Sero-negative and Spondylo-arthropathies



Aetiology

HLA B27 found in 4 - 8% of the normal population and is a marker for a specific haptotype of the Class 1 antigens of the major histocompatability complex of antigens
Up to 20% of HLA B27 patients develop spondylo-arthropathy after exposure to shigella or other environmental agents
HLA B27 is passed on to 50% of the offspring
Randomly selected individuals with HLA B27 may have only a 2 - 10% chance of developing disease whereas the risk for HLA B27 positive relatives of HLA B27 patients with spondylitis is 25 - 50%
The link between HLA B27 and spondylo-arthropathies remains unknown but it may be that;
HLA B27 acts as a receptor site for infective agents
It may be a marker for immune response gene that determines susceptibility to environmental triggers
HLA B27 may induce tolerance to foreign antigens with which it cross reacts
HLA B27 also increased neutrophil motility (? significance)
HLA B27 is associated with;
Ankylosing Spondylitis 95%
Reiters 60 - 70%
Psoriatic Arthropathy 20% (60% if sacroiliitis)
JCA, (Pauciarticular Type II) 20% (50% if sacroiliitis)
Enteropathic Arthritis 5% (50 - 70% if sacroiliitis)

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Definitions

Enthesopathies

Inflammation with cellular infiltration by lymphocytes plasma cells and PMN is associated with erosion and eburnation of sub-ligamentous bone

Syndesmophyte

Ossification within the annulus fibrosus leading to thin vertical radio dense areas. Predominantly in anterior and lateral aspects of the spine

Dagger Sign

Single dense central line on frontal radiographs related to ossification of supra spinous and inter spinous ligaments

Spondylodiscitis

Loss of inter vertebral disk height and extensive new bone formation resembling infection without clinical or laboratory evidence to support the diagnosis

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Ankylosing Spondylitis

Definition

Chronic inflammatory condition of the spine and sacro-iliac joints characterised by osseous proliferation and associated with HLA B27
Bilateral and asymmetric involvement predominate PIP, DIP & MCP joints may be involved. Osteoporosis, erosions and deformity are less marked than in RA
Osseous proliferation may be exuberant

Incidence

Affects 1 per 1,000 people in Western Europe
Prevalence ~ 1% whites
Low incidence in black Americans and Negro's
Classic Ank Spond ® Male : Female 3 or 4:1
May be the incidence is equal but female form less likely to have progressive spinal deformity.
Onset usually aged 15 - 25 years ( less than 40 years)

Aetiology

Genetic predisposition HLA B27 but only a relatively small percentage of people with HLA B27 go on to have Ankylosing Spondylitis
Virtually all patients with Ank Spond have HLA B27.
50% of first degree relatives of spondylitic patients also HLA B27 and of this group 20% ® spondylitis
Trigger ?, similar to Reiters, ulcerative colitis, ? lymphatic drainage to SI and spinal region important.
? Environmental trigger

Pathology

Primary process is enthesopathy, inflammation at fibro-osseous junctions of syndesmotic joints (inter vertebral discs, sacroiliac ligaments, symphysis pubis, manubrium sterni and bony insertions of ligaments and tendons; entheses)
Three stages of the disease
  1. Inflammatory reaction with round cell infiltrate, granulation tissue and bony erosion
  2. Replacement of granulation tissue with fibrous tissue
  3. Ossification of fibrous tissue ® ankylosis
Also see synovitis of diarthrodial joints
Fibroplasia ® cartilaginous metaplasia ® chondro-ossification and bony ankylosis which is typical of Ank Spond (and psoriasis) but rare in RA
SI joints, facet joints ® joint destruction, costo-vertebral joints also frequently involved ® reduced respiratory excursion

