Seronegative Arthritis Or Spondyloartropaties

Introduction Spondyloarthritis or Seronegative Spondyloarthritis Refers to inflammatory changes involving the spine and the spinal joints. Absence of Rheumatoid Factor and ANA

Spondyloarthritis A group of autoimmune diseases that in common appear mediated by activation of autoreactive CD8 T cells Primarily affect joints, skin, eyes and mucous membranes Physical stress, inflammation and infection with specific microorganisms trigger the immune response

Spondyloarthropathies (SpA) Frequent – prevalence ~ 0.5% Chronic Inflammatory With potential disabling outcomes Consist of several disorders

SpA consist of several disorders Ankylosing spondylitis (ASp) Reiter’s syndrome (RS) / reactive arthritis (ReA) Psoriatic arthritis (PsA) Undifferentiated spondyloarthritis (USpA) Enteropathic arthritis (ulcerative colitis, regional enteritis)

Spondyloarthritis Diseases-features common to all 1. Clinical: - Affect joints, skin, eyes and mucous membranes in varying proportions with characteristic joint involvement: Spondylitis(inflammation of vertebral discs), sacroiliitis (sacroiliac joints) and enthesitis (tendon insertions). All with granulomatous fibrosis and newbone formation

Spondyloarthritis Diseases-features common to all peripheral articular involvement asymmetric mono-oligoarticular Common in male Sausage digits

Spondyloarthritis Diseases-features common to all Enthesopathy– Achilles tenosynovitis Extra-articular manifestations Oral aphtae, Erythema nodosum, uveitis Absence of RF and Rheumatoid nodules Absence of Raynoud’s phenomenon

Spondyloarthritis Diseases-features common to all 2. Genetic: Susceptibility to develop disease is associated with inheritance of certain MHC class I alleles, notably HLA-B27 Positive family history 3. Pathogenesis: Effector/ memoryCD8 T cells are activated and clonally expanded while CD4 T cells or B cells are not involved

Spondylitis leads to the development of syndesmophytes and ankylosis T cells invade the junction of annulus fibrosis and vertebral body forming granulation tissue (activated macrophages, T cells and fibroblasts) Annulus fibers are eroded, then replaced by fibrocartilage that ossifies to form a syndesmophyte. Subperiosteal new bone formation ensues Progressive cartilaginous and periosteal ossification forms a “bamboo spine”, osteoporosis develops

Sacroiliitis The subchondral regions of the synarthrotic SI joints are invaded by T cells leading to the formulation of granulation Tissue The cartilage on the iliac side is eroded first, causing bone plate blurring, joint space “widening” and reactive sclerosis. Ultimately the resultant fibrous ankylosis is replaced by bone, obliterating the SI joint

Enthesitis (enthesopathy) Entheses are the specialized fibrocartilagenous region of bone where ligaments, tendons, fascia or joint capsules insert Infiltration of entheses by T cells, enthesitis, produces a combination of bone erosions and heterotopic new bone formation. Calcaneal spurs at insertion of plantar fascia and Achilles ligament are classic examples .

Inflammatory back pain Onset before age 40 Insidious persistent (> 3 mo) dull deep buttock or low back pain Stiffness/pain upon arising in the morning, or during sleep Improvement with exercise Due to the initial inflammation of enthesitis, spondylitis or sacroiliitis • Poorly localized, does not follow nerve root

Genetic epidemiology HLA-B27 increased, but unevenly, among spondylitis diseases HLA-B27 frequency (%) Ankylosing spondylitis 95 Reiter’s syndrome (reactive arthritis) 70 Psoriatic arthritis 20-40 Ethnically matched controls 8 Other class I alleles may also be involved, especially in PsA

Spondyloarthropathies ESSG Criteria Primary Inflammatory Back Pain OR Synovitis Asymmetric Predominantly in lower extremities Secondary Plus one of following: Psoriasis IBD Positive family history Urethritis, cervicitis, or acute diarrhea within 1 month of arthritis Alternating buttock pain Enthesopathy Sacroiliitis

