Review Article

Ankylosing Spondylitis

Nazanin Ebrahimiadib1,2, MD; Sahar Berijani2, MD; Mohammadreza Ghahari2, MD
Fatemeh Golsoorat Pahlaviani2, MD

1Retina Service, Ocular Immunology and Uveitis Foundation, Farabi Eye Hospital, Tehran University of Medical Sciences,
Tehran, Iran

2Retina Service, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran

ORCID:
Nazanin Ebrahimiadib: https://orcid.org/0000-0002-2058-9225

Fatemeh Golsoorat Pahlaviani: https://orcid.org/0000-0002-5792-295X

Abstract

The seronegative spondyloarthropathies are a group of autoimmune inflammatory
diseases lacking rheumatoid factor or antinuclear antibody in their serum. They
include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, spondylitis
associated with Crohn’s disease and ulcerative colitis, and undifferentiated
spondyloarthropathies. Inflammation mostly affects the axial joints, entheses, and
extra-articular structures such as uveal tract, gastrointestinal tract, mucocutaneous
tissue, and heart. Uveitis is the most common extra-articular manifestation.
Spondyloarthropathies, especially AS, have a strong association with the presence
of Human Leukocyte Antigen (HLA)-B27 gene. AS happens earlier in HLA-B27
patients and men are more prone to the disease. Uveitis, typically unilateral non-
granulomatous acute anterior uveitis, occurs in up to 50% of the patients with
AS. HLA-B27 positivity correlates with more frequent flare-ups. Conjunctivitis and
scleritis are rare ocular manifestations of AS. To establish the diagnosis of AS,
at least one clinical and one radiologic parameter are required for definitive
diagnosis. Magnetic resonance imaging (MRI) or bone scan can help early detection
of the axial skeleton inflammation. The course of eye and joint involvement are
not correlated. Short-term treatment with topical corticosteroids and cycloplegic
agents control the uveitis attack. In resistant cases, local or systemic therapy with
corticosteroids are recommended. NSAIDs, disease-modifying anti-rheumatic drugs
(DMARDs), methotrexate, azathioprine, anti-IL-17A monoclonal antibodies, and TNF-
α antagonists are effective treatments for ocular and systemic manifestations of AS.
If not treated adequately, uveitis may become recalcitrant and extend posteriorly.
Functional impairment due to joint destruction can also occur as a result of under-
treatment.

Keywords: Ankylosing Spondylitis; Spondyloarthritis; Uveitis

J Ophthalmic Vis Res 2021; 16 (3): 462–469

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Ankylosing Spondylitis; Ebrahimiadib et al

INTRODUCTION

Origin/History

The seronegative spondyloarthropathies include
the following:

• Ankylosing Spondylitis (AS)
• Reactive arthritis (also referred to as Reiter’s
syndrome)

• Psoriatic arthropathy
• Spondylitis associated with nonspecific
inflammatory bowel diseases (IBD) such as
Crohn’s disease and ulcerative colitis

• Undifferentiated spondyloarthropathies.[1, 2]

In 1970, physicians described the shared
clinical symptoms of the seronegative
spondyloarthropathies as a distinct category
of diseases distinct from rheumatoid arthritis.[3]

When referring to patients with AS (Bechterew
disease, Marie-Strumpell disease), they are
considered “seronegative” because they typically
have a negative rheumatoid factor and antinuclear
antibody. Spondyloarthropathy is an umbrella
term for a group of rheumatologic diseases that
have common clinical features: (1) Inflammation
of joints (primarily axial spine and sacroiliac,
though peripheral joints may also be affected),
(2) Enthesitis, which is defined by inflammation
of where tendons, ligaments, and joint capsules
are attached to the bone, (3) Extra-articular
involvement such as uveitis, gastrointestinal (GI)
disease, mucocutaneous lesions and cardiac
abnormalities, and (4) the presence of Human
Leukocyte Antigen (HLA)-B27 gene.[2]

Ocular involvement, especially in the form
of anterior uveitis, is the most common

Correspondence to:

Fatemeh Golsoorat Pahlaviani, MD. Retina Service,
Farabi Eye Hospital, Tehran University of Medical
Sciences, Tehran, Iran. Unit 9, No. 38, 14th east Alley,
North Allameh Tabatabaee St., Sa’adat abad St., Tehran
1997863811, Iran
E-mail: arezoupahlaviani@gmail.com
Received: 23-05-2020 Accepted: 21-11-2020

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v16i3.9440

extra-articular manifestation of the seronegative
spondyloarthropathies.[4] Among the seronegative
spondyloarthropathies, AS is known to have the
highest association with anterior uveitis.[1] This
section will focus on the ocular manifestations of
AS.