Clinical Features

Many remain undiagnosed
Insidious onset ® back-ache and stiffness
May have referred pain similar to sciatica
In woman diagnosis often delayed, progressive disease is less common and there is likely to be more peripheral joint involvement and less spinal involvement
Pain and swelling of other joints and at the point of tendon insertions (enthesopic features)
10% start as an asymmetrical poly arthritis
Morning stiffness with improvement following exercise
20% have a peripheral arthropathy ® up to 35% eventually
Loss of spinal mobility (extension first) with flattening of lumbar lordosis

Wright / Schober

Mark two points one 10cm above and one 5cm below the level of the iliac crests and flex ® should lengthern 5cm

Wall test ® heels, buttock and scapulae all should be able to touch but if decreased extension unable to do this
Chest expansion should be at least 5cm and is often markedly reduced in this disease due to costo-chondral arthrosis (not a reliable sign in the elderly or in those with COAD)
Ocular inflammation occurs in ~ 1/3 of patients (uveitis ~20% and conjunctivitis in 25%)
Aortic valve disease rarely a clinical problem present in ~ 3% and pericarditis and myocarditis may also be a feature
Occasionally pulmonary fibrosis
Associated with weight loss, fatigue, low grade fever
Spinal fractures (? stress #) often ® pseudarthrosis at the disco-vertebral junction. Epidural haematomas seen in ~ 20%
Cervical spine #'s heal well in halo
If neurological involvement 46% chance of being fixed and 29% mortality
Risk of massive epidural haemorrhage may ® ascending paralysis

Investigations

Rh factor is negative
ESR increased during active phase
HLA B27 present in 95% of cases (present in 5 - 10% normals)
95% of whites with Ank Spond have HLA B27 but only 60% of blacks
ALP & CPK increased

X-Rays


Erosions / fuzziness of the SI joints often the earliest feature ® bony ankylosis
Vertebral squaring due to flattening of the normal anterior convexity secondary to inflammation at point of annulus insertion ® ossification across the inter-vertebral discs ® bamboo spine
Peripheral joints erosive arthritis and ankylosis
Protrusio Acetabulae may be a feature
Three types of disco-vertebral lesions
  1. Central intra osseous discal displacement (Schmorls' node)
  2. Enthesopathy, peripheral lesion
  3. Both peripheral and central

Diagnostic Criteria

  1. Low back pain of more than 3/12 duration
  2. Pain & stiffness in the thorax
  3. Limited chest expansion
  4. Limited lumbar motion
  5. Past or present iritis
  6. Radiological sacroiliitis
  7. Radiological syndesmophytes
Need 4 of the five clinical criteria or the radiological criteria plus one other

Differential Diagnosis

Other sero-negative spondylo-arthropathies ® vertebral and SI joint disease (Reiters, psoriatic arthritis, ulcerative colitis & Crohns disease, Whipples disease, Behcets syndrome) all show some familial aggregation and are associated with HLA B27

Forestiers Disease

(Ankylosing Hyperostosis) Common disorder predominantly in older men ® widespread ossification of ligaments and tendon insertions (ALL in the cervical spine and in the lumbar spine ® pronounced but asymmetrical inter vertebral spur formation and bridging) Not an inflammatory disease and spinal pain and stiffness seldom severe. SI joints are not eroded and ESR normal. Associated with obesity and diabetes

Treatment

Anti inflammatory medication
Analgesics
Physiotherapy etc to preserve movement and prevent deformity
Rest and immobilisation contraindicated as ® increased osteoporosis and ankylosis
Significant hip involvement ® THR (often left with limited ROM)
Spinal osteotomy (lumbar or cervical) to "improve outlook on life"

Prognosis

Age of onset is the most important factor in determining prognosis and outcome

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Reiters Disease (Reactive arthropathy)

Definition

Sero negative arthritis that follows urethritis, cervicitis or dysentery
Triad; (described by H. Reiter (1916)
Poly arthritis, urethritis and iritis / conjunctivitis

