“Juvenile SpA”

Reactive

Arthritis

Arthritis

associated with

Ulcerative Colitis/

Crohn’s Disease

Psoriatic

Arthritis

Undifferentiated

SpA

Acute

anterior

Uveitis

Ankylosing

Spondylitis

Concept of Spondyloarthritis (SpA)

1 www.asas-group.org

1

2

Amor Classification Criteria for Spondyloarthritis

Amor B et al. Rev Rhum Mal Osteoartic 1990;57:85-89 2

3

ESSG-Classification Criteria

(European Spondylarthropathy Study Group)

Dougados M et al. Arthritis Rheum 1991;34;1218 3

Good response to NSAIDs

Symptoms

Imaging

Lab

Patient‘s history

Inflammatory

back pain

ESR/CRP

Spondyloarthritis:

Characteristic Parameters Used for Diagnosis-I

4 4

Genetics

Predisposing/concomitant diseases

Infection* psoriasis Uveitis

*positive staining for Chlamydia in synovial membrane1

Spondyloarthritis-Characteristic

Parameters Used for Diagnosis II

1. Schumacher HR et al. Arthritis Rheum 1988; 31:937-46

Spondyloarthritis:

Characteristic Parameters Used for Diagnosis-II

HLA-B27

positive

family

history

Crohn‘s

5 5

6

SpA and HLA-B27

Disease Approximate Prevalence of HLA-B27 (%)

AS 90

Reactive arthritis (ReA) 40-80

Juvenile spondyloarthropathy 70

Enteropathic spondyloarthropathy 35-75

Psoriatic arthritis 40-50

Undifferentiated spondyloarthropathy 70

Acute anterior uveitis 50

Aortic incompetence with heart block 80

Khan MA. Ann Intern Med 2002;136(12):896-907

Spondyloarthropathies: group of

disorders characterized by:

Inflammatory axial spine involvement

Asymmetrical peripheral arthritis

Enthesopathy

Inflammatory eye disease

Mucocutaneous features

Rheumatoid factor negative

High frequency of HLA B27 antigen

Familial aggregation

Predominantly Axial

SpA

Ankylosing Spondylitis

Non-radiographic

axial SpA

Predominantly Peripheral

SpA

Reactive arthritis

Psoriatic Arthritis

Arthritis with inflammatory

bowel disease

Undifferentiated SpA

Concept of Spondyloarthritides (SpA)

9 9

Time (years)

Back pain Back pain

Radiographic

sacroiliitis

Back pain

Syndesmophytes

Radiographic stage

Axial Spondyloarthritis

Non-radiographic stage

Sacroiliitis on MRI

Rudwaleit M et al. Arthritis Rheum. 2005;52:1000-8.

Modified New York Criteria 1984

10 10

Ankylosing spondylitis

ASAS Classification Criteria for Axial Spondyloarthritis

(SpA)

Rudwaleit M et al. Ann Rheum Dis 2009;68 777-83

In patients with ≥3 months back pain and age at onset <45 years

#SpA features

• inflammatory back pain

• arthritis

• enthesitis (heel)

• uveitis

• dactylitis

• psoriasis

• Crohn‘s/colitis

• good response to NSAIDs

• family history for SpA

• HLA-B27

• elevated CRP

Sacroiliitis on imaging*

plus

≥1 SpA feature#

HLA-B27

plus

≥2 other SpA features#

OR

*Sacroiliitis on imaging

• active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA

• definite radiographic sacroiliitis according to mod NY criteria

n=649 patients with back pain;

Sensitivity: 82.9%, Specificity: 84.4%

Imaging alone: Sensitivity: 66.2%, specificity: 97.3%

Clinical arm alone: Sensitivity: 56.6%, specificity: 83.3%

11 11

12

ASAS Classification Criteria for Peripheral

Spondyloarthritis (SpA)

Rudwaleit M et al. Rheum Dis 2011;70:25-31 (with permission) 12

Symptoms at presentation determine which

pathway

Apply ASAS Criteria

for Axial SpA1

Apply ASAS Criteria

for Peripheral SpA2

Purely peripheral

symptoms at time of

presentation*

Axial ± peripheral

symptoms at time of

presentation

*Past inflammatory back pain allowed

1Rudwaleit et al. Ann Rheum Dis 2009;68:777-783. 2Rudwaleit et al. Ann Rheum Dis 2011;70:25-31. 13 13

