Rheumatology Panel for Primary Care Dr. Vu Kiet Tran, MD

Objectives Recognize history and physical exam are the cornerstone of diagnosis for most rheumatologic diseases Analyze rheumatology panels in conjunction with history and physical exam to derive a diganosis Enumerate the limitations of these rheumatology panels

Disclosure Medical advisor Medical director Dynacare laboratories Best Doctors Canada

Case 1 56yo female with joint pain in both knees for 3-4 months. It is worse after a long day standing at work. She has a hard time going up and down stairs It is worsening She wants testing for Rheumatoid arthritis

What will you do and what tests would you order (if any)? Case 2 36yo female presents with fatigue and shortness of breath on exertion. She is losing hair and has a facial rash that appeared 3 weeks ago. She is concerned she has Lupus like her mother. What will you do and what tests would you order (if any)?

Case 3 37yo male sees you because her has been c/o joint pains in the hand for 3-4 weeks He feels the joint are stiff in the morning What other symptoms are you looking for?

Take Home Messages History and physical exam are the fundamentals for an accurate diagnosis The lab tests are used to confirm or refute your clinical impression Lab testing is not always necessary to make a diagnosis Can sometimes be misleading High degree of false positives Lead to additional and unnecessary testing

Major causes of Inflammatory Polyarthritis Etiologies Infectious arthritis Bacterial Lyme Bacterial endocarditis Viral Reactive Arthritis Rheumatic fever Reactive arthritis Enteric infection Rheumatoid Arthritis Inflammatory Osteoarthritis Crystal-induced arthritis Etiologies Systemic rheumatic illnesses SLE Vasculitis Systemic Sclerosis Polymyositis/dermatomyositis Still’s disease Behcet’s disease Relapsing polychondritis Seronegative Spondyloarthritis Ankylosing spondylitis Psoriatic arthritis IBD Systemic illnesses Sarcoidosis Palindromic rheumatism Familial Mediterranean fever Malignancy Hyperlipoproteinemias

History Presence of arthritis (synovitis) or not Mono or polyarthritis Seek out join emergencies Fever Hot and swollen joints Weight loss/malaise

History Joint symptoms Pain quality Time of onset Duration Exacerbating or relieving factors

Joint symptoms Inflammatory Non-inflammatory Pain is worsened with immobility Morning stiffness or “gelling” Joint involvement is usually symmetrical Pain is worsened by mobility and weight-bearing Pain is relieved by rest Joint involvement in OA is frequently asymmetrical, especially in the larger joints

Associated symptoms Non-rheumatic Rheumatic Weakness (neurologic or myopathic illnesses) Fever Night sweats Weight loss Multi-system involvement Fatigue Rash Adenopathy Alopecia Oral or nasal ulcers Pleuretic chest pain Raynaud’s phenomenon Dry eyes or mouth 1. Presence of extra-articular symptoms help narrow the Ddx.

History Focus on Usual areas PMHx Medication list Family history Social history ROS History of joint injury Functional capacity Psychological state and social support

Physical exam Establish the presence of synovitis Axial involvement Soft tissue swelling Warmth over the joint Joint effusion Loss of motion Axial involvement Seronegative spondyloarthritis

Physical exam Subcutaneous nodules (rheumatoid nodules vs tophi) Skin lesions Eye manifestations Keratoconjunctivitis sicca Uveitis Conjunctivitis Episcleritis

Classification Criteria

Adding radiographs

Diagnosis of RA Classification criteria is not diagnostic criteria There is no diagnostic criteria for RA Classification criteria might be a guide to “clinical diagnosis”

SLE Diagnosis is based on clinical judgment, after excluding other diagnoses Heterogeneity (broad range) of clinical presentation is often a challenge

SLE Classic triad Fever Joint pain Rash In women of child-bearing age

Symptoms of Lupus Constitutional symptoms Photosensitivity Fever Weight loss Fatigue Lymphadenopathy Photosensitivity Malar rash Painless oral or nasal ulcer Patchy hair loss Raynaud’s phenomenon Migratory/symmetrical joint swelling Serositis Pleuretic chest pain or dyspnea Pericarditis Pleuretic chest pain Leg edema Seizure/psychosis

Laboratory studies Not always necessary to make a diagnosis Can sometimes be misleading

Laboratory studies ESR CRP ANA Rheumatoid factor (RF) Anti-citrullinated peptides (Anti-CCP) Uric acid Antibodies Strept A Hep B Hep C Borrelia Burgdorferi (Lyme)

ESR Non-specific marker of inflammation Never diagnostic May be abnormal in Advancing age Gender Infectious, malignant, rheumatic diseases Renal failure Diabetes obesity Occult malignancy May be normal in up to 70% of RA patients

CRP Synthesized in the liver in response to tissue injury Levels change more quickly than the ESR can increase within 4-6 hours peak at 24-72 hours normalize within a week Non-specific marker of inflammation Never diagnostic It is more stable and less variable than ESR More reliable for longitudinal measurement/monitoring disease activity than RF

ANA High sensitivity for SLE Low specificity for SLE Therefore, a negative test essentially rules-out SLE High false positives Up to 30% of healthy people may turn out to have a positive titer Even in the presence of a positive ANA, a patient with few or no clinical features of SLE is unlikely to have SLE