Incidence

Male : Female ratio 5:1
Probably the commonest type of large joint poly arthritis in young men
Usually males aged 15 - 40 years, rare in women, children & the elderly
Familial aggregation
Arthritis appears 2 - 6 weeks after initiating infection ® acute onset with asymmetric poly or oligo arthritis

Aetiology

Sero negative arthritis that follows urethritis, cervicitis or dysentery
Associated organisms
Lymphogranuloma venereum
Chlamydia trachomatis
Campylobacter
Shigella
Salmonella
Yersinia enterocolitica
Clostridia difficile
Asymmetrical changes are typical
Lack of osteoporosis and exuberant periostitis as in psoriatic arthropathy and Ank Spond
Also used to describe reactive arthritis associated with non-specific urogenital (urethritis, cystitis, prostatitis, cervicitis, balanitis) or bowel infection

Pathology

Organisms found in the joint (intracellular) ® triggers of local rather than systemic immune response

Clinically

Normal progression Urethritis ® Uveitis ® Arthritis
Urethritis not necessarily sexually transmitted and may occur in children

Skeletal


Affects particularly the large joints (knee and ankle)
Severe swelling of entire fingers and toes may be associated (sausage digits)
Involvement of DIP joints of toes think of Reiters or psoriasis
Backache and stiffness secondary to sacroiliitis and spondylitis common
3% of patients with Reiters syndrome will develop Ank Spond

Entheses

Tenosynovitis and plantar fasceitis common (enthesopathy)

Eyes

Unilateral or bilateral non infectious conjunctivitis occurs in ~ 40% and more disabling involvement includes iritis (~ 5%), uveitis, episcleritis and corneal ulceration

Integument


May have buccal ulcers and skin lesions
Balanitis Circinata (small shallow painless ulcers on the glans and urethral meatus)
Keratoderma Blenorrhagica (hyperkeratotic skin lesions, predominantly on the soles of the feet occurs in 10%)
Amyloidosis and pleurisy may develop
80% have symptoms for many years

Investigations

HLA B27 positive in 60 - 70% of cases
ESR may be high during the active phase
Cultures (urine, stool)

X-Rays

Initially normal ® erosive arthropathy eventually
Sacroiliitis in 25% of patients but more asymmetric than in Ank Spond
Vertebral changes similar to Ank Spond
Periosteal changes in ischial tuberosity, greater trochanter or site of insertion of Achilles tendon

Differential Diagnosis

Gouty arthritis
Other enteropathic arthritis
Gonococcal arthritis ® septic arthritis or reactive sterile arthritis

Treatment

General treatment for active bowel or urinary infection (Tetracyclines for urethritis)
Rest, splintage, anti-inflammatories
Local or oral steroids
Resistant cases not responding to NSAIDs may try methotrexate or azathiaprine
Generally today use tetracycline for 6 - 8 weeks to decrease the incidence and severity of recurrent attacks (especially if Chlamydia cultured in the urine)

Prognosis

Minority ® spontaneous remission and no recurrent episodes
Majority ® recurrent episodes of arthritis with the episodes lasting less than 6 months usually
Smaller minority ® continuous unremitting course

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Psoriatic Arthropathy

Incidence

About 7% of patients with psoriasis ® evidence of inflammatory arthritis
? More common in men and tends to run in families
Usually over 30 years of age and skin disease usually precedes joint disease

Aetiology

~ 4% of chronic poly-arthritis pts ® have psoriasis but not all of these have psoriatic arthritis

Pathology

Similar to RA but
Less cellular infiltrate and more fibrosis
Pannus mainly on the surface and not eroding underneath cartilage
More bony proliferation and often ankylosis

