Concept of Spondyloarthritis (SpA)

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1 Concept of Spondyloarthritis (SpA) Undifferentiated SpA Juvenile SpA Ankylosing Spondylitis Psoriatic Arthritis Arthritis associated with Ulcerative Colitis/ Crohn s Disease Reactive Arthritis Acute anterior Uveitis 1

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

3 ESSG-Classification Criteria (European Spondylarthropathy Study Group) 3 Dougados M et al. Arthritis Rheum 1991;34;1218

4 Spondyloarthritis: Characteristic Parameters Used for Diagnosis-I Symptoms Inflammatory back pain Imaging Lab ESR/CRP Patient s history Good response to NSAIDs 4

Uveitis *positive staining for Chlamydia in

5 Spondyloarthritis-Characteristic Parameters Used for Diagnosis II Spondyloarthritis: Characteristic Parameters Used for Diagnosis-II Genetics HLA-B27 positive family history Predisposing/concomitant diseases Infection* psoriasis Crohn s Uveitis *positive staining for Chlamydia in synovial membrane Schumacher HR et al. Arthritis Rheum 1988; 31:937-46

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7 Khan MA. Ann Intern Med 2002;136(12): SpA and HLA-B27 Disease Approximate Prevalence of HLA-B27 (%) AS 90 Reactive arthritis (ReA) Juvenile spondyloarthropathy 70 Enteropathic spondyloarthropathy Psoriatic arthritis Undifferentiated spondyloarthropathy 70 Acute anterior uveitis 50 Aortic incompetence with heart block 80

8 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

9 Concept of Spondyloarthritides (SpA) Reactive arthritis Non-radiographic axial SpA Ankylosing Spondylitis Psoriatic Arthritis Arthritis with inflammatory bowel disease Undifferentiated SpA Predominantly Axial SpA Predominantly Peripheral SpA 9

10 Axial Spondyloarthritis Ankylosing spondylitis Non-radiographic stage Radiographic stage Modified New York Criteria 1984 Back pain Sacroiliitis on MRI Back pain Radiographic sacroiliitis Back pain Syndesmophytes Time (years) 10 Rudwaleit M et al. Arthritis Rheum. 2005;52:

11 ASAS Classification Criteria for Axial Spondyloarthritis (SpA) In patients with 3 months back pain and age at onset <45 years Sacroiliitis on imaging* plus 1 SpA feature # OR HLA-B27 plus 2 other SpA features # # 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 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 Rudwaleit M et al. Ann Rheum Dis 2009;

12 ASAS Classification Criteria for Peripheral Spondyloarthritis (SpA) 12 Rudwaleit M et al. Rheum Dis 2011;70:25-31 (with permission)

13 Symptoms at presentation determine which pathway Axial ± peripheral symptoms at time of presentation Purely peripheral symptoms at time of presentation* Apply ASAS Criteria for Axial SpA 1 Apply ASAS Criteria for Peripheral SpA 2 *Past inflammatory back pain allowed 13 1 Rudwaleit et al. Ann Rheum Dis 2009;68: Rudwaleit et al. Ann Rheum Dis 2011;70:25-31.

14 ASAS Classification Criteria for Spondyloarthritis (SpA) 14 Rudwaleit M et al. Ann Rheum Dis 2011;70:25-31 (with permission

15 Ankylosing Spondylitis

16 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:

17 Epidemiology 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

18 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.

19 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

20 AS: Characteristic Pathologic Features 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 Sieper J. Arthritis Res Ther 2009;11:208 Elewaut D & Matucci MC. Rheumatology 2009;48:

21 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

22 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

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24 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

25 Buttock pain

26 Physical Exam: Reduced range of motion: Schober test

29 skier position

30 Physical Examination Chest expansion: expansion of less than 2.5cm abnormal (5cm considered normal) Sacroiliac joint tenderness Hip joint involvement Peripheral joint involvement (dactylitis- sausage toes )

AS: Signs and Symptoms Peripheral manifestations

patients with enthesitis 1 Up to 58% patients

31 AS: Signs and Symptoms Peripheral manifestations Enthesitis Peripheral arthritis Dactylitis 50% patients with enthesitis 1 Up to 58% patients ever had arthritis 1 Mch smaller number of patients 1 Cruyssen BV et al. Ann Rheum Dis 2007;66: Sidiropoulos PI et al. Rheumatology 2008;47:

1 The first abnormality to appear in swollen joints associated with

32 Why are Dactylitis and Enthesitis Important? Likelihood of erosions is higher for digits with dactylitis than those without 1 The first abnormality to appear in swollen joints associated with spondyloarthropathies is an enthesitis 2 1 Brockbank. Ann Rheum Dis 2005;62:188-90; 2 McGonagle et al. The Lancet 1998;352.

33 Enthesopathy Erosion New bone

34 Heel tendonitis in AS

Missaoui B. et al. Ann Readapt Med Phys 2006;49:305-8, 389-391 Linden VD et al. Chapter 10.