Methodology: We used PubMed and Google
Scholar databases to review the literature. The
keywords used were “Spondyloarthritis” AND
“Ankylosing Spondylitis” AND “Uveitis”. Out of the
212 results obtained from the search, we selected
the articles based on the relevancy to our topic and
validity of the studies.

Epidemiology

AS is the most common form of seronegative
spondyloarthropathies with the prevalence of
0.03–1.8%, which varies according to the frequency
of HLA-B27 in the population.[3] In the Caucasian
population, it ranges between 0.15% and 1.8%.
The incidence has been estimated between 0.49
(Japan) and 10 (Norway) per 100,000.[3] Correlation
between HLA-B27 and acute anterior uveitis is
weakest in African–Americans, intermediate in
Asians, and strongest in Whites.[4] Uveitis affects
up to 50% of patients with AS while it occurs in
approximately 2–5% of patients with inflammatory
bowel disease and in about 7% of patients with
psoriatic arthritis.[5]

Among the seronegative spondyloarthropathies,
AS has the strongest association with HLA-B27.
Up to 90% of patients with AS have the HLA-
B27 haplotype, while this number in the general
population is <10%. Nevertheless, only 1–5% of
all HLA-B27-positive individuals will develop the
disease, indicating that other genes may play a role
in the pathogenesis.[6, 7] The association of HLA-
B27 and AS disease is, however, less dramatic
in non-Caucasians. For example, in a study of a
Moroccan population with AS, the HLA-B27 had a
frequency of 64%.[8]

In terms of clinical presentation, the typical
patient with AS is a young man who presents

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How to cite this article: Ebrahimiadib N, Berijani S, Ghahari MR, Pahlaviani
FG. Ankylosing Spondylitis. J Ophthalmic Vis Res 2021;16:462–469.

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Ankylosing Spondylitis; Ebrahimiadib et al

with insidious onset of low back pain and morning
stiffness. The disease onset is earlier in HLA-B27
patients. It usually occurs in the second decade
of life and rarely occurs after the age of 45. Men
are more prone to the disease and they more
frequently develop anterior uveitis.[1]

Pathophysiology/Etiology

The pathogenesis of AS is unknown. However,
the trigger of the inflammation may be an
immune reaction to an environmental or
bacterial antigen in a person with a predisposed
genetic background.[2] This may prompt the
overexpression of interleukin-12 (IL-12), IL-17,
and tumor necrosis factor alpha (TNF-α).[9, 10]
High levels of TNF-α have been detected in
the aqueous and sera of patients with different
underlying causes of anterior uveitis including
AS.[2]

The genetic component, HLA-B27, has been
identified as the major predisposing factor for the
disease. Like many other HLA class one molecules,
it has a high degree of genetic polymorphism. To
date, up to 105 subtypes, encoded by 132 alleles,
have been identified. The correlation of these
subtypes with susceptibility to AS varies. Dominant
subtypes that are most commonly associated with
the disease are HLA-B*27:05 (Caucasians), HLA-
B*27:02 (Mediterranean populations), and HLA-
B*27:04 (Chinese).[11] HLA-DRB1 alleles have been
also identified as another genetic risk factor for AS.
HLA-DRB1*08 positivity is associated with higher
levels of TNF-α in the aqueous humor of patients
with active uveitis.[11]