Clinically

Characteristically involves distal joints of the hands and feet with 95% of patients having peripheral joint involvement
Usually pauci-articular asymmetric arthritis
25% have poly articular arthritis indistinguishable from RA
Bone and cartilage destruction may be unusually severe (Arthritis Mutilans)
Nail changes evident in 10% of psoriatics but 80% of those with arthritis ( oil droplet
discoloration, subungal hyperkeratosis and onycholysis)
5% have exclusively spinal involvement
10% arthritis preceeds psoriasis
Large joints may be involved
Tendon involvement may ® fixed deformities
40% develop spondylitis and 25% develop sacroiliitis and or Ank Spond
Ocular inflammation (iritis, conjunctivitis, episcleritis and keratoconjunctivitis sicca ) in 30%

Clinical forms

70% Asymmetric oligoarticular disease involving 2-3 joints, involvement of distal joints of hands and feet
15% Systemic poly arthritis similar to RA but Rh factor negative
10% Predominantly distal IP joint involvement
5% Arthritis Mutilans

Investigations

Rheumatoid factor negative
May have increased ESR
Mild normochromic normocytic anaemia
HLA B27 present in 20 - 60% of patients (especially those with overt sacroiliitis)
X-Rays Destruction of DIP and or PIP joints with erosions ® pencil in cup deformities
Fluffy periostitis of long bones
Changes in large joints similar to rheumatoid
SI joint involvement fairly common, bilateral more than unilateral
Spinal involvement similar to Ank Spond

Treatment

Control skin disorder with topical preparations
Splintage to prevent or limit deformity
NSAIDs ® relief of joint symptoms
Intra-articular steroid injections no more than 3/year/joint and not for multiple joints
Gold ® improvement in more than 50% of patients
Immuno-suppressives for resistant cases eg methotrexate in 3 divided doses, 2.5mg increasing to a maximum of 15mg per week
Surgery: arthrodesis of distal joints may improve function
Care at surgery due to staph skin carriage ® infection risk

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Enteropathic Arthropathy

Arthritis usually follows onset of colitis by at least 6 months to several years. Uncommonly onset may coincide
HLA B27 found in 70% of patients with spondylitis

Incidence

Synovitis seen in
11% patients with Ulcerative colitis
21% patients with Crohns

Aetiology

Associated with
Crohns
Ulcerative colitis
Bacillic dysentery
Whipples disease
Behcets disease

Clinically

Usually mono-articular affecting larger joints (knees and ankles) and resolves without residual defect

Treatment

Best treatment is control of the bowel disease
Give NSAIDs in short courses due to side effects
In ulcerative colitis procto-colectomy ® cure joint problems
In Crohns arthritis may appear before the bowel symptoms and surgery often not effective possibly due to the difficulty identifying the extent of the disease at the time of surgery.

Behcets' Syndrome

Definition

Muco-cutaneous ulceration of oral cavity and genitalia
Unknown aetiology

Clinically

Characterised by uveitis, corneal ulceration, erythema nodosum, cutaneous pustules, peripheral arthropathy
Arthritis is usually destructive and usually self limiting
Knees most commonly affected
SI joints sometimes involved

Whipples' Disease

Definition

Rare systemic disease which may affect any organ system

Incidence

Affects predominantly middle aged males

Aetiology

Evidence supports infectious aetiology
Strong association with Ank Spond

Pathology

Infiltration of involved tissue with large glycoprotein laden macrophages with small rod shaped bacilli is diagnostic of the condition

Clinically

Greater than 70% have an associated peripheral arthropathy

Treatment

Responds to antibiotics

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Sarcoidosis

Definition

Granulomatous disorder of unknown aetiology affecting multiple organ systems especially in young adults

Incidence


Male = Female
Blacks more than whites
Usually aged 20 - 40 years

Pathology

Granulomata are non caseating with predominantly epithelioid cells but also lymphocytes, granulocytes and plasma cells.
Granulomas may occur in any organ- May increase in size, decrease in size or remain static.
Lesions resolve by fibrosis
Involvement of bone in the absence of other clinical involvement or X-Ray manifestations is highly unusual
Osteoporosis most common feature with cortical thinning and striations, coarsened trabeculae along with lytic lesions

Clinically: (highly variable)

