Manifestations and Presentations of Collagen Vascular Diseases Joseph LaConti, M.D., Ph.D. Center for Arthritis and Rheumatic Diseases Miami, FL June 29, 2018 Disclosures Joseph LaConti, M.D., Ph.D., has indicated that neither he nor his spouse/partner has relevant financial relationships with commercial interest companies, and he will not include off-label or unapproved product usage in his presentation or discussion. Non-faculty contributors and others involved in the planning, development and editing/review of the content have no relevant financial relationships to disclose. Educational Objectives What does a rheumatology patient look like? The skin The joints The constitutional symptoms The labs The review questions 1
Reviews and References Am Fam Physician. 2016 Aug 15;94(4):284-94.Systemic Lupus Erythematosus: Primary Care Approach to Diagnosis and Management. Lam NC1, Ghetu MV, Bieniek ML. Am Fam Physician. 2005 Sep 15;72(6):1037-47. Diagnosis and management of rheumatoid arthritis. Rindfleisch JA, Muller D. JAMA. 2002 Jan 2;287(1):92-101. Does this patient have temporal arteritis? Smetana GW1, Shmerling RH Rheumatology.org official American College of Rheumatology website Ann Rheum Dis. 2015 Feb; 74(2):326-32. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis, and rheumatoid arthritis: a population-based cohort study. Ogdie A, et al. Who Presents With Rheumatologic Problems? Prevalence in the USA Percent Population Osteoarthritis 12% 27 million Osteoporosis 10% 9 million Soft tissue 3-5% 5-10 million Gout 4% 8 million Fibromyalgia 2% 3-5 million Rheumatoid Arthritis 1% 1.5 million Spondyloarthritis 0.25% 0.4 to 1 million Polymyalgia rheumatica <0.01% 0.3 to 0.7 million Systemic lupus erythematosus <0.01% 0.25 million Scleroderma <0.01% 0.05 million Who Presents With Rheumatologic Problems? Female to male ratio Hashimoto s diseae 9:1 SLE 9:1 Sjorgens 9:1 Antiphospholipid syndrome 9:1 Mixed connective tissue disease 8:1 Grave s disease 7:1 Rheumatoid Arthritis 4:1 Scleroderma 3:1 Multiple sclerosis 2:1 Polymyositis 2:1 2
The Skin Which of These Needs The Quickest Rheum Referral? Skin: The Immune System s First Line of Defense The skin is rich is antigen presenting cells that help to activate the innate immune system and initiate the adaptive immune system. Skin involvement can be the major driver of the disease, or a part of a more systemic syndrome. A biopsy is always worth it. Some patients ignore the skin, especially if condition is chronic. 3
Lupus and The Skin Of the 11 classification criteria for SLE from ACR guidelines, four are skin related. Acute or subacute cutaneous lupus - 60-70% Photosensitivity usually accompanies acute and subacute lupus along with positive SSA. The differential for malar rash and oral ulcers is large. Lupus oral ulcers are usually painless, as opposed to herpes lesions. Discoid or chronic lupus -30% Malar rash and alopecia - 50-60% Oral ulcers - 15-45% Lupus and The Skin Skin lupus does not always mean systemic lupus. Always rule out medication causes, as drug induced lupus typically has skin manifestations. Treatments range and include: topical steroids, hydroxychloroquine, oral steroids, mycophenolate, dapsone (for specific pathologies), and belimumab. All patients are advised to avoid the sun: clothing, UVA and UVB SPF with minimal PABA. Stop smoking. Limit certain exacerbating substances: sulfas, thiazides, garlic, echinacea. Psoriasis Psoriasis precedes arthritis by average 8-10 years in 67% Arthritis and psoriasis occur together in 33% Check the nails, umbilicus, scalp, gluteal fold, behind the ears Five subtypes of psoriatic arthritis: Asymmetric Polyarthritis - rheumatoid like Mutilans Predominant DIP Isolated Axial involvement Treatments include: UV light therapy, topical steroids, Dmards, biologic Dmards Risk of major adverse cardiovascular events is 1.24, [95% CI 1.03 to 1.49] for patients with psoriatic arthritis (even higher for RA) 4