14

ASAS Classification Criteria for Spondyloarthritis

(SpA)

Rudwaleit M et al. Ann Rheum Dis 2011;70:25-31 (with permission 14

Ankylosing Spondylitis

16

Ankylosing Spondylitis (AS)

– AS is a chronic, progressive immune-mediated inflammatory disorder that results in ankylosis of the vertebral column and sacroiliac joints

– The spine and sacroiliac joints are the common affected sites

– Chronic spinal inflammation (spondylitis) can lead to fusion of vertebrae (ankylosis)

1 Taurog JD. et al. Harrison‘s Principles of Internal Medicine, 13 th Ed. 1994: 1664-67.

• Peak onset between 20 and 30 years

• Form of spondyloarthritis (cause inflammation around site of ligament insertion into bone) and association with HLA-B27

• Prevalence as high as 5% in adults with chronic low back pain

• Male to female ratio 2-3:1

• B27 is pozitive in 90-95% of AS.

• B27 pozitive individuals have a 2-5% chance of developing AS

•

Epidemiology

Pathogenesis

• ?development in genetically predisposed individuals, triggered by an environmental factor eg gastro-intestinal infection: Klebsiella pneumoniae

• Reactive arthritis has a similar pathogenesis whereby Chlamydia trachomatis, Yersinia enterocolitica, Shigella flexneri, Campylobactor jejuni, Salmonella typhymurium have been implicated.

Pathogenesis

• There is a high incidence of GI mucosal inflammation (both symptomatic and asymptomatic), this raises the possibility that the gut, with breakdown of the mucosal lining is a triggering event.

• Activated T-cells and macrophages found at sites of inflammation with expression of IL-1β, tnf-α and IF-γ. These inflammatory cytokines cause erosion of cortical bone, new bone formation and loss of bone mass

AS: Characteristic Pathologic Features

Sieper J. Arthritis Res Ther 2009;11:208

Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035

• Chronic inflammation in:

– Axial structures (sacroiliac joint, spine, anterior chest

wall, shoulder and hip)

– Possibly large peripheral joints, mainly at the lower limbs

(oligoarthritis)

– Entheses (enthesitis)

• Bone formation particularly in the axial joints

Inflammation

Disease activity

Structural damage

Syndesmophytes formation

Clinical Features of AS

Skeletal Axial arthritis (eg, sacroiliitis and spondylitis)

Arthritis of ‘girdle joints’ (hips and shoulders)

Peripheral arthritis uncommon

Others: enthesitis, osteoporosis, vertebral,

fractures, spondylodiscitis, pseudoarthrosis

Extraskeletal Acute anterior uveitis

Cardiovascular involvement: aortic regurgitation,

conduction abnormalities

Pulmonary involvement: apical fibrobullous

disease

Cauda equina syndrome

Enteric mucosal lesions

Amyloidosis

Symptoms • Chronic systemic inflammatory disease involving axial

skeleton of younger patients

• Develops in second/third decade

• Typically dull aching pain of insidious onset in lower lumber/ buttock region

• Early morning stiffness and nocturnal pain

• Stiffness improves with exercises and recurs after periods of inactivity

• Some patients present with painful hips, shoulders, asymmetrical arthritis of lower limbs prior to spinal involvement

• Cervical and thoracic pain and stiffness is frequent

23

Inflammatory back pain - characteristics

• insidious onset before age 40

• persistence for at least 3 months

• accentuation of back pain at night

or after prolonged rest

• back pain improves with exercise

Buttock pain

Physical Exam: Reduced range of

motion: Schober test

14.10.2014 29

“ skier position”

• Chest expansion: expansion of less than 2.5cm abnormal (5cm considered normal)

• Sacroiliac joint tenderness

• Hip joint involvement

• Peripheral joint involvement (dactylitis- “sausage toes”)

Physical Examination

Peripheral manifestations

Enthesitis Peripheral arthritis Dactylitis

AS: Signs and Symptoms

50% patients with

enthesitis1

1Cruyssen BV et al. Ann Rheum Dis 2007;66:1072-1077 2Sidiropoulos PI et al. Rheumatology 2008;47:355-361

Up to 58% patients

ever had arthritis1

Mch smaller number

of patients

Why are Dactylitis and Enthesitis Important?

