Spondyloarthritides N.Movaffagh MD Rheumatologist

SPA include: ankylosing spondylitis (AS) reactive arthritis psoriatic arthritis and spondylitis enteropathic arthritis and spondylitis juvenile onset spondyloarthritis (SpA) undifferentiated SpA

ANKYLOSING SPONDYLITIS an inflammatory disorder of unknown cause that primarily affects: axial skeleton Peripheral joints extraarticular structures

AS begins in the second or third decade male-to-female prevalence is between 2:1 and 3:1

EPIDEMIOLOGY correlation with the HLA-B27 90% in patients with AS, HLA-B27 is positive AS is present in 1–6% of adults inheriting B27 prevalence is 10–30% among B27+ adult first-degree relatives of AS probands

PATHOLOGY Sacroiliitis is often the earliest manifestation of AS Synovitis represent the earliest change pannus and subchondral granulation tissue Marrow edema, enthesitis, and chondroid differentiation Macrophages, T cells, plasma cells, and osteoclasts are prevalent eroded joint margins fibrocartilage regeneration ossification joint may become totally obliterated Erosion of joint cartilage by pannus bony ankylosis

spine Inflammatory granulation tissue in the paravertebral connective tissue at the junction of annulus fibrosus and vertebral bone outer annular fibers are eroded bone forming the beginning of a syndesmophyte endochondral ossification bridging the adjacent vertebral bodies bamboo spine

spine diffuse osteoporosis erosion of vertebral bodies at the disk margin “squaring” or “barreling” of vertebrae Inflammatory arthritis of the apophyseal (facet) synovitis, inflammation at the bony attachment of the joint capsule

Peripheral synovitis Peripheral synovitis in AS shows marked vascularity Lining layer hyperplasia, lymphoid infiltration, and pannus formation Central cartilaginous erosions caused by proliferation of subchondral granulation tissue

characteristic lesion in AS and other SpAs: Enthesitis characterized by erosive lesions that eventually undergo ossification

PATHOLOGY Subclinical intestinal inflammation in the colon or distal ileum in SpA

PATHOGENESIS immune-mediated little direct evidence for antigen-specific autoimmunity (TNF-α) plays a central role (IL) 23/IL-17 cytokine pathway TGF-β in more advanced lesions enteric bacteria may play a role Misfolding of B27 heavy chain lack of regulation of the Wnt signaling pathway

Mast cell neutrophils γδ T cells CD4+ and CD8+ Tcells macrophages B cells NK cell

PATHOGENESIS peptide antigen presentation to CD8+ T cells may not be the primary disease mechanism association of AS with ERAP1

ERAP_1 a proteolytic enzyme that tailors peptides for presentation by class I molecules.

association of AS with ERAP1 a proteolytic enzyme that tailors peptides for presentation by class I molecules strongly influences the MHC class I peptide repertoire only found in B27+ patients and this suggests that peptide binding to B27 is important. Pairs of ERAP1 alleles found in AS patients show diminished peptidase activity

CLINICAL MANIFESTATIONS late adolescence or early adulthood median age is approximately 23 years in Western countries In 5% of patients, symptoms begin after age 40

The initial symptom: dull pain, insidious in onset, felt deep in the lower lumbar or gluteal region low-back morning stiffness of up to a few hours’ duration that improves with activity and returns following inactivity

the pain has usually become persistent and bilateral Nocturnal exacerbation of pain often forces the patient to rise and move around bony tenderness (presumably reflecting enthesitis or osteitis) may accompany back pain or stiffness

Common sites of bony tenderness include: costosternal junctions spinous processes iliac crests greater trochanters ischial tuberosities tibial tubercles heels

Hip and shoulder arthritis Severe isolated hip arthritis or bony chest pain may be the presenting complaint

Arthritis of peripheral joints (asymmetric) Neck pain and stiffness (late manifestations) constitutional symptoms in older age(Rarely) AS often has a juvenile onset in developing countries Peripheral arthritis and enthesitis usually predominate, with axial symptoms supervening in late adolescence

physical findings loss of spinal mobility Limitation of anterior and lateral flexion Limitation of extension of the lumbar spine and of chest expansion Limitation of motion is thought to possibly reflect muscle spasm secondary to pain and inflammation

Pain in the sacroiliac joints may be elicited either with direct pressure or with stress on the joints. tenderness upon posterior spinous processes

modified Schober test: patient stands erect with heels together marks are made on the spine at the lumbosacral junction(identified by a horizontal line between the posterosuperior iliac spines) and 10 cm above then bends forward maximally distance between the two marks is measured

distance increases by <4 cm positive test distance increases by ≥5 cm in the case of normal mobility distance increases by <4 cm positive test

Chest expasion is measured as the difference between maximal inspiration and maximal forced expiration in the fourth intercostal space in males below the breasts in females with the patient’s hands resting on or just behind the head Normal chest expansion is ≥5 cm