Definition and Criteria for Diagnosis

The modified New York Criteria described in
1984 outlines the diagnostic criteria for AS. It is
based on clinical manifestations and evidence
of sacroiliitis on X-ray. At least one clinical
and one radiologic parameter are required
for definitive diagnosis of AS.[1] The clinical
manifestations/parameters include: (1) history
of inflammatory pain and morning stiffness in
the lumbar spine for at least three months that
improves with exercise and is not relieved by
rest, (2) limitation of lumbar spine motion in both
frontal and sagittal planes, and (3) limitation of
chest expansion compared to normal values for

age and gender. The radiographic parameters
include X-ray evidence of grade two to four
sacroiliitis bilaterally or grade three or four
sacroiliitis unilaterally.[12] Sclerosis and obliteration
of the joint space, ligamentous calcification,
squaring of the vertebrae, and in end stage
disease, the characteristic ankylosed “bamboo”
spine can be seen on plain radiography. It is
noteworthy that seropositivity is neither necessary
nor sufficient for establishing the diagnosis of
AS.[13]

Establishing the diagnosis of AS relies on a
thorough history and physical examination besides
radiologic confirmation. The disease should not
be ruled out if the aforementioned criteria are
not met.[2] Radiologic evidence of lumbar spine
involvement may not appear in the first year
of disease onset, so probable diagnosis of AS
in the presence of typical clinical manifestation
must continue to be a consideration. Other risk
factors that may help to establish an earlier
diagnosis are: absence of rheumatoid factor, HLA-
B27 seropositivity, family history, male gender,
disease onset prior to the age of 40 years, and
frequent gastroenteritis.[2, 14]

During the Annual Scientific Meeting of the
American College of Rheumatology in 2009, new
criteria for the diagnosis of AS were discussed
and magnetic resonance imaging (MRI) was
included to aid with the diagnosis of axial skeleton
inflammation.[2] This imaging modality has been
proven to be more sensitive in detecting joint
inflammation many years earlier than conventional
radiography. With earlier diagnosis and treatment,
permanent cartilage damage and bony erosions
causing spinal deformity can be prevented.[15, 16]
Therefore, it is of utmost importance to suspect
AS in patients with a history of inflammatory spinal
pain or recurrent attacks of anterior uveitis. If plain
radiography is negative in situations of high clinical
suspicion, MRI and HLA-B27 testing should be
requested. If MRI is contraindicated, bone scan
can also be helpful in diagnosis of AS if plain films
are normal.[15, 16]

Laboratory findings in patients with AS
may serve as markers of chronic disease but
are not specific or diagnostic. These include
normochromic and normocytic anemia, mild
leukocytosis, increased erythrocyte sedimentation
rate (ESR), increased C-reactive protein (CRP), and
elevations in alkaline phosphatase and IgA.[2]

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Symptoms and Signs

Systemic Inflammation

Systemic inflammation primarily affects the
sacroiliac joint, the spine, and the entheses.
The patient may feel a unilateral or intermittent
pain in the gluteal region or the lumbosacral area
that within a few months becomes persistent
and bilateral. In advanced disease, chronic and
progressive inflammation leads to fusion of the
sacroiliac joint and spine with progressive loss
of spinal movement, loss of lumbar lordosis and
kyphosis, and restricted respiratory excursion.
“Bamboo spine” is a radiologic sign for an
advanced disease. In addition, enthesopathy,
such as Achilles tendonitis, plantar fasciitis,
intercostal muscle tendonitis, and dactylitis can
occur early in the disease and are painful and
recurrent, resulting in structural damage. Other
peripheral joints such as knee, hip, and shoulder
can also be involved, typically as an asymmetric
oligoarthritis that predominantly affects the lower
limbs.[2]

Rare extra-articular manifestations of the
disease include upper lobe pulmonary fibrosis,
cardiac involvements, aortic regurgitation,
chronic prostatitis, cauda equina syndrome,
occult bowel lesions, and amyloid deposition.
These manifestations may present years after
active disease.[2] Patients may also present with
constitutional symptoms including low grade fever,
anorexia, fatigue, and weight loss.[2]