The first abnormality to appear in swollen joints associated with

spondyloarthropathies is an enthesitis2

Likelihood of erosions is higher for digits with dactylitis than

those without1

1Brockbank. Ann Rheum Dis 2005;62:188-90; 2McGonagle et al. The Lancet 1998;352.

Enthesopathy

Erosion

New bone

Heel tendonitis in AS

AS: Extra-skeletal Signs and Symptoms

Other common symptoms seen during the early stages of disease

include:

• Anorexia

• Malaise

• Low grade fever

• Weight loss

• Fatigue

1Missaoui B. et al. Ann Readapt Med Phys 2006;49:305-8, 389-391

Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s

Textbook of Rheumatology: Spondyloarthropathies. 8th ed. Saunders Elsevier;2009:p.1176

Fatigue is a frequent complaint

of patients with AS1

AS: Extra-articular Manifestations

Extra-articular manifestations Prevalence in AS

Patients (%)

Anterior uveitis 30-50

IBD 5-10

Subclinical inflammation of the gut 25-49

Cardiac abnormalities

Conduction disturbances

Aortic insufficiency

1-33

1-10

Psoriasis 10-20

Renal abnormalities 10-35

Lung abnormalities

Airways disease

Interstitial abnormalities

Emphysema

40-88

82

47-65

9-35

Bone abnormalities

Osteoporosis

Osteopenia

11-18

39-59

Elewaut D & Matucci MC. Rheumatology 2009;48:1029-1035

Terminal ileitis

Anterior uveitis

Cardiac

abnormalities

Recurrent Iritis caused Synechiae (adhesions

between the lens and iris)

Acute anterior uveitis: occurs in 25-40% of patients

- Presents as acute unilateral pain, photophobia, and blurring of vision

• ESR and CRP typically elevated

• HLA-B27: present in 8% of population, prevalence in HLA-B27 positive population is only 5%

• Normocytic, normochromic anemia

Laboratory Tests

X Ray:

• Widening, erosions, sclerosis, or ankylosis of sacroiliac joint

• Early signs: squaring of vertebral bodies due to anterior and posterior spondylitis

• Late stages: proliferative changes, anterior atlantoaxial subluxation

MRI: more sensitive- can use in patients who do not have sacroiliitis on plain radiographs (can see “bone marrow edema”)

Imaging

Sacroiliitis: Scoring System • Grade 0 : Normal

• Grade 1: Suspicious changes

• Grade 2: Minimal Change. Localized erosions or sclerosis not altering joint width

• Grade 3: Definite moderate to severe change, with one or more of the following:

• Erosions; Sclerosis; Joint Space Widening; Joint Space Narrowing; Partial ankylosis

• Grade 4: Severe. Total Ankylosis

SpA Characteristic XRAY

change

Erosions

Osteitis (Sclerosis)

Bridging Syndesmophytes

Ankylosis of joints

Symmetrical Sacroiliitis Ankylosing Spondylitis

(abnormal) (abnormal)

42

Sacroiliitis Grade 3 Bilaterally

42

Sacroiliitis grade II

bilat.

Sclerosis Erosions

45

Definition of Positive MRI-SI Joint

ASAS handbook, Ann Rheum Dis 2009;68 (Suppl II) (with permission) 45

How to Define Active Inflammatory Lesions (‘positive MRI‘)

of the Sacroiliac Joint

• The presence of definite subchondral bone marrow edema/osteitis

highly suggestive of sacroiliitis is mandatory.

• The presence of synovitis, capsulitis, or enthesitis only without

subchondral bone marrow edema/ osteitis is compatible with but

not sufficient for making a diagnosis of active sacroiliitis.