Leads principally to bilateral hilar adenopathy, pulmonary infiltrates and skin or eye lesions
General: malaise, fever

Skeletal

Acute poly arthritis (symetrical & peripheral) and tenosynovitis
May get osteosclerosis either nodular or generalised especially affecting the axial skeleton (differentiate from Pagets)
Hand most commonly involved site - May be associated with symmetrical small joint erosive poly-arthropathy affecting DIPJs particularly
Chronic poly arthritis may develop with relapsing and remitting caurse eventually ® subchondral collapse and permanent disability

Myopathy

CNS & PNS involvement

Skin

granulomas (erythema nodosum)

Respiratory

Cough and dyspnoea
Asymptomatic hilar lymphadenopathy

GIT

hepato-splenomegaly

Eye

granulomatous uveitis
Symptoms usually resolve in 4-6/52

Investigations

ESR usually increased
Kveim test positive ® granulomatous reaction

Diagnosis

Diagnosis historically by non-caseating epithelioid-cell granulomas

Differential Diagnosis

Skull abnormalities ® EG or neoplasm
Spinal ® infection
Joints ® RA, gout, septic arthritis
Cyst like lesions of MC and phalanges
Gout TB
Fungal disease RA
Metastasis Xanthomatosis
Myeloma Tubero sclerosis
Hyperparathyroidism Fibrous dysplasia
Haemangiomas Enchondromatosis (Olliers')

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Polymyalga Rheumatica

Usually middle aged women ® marked post inactivity stiffness
Pain most often around pelvic and pectoral girdles
Tenderness in muscles rather than joints
ESR almost always increased

Pathology

Form of giant cell arteritis and associated with temporal arteritis, therefore risk of ® blindness

Treatment

Corticosteroids ® rapid and dramatic relief

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SLE

Definition:

Chronic inflammatory condition characterised by the presence of anti-nuclear antibodies.

Incidence

Prevalence 3-400 / 100,000
Occurs mainly in young women
Male : Female ® 1:9 increases to 1:30 in child bearing years
Probable viral trigger in genetically susceptible individual

Aetiology

Genetic or environmental mediators may ® triggers

Pathology

Fibrinoid necrosis of small vessels ® variety of inflammatory lesions in the kidney, spleen, lungs, and other organs
Fibrinoid deposits in synovium ® mild inflammation
Cartilage destruction is seldom severe

Clinically

Malaise, anorexia, weight loss and fever
Non destructive, non deforming arthritis -Joint pain is usual but not a salient feature
May be tenosynovitis rather than arthritis
May ® tendon ruptures
Severe cases may resemble rheumatoid
Aseptic necrosis of the hip and other joints is not uncommon (? related entirely to steroid therapy)
Associated with skin rashes (butterfly rash) and ulceration
Raynauds syndrome
Hepatosplenomegaly
Associated with
Nephritis (50% of patients)
Pericarditis (30% patients)
Myocarditis (25% of patients)
Pleuritis (40-50% of patients)
Normochromic normocytic anaemia (common)
Thrombocytopenia (25% of patients)
Hepatitis, splenomegaly and chorea

Investigations

Anaemia, leucopoenia and increased ESR are common
Anti-nuclear factor always positive
Rh factor also positive in 25%

Treatment

Steroids both topical and systemically administered
NSAIDs for minor clinical manifestations of SLE
Antimalarials also used for mild systemic disease, cutaneous and musculo-skeletal manifestations

Prognosis

Survival 85% at 5 years and 65% at 10 years
Death usually secondary to renal failure

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Scleroderma

Definition


Uncommon generalised disorder of connective tissue affecting primarily the skin, lungs, GIT, heart, kidneys and musculo-skeletal system

Incidence

Female : Male 4:1
Usually 30 - 50 years at onset

Aetiology:

Chromosomal abnormalities have been noted in as many as 90% of patients
? significance

