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Definition

Seronegative spondarthritis are a diverse


group of chronic, systemic inflammatory
conditions involving the spine and share
distinctive clinical, radiographic and genetic
features.

They all have a strong association with Human


leukocyte antigen (HLA)-B27.
Inflammatory
Enthesitis
back pain
Classification
Undifferentiated
SpA

Reactive Psoriatic
Arthritis Arthritis
Ankylosing
Spondylitits

Enteropathic Enthesitis-
Arthritis Related JIA
Clinical Features 1
Clinical features

AS common to all
seronegative
spondarthritis
1) Familial aggregation.
2) Seronegative RF.
3) Asymmetrical inflammatory
oligoarthritis (lower>upper limbs) &
PsA episodic.
4) Inflammatory sacroiliitis &
ReA
spondylitis.
5) Inflammatory Enthesitis.
6) Absence of nodules & other extra
articular features of RA.

Enteropathic
Arthritis
Spondarthritis & HLA-B27

Approximate
Disease prevalence
of HLA-B27
Ankylosing spondylitis (AS) 90 %
HLA-B27 is an
Reactive arthritis (ReA) 40-80% HLA Class I
molecule
Juvenile spondyloarthropathy 70% found in 8% of
healthy white
Enteropathic spondyloarthropathy 35-75% Caucasians
Psoriatic arthritis 40-50%

Undifferentiated spondyloarthropathy 70%


ANKYLOSING SPONDYLITIS
Definition
It is a chronic inflammatory disease of the
sacroiliac joints & spine as well as extra-spinal
lesions involving the eye, bowel & heart.

Epidemiology
• Ranges from 1-6% across different populations.
• The peak onset is in the 2nd &3rd decades.
• Male to female ratio is 3:1.
Etiology
Genetic
• Human leukocyte antigen (HLA)-B27 is a strong
genetic risk factor for .
• 90% persons of affected persons in Europe are
HLA B 27+ve.
Environmental
• Infective triggers have not clearly been linked to
cause AS.
• Increased fecal carriage of Klebsiella aerogenes
was found in AS.
Etiology
Immunological:
• TNF alpha, interferon gamma and IL-6, 17 & 23 play a
role in pathogenesis of AS
• Their role is not fully understood yet.
• Abnormal IL-23 and its receptor (IL-23R) was detected
in AS patients.
• Higher serum levels of IL-6 were demonstrated in
patients with active AS.
Role of HLA B27 in Pathogenesis

4 Theories:
• The arthritogenic peptide hypothesis: HLA-B27
binds a unique set of antigenic peptides, bacterial or
self  activate cytotoxic T-cell  arthritis
• Self-association of the HLA-B27 molecule: HLA-B27
binds to itself  homodimers  intracellular stress
 activation of immune system
• Alteration of intracellular handling of microbes due
to HLA-B27: e.g.; Salmonella  cytokines
• Recognition of HLA-B27 as an autoantigen: HLA-B27
presented by APC to T-helper lymphocyte
Role of HLA-B27

• 1-The chance of developing AS if one have


HLA-B27 positive is 1-5% and this increasing
to 15-20% in case of an affect first degree
relative.
• 2- HLA-B27 positive in 90% of AS patients and
it is not diagnostic (since 8% of healthy
individuals are positive of HLA-B27).
• HLA-B27 not mandatary in clinical assessment
but helpful in ASAS criteria.
Clinical Features 1

• Spinal features of AS seldom appear before


age 16-18 years.
• Inflammatory backache 75% (presenting ):
insidious in onset, worsened by rest &
improved by exercise & night pain is frequent.
• Sacroiliitis is the most common initial feature,
causes pain in buttocks, radiates sometimes to
thighs but never below knees.
Clinical Features 2

• Planter fasciitis with heel pain, achilles


tendonitis & tenderness over bony
prominences as iliac crest reflecting
enthesopathy.
• Fatigue is common.
• Peripheral arthritis in 40% of AS patients.
• 10% of AS cases have peripheral arthritis
preceding spinal symptoms.
Clinical Features 3
Synovitis in AS:
Peripheral oligoarthritis, episodic & asymmetrical.
• Lower limbs > upper limbs.

• Temporomandibular joints may be affected.

• Dactylitis may lead to pain at one toe or more toes lasting


many months but usually resolve spontaneously.

