinary tract infections.5,6
We have also found similar cases in our
hospital that support this view.
PATHOGENESIS
‘Reactive’ refers to the temporal
association between infection and the
onset of one or more of the ‘triad’ of
clinical manifestations. Infection is thought
to result in cross-reactivity between
antibodies produced during the infection
and cells that express HLA-B27 in the
joints, eyes and genitourinary tissues. The
exact mechanism remains unclear. Joint
aspirates in patients are often culturenegative, supporting the autoimmune
rather than infective aetiology, although
this may simply reflect a deficit in our
current screening modalities. A recent
report from Malaysia even describes an
unusual case of reactive arthritis following
instillation of Bacillus Calmette-Guérin
(BCG) for bladder cancer.7
With the exact pathogenesis still unclear,
the American College of Rheumatologists
set out a series of sensitivity and specificity
criteria aimed at aiding the diagnosis of
this condition (Table 1).
The diagnosis of reactive arthritis remains
a clinical one. It may be aided by stool,
urine or throat cultures, although negative
results do not rule out the condition. Blood
tests, including C-reactive protein (CRP)
and erythrocyte sedimentation rate (ESR),
can be helpful. Increasingly, HLA-B27
genetic testing is employed as an adjunct.
UROLOGICAL MANIFESTATIONS
Urethritis represents invasion and
inflammation of the normally impermeable
urothelial interface that lines the
genitourinary tract. A breach in this
mucosal surface with endotoxins or
cytokines, in the context of infection
with enteric (eg E. coli) or venereal `
(eg Chlamydia trachomatis or Neisseria
gonorrhoeae) pathogens, commonly
results in symptoms of dysuria, urgency,
frequency, visible haematuria and/or
urethral discharge. A mid-stream urine
analysis (MSU) should be undertaken to
Clinical feature
Sensitivity (%)
Specificity (%)
Asymmetric oligoarthritis
44.3
95
Sausage digit
26.6
99
Heel pain
51.6
92.2
Inflammatory dorsal or lower back
or buttock pain
71.4
77.3
Table 1. Sensitivity and specificity of ‘distinctive’ clinical features in reactive arthritis8
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rule out simple urinary tract infections.
The diagnosis of gonococcal or nongonococcal urethritis (NGU) is made
through microscopic assessment of
first-pass urine or by urethral smear. Gram
stain analysis remains the gold standard
for detection of gonococcal urethritis. The
presence of polymorphonuclear leucocytes
is otherwise pathognomonic for NGU.
Antibiotic treatment is empirical, with
reference to local policy guidelines. Contact
tracing/treatment is recommended.
If untreated, urethritis may progress (in
males) to epididymitis, orchitis, prostatitis
and chronic pelvic pain. Long-term, this
is complicated by the increased risk of
urethral stricture formation, leading
to incomplete bladder emptying and
urinary retention. Serial flow rates, postvoid residuals with urodynamic and/or
cystoscopic investigations will elucidate
worsening mechanical obstruction of the
urethra. Any such outflow obstruction can
predispose further genitourinary infection
and ultimately propagate persistent lower
urinary tract symptoms in varying degrees
of severity.
In females, urethritis is closely associated
with the development of cervicitis,
salpingitis and pelvic inflammatory disease.
Infection with the obligate intracellular
venereal pathogen C. trachomatis may be
asymptomatic. Long-term, this aetiology
and its sequelae have significant potential
implications on fertility if unidentified and
untreated.
OPHTHALMIC MANIFESTATIONS
The ophthalmic manifestations of reactive
arthritis include conjunctivitis, anterior
uveitis, episcleritis, scleritis and keratitis,
similar to other seronegative HLA B27associated arthropathies, including
psoriasis. Less common presentations
include retinal vasculitis, optic neuritis
and glaucoma.
Conjunctivitis is one of the hallmarks of
reactive arthritis and is seen in 33–100%
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JANUARY/FEBRUARY 2016
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of cases, usually early on in the disease,
with spontaneous remission after around
two weeks.4 Symptoms can be mild, with
injected, dry eyes, or severe, with intense
pain, oedema and purulent discharge.
The second most common ocular
manifestation is uveitis (iritis, iridocyclitis),
seen in 12–37% of patients (see Figure 1).