Pathogenesis

Abnormal regulation of connective tissue synthesis
Primary event seems to be endothelial cell damage ® narrowing, decreased distensibility ® obliteration of vessels

Pathology

Target organ oedema ® fibrosis
Hyper-gammaglobulinaemia and ANF are frequent findings

Clinically

Raynauds
Skin ® firm, thickened and leathery
Lower limbs relatively spared
Taut skin over fingers ® limit extension and may ® FFD
Resorption of bone of terminal phalanx may occur
Facial skin contracture ® unable to open mouth fully
CREST syndrome: Subcutaneous calcinosis, Raynauds, oesophageal abnormalities, sclerodactyly and telangiectasia
Greater than 50% ® pain / stiffness of fingers and knees
Systemic poly arthritis similar to rheumatoid may occur
Associated with intestinal malabsorption
Pulmonary fibrosis and pulmonary hypertension may occur
Cardiac involvement ® degree of heart block & arrhythmias
Acute and chronic pericarditis may occur ®cardiac tamponade and accounts for 15% of deaths
Renal failure is the leading cause of death and is usually evident within 3 years of the onset of the disease

Investigations


Increased ESR
Normochromic, normocytic anaemia
ANF evident in 40-90% of patients

Treatment

No specific treatment effective
® use appropriate treatment for the organ systems involved

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Rheumatic Fever

Systemic non supperatve inflammatory disease often recurrent and most likely related to prior infection with a group A b haemolytic strep.
® auto-immune response
Affects joints, the heart, skin, serosa, lungs
Joints are involved most often but the most significant effects are on the heart as the other effects are nearly always benign and transient
4% ® bacterial endocarditis ® prophylactic antibiotics

Peripheral arthropathy is also sometimes seen with

Serum sickness
Haemochromatosis
Hyperthyroidism
Giant cell arteritis
Occult neoplasm
Self limited viral illness
Hypertrophic osteodystrophy
Tietzes' syndrome
Erythema nodosum
Erythema multiformae

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Pigmented Villo-nodular Synovitis

Usually occurs in the knee as a mono-articular proliferative process

Incidence

2 per 1,000,000 population
Knee involved more frequently than other joints and in diffuse rather than localised form
Male : Female ® 1:1 (Male may be slightly more than )

Pathogenesis

Inflammation with haemosiderin laden macrophages
? triggering mechanism
May be a benign neoplastic condition

Pathology

Histological


lesion characterised by fibrous stroma, deposition of haemosiderin, histiocyte infiltration and giant cells occurring in the synovial membrane of tendon sheaths and large joints
Sub-synovial nodular proliferation of larger round polyhedral or spindle cells with prominent cytoplasm and pale nuclei
Phagocytic, histiocytic cells are also present
Lipid laden foam cells and multi-nucleated giant cells are interspersed with haemosiderin laden cells

Gross

Most lesions are a single nodular outgrowth more likely pedunculated than sessile with a firm elastic consistency

Clinically

Two forms: Localised, nodular
Diffuse
Mon-articular arthritis affecting adults in the 3rd to 4th decade
Onset insidious
50% or less recall an episode of trauma
Associated with a joint effusion
No abnormality may be evident or only evidence of effusion

X-Rays


Soft tissue mass
Cysts or bony erosions in ~ 33%
Diffuse bony lesion in ~ 25%
Arthrography may identify the synovial mass
Arteriography ® richly vascular soft tissue masses
MRI ® may give typical picture due to haemosiderin

Treatment

Recurrence more common in the diffuse form
Local excision acceptable for isolated lesions
Radiotherapy, wide excision arthrodesis and grafting have been used for diffuse disease
No treatment has ® universally good results
Radiotherapy best early or when lesions are vascular rather than later when they become fibrosed
Most commonly reported technique is wide synovectomy but ® high incidence of recurrence
Diffuse form associated with significant morbidity but total synovectomy seems the treatment of choice

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