• Radiographic sacroiliitis and Enthesitis are considered a


hallmark in AS .
Clinical Features 4
Peripheral
Enthesitis arthritis
(Achilles (Synovitis)
tendinitis)

Dactylitis
Clinical Features 5
Early physical signs include:

1. Restriction of lumbar spine movement:


lateral rotation 1st, then progression to all
directions.
2. Pain on sacroiliac compression.
3. Failure to obliterate the lumbar lordosis on
forward flexion.
Clinical Features 6
Clinical Features 7
Late physical signs include:

1. Increased stiffness throughout the spine.


2. Restriction of chest expansion.
3. Few patients may develop marked kyphosis of
dorsal & cervical spine.
Clinical Features 8
Extra articular manifestations:

1. Acute anterior uveitis 25%.


2. Conjunctivitis 20%.
3. Prostatitis (usually asymptomatic) 80%.
4. AR, MR, pericarditis, conduction defect.
5. Amyloidosis.
6. Apical fibrosis in the lungs.
7. IBD (subclinical 60%, overt 15%).
Examination
Schober’s test
A mark is made at the
level of dimple of
Venus(L5) and a second
mark is made 10 cm
above the first mark
and another one 5 cm
below it.
Normally during full
flexion the distance
between them should
be more than 20 cm
while in AS it is less
than 20 cm.
Sequence of the disease progression
Sequence of the disease progression
ASAS Criteria:
1- Possible diagnosis AS pre-radiographic.
2- Diagnosis of AS is still even when negative MRI for
sacroiliac joint with HAL-B27 positive with two SPA
features .
3- IN ASAS criteria that inflammatory backache no
longer a compulsory .
4- Diagnosis of AS is unlikely in the negative image and
a negative HLA-B27.
5- Sensitivity: 82.9%, Specificity: 84.4%

KELLEY’S Textbook of Rheumatology NINTH EDITION


Differential Diagnosis
1. Prolapsed intervertebral disc.
2. Fibromyalgia.
3. Infection in the spinal or sacroiliac joints e.g.; TB,
Brucellosis.
4. Spinal tumors e.g.; chondroma, ependymoma.
5. Bone tumors e.g.; osteoid, secondary
carcinoma, leukemic infiltration.
6. Metabolic bone disease e.g.; osteomalacia,
hypophosphatemic rickets.
7. Diffuse interstitial spinal hyperostosis (DISH).
Delayed Diagnosis? 1
• Low awareness of AS among non-
rheumatologists [AS is a rare cause of a
common complaint (backache)]
• NY modified criteria  Need for radiographic
sacroilliitis to diagnose definite AS while X-rays
are normal or equivocal in early disease
• Absence of pathognomonic C/F or lab test
• Underestimation of women with AS
• Negative HLA-B27 in ~10% of AS patients
Delayed Diagnosis? 2

Pre-radiographic stage Radiographic stage


(Axial undifferentiated SpA)

Back pain Back Pain


Radiographic
Back Pain
IBP
Syndesmophytes
MRI active sacroiliitis sacroiliitis

Modified NY criteria (1984)

Time (years)
Investigations
1. ESR & CRP are usually raised.
2. S.alkaline phosphatase is raised in 50%
3. RF, ANA, ACPA is –ve.
4. IgA levels are usually elevated.
5. Radiographic signs:
i. Sacroiliitis is the 1st abnormality: starts in lower synovial
parts of the joints.
ii. Anterior squaring of the vertebrae in lateral views of
thoracolumbar spine.
iii. Bridging syndesmophytes.
iv. Ossification at antero-longitudinal ligament with
bamboo spine formation.
v. Osteoporosis & atlanto-axial dislocation can occur.
Imaging 1
Imaging 2
Imaging 3
Imaging 4
Imaging 5
Imaging 6
Shiny corner sign (Romanus lesion)
Inflammatory
vertebral entheses
result in sclerosis of
superior and inferior
margins of the
vertebral bodies.
Dagger sign
Dense line
caused by
ossification of
supraspinous
and interspinous
ligaments in AS.
Management
 The aim is to relieve pain & stiffness while
maintaining skeletal mobility & avoiding
deformity.
 Education & appropriate physical activity are
the corner stones of management.
 Regular daily chest and back extension
exercises
 Swimming, yoga and deep breathing exercises
 Baseline ROM exercises
Management
• NSAIDs (especially indomethacin) for
symptoms especially stiffness but they do not
alter the natural course of the disease.
• Pain management by heat, massage.
• Excessive physical exertion, flexion and heavy
lifting should be avoided.
• Proper positioning at rest.
• Avoid poor bed & chair posture.
• The mattress should be firm at sleep, pillows
should be avoided.
Management
 Sulfasalazine with /without Methotrexate may
be effective for peripheral joints synovitis but
not useful for axial disease.
 Local steroid injection for planter fasciitis &
enthesopathy.
 Oral steroid for anterior uveitis.
 Biologic agents (TNF alpha blockers):
 Etanercept.
 Infliximab.
 Adalimumab.
BEST CLINICAL PRACTICE GUIDELINES FOR THE USE OF
ANTI–TUMOR NECROSIS FACTOR AGENTS IN
ANKYLOSING SPONDYLITIS:
Clinical presentation and extra-articular features
Peripheral
Enthesitis
Axial arthritis
(excluding hip)