Ocular Manifestations

Acute anterior uveitis is the most common non-
articular manifestation of AS and presents in up to
30% of patients during the course of the disease
and may increase to 50% with longer follow-up.[4]
Uveitis is most often characterized by recurrent,
asymmetric and bilateral iridocyclitis, involving only
one eye at a time and is not related to the severity
and course of joint involvement.[17] It may be the first
manifestation of AS, preceding the other articular
symptoms. Underlying AS is diagnosed in about
24.3% of patients presenting with idiopathic acute
anterior uveitis.[18] As a result, ophthalmologists
play an important role in early diagnosis and
treatment of the disease, which can lead to a
more favorable prognosis.[19] HLA-B27 positivity
correlates with more frequent relapses and worse

prognosis of uveitis. The interval between attacks
is highly variable and can range from one month
to 35 years, although most commonly they occur
between 14 and 25 months.[4]

Common forms of anterior uveitis in AS are
iritis (with inflammatory cells in the anterior
chamber and no involvement of the anterior
vitreous), iridocyclitis (primary inflammation of the
iris and secondary inflammation of the ciliary
body; inflammatory cells present in both the
anterior chamber and anterior vitreous), and
cyclitis (inflammation of mainly the ciliary body).[2]
Patients typically present with sudden ocular pain,
redness, photophobia, and decreased vision.[20]
The main findings on examination are limbal
injection, fine whitish–gray keratic precipitates,
moderate to severe amounts of cells which may
sometimes cause hypopyon and fibrinous exudate
in the anterior chamber.[5] Inflammatory cells in the
anterior chamber of patients with AS are more
static in nature. Thus, hypopyon seen in patients
with AS can be distinguished from hypopyon that
shifts easily in patients with Bechet’s disease.[21]
Although, non-granulomatous anterior uveitis is the
typical manifestation, patients may present with
posterior uveitis (choroiditis or retinochoroiditis),
intermediate uveitis (vitritis, peripheral retinitis, and
pars planitis), or panuveitis.[1, 4]

Initial therapies include topical corticosteroids
and mydriatic drugs to avoid posterior synechia.[2]
If not treated properly, inflammation can extend
to the posterior segment of the eye and vitritis,
papillitis, retinal vasculitis, cystoid macular edema,
epiretinal membrane, and pars plana exudate can
occur.[22]

Conjunctivitis and scleritis are other less
common ocular manifestations of AS. Conjunctivitis
is often bilateral, non-purulent, and self-limited.
Scleritis may occur early or years after the disease
activation.[2]

Disease Monitoring

There is no individual blood marker to measure
disease activity. Monitoring of the disease is
subjective and is based on the clinical assessment.
Functional deterioration can help monitor disease
activity.[23] Ophthalmologists can schedule the
frequency of follow-up visits based on the number
and severity of uveitis episodes per year.

Radiographic imaging such as contrast
enhanced MRI of the sacroiliac joint helps

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Ankylosing Spondylitis; Ebrahimiadib et al

in evaluating joint damage and gives further
information about ongoing inflammation. This
information in addition to measuring serologic
acute phase reactants, such as CRP and ESR,
may be useful in monitoring disease activity and
the potential for further damage to the sacroiliac
joint.[23]

Risk Factors

Acquired

Acquired risk factors that have been proposed
include previous urogenital or GI infections.
Previously implicated bacteria include Chlamydia
trachomatis, gram-negative enterobacteria
including Klebsiella, Salmonella, Yersinia,
Shigella, and Campylobacter jejuni.[2] Patients
with spondyloarthropathy, especially male
gender, have increased colonization of these
bacteria and subsequently higher titers of
related antibodies. Colonization of Klebsiella
in the bowel has been shown to be associated
with higher number of anterior uveitis episodes in
these patients.[14]

Genetic

The most important factor is the presence of HLA-
B27 on the short arm of chromosome six. However,
other genes that are believed to have a role in
this disease are HLA-B60, HLA-B61, HLA-DR8, HLA-
DRB1, and MICA (MHC class I chain-related gene
A).[2, 6, 7, 9, 11]