Lateral bending measures the distance the patient’s middle finger travels down the leg with maximal lateral bending. Normal is >10 cm. Limitation or pain with motion of the hips or shoulders Early in the course of mild cases, symptoms may be subtle and nonspecific, and the physical examination may be unrevealing

course of the disease: mild stiffness and normal radiographs totally fused spine and severe bilateral hip arthritis severe peripheral arthritis and extraarticular manifestations Pain tends to be persistent early in the disease intermittent later

Typical severe untreated case: progression of the spondylitis to syndesmophyte formation obliterated lumbar lordosis buttock atrophy accentuated thoracic kyphosis forward stoop of the neck or flexion contractures at the hips,compensated by flexion at the knees

Disease progression: loss of height limitation of chest expansion and spinal flexion and occiput-to-wall distance

Predictive factors of radiographic progression: syndesmophytes high inflammatory makers smoking

worse prognosis: onset of AS in adolescence early hip involvement

In women ,AS : tends to progress less frequently to total spinal ankylosis increased prevalence of isolated cervical ankylosis and peripheral arthritis

In industrialized countries: peripheral arthritis usually as a late manifestation (distal to hips and shoulders)

in developing countries: Prevalence of peripheral arthritis is much higher onset typically early in the disease course

Pregnancy has no consistent effect on AS symptoms improving remaining the same deteriorating in onethird of pregnant patients

most serious complication of the spinal disease: spinal fracture lower cervical spine is most commonly

Pseudoarthrosis: fracture through a diskovertebral junction and adjacent neural arch most common in the thoracolumbar spine

extraarticular manifestation most common extraarticular manifestation : acute anterior uveitis typically unilateral, causing pain, photophobia, and increased lacrimation tend to recur, often in the opposite eye

extraarticular manifestation inflammation in the colon or ileum frank IBD occurs in 5–10% of patients with AS Aortic insufficiency Congestive heart failure Third-degree heart block Subclinical pulmonary lesions cardiac dysfunction

extraarticular manifestation Cauda equina syndrome and upper pulmonary lobe fibrosis are rare late complication Retroperitoneal fibrosis Prostatitis: increased prevalence Amyloidosis is rare

AS shortens life span,(some of study) Causes of mortality: spinal trauma aortic insufficiency respiratory failure amyloid nephropathy upper GI hemorrhage

validated measures of disease activity and functional outcome BASDAI ASDAS BASFI

LABORATORY FINDINGS No laboratory test is diagnostic of AS HLAB27 is present in 80–90% of patients ESR and CRP Mild anemia alkaline phosphatase in severe disease serum IgA levels are common

Rf ,anti- CCP, (ANAs) are absent CD8+ T cells tend to be low serum matrix metalloproteinase 3 levels correlate with disease activity Synovial fluid from peripheral joints in AS is nonspecifically inflammatory

In cases with restriction of chest wall motion: vital capacity and increased functional residual capacity are common airflow is normal

RADIOGRAPHIC FINDINGS sacroiliitis, usually symmetric earliest changes: blurring of the cortical margins of the subchondral bone Erosions Sclerosis pseudowidening”of the joint space fibrous and then bony ankylosis Obliteration of joints

RADIOGRAPHIC FINDINGS lumbar spine: Straightening osteitis of the anterior corners of the vertebral bodies with subsequent erosion reactive sclerosis “squaring” or “barreling” of vertebral body Marginal syndesmophytes

IMAGING dynamic MRI with fat saturation T2-weighed STIR (short tau inversion recovery ) T1-weighted images with contrast

Early sacroiliitis in AS interosseous ligaments edema (thick arrow)

bone mineral density Use of a lateral projection of the L3 vertebral body

DIAGNOSIS ASAS Criteria are applicable to: individuals with ≥3 months of back pain with age of onset <45 years old

criterion for inflammatory back pain of axial SpA chronic(≥3 months) back pain should have four or more of the following characteristic features (1) age of onset <40 years old (2) insidious onset (3) improvement with exercise (4) no improvement with rest (5) pain at night with improvement upon getting up

Other common features of inflammatory back pain include: morning stiffness >30 min alternating buttock pain awakening from back pain during only the second half of the night

ASAS Criteria for Classification of Axial Spondyloarthritis

Modified New York Criteria for ankylosing spondylitis Grading of Radiographs Normal, 0; suspicious, 1 minimal sacroiliitis, 2 moderate sacroiliitis 3 ankylosis,4 Sacroiliitis grade ≥ 2 bilaterally grade 3-4 unilaterall

metabolic, infectious, and malignant causes of back pain must also be differentiated from AS including: infectious spondylitis , spondylodiskitis ,sacroiliitis primary or metastatic tumor Ochronosis DISH