Failure of at NSAID failure and failure of


least two methotrexate or sulfasalazine at
NSAIDs either maximally tolerated doses for
due to 3 months.
inefficacy or
toxicity. For 4
weeks Suggested disease activity
Anti TNFᾳ BASDAI Score of ≥4 (0–10).
Primer on the Rheumatic Diseases THIRTEENTH EDITION
Surgical Intervention

1-Total hip replacement ,


• Hip involvement (1/3) of long standing AS
after 10 years ,
• 5% need total replacement.

2- Fusion to prevent instability of the spine .


3- Atlanto-axial& Atlanto-occiputal subluxation
and spinal canal stenosis.
Management
ASAS/EULAR recommendations for the
management of AS
D
Non steroidal anti inflammatory drugs I
(NSAIDs) S
E
Education, A
exercise, A S
Axial Peripheral n E
physical Disease Disease
therapy, a P
S
rehabilitation, l R
u O
patient Sulfasalazine (SSZ) g G
r
associations, e R
g E
self-help Local corticosteroids s
e S
groups i S
r
c I
TNF blockers s
y O
N
Prognosis
Poor prognostic factors includes:

• Hip arthritis associated with 23-fold


increase in the risk of severe arthritis.
• Age of onset before 16 yr.
• High ESR.
• Unresponsive to NSAID.
• Limitation of lumbar spinal movement.
Prognosis
AS patients have decreased life expectancy due
to:
1. Amyloidosis.
2. Malignancy with multiple courses of
radiotherapy.
3. Aortic valve disease.
4. Traumatic spinal fractures.
5. Risk of drugs & surgical procedures.
6. Associated diseases e.g.; IBD.
7. Increased risk of atherosclerosis  IHD.
Note

• In contrast to RA,
pregnancy does not
improve the
symptoms of AS.
• In the majority of
patients disease
activity is not
substantially altered
during pregnancy.
REACTIVE ARTHRITIS
Reactive arthritis
• Reactive arthritis is an acute aseptic arthritis
that develops in response to an extra –
articular infection ,typically originating from
gastrointestinal or genitourinary tract.

• It is a seronegative spondyloathropathy
classically presenting with asymmetrical
oligoarthritis, usually in the lower limbs.
Pathophysiology

• Reactive arthritis is thought to be caused by


an infectious trigger usually a bacterial GI or
GU infection in genetically individuals.

• Bacterial antigenicity , host response


(i.e.Th1/Th2 imbalance), and various genetic
factors (i.e.HLA-B27) play an important role in
the pathogenesis of ReA.
Pathophysiology
• This leads to immune activation and cross-
reactivity with self-antigens causing acute
inflammation in the affected joint and other
tissues approximately 2-6 weeks after the
initial infection.
• GI infection (Salmonella ,Yersinia, Shigella and
Campylobacter ).
• GU infection (Chlamydia).
• Active TB can rarely be complicated by ReA
which is known as Poncet disease
Pathophysiology
• It is thought that there is bacterial(dead or
dormant ) migration from gut to joints and
enthesis within macrophages/dendritic cells
through blood or lymphatics.
• The microbial agent causing the primary
infection cannot be cultured from the
synovial fluid by the standard methods.
• Bacterial antigens and nucleic acids from
chlamydia trachomatis and others can be
detected within joint material.
Pathophysiology
• As well as inflammation of joints,
inflammation of entheses, axial skeleton, skin,
mucous membranes ,GI tract and eyes may
also occur.
• HLA-B27 is positive in most patients and its
not only a strong risk factor of reactive
arthritis , but it may also predict the severity
and chronicity of the disease.
20% of HLA-B27 positive men will develop Reactive
Arthritis if they are exposed to an epidemic of Shigella
dysentery.
Risk factors for reactive arthritis.
GI/GU infection Reactive arthritis occurs after exposure to certain
GI or GU infections.