Vasculitis, Purpura, and Raynaud s BIOPSY!!! Non blanching, usually raised, painless, in dependent areas of the body. The most common pathology is leukocytoclastic vasculitis. Differential is wide: Infection- must be ruled out Paraneoplastic - must be considered Drugs - often the cause Rheumatoid Arthritis, lupus, small and medium vessel vasculitis Raynaud s is very common - 1% of the world, and not always associated with autoimmunity. These are the diseases that need the quickest rheumatologic consult. The work up will focus on end-organ damage (lungs, kidneys, eye), and a place to biopsy. The Joints Inflammatory vs. Non-inflammatory Inflammatory Swelling Worse in morning Better with movement Morning stiffness over 1 hour Associated with systemic symptoms Non-weight bearing joints Dramatic response to NSAIDs or steroids Non-inflammatory Minor swelling Worse after work or with use Worse with movement Stiffness less than one hour Associated with metabolic syndrome Most load bearing joints Blunted response to NSAIDs or steroids 5
RA vs. OA Distribution: RA never in the DIPs or lumbar spine. X-rays: RA affected joints all may show erosions, OA joints only erosive in the PIPs and DIPs. MRI and musculoskeletal ultrasound are sensitive and specific to identify the synovitis of RA vs OA. 95% of RA patients will have RF or CCP antibodies positive. MRI and musculoskeletal ultrasound are sensitive and specific to identify the synovitis of RA vs OA. This patient had symmetrical pain, swelling, and morning stiffness. Xrays were not overly impressive. US can detect synovial fluid and synovitis. Better Diagnosis, Better Treatment Rheumatoid requires Dmard therapy: methotrexate, hydroxycloroquine, sulfasalazine Flares can be treated with NSAIDs or low dose prednisone (15-10 mg) Biologic Dmards are safe, and plentiful 1 in 1000 get sinusitis, more significant infections are rarer TNF inhibitors as causes of lymphoma is not accurate, uncontrolled RA has a higher risk OA has no disease modifying drugs, but... 6
Treatment Approach To OA Make sure it is OA The only modifiable risk factors for OA: Physical therapy weight loss injury avoidance Fountain of Youth NSAIDS - depending on co-morbidities Acetaminophen - at adequate doses, up to 3 g/day if needed Supplements - glucosamine and chondroitin - 50% see pain reduction Viscosupplementation - 60-70% of patients see pain reduction Intra articular steroids - will not regrow cartilage, but can offer short term pain relief Platelet rich plasma - safe in joints, similar response to viscosupplementation, but not covered by insurance Duloxetine approved for OA pain Nerve growth factor maybe in the pipeline, causes worsening OA in a subset of patients CBD oil reduced pain scores in the elderly Replacement - best response is when function is severely impaired Is It Really Arthritis? Soft tissue rheumatism Pre-patellar bursitis, olecranon bursitis, trochanteric bursitis Rotator cuff tendinitis or tears Lateral and medical epicondylitis Plantar fasciitis Carpal tunnel, ulnar tunnel, tarsal tunnel, spinal stenosis, radiculopathy Certain medications- filgrastim, aromatase inhibitors, DPP-4 inhibitors (gliptins), bisphosphonates Is It Fibromyalgia? The tender points are important but are given too much authority in diagnosis. Fibromyalgia does NOT have: rashes, synovitis, autoantibodies, response to steroids, bone changes. Fibromyalgia DOES have: poor un-restorative sleep and depression. Physical activity is paramount. Treatments include cyclobenzaprine for muscle relaxation and sedation, SNRIs like duloxetine, pregabalin. 7
Breaking the Cycle of Fibromyalgia Pain leads to poor sleep leads to fatigue leads to less exercise leads to weight gain and more pain, back to the start Arguing for fibromyalgia subtypes: Poor sleepers: need sleep studies for OSA, flexeril, less benzos Depressive patients: therapy, duloxetine, PTSD screening Pain: focus on the complaining symptom, exercise and PT, pregabalin The Constitutional Symptoms The Constitutional Symptoms Fever (a real one) Weight loss (significant) Poor appetite Stiffness, rashes (but we already know what these mean) High sedimentation rate, C-reactive protein Anemia What am I thinking? 8
