Disclosures. Rheumatological Approaches to Differential Diagnosis, Physical Examination, and Interpretation of Studies. None

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1 Rheumatological Approaches to Differential Diagnosis, Physical Examination, and Interpretation of Studies Sarah Goglin MD Assistant Professor of Medicine Division of Rheumatology Disclosures None 1 [footer text here]

2 Objectives By the end of this talk, you will: Have a basic understanding of the major categories of systemic autoimmune disease Develop an approach to the history and physical exam of a patient with suspected rheumatic disease Develop an approach to ordering and interpreting rheumatologic serologies Categories of rheumatic disease Connective tissue disease Antiphospholipid syndrome IgG4- related disease Vasculitis Inflammatory arthritis Sarcoidosis 2 [footer text here]

3 Case 1 Case 1 54 yo woman with hypothyroidism presents with slowly progressive symmetric numbness and paresthesias affecting her distal lower extremities ROS: +joint pain in the small joints of her fingers, +dry eyes when she wears her contacts ANA 1:160 diffuse, SSA 24 (<20) 3 [footer text here]

4 Case 1 What is the most appropriate next step? A. Refer her to rheumatology for likely diagnosis of SLE B. Check a Hba1c and start gabapentin for her neuropathic symptoms C. Refer to oral medicine for minor salivary gland biopsy to confirm suspected diagnosis of Sjogren s syndrome D. Start prednisone for possible immune-mediated neuropathy Inflammatory versus non-inflammatory pain Inflammatory Non-inflammatory Morning stiffness + - Change with activity Improves Worsens Constitutional symptoms + - ESR/CRP Elevated Normal Extra-articular manifestations + -** Rheumatoid arthritis Osteoarthritis Fibromyalgia 4 [footer text here]

5 But what about her facial rash? Acute cutaneous lupus Indurated Overlying scale Tends to occur in photo-exposed areas Spares nasolabial folds 5 [footer text here]

6 Back to Case 1 Erythrotelangiectatic rosacea w a few small acneiform papules Not indurated No scale Doesn t spare nasolabial folds Not acute cutaneous lupus! Subacute cutaneous lupus 6 [footer text here]

7 Discoid lupus But what about her positive ANA and SSA? 7 [footer text here]

8 Causes of positive ANA ANA is not specific for SLE; found in low titers in 10-20% of the healthy population Also seen in other autoimmune diseases, infections, malignancies Autoimmune thyroid disease (ATD) is a well known cause of a positive ANA - Up to 50% of patients with ATD have a positive ANA - Up to 15% have been found to have a positive SSA Case 1 What is the most appropriate next step? A. Refer her to rheumatology for likely diagnosis of SLE No, although she has a positive ANA, she has no other features to suggest a diagnosis of SLE. Her facial rash is rosacea. B. Check a Hba1c and start gabapentin for her neuropathic symptoms Standard work up and treatment for peripheral neuropathy is indicated based on lack of evidence of an underlying systemic disease. C. Refer to oral medicine for minor salivary gland biopsy to confirm suspected diagnosis of Sjogren s syndrome No, although she has a low titer SSA antibody, this can be explained by autoimmune thyroid disease and she lacks the severe Sicca symptoms that are typical for patients with Sjogren s syndrome. D. Start prednisone for possible immune-mediated neuropathy No, there is nothing to support a systemic autoimmune disease as the cause of her neuropathy. 8 [footer text here]

9 Case 2 Case 2 37 yo woman transferred to UCSF with altered mental status, progressive urinary retention, and bilateral lower extremity weakness MRI spine consistent with transverse myelitis 9 [footer text here]

10 Case 2 WBC 3.5 (ALC 0.5), Hb 9, Hct 26.7, Plt 91 ANA screen negative at transferring hospital C3 41 ( mg/dl), C4 2.8 (13-30 mg/dl) Case 2 What is the best next step? A. Recheck ANA B. Check ANCA C. Consult hematology for evaluation of pancytopenia D. Start empiric RIPE therapy for possible TB myelitis 10 [footer text here]

11 Case 2 ANA 1:80 diffuse Anti-dsDNA 197 (<20) Sm, RNP, SSA, SSB negative NMO antibody negative Diagnosed with SLE-associated longitudinally extensive transverse myelitis Types of connective tissue disease Myositis Scleroderma Systemic lupus Connective Tissue Diseases Mixed connective tissue disease Sjogren If you suspect a connective tissue disease, an ANA alone is the appropriate first screening autoantibody test 11 [footer text here]