Rudwaleit M et al, Ann Rheum Dis 2009;68:1520-27

• STIR images are usually sufficient to detect active (acute) inflammatory

lesions; exception: synovitis (not detectable with STIR only).

• Amount of signal required

– If there is 1 signal (lesion) only, this should be present on at least 2

slices. If there is more than 1 signal on a single slice, 1 slice may be

enough.

46 46

Syndesmophytes, apophyseal joint fusion, disc

peripheral ossification (AS)

Ankylosing Spondylitis

“Bamboo Spine”

Repeated process of healing and bone

formation leads to formation of

syndesmophytes

‘bone bridges’

ACR Slide Collection on the Rheumatic Diseases; 3rd edition. 1994.

Ankylosing Spond. Left: squaring of vertebra, Rt:

ant. longitudinal lig.calcification

Ankylosing Spondylitis: Bamboo spine ,ossification

follow the contour of intervertebral discs

Bamboo spine:

1. Syndesmophyte

2. “rail”=the ossification of

the posterior apophyseal joints

3.” wire”= ossification of the

ligaments

14.10.2014 52

Ankylosing Spondylitis: calcaneal spur and erosion

Plantar periostitis seen in AS

Unilateral sacroiliitis

AS: A Debilitating Rheumatic Disease

Over time, joints in the spine can fuse together and cause a fixed, bent-forward posture

1Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s

Textbook of Rheumatology: Spondyloarthropathies. 8th ed. Saunders Elsevier;2009:p.1171 2 Braun J & Sieper. J Rheumatology 2008;47:1738-40

AS patients have an important

impact on health care and non

health-care resource utilization,

resulting in a mean total cost

(direct and productivity) of about

$6700 to $9500/year/patient1

More than 30% of patients

carry a heavy burden of

disease and have a decreased

QoL2

57

Modified New York Criteria for Ankylosing Spondylitis

(1984)

van der Linden et al. Arthritis Rheum. 1984 Apr;27(4):361-8. 57

Reiter's syndrome

Rheumatoid arthritis

Gonococcal arthritis

Psoriatic arthritis

Age Young Middle Young Middle

Gender Male>female Female>male Female>male No effect

Onset Abrupt Insidious Abrupt Insidious

Joint numbr Oligoarthritis Polyarthritis Monoarthritis or oligoarthritis

Oligoarthritis

Symmetry of arthritis

No Yes No No

Sausage digits

Yes No No Yes

Back pain Yes No No Yes

Urethritis Yes No Yes No

Skin lesions Palms and soles in 10 percent

Subcutaneous nodules

Pustular, nodular or vesicular

Psoriasis

Gonococcus No No Yes No

59

• Symptomatic relief

• Restore function

• Prevent joint damage

• Prevent spinal fusion (prevent progressive bony erosions and ankylosis of the spine)

• Minimize extraspinal and extraarticular manifestations

• Prevent complications of spinal disease

Goals of Therapy

• Global pain

• Axial pain

• Degree and duration of morning stiffness

• Activities that are limited

• ESR or CRP are useful as laboratory parameters of active disease

Assessment of disease activity

• Hip arthritis

• Dactylitis

• Poor efficacy of NSAIDs

• High ESR

• Limitation in ROM of lumbar spine

• Oligoarthritis

• Onset less than 16 years of age

Prognostic Indicators

Treatment

Treat symptoms with NSAIDs

Physical therapy,stretching and exercises to preserve spine and joints function

Maintain good posture

Sulfasalazine,Methotrexate used ,found beneficial (in peripheral disease)

Anti TNF drugs emerging role

Prevent eye complications by early recognition and treatment

14.10.2014 65

Management recommendations

66 66

ASAS-Recommendations for the treatment of AS Patients

with TNF-Blockers

Diagnosis: fulfillment of the mod. New York criteria for

AS or the ASAS criteria for axial SpA

Failure of standard treatment:

• at least 2 NSAIDs over 4 weeks (in total)

• one local steroid injection if appropriate

• normally a therapeutic trial of a DMARD,

preferably sulfasalazine (not mandatory)

High disease activity: BASDAI ≥4

Predominant

peripheral

manifestations

Positive expert opinion based on parameters such as:

• Positive CRP/ESR

• Positive MRI

• Radiological Progression

• Clinical examination

plus

Predominant axial manifestations

van der Heijde et al. Ann Rheum Dis 2011:905-8.