Treatment

Acute episodes of anterior uveitis associated with
AS respond well to frequent topical corticosteroids
and cycloplegic agents for a short period of time.
Most patients recover full vision within two months
of resolution of a flare.[4] Delayed or insufficient
treatment makes uveitis more recalcitrant to
therapy. Approximately 13–19% of patients are
resistant to topical therapies, and often the
disease in these patients becomes chronic.[2] If
topical therapies alone are not effective, periocular
injection of triamcinolone (40 mg/ml), intraocular
injection of corticosteroids, or a short course of
systemic corticosteroid therapy may be necessary,
particularly in cases complicated by cystoid
macular edema.[1]

Non-steroidal anti-inflammatory drugs (NSAIDs)
or coxibs alleviate symptoms of inflammatory back
pain and may have positive effects on uveitis
attacks and provide the opportunity for steroid-
free remission.[24] Coxibs carry less risk of GI side-
effects than NSAIDs and can be used in patients
who are intolerant to NSAID therapy.[24]

Disease-modifying Anti-Rheumatic Drugs
(DMARDs) are a group of medications that are
effective in inducing remission in AS. Sulfasalazine
works by inhibiting the synthesis of prostaglandins.
It has been used in recurrent acute anterior uveitis
in AS, especially in patients with peripheral
arthritis.[2] It has been shown to reduce the number
and severity of uveitis relapses.[20] Uveitis that
is refractory to sulfasalazine may benefit from
steroid-sparing immunosuppression which can
decrease the number of flares. Methotrexate
(7.5–25 mg), dosed weekly, and azathioprine
(1–2 mg/kg), dosed daily, are two examples of
immunosuppressive therapy that may be used for
the uveitis associated with AS.[25]

Methotrexate is considered an anti-metabolite
and works by competitively inhibiting dihydrofolate
reductase (DHFR), ultimately interfering with DNA
synthesis. The role of methotrexate on the natural
course of uveitis is conflicting in the literature.
Some studies report that it can reduce the
number of uveitis relapses, while others refute
its ability to modify the disease or reduce the
uveitis crisis.[2, 25, 26] Patients taking methotrexate
or azathioprine must be monitored with questions
about side effects and frequent blood tests.[25]

In cases refractory or intolerable to NSAIDs,
sulfasalazine and immunosuppressant drugs or
in severe disease with extension of inflammation
into the posterior segment, anti-TNF-α therapy is
indicated.[27] Some authors even suggest that after
failure of two trials of NSAIDs for more than three
months or intolerable side-effects, therapy with
TNF-α inhibitors should be initiated.[27]

Biologic agents, including TNF-α inhibitors,
have revolutionized the treatment of
spondyloarthropathies as they have been shown to
modify the course of the disease and significantly
reduce the rate of uveitis recurrences.[4] TNF-α
inhibitors consist of four monoclonal antibodies
(adalimumab, certolizumab, golimumab, and
infliximab) and one TNF-receptor fusion protein
(etanercept). By binding to TNF-α, they prevent
it from binding to lymphocyte Fc receptors.

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Therefore, cellular immunity is suppressed.
In addition to their rapid onset of action and
promising results in modifying the inflammatory
course of the disease, this class of medications
has substantially contributed to improved joint
mobility and visual recovery,[28, 29] and can be used
as monotherapy.[2]

All four TNF-α antagonists have been proven
to be equally effective in controlling the spinal
manifestations of AS and uveitis; however,
infliximab and adalimumab have been shown
to be slightly more effective for the treatment of
extra-spinal features of the disease including acute
uveitis. These two agents, especially infliximab,
significantly reduce the number of uveitis flare-
ups.[30] However, their high cost and potential
complications prevent them from being used as
the first-line therapy in uveitis. Etanercept, although
in the same overall class of medications, is not
efficacious in the treatment of ocular inflammation
and has been reported to paradoxically cause
uveitis.[10]

Some potential side-effects of TNF-α
antagonists include infection (particularly
tuberculosis and histoplasmosis), exacerbation
of demyelinating diseases, bilateral anterior optic
neuropathy, and sudden death in patients with
congestive heart failure.[2]

Anti-IL-17 monoclonal antibodies have been
approved for the treatment of AS; however, they
are mostly effective for the joint manifestations
rather than ocular inflammation.[32]