DIFFERENTIAL DIAGNOSES Calcification and ossification of paraspinous ligaments occur in diffuse idiopathic skeletal hyperostosis(DISH) in the middle-aged and elderly usually not Symptomatic Ligamentous calcification on the anterior bodies of the vertebra(appearance of(“flowingwax”) generally accompanied by osteophyte formation Intervertebral disk spaces are preserved sacroiliac and apophyseal joints appear normal

diffuse idiopathic skeletal hyperostosis

ASAS Criteria for Peripheral SPA

TREATMENT exercise program NSAIDs continuous high-dose NSAID therapy slows radiographic progression anti-TNF-α therapy

PSORIATIC ARTHRITIS an inflammatory musculoskeletal disease that has both autoimmune and autoinflammatory features characteristically occurring in individuals with psoriasis

EPIDEMIOLOGY prevalence of PsA among individuals with psoriasis range from 5 to 42% First-degree relatives of PsA patients have an elevated risk for psoriasis, for PsA itself, and for other forms of SpA

PATHOLOGY inflamed synovium in PsA resembles that of RA less hyperplasia and cellularity than in RA synovial vascular pattern is generally greater than in RA prominent enthesitis

CLINICAL FEATURES frequency in men and women is almost equal begin in childhood or late typically begins in the fourth or fifth decade(age of 37 year )

five patterns for PSA: arthritis of the DIP joints5% asymmetric oligoarthritis30% symmetric polyarthritis40% axial involvement (spine and sacroiliac joints)5% arthritis mutilans

Nail changes in the fingers or toes dactylitis and enthesitis(hallmark features) Tenosynovitis Shortening of digits because of underlying osteolysis (characteristic of PsA) fibrous and bony ankylosis of small joints Rapid ankylosis of one or more(PIP) joints early in the course of diseas Back and neck pain and stiffness are also common

DIP joints nail changes are almost always present These joints are also often affected in the other patterns of PsA.

Asymmetric oligoarthritis A knee or another large joint with few small joints in the fingers or toes often with dactylitis

Symmetric polyarthritis indistinguishable from RA Almost any peripheral joint can be involved.

Axial arthropathy indistinguishable from idiopathic AS,but: More neck involvement and less thoracolumbar spinal involvement are characteristic and nail changes are not found in idiopathic AS

Arthritis mutilans shortening of digits (“telescoping”) sometimes coexisting with ankylosis and contractures in other digits.

Six patterns of nail involvement: Pitting Horizontal ridging Onycholysis yellowish discoloration of the nail margins dystrophic hyperkeratosis combinations of these findings

Extraarticular manifestations Conjunctivitis uveitis (often bilateral, chronic, and/or posterior) Aortic valve insufficiency

psoriasis and associated arthropathy with HIV tend to be severe Severe enthesopathy, dactylitis, and rapidly progressive joint destruction axial involvement is very rare prevented by or responds well to antiretroviral therapy

mortality significantly increased Greater incidence of cardiovascular death

LABORATORY AND RADIOGRAPHIC FINDINGS ESR and CRP low titers of RF& ANA anti-CCP antibodies10% Uric acid HLA-B27 is found in 50–70%(with axial disease) ≤20% with only peripheral joint

Characteristics of peripheral PsA include: DIP involvement (the classic “pencil-in-cup” deformity) marginal erosions with adjacent bony proliferation (“whiskering”) small-joint ankylosis osteolysis of phalangeal and metacarpal bone with telescoping of digits periostitis and proliferative new bone at sites of enthesitis

new bone formation

Characteristics of axial PsA include: Asymmetric sacroiliitis less zygapophyseal joint arthritis Nonmarginal, bulky, “comma”-shaped syndesmophytes.fewer and less symmetric fluffy hyperperiostosis on anterior vertebral bodies severe cervical spine involvement (AA subluxation) paravertebral ossification

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CASPAR (Classification Criteria for Psoriatic Arthritis) Criteriaa 1.Evidence of current psoriasis, personal history of psoriasis, or a family history of psoriasis 2. Typical psoriatic nail dystrophy observed on current physical examination 3. A negative test result for rheumatoid factor 4. Either current dactylitis or a history of dactylitis recorded by a rheumatologist 5. Radiographic evidence of juxtaarticular new bone formationg in the hand or foot

psoriasiform lesions should be sought in the scalp, ears, umbilicus, and gluteal folds in addition to more accessible sites finger and toe nails Axial symptoms or signs, dactylitis, enthesitis, ankylosis, the pattern of joint involvement, and characteristic radiographic changes can be helpful clues

differential diagnosis Osteoarthritis (Heberden’s nodes) Gout Multicentric reticulohistiocytosis RA

Radiography can be helpful History of trauma (reflecting the Koebner phenomenon)

TREATMENT anti-TNF-α agents Methotrexate Ustekinumab monoclonal antibody to the shared IL-23/IL-12p40 subunit Sulfasalazine Cyclosporine retinoic acid derivatives psoralens plus ultraviolet A light (PUVA) leflunomide