Ankylosing Spondylitis

Ankylosing Spondylitis A progressive autoimmune inflammatory disease characterized by widespread spondylitis and sacroiliitis Onset, age 10-35 with dull pain in lumbar or gluteal regions Hip, shoulder, knee arthritis in ~30% Epidemiology: >95% of those affected are positive for HLA-B27 Affects 1-3% of HLA-B27 individuals, Begins in the Sacroiliac Joints and progresses upwards and can involve the entire spine

Ankylosing Spondylitis Inflammatory Stages Can be extremely painful (flares) Prolonged morning stiffness (hours) Fatigue (pain & lack of sleep) Ankylosis Stiffness increases Significantly reduced ROM Abnormal posture

Postural changes • Postural changes include loss of lumbar lordosis, buttock atrophy and thoracocervical kyphosis, chest expansion compromised • Peripheral joints, notably the hips may develop flexion contractures or ankylosis. Compensatory knee flexion

Other Joints Involved Enthesitis Inflammatory Arthritis of the hips and shoulders Enthesitis

Extra-Articular Features Eyes: Acute anterior uveitis (40%) most common extraarticular features of AS Anterior uveitis can precede the onset of AS by several years Strongly associated with HLA B27 Lungs: Rigidity of the chest wall and fibrosis in the upper lungs Kidneys: IgA nephropathy (rare) Heart: Aortitis (dilation of aortic root), aortic regurgitation

Laboratory Investigations Evidence of Inflammation Normochromic normocytic anemia Elevated ESR/CRP Reactive thrombocytosis HLA-B27 found in 90-95% of patients with Ank Spond vs 6-8% of general population

Imaging Studies Sacroiliac joints: Scintigraphy Standard anteroposterior radiograph of the pelvis Ferguson view-15 degree angle to the prone pelvis Erosions-pseudowidening of SI Joint Obliteration of SI joint Scintigraphy MRI-visualization of acute sacroiliitis CT-erosions

Psoriatic Arthritis

Psoriatic arthritis Psoriatic arthritis: an often clinically distinctive complex of enthesitis and arthritis that occurs in the setting of psoriasis It may involve the spine or peripheral joints in a variety of patterns,and is initiated or exacerbated by stress or non specific infection

Progression Polyarticular in 30-50% Oligoarticular in 40-50% Like Rheumatoid Arthritis Oligoarticular in 40-50% Predominant Spinal Disease in 5% Spinal symptoms usually occur after many years of peripheral arthritis DIP involvement in 5% Arthritis Mutilans in 5%

Arthritis mutilans Osteolytic dissolution of joint with redundant overlying skin and telescoping motion of the digit (opera-glass hand)

Sacroiliac Involvement Sacroiliitis in 1/3 of patients Usually asymmetric (unilateral) May be asymptomatic Spinal Involvement May affect any part of the spine in a random fashion Different from ankylosing spondylitis

Rheumatologic Review of Systems Mucocutaneous Involvement Psoriatic skin lesions Psoriatic Nail lesions Entheseal Involvement Dactylitis Ocular Involvement

Psoriatic Arthritis Nail involvement ~80% Often seen in digit involved with DIP Arthritis • Pitting • Onycholysis • Onychodystrophy • Transverse ridging

History - Psoriasis Psoriasis present before the onset of joint disease (70%) Psoriasis comes with the arthritis (15%) Psoriasis comes after the arthritis (15%)

Psoriatic Plaque Under the Knee

Umbilical Psoriasis

Dactylitis Entire digit is involved compared to “fusiform” swelling around a joint Dactylitis – represents inflammation of the flexor tenosynovium – “flexor tenosynovitis”

Progression of DIP arthritis Narrowed joint space & condylar erosions Reactive sub periosteal new bone Pencil in cup appearance

Management AS and Psoriatic Arthritis Goals of Treatment Improve pain Improve Function Prevent Long-term Damage Safely Psoriatic arthritis can lead to a deforming and destructive arthropathy in 20-30% Ankylosing spondylitis can result in significant disability

Management NSAIDs Can be useful in some cases of mono/oligo arthritis Useful for enthesitis Useful for spinal disease

Ankylosing Spondylitis Management: DMARDs Medication Psoriatic Ankylosing Spondylitis Hydroxychloroquine (Plaquenil®) Rarely with little evidence NO Methotrexate YES Rarely with poor efficacy in spinal disease Sulfasalazine Leflunomide (Arava®) Gold Steroids

Management: Biologics Biologics Approved for Psoriatic Arthritis and Ankylosing Spondylitis Etanercept (Enbrel®) Infliximab (Remicade®) Adalimumab (Humira®) Biggest advance in the treatment of spondyloarthropathies in decades!