Functional impairment and pain are the two
major areas that should also be addressed in the
treatment of arthritis in AS. Depending on the
joint involved, patients with AS need to undergo
physical therapy to improve function and mobility.
Patient education is critical. Posturing exercises,
local heat, and job modification can help patients
to maintain muscle strength and flexibility even with
progression of ossification and ankyloses.[33]

Similar to other types of uveitis, patients may
develop complications such as glaucoma and
cataract which require surgical management.[34]
Trabeculectomy and Ahmed valve procedure
are the most common surgeries performed for
glaucoma, although valve surgery is usually
preferred due to the propensity of these patients
to scar.[35] Cataract extraction is often complex.
Patients often have small pupils secondary to
posterior synechia requiring lysis and pupil-dilating

devices at the time of surgery. Before proceeding
with cataract surgery, the patient must be free of
inflammation for at least three months and the
surgeon should counsel the patient about the
need for frequent corticosteroid drops and/or oral
corticosteroids as well as topical NSAIDs before
and after surgery.[36] In rare cases of extension of
inflammation to the vitreous cavity or vitreomacular
traction, vitrectomy may be required.[37]

Prognosis

Long-term treatment with anti-inflammatory drugs
is usually required in patients with AS. The goal
of treatment is preserving the high quality of life
with maximum function. Some risk factors for poor
prognosis are as follows: involvement of peripheral
joints, disease onset during youth, endless steroid
therapy, and poor response to NSAIDs.[2]

The prognosis of uveitis in AS is usually good
except for refractory cases with involvement of
the posterior segment. Most patients regain full
vision in two months.[4] Unfortunately, delayed and
ineffective therapy of patients is very common.
HLA-B27 positivity is associated with higher
frequency of uveitis recurrence and therefore with
worse visual prognosis.[4] Early stages of sacroiliitis
can be detected in about 63% of patients with acute
anterior uveitis using sophisticated techniques of
imaging such as bone scan.[30] This may allow a
prompt diagnosis and earlier effective care.

The prognosis of joint involvement is also good;
however, intermittent flare-ups between bouts
of clinical remission can cause complete spinal
ankylosis. Vertebral fusion, which includes the
cervical region, results in severe kyphosis and
limited mobility. This makes patients vulnerable to
fracture even with trivial trauma. Hip and shoulder
involvement require total joint replacement.[2]
These are important signs that the ophthalmologist
should pay attention to in the evaluation of their
patients.

Some patients remain in the “non-radiographic”
phase for years. The major predictor of progression
of disease from non-radiographic to radiographic
stage is the amount of inflammation. Therefore,
in patients with an elevated CRP and evidence of
active inflammation in the sacroiliac joint detected
by MRI, structural damage of the sacroiliac joint is
more likely to occur.[19, 31]

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Ankylosing Spondylitis; Ebrahimiadib et al

Complications

Complications can occur secondary to chronic
and recurrent episodes of uveitis or delayed and
insufficient treatment. Posterior synechia is the
most common anterior segment complication
(13–91%) followed by cataract (7–28%). This
complication can make cataract surgery more
complicated. Glaucoma, diffuse vitritis (the most
common form of posterior segment involvement),
as well as cystoid macular edema (the most
common cause of visual impairment) are often
observed.[18]

Cervical spinal subluxation, aortic regurgitation,
respiratory failure, and amyloidosis are rare
potentially fatal systemic complications of the
disease.[2]

Future Directions

NSAIDs and TNF-α antagonists are two mainstays
of therapy in AS. TNF-α antagonists are the
most effective agent in controlling inflammation,
however, about 20–30% of patients are
unresponsive to this class of drugs. Other new
biologic response modifiers that target IL-23
or IL-17, especially IL-17, are being considered
as an alternative to anti-TNF-α antagonists in
treatment of seronegative spondyloarthropathies.
Secukinumab is an example of anti-IL-17A
monoclonal antibody that has shown promising
results in these patients.[32] New therapies that
may provide functional relief to patients are on the
horizon. Further studies are expected to include
ocular manifestations of the disease, as these
can cause significant morbidity in patients with
ankylosing spondyloarthropathies.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

There are no conflicts of interest.

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