Gender There is a 9:1 male : female incidence ratio of


Chlamydia –induced reactive arthritis and 1:1 for
post-dysentery reactive arthritis.

HLA-B27 HLA-B27 is positive in approximately 75% of


reactive arthritis patients .

Age Most patients with reactive arthritis are aged 20-


40 .

Ethnicity Reactive arthritis is more common in Caucasians.


ReA, Clinical Features 1

• Reactive Arthritis characteristically involves


the lower limbs with asymmetrical
oligoarthritis, the pattern may be additive.
• Hip disease is uncommon.
• Exclusive upper extremities involvement is
extremely rare.
• Dactylitis pattern in the feet is uncommon.
• Arthritis is sterile synovitis.
ReA, Clinical Features 2

• Enthesitis is a characteristic of Reactive


Arthritis, Achilles‘ tendonitis and plantar
fasciitis are most common sites of
involvement, but pain in the iliac crest and
ischial tuberosities is also detected.
Clinical Features3

• Low back pain and buttock pain reflecting


sacroilliitis occurs in up to 50%, but
progression to AS is an uncommon and late
event & it is strongly associated with HLA-B27.

• Reiter’s syndrome –triad of reactive arthritis ,


conjunctivitis and urethritis .Although rare, it
follows a GU or GI infection .
ReA, Extra- articular Features 1
Extra-articular features can be helpful in
establishing the diagnosis particularly in
circumstances when it is difficult to identify a
triggering infection.

• Keratoderma blenorrhagicum (15%) is


papulosequamous rash most commonly
affecting the palms and soles. The lesions can
be indistinguishable clinically and
histopathologically from pustular psoriasis.
ReA, Extra- articular Features 2
• Nail dystrophy can occur with ReA (Reactive Arthritis),
further high lightening the clinical overlap of some
features with PsA.
• Circinate balanitis occurs in (20-50%) of patients and is
usually painless.
• Buccal erosions occurs in (10%) and are usually
painless red patches.
• Oral ulcers on the hard palate or tongue, typically
painless.
• Dysuria and pyuria present clinical features of
urethritis.
• Acute anterior uveitis occurs in 20% of ReA patients,
and usually unilateral .
• Conjunctivitis usually bilateral.
ReA, Clinical Features 3
ReA, Uncommon Complications

• Aortic Incompetence.
• Conductive Defect.
• Pleuro-pericarditis.
• Peripheral Neuropathy.
• Seizures.
• Amyloidosis.
ReA, Investigations
• ESR and CRP are raised.
• RF and ANA are negative.
• Normochromic normocytic anaemia.
• Sterile and inflammatory synovitis.
• Stool culture.
• Urine culture.
• Urethral culture.
• High vaginal swab.
• Radiological, the most important findings are:
– Fluffy calcaneal spur.
– Asymmetrical and unilateral sacroiliac joint involvement.
ReA, Treatment
• NSAIDS.
• Local and intra-articular steroid injection.
• Topical and systemic steroids for anterior
uveitis.
• Sulfasalazine and Methotrexate are used in
persistent chronic symptoms or recurrent
arthritis and in severe keratoderma
blennorrhagica.
• Antibiotics for infections.
• Anti-TNF-a therapy.
ReA, Prognosis
• The first attack of arthritis is self-limiting with
spontaneous remission within 2-4/12 of onset,
representing (60%) of patients.
• 15% of patients of ReA relapse.
• 15% of patients of ReA continue to a chronic
state.
• 10% of patients develop ankylosing
spondylitis.
• Mortality in ReA results from cardiac
complications and amyloidosis.