REACTİVE ARTHRITIS

Reactive arthritis Reactive arthritis has generally been defined as sterile synovitis developing after a distant infection. Occurs 2-4 weeks after inciting infection Most responsible organisms have an affinity for mucous membranes VUCUDUN her hangi bir yerinde ki enfeksiyon sonrası ve sırasında gelişen 53

Terms Reactive Arthritis & Reiter’s Syndrome Synonamous 1916, Hans Reiter Arthritis, Conjunctivitis, Non Gonococcal Urethritis Irksal hyjen kitabı- tifo inokulasyon –kamplarda Reiter Syndrome ? 54

Classic triad: Arthritis, Urethritis, Conjunktivitis

Etyology Infectious agent GIS GUS Others Shigella (flexneri)* Salmonella Yersinia Campylobacter Clostridium(difficile) Chlamydia (trachomatis) C.pneumoniae Borrelia Neisseria Streptococus *HLA-B27 (+) hastaların %25 inde ReA gelişir. 56

- symptoms of the triggering infection have often been mild and, in about 10% of cases, the infection has passed unnoticed - Symptoms • malaise, • fatigue • fever • mild arthralgias to severely disabling polyarthritis

Reactive Arthritis Conjunctivitis follows urethritis by several days Sx often mild and transient acute anterior Uveitis possible

Articular manifestations Starts 2-4 weeks after the initial infection Articular symptoms typically appear last additive oligoarticular lower limbs most common

asymetric, oligoarticular Knee Ankle Foot joints Occasionally Wrist, Elbow, Shoulder, SIE asymetric, oligoarticular Chronic cases Dactilitis Entesopathy. tenosynovitis, plantar facitis, achill tendinitis, bursit

Reactive arthritis Dactilitis

Aphtous ulceration

Erithema nodosum

Reactive Arthritis Clinical course Normally limited course running 3-12 months 15% with prolonged relapsing arthritis ? Relapse ?Reinfection Ankylosing Spondylitis in 10% of cases

Reactive Arthritis Laboratory findings Normochromic, normocytic anemia Leukocytosis Acute phase reactants: ESR C-reactive Protein Patients with genitourinary symptoms should be tested for infection with C trachomatis

Reactive Arthritis Treatment: Antibiotics?-chlamydia-tetracyclines Rest NSAIDs Methotrexate and sulphasalazine Intralesional and intraarticular glucocorticoids Uveitis-glucocorticoids

Enteropathic Arthritis Or SpA associated with inflammatory bowel disease

Enteropathic arthritis Arthropathy associated with IBD – (5-20%) Peripheral arthritis Axial involvement – sacroiliitis w/o spondylitis HLA-B27 not implicated here

Enteropathic arthritis Acute, oligoarticular onset Predominantly lower extremities Non-deforming, self-limiting arthritis Association with active bowel symptoms

Enteropathic arthritis Periarticular features Enthesopathy Tendonitis Extraarticular features Erytema nodosum Uveitis

Enteropathic arthritis-Therapy NSAID Sulphasalazine Methotrexate Biologic agents – Anti TNF therapy

Clinical and epidemiological features of the spondyloarthropathies Prevalence M/F ratio Axial Arthritis Frequency sacroilitis Ankylosing Spondylitis 0.1% 3:1 100% Bilateral Psoriatic Arthritis 1:1 20% Unilateral Reactive Arthritis >0.05% 9:1 Enteropathic Arthritis 15%

Clinical and epidemiological features of the spondyloarthropathies Peripheral arthritis Uveitis Frequency Dactylitis frequency distribution Affected joints Ankylosing Spondylitis 25% Mono oligo Hip,knee, ankle 30% uncommon Psoriatic Arthritis 60-95% Oligo poly Knee,ankle,DIPs 15% Reactive Arthritis 90% Knee,ankle 15-20% 30-50% Enteropathic Arthritis 20% 5%