It is characterised by photophobia,
impaired vision, scleral injection and
hypopyon (sterile exudate within the
anterior chamber). Slit-lamp examination
of the posterior segment of the eye is
warranted to ensure that there is no
evidence of posterior uveitis. One of the
complications of uveitis associated with
reactive arthritis is the formation of
posterior synechiae (adhesion of the iris to
the surface of the lens or vitreous body),
which can lead to angle-closure glaucoma
and blindness.
Management of ocular complications
varies depending on the severity of
presentation. Mild conjunctivitis is treated
conservatively, with an emphasis on ocular
hygiene, whilst cycloplegics, such as
atropine, may be administered for comfort
for iritis. Severe ocular complications may
necessitate topical, oral and/or intravenous
steroid treatment. Immunosuppression
is the mainstay of treatment in patients
with recurrent symptoms or flare-ups
of reactive arthritis.9 The use of topical
antibiotics is controversial, but some
studies have found evidence that topical
azithromycin was effective when
applied for a period of two weeks in
Chlamydia-associated conjunctivitis in
reactive arthritis.10
50% of patients and can be confused with
other HLA-B27 arthropathies, such as
ankylosing spondylitis.11 On examination,
the joints are red, swollen and tender.
Joint aspirates are usually non-specific,
showing only a raised white cell count
(>10 000 /µl) with polymononuclear
cells predominating. However, while
they have limited diagnostic value in
confirming reactive arthritis, synovial
fluid cultures must be done to rule out
septic arthritis.
OTHER MANIFESTATIONS
Skin manifestations, although less
common, have also been described in the
literature. Keratoderma blennorrhagicum,
the formation of hyperkeratotic lesions on
the palms and soles of the feet, is typical
(Figure 2).12 These lesions can coalesce
to form pustules, which may be clinically
and histologically indistinguishable from
pustular psoriasis.
Erythematous lesions may form on the
oropharyngeal mucosa in up to 60% of
patients, typically the tongue, leading to
erosions and bleeding. 11
JOINT MANIFESTATIONS
An asymmetrical oligoarthritis of no more
than six large joints is typical for this
disease. The knees and sacroiliac joints
are typically affected, but involvement of
the interphalangeal joints can also occur.
Patients may present with heel pain due to
enthesitis of the Achilles tendon, or plantar
fasciitis. Lower back pain is seen in around
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JANUARY/FEBRUARY 2016
Figure 2. Keratoderma blennorrhagica can
occur in reactive arthritis, and can be difficult
to distinguish from pustular psoriasis
A small proportion of patients with chronic
reactive arthritis will present with cardiac
manifestations, including aortitis and
aortic regurgitation.13
MANAGEMENT
Treatment is symptomatic and not
curative, as two-thirds of patients have
a self-limiting course. Patients should
be advised to rest in the acute phase
and start physiotherapy once this has
subsided. NSAIDs are used for joint pain,
together with short courses of steroids
if required. Disease-modifying agents,
including methotrexate and sulfasalazine,
KEY POINTS
•R
eactive arthritis is likely under-diagnosed and requires an increased
awareness of proposed diagnostic criteria amongst clinicians to minimise
long-term morbidity
• T here remains a persistent emphasis on early identification (and treatment)
of antecedent infections. These should be culture-proven, if possible
• P atients with recurrent manifestations or chronic reactive arthritis pose
more of a challenge for clinicians, and should be under the care of a
rheumatologist
•S
exual history should be included within systems review in all patients under
40 with new onset joint pain in the absence of trauma
•C
linicians are encouraged to signpost high-risk patients towards STI
screening
• T he most common ophthalmic manifestation is conjunctivitis, for which
conservative management is generally sufficient, although some advocate
the concurrent use of topical azithromycin. For more severe manifestations,
such as uveitis and scleritis, there may be a role for immunosuppressants
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have been used under the supervision
of rheumatologists to great effect.14 The
efficacy of antibiotics to target the initial
infection is still controversial; studies
have found no effect with azithromycin10
and some effect with combined antibiotic
therapy.14 The current consensus is that
antibiotic therapy does not alter the course
of the disease.
PROGNOSIS
Whilst the majority of patients can expect
to recover fully from the disease within
three to five months, there are reports of
patients who suffer a chronic course of
potentially destructive arthritis. Only a
limited number of studies have looked at
this. One study by the European League
again Rheumatism followed 152 patients.
They described low disease activity
in all patients, 32 weeks after initial
presentation, as assessed by clinician and
patient global assessments.10 Another
Finnish study found that up to 19% of
patients remained symptomatic for over
one year.3
Declaration of interests: none declared.
www.trendsinmenshealth.com
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