ANA The higher the ANA titer, the more likely that the patient has either SLE or another ANA-associated disease ANA is positive in all SLE patients at some time in the disease

Diseases associated with positive ANA

Rheumatoid Arthritis Panel Rheumatoid factor Anti-CCP (anti-cyclic citrullinated peptide) Commonly used in the diagnosis of RA Positivity implies a more severe course but is not specific Sensitivity for RA varies (around 50% – 80%) Usually lower in early RA and higher in established clinical disease. Higher titers are associated with more severe disease but fare poorly as a longitudinal measure of disease activity. Measurement of RF isotypes have been found to be clinically useful IgA RF isotype has been linked to erosive disease Sensitivity to RA is similar to that of RF (50-85%) More specific (90-95%) Most useful in the setting of seronegative subjects suspected of having RA Detected in early RA & may even antedate onset of inflammatory synovitis Better predictor of erosive disease than RF Does not correlate with extra-articular disease Positive anti-CCP + RF (IgM) correlates strongly with radiographic progression Not useful in longitudinal monitoring of RA disease activity

SLE specific antibodies Anti-DsDNA high specificity for SLE Often correlates with more active/severe disease Positivity in SLE is also associated with renal disease or involvement Tends to decrease or become undetectable in quiescent disease Anti-Sm Autoantibody with high specificity for SLE But only seen in 25-30% of SLE patients Unlike anti-ds DNA, it remains elevated even in quiescent disease Anticardiolipin antibodies Associated with an increased risk of vascular thrombosis, thrombocytopenia and recurrent fetal loss in patients with SLE Also seen in Anti-Phospholipid Syndrome Lupus anticoagulant Immunoglobulin that binds with phospholipids that line cell membranes and which usually prevents clotting in a test tube (in vitro)

SLE specific antibodies Anti-SSA (Ro) Anti-histone VDRL C3, C4, CH50 complements ENA (Extracted Nuclear Antigen) antibodies Anti-RNP Anti-Sm Anti-SSB (La) Scl-70 Anti-Jo-1 Urine protein-to-creat ratio

Systemic Scleroderma panel Positive in 20-60% of patients with diffuse Systemic Sclerosis Specificity is almost 100% Sensitivity is low When present, diagnosis of Scleroderma is almost certain Positivity is associated with an increased risk of radiographic pulmonary fibrosis Anti-centromere Almost certainly rules in limited cutaneous Systemic Sclerosis/ CREST Indicates a high rate of pulmonary hypertension and primary biliary sclerosis Anti-U3 RNP Its presence is associated with muscle, small bowel, renal and cardiac involvement as well as pulmonary hypertension

Sjogren’s Syndrome panel Anti-SSA (Ro) Associated mainly with Sjogren’s Syndrome Found in 75% of patients with primary Sjogren’s Found in 10-15% of patients with secondary Sjogren’s Found in 50% of patients with SLE (Subacute Cutaneous Lupus), Cutaneous Vasculitis, Interstitial Lung Disease Also associated with other conditions such as Neonatal Lupus Syndrome and congenital heart block Anti-SSB (La) Found in 40-60% of those with Sjogren’s Syndrome Rarely present without Anti-SSA (La) May also be positive in SLE (associated with ANA-negative Lupus) and Scleroderma

Polymyositis/dermatomyositis panel Anti-jo-1 Associated with Polymyositis/ Dermatomyositis and Interstitial Lung Disease Presence typically implies severe muscle involvement and resistance to treatment Anti-SRP Presence indicate patients who have severe, refractory disease those who may have cardiac involvement or cardiomyopathy CK Aldolase Anti-Mi2

Mixed Connective Tissue Disease Panel Anti-U1 RNP Highly associated with MCTD Positive in 95-100% of MCTD patients May also be positive in SLE and Scleroderma

Vasculitis Panel ANCA Used in the evaluation of vasculitis (i.e. Wegener’s granulomatosis, microscopic polyarteritis, Churg-Strauss syndrome) Two target antigens are PR3 (proteinase-3) and MPO (myeloperoxidase) Two basic staining patterns are cytoplasmic (c-ANCA) and perinuclear (p-ANCA) some diseases have a predilection for one pattern. c-ANCA pattern is highly sensitive and is seen in more than 90% of active Wegener’s granulomatosis wherein PR3 is the antigen involved p-ANCA pattern is commonly associated with microscopic polyarteritis and is directed against MPO The more active and extensive the vasculitis, the more likely are ANCA assays to be positive

Imaging Plain radiographs RA Ankylosing Spondylitis Erosion at wrist, hand, foot Ankylosing Spondylitis Calcium pyrophosphate crystal deposition disease (CPPD) chondrocalcinosis

Imaging Ultrasound Tendonitis Bursitis

Joint aspiration

summary

Take Home Messages History and physical exam are the fundamentals for an accurate diagnosis The lab tests are used to confirm or refute your clinical impression Lab testing is not always necessary to make a diagnosis Can sometimes be misleading High degree of false positives Lead to additional and unnecessary testing

Vukiet.tran@rogers.com Thank you