35 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 Fatigue is a frequent complaint of patients with AS 1 1 Missaoui B. et al. Ann Readapt Med Phys 2006;49:305-8, Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley s Textbook of Rheumatology: Spondyloarthropathies. 8 th ed. Saunders Elsevier;2009:p.1176

AS: Extra-articular Manifestations Anterior uveitis Cardiac abnormalities Extra-articular

inflammation of the gut 25-49 Cardiac abnormalities Conduction disturbances Aortic

Airways disease Interstitial abnormalities Emphysema Bone abnormalities Osteoporosis

36 AS: Extra-articular Manifestations Anterior uveitis Cardiac abnormalities Extra-articular manifestations Prevalence in AS Patients (%) Anterior uveitis IBD 5-10 Subclinical inflammation of the gut Cardiac abnormalities Conduction disturbances Aortic insufficiency Psoriasis Renal abnormalities Lung abnormalities Airways disease Interstitial abnormalities Emphysema Bone abnormalities Osteoporosis Osteopenia Terminal ileitis Elewaut D & Matucci MC. Rheumatology 2009;48:

37 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

38 Laboratory Tests ESR and CRP typically elevated HLA-B27: present in 8% of population, prevalence in HLA-B27 positive population is only 5% Normocytic, normochromic anemia

39 Imaging 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 )

40 Sacroiliitis: Scoring System SpA Characteristic XRAY change Erosions Osteitis (Sclerosis) Bridging Syndesmophytes Ankylosis of joints 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

41 Symmetrical Sacroiliitis Ankylosing Spondylitis (abnormal) (abnormal)

42 Sacroiliitis Grade 3 Bilaterally 42

44 Sacroiliitis grade II bilat. Sclerosis Erosions

45 Definition of Positive MRI-SI Joint 45 ASAS handbook, Ann Rheum Dis 2009;68 (Suppl II) (with permission)

46 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. 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 Rudwaleit M et al, Ann Rheum Dis 2009;68:

47 Syndesmophytes, apophyseal joint fusion, disc peripheral ossification (AS)

48 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; 3 rd edition

49 Ankylosing Spond. Left: squaring of vertebra, Rt: ant. longitudinal lig.calcification

50 Ankylosing Spondylitis: Bamboo spine,ossification follow the contour of intervertebral discs

51 Bamboo spine: 1. Syndesmophyte 2. rail =the ossification of the posterior apophyseal joints 3. wire = ossification of the ligaments

53 Ankylosing Spondylitis: calcaneal spur and erosion

54 Plantar periostitis seen in AS

55 Unilateral sacroiliitis

AS: A Debilitating Rheumatic Disease Over time, joints in the spine can fuse together and cause a fixed, bent-forward posture AS patients have an important

More than 30% of patients carry a heavy burden of disease and have a decreased QoL 2 1 Linden VD et al. Chapter 10.

56 AS: A Debilitating Rheumatic Disease Over time, joints in the spine can fuse together and cause a fixed, bent-forward posture 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/patient 1 More than 30% of patients carry a heavy burden of disease and have a decreased QoL 2 1 Linden VD et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley s Textbook of Rheumatology: Spondyloarthropathies. 8 th ed. Saunders Elsevier;2009:p Braun J & Sieper. J Rheumatology 2008;47:

57 Modified New York Criteria for Ankylosing Spondylitis (1984) 57 van der Linden et al. Arthritis Rheum Apr;27(4):361-8.

58 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 Oligoarthrit is Symmetry of arthritis Sausage digits No Yes No No 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 59

60 Goals of Therapy 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

61 Assessment of disease activity 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

62 Prognostic Indicators Hip arthritis Dactylitis Poor efficacy of NSAIDs High ESR Limitation in ROM of lumbar spine Oligoarthritis Onset less than 16 years of age

64 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

66 66 Management recommendations

67 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: Predominant axial manifestations 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 Positive expert opinion based on parameters such as: Positive CRP/ESR Positive MRI Radiological Progression Clinical examination plus Predominant peripheral manifestations van der Heijde et al. Ann Rheum Dis 2011:905-8.

68 Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 68 The BASDAI is measured using the following VAS (0 to 10 cm) of subject self-assessments: Fatigue Spinal pain Joint pain Enthesitis Inflammation Duration morning stiffness Severity morning stiffness Garrett S, et al. J Rheumatol. 1994;21:

69 69

70 TNFα PATHOGENIC IMPLICATIONS IN AS 70 Biopsy o the sacroiliac joint Higher level of TNF-α in the serum Overasserting of TNF-α in the synovial tissue of the SIJ Toussirot and Wendling, Gratacos, 1994.Cannete et al Grom et al.1996.braun et al. 1995

71 INFLIXIMAB (REMICADE) 71 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 72 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 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 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 75 ADALIMUMAB (HUMIRA ) dose: 40 mg, subcutaneously, at 2 weeks ETANERCEPT (ENBREL ) dose: 50mg/week, subcutanously

ANTI-TNF-α BIOLOGICAL THERAPY 76 Before of the beginning of the treatment it is obligatory to: Screen for tuberculosis: tuberculin test (PPD) and chest X-ray

76 ANTI-TNF-α BIOLOGICAL THERAPY 76 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) 77

78 BIOLOGICAL THERAPY - MAIN SIDE EFFECTS 78 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.

Sronegative Spondyloarthropathies. Dr. M Jokar

Sronegative Spondyloarthropathies Dr. M Jokar 1 Definition The spondyloarthropathies are a group of disorders that share certain clinical features and an association with the HLA-B27 allele 2 Spondyloarthropathies