12 Pitfalls of ANA testing ANA by indirect immunofluorescence (IIF) ANA by ELISA Non-IIF assays have increased specificity but decreased sensitivity for ANA -> ANA negative lupus If ANA is negative and clinical suspicion is high, check by another assay ANA testing Pattern Nuclear antigen Clinical associations Homogenous Double-stranded DNA SLE Diffuse Speckled Histone Topoisomerase I Extractable nuclear antigens (Sm, RNP) Ro-SSA**/La-SSB Other Drug-induced lupus SLE Systemic sclerosis MCTD SLE Sjogren s syndrome Poly/dermatomyositis Various autoimmune diseases Infection Neoplasia Nucleolar RNA-associated antigens Systemic sclerosis Peripheral Double-stranded DNA SLE Centromere Centromere Limited systemic sclerosis Only check subserologies if ANA is positive by IIF **SSA is exception Don t repeat the ANA once you know it is positive it doesn t track with disease activity 12 [footer text here]

13 ANA subserologies % Autoantibodies % in Autoantibodies Patients with Rheumatic in Patients with Diseases Rheumatic Diseases ease ANA Disease & RF ANA dsdna & Sm RF dsdna Ro La Sm Scl-70 Ro Cent La Scl-70 Jo RNP Cent Jo RN Pattern Pattern SLE D, S, N D, S, N 15 35D RA D < < gren s >90 Sjögren s 75 >90 < < D, S D, S use >90 Diffuse 30 > < <5 0 3 N, S, SSc D N, S, D ted >90 Limited 30 > < < S, N, SSc D S, N, D DM PM-DM TD MCTD <5 0 <5 0 0 <5 0 < S, D S, D Wallace et al. Pocket Medicine 5 th edition 13 [footer text here]

14 Case 2 What is the best next step? A. Recheck ANA Yes! Clinical suspicion for SLE is high, so check ANA by IIF. B. Check ANCA No, there is nothing to suggest small vessel vasculitis as the cause of her presentation. C. Consult hematology for evaluation of pancytopenia No, her cytopenias are likely due to SLE. D. Start empiric RIPE therapy for possible TB myelitis No, there are many red flags for lupus myelitis here and she lacks any risk factors or other clinical evidence of TB. Case 3 14 [footer text here]

15 Case 3 71 yo woman with adult-onset asthma presents with acute onset right hand weakness and numbness, followed by left hand weakness, and subsequent bilateral foot drop over the period of a month Also concomitantly developed digital ischemia ROS: +40 lb weight loss, +oral ulcers, +uncontrolled asthma symptoms Case 3 Lessons for the Practicing Neurologist 15 [footer text here]

16 Case 3 WBC 20.2 (absolute eos 9.6), Hb 11, Hct 33.3, Plt 490 ESR >100 C3 and C4 are normal UA with RBCs, 2+ protein Case 3 What is the best next step? A. Order an ANCA B. Order a conventional mesenteric angiogram C. Order antiphospholipid antibodies D. Order cryoglobulins 16 [footer text here]

17 Vasculitis schema by vessel size Diagnostic schema for vasculitis Imboden et al. Current Diagnosis and Treatment Rheumatology 3 rd edition 17 [footer text here]

18 Small vessel vasculitis Cutaneous manifestations Palpable purpura Medium vessel vasculitis Cutaneous manifestations Ulcers Nodules 18 [footer text here]

19 Small vessel vasculitis Pulmonary manifestations Nodules (GPA) Diffuse alveolar hemorrhage Asthma (severe, adult-onset), fleeting infiltrates = EGPA Medium vessel vasculitis Pulmonary manifestations None! 19 [footer text here]

20 Small versus medium vessel vasculitis Renal manifestations Small vessel vasculitis Clinical features: HTN, proteinuria, hematuria, renal failure (but not always, esp early in course) Medium vessel vasculitis Clinical features: HTN, occasionally hematuria, NO PROTEINURIA Case 3 What is the best next step? A. Order an ANCA Yes, you are concerned for EGPA due to eosinophilia, asthma, and signs of small-med vessel vasculitis (digital necrosis, mononeuritis multiplex, hematuria/proteinuria suggesting GN) B. Order a conventional mesenteric angiogram This would be the appropriate test if you suspected PAN. Although mononeuritis and digital ischemia can be seen in PAN, there are many features of this case that are not consistent with this diagnosis. C. Order antiphospholipid antibodies No, hypercoagulability alone would not explain this presentation. D. Order cryoglobulins No, the normal complement levels (esp C4) essentially excludes cryo vasculitis. In addition, this would not explain eos and asthma. 20 [footer text here]

21 Conclusions Always use your history, physical exam, and basic labs to guide autoantibody serologic testing Know the limitations of lab tests When considering a diagnosis of a systemic rheumatic disease, use the extra-neurologic organ involvement to help narrow differential diagnosis and direct work up Don t hesitate to call your friendly neighborhood rheumatologist! 21 [footer text here]