68

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

• The BASDAI is measured using the following VAS (0 to 10 cm) of subject self-assessments:

Garrett S, et al. J Rheumatol. 1994;21:2286–2291.

• Fatigue

• Spinal pain

• Joint pain

• Enthesitis

• Inflammation

– Duration morning stiffness

– Severity morning stiffness

69

70

TNFα PATHOGENIC IMPLICATIONS IN AS

Toussirot and Wendling, 1994. Gratacos, 1994.Cannete et al. 1997. Grom et al.1996.Braun et al. 1995

Biopsy o the sacroiliac joint

• Higher level of TNF-α in the serum

• Overasserting of TNF-α in the synovial tissue of the SIJ

71

INFLIXIMAB (REMICADE)

– Chimeric monoclonal antibody

– Made of the constant region of the G1 human Ig to which the variable region of a murine Ig with high specificity for TNF-α of which it was fixed.

72

14.10.2014 7

2

INFLIXIMAB (REMICADE®)

• dose: 5 mg/kg body weight, in perfusion, in weeks So, S2, S6 and later once at 8 weeks.

• Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT)

• Insufficient response: the dose is risen up to maximum 10 mg/kg

body weight or

the dosing interval can be diminished to 4-6 weeks

73

ADALIMUMAB (HUMIRA)

• Fully-human monoclonal antibody

• Specific binding to TNFα

• Dual mechanism of action:

– neutralization of TNFα

– rapid removal of TNFα from circulation

74

ETANERCEPT (ENBREL)

• A molecule made of 2 extracellular regions that connect the p75 receptor of the TNFα connected to the Fc of G1 human Ig.

• Binds TNFα and TNFβ.

75

14.10.2014 7

5

ADALIMUMAB (HUMIRA®)

• dose: 40 mg, subcutaneously, at 2 weeks

ETANERCEPT (ENBREL®)

• dose: 50mg/week, subcutanously

76

ANTI-TNF-α – BIOLOGICAL THERAPY

• Before of the beginning of the treatment it is obligatory to:

– Screen for tuberculosis: tuberculin test (PPD) and chest X-ray

– Screen for viral infection: B and C hepatitis, HIV

– Exclusion of neoplasia and demyelination diseases

– Exclusion of asociate autoimmune phenomena (anti ds DNA antibodies)

77

BIOLOGICAL THERAPY MAIN EXCLUSION CRITERIA/CONTRAINDICATIONS

• Pregnancy /breast-feeding

• Autoimmune diseases associated : systemic lupus erythematosus and multiple sclerosis

• Severe chronic heart failure (class III/IV NYHA)

• Demyelinating diseases

• Optical Neuritis

• Tuberculosis: active infection or a history of tuberculosis or positive PPD test

• Cancer, personal history of neoplasia (except neoplasia without recurrence for ≥ 10 years)

• Active/chronic/recurrent infections (infection with HBV, HCV, HIV)

• Septic arthritis (≤ 12 months)

• Infection of joint prostheses (≤ 12 months-if the prosthesis is extracted or is on an indefinite period - if the prosthesis remains in situ)

78 BIOLOGICAL THERAPY - MAIN SIDE EFFECTS

• Acute side effects of intravenous perfusion: fever, headache, pruritus, urticaria, hypotension, dyspnoea - infliximab;

• Infections - tuberculosis relapse - all anti-TNF-α biological agents;

• Hypersensitivity of delayed type: myalgia, arthralgia, erythema, oedema;

• Autoimmune Phenomena: human antichimeric antibodies (HACA), antinuclear antibodies (ANAs), anti-double-stranded DNA autoantibodies (lupus-like phenomena)-infliximab;

• Cardio-vascular events: worsening of heart failure, arrhythmias;

• Digestive manifestations: nausea, diarrhea;

• Neurological manifestations: demyelinating syndromes;

• Hematological manifestations: leucopenia, anemia, thrombocytopenia;

• Neoplasias, lymphomas.