The Differential Lymphoma Infection When I have satisfied these are not present beyond a reasonable doubt: Polymyalgia rheumatica Gout or pseudo gout Vasculitis The Differential Lymphoma Infection When I have satisfied these are not present beyond a reasonable doubt: Polymyalgia rheumatica Gout or pseudo gout Vasculitis Work-up of Fever Related Conditions These are the few rheumatology conditions that can have definitive diagnoses...because a biopsy is paramount. Gout or pseudo gout: require a liquid biopsy of crystals in the synovial fluid. Polymyalgia rheumatica: ok, doesn t require a biopsy, but is exquisitely sensitive to prednisone at a low dose. Vasculitis: has many presentations, so how to tell the difference and make a diagnosis? 9
The Vasculititudes The Vasculititudes Small and medium vessel: purpura, neuritis, nephritis, pulmonitis - can all be biopsied When we see these patients, the work up is working towards tissue, either with lung CTs, NCS, proteinuria analysis Large vessel vasculitis - also needs a biopsy - but morbidity prevents aorta or subclavian biopsy For GCA we need to initially rely on the history and physical jaw claudication: LR of 4.2 diplopia: LR of 3.4 TA beading LR of 4.6 TA prominence LR of 4.3 TA tenderness LR of 2.3 Negative ESR Negative LR of 0.2 The Labs 10
The Anti-nuclear Antigen Can be either ELISA or immunofluorescence based Most commercial labs do ELISA, unless specifically ordered IF gives a pattern, which is helpful But confirmatory antibodies have supplanted this to a degree Classification of Human Epithelial Type 2 Cell Indirect Immunofluoresence Images via Codebook Based Descriptors Arnold Wiliem, http://www.uq.id.au/a.wiliem/datasets/snphep2/index.html Sensitivity and Specificity The ANA test is best performed with a high pre-test probability, like symptoms we have discussed A positive ANA does NOT equal a diagnosis of lupus The differential for positive ANA is high More specific antibodies help to clarify An Example Positive ANA Positive Sm, Chromatin, and RNP: specific for lupus Positive DsDNA: specific for nephritis Low C3 and C4: specific for antibody-antigen complexes ositive SSA: present in lupus, Sjogrens Positive ANCA: likely a false positive 11
An Example Positive ANA Positive Sm, Chromatin, and RNP: specific for lupus Positive DsDNA: specific for nephritis Low C3 and C4: specific for antibody-antigen complexes Positive SSA: present in lupus, but more specific for Sjogrens Positive ANCA: likely a false positive An Example Positive ANA Positive Sm, Chromatin, and RNP: specific for lupus Positive DsDNA: specific for nephritis Low C3 and C4: specific for antibody-antigen complexes Positive SSA: present in lupus, but more specific for Sjogrens Positive ANCA: likely a false positive Approach To Lab Testing Only order when there are symptoms present RA and SLE are clinical diagnoses Any type of vasculitis; I am looking for something to biopsy A positive RF should have a positive CCP to be most helpful A positive ANA should have a positive confirmatory antibody to be most helpful Even if many antibodies are positive, immunosuppression may not be needed, unless symptoms or signs are present There will still be positive ANA's with nothing else to find Undifferentiated Connective Tissue Disease (UCTD) or seronegative non-axial 12
Approach To Lab Testing Only order when there are symptoms present. RA and SLE are clinical diagnoses. Any type of vasculitis; I am looking for something to biopsy. A positive RF should have a positive CCP to be most helpful. A positive ANA should have a positive confirmatory antibody to be most helpful. Even if many antibodies are positive, immunosuppression may not be needed, unless symptoms or signs are present. There will still be positive ANA's with nothing else to find. Undifferentiated Connective Tissue Disease (UCTD) or seronegative non-axial peripheral arthritis. 33% stay the same, 33% have a syndrome present itself, 33% improve with no continuing symptoms. Take Home Points Rheumatology patients can present with many symptoms. The skin can show varying signs of lupus, psoriasis, and vasculitis. Vasculitis will likely be biopsied. The joint exam focuses on inflammatory versus non-inflammatory signs and symptoms. Constitutional symptoms are seen in lymphoma, infection, and rheumatologic conditions. Lab tests are best used for confirmation of diagnoses already suggestive by symptoms. The Review Questions? 13
Question 1 What is the prevalence of rheumatoid arthritis in the USA? A: 1% B: 10% C: 20% D: 50% Question 1 What is the prevalence of rheumatoid arthritis in the USA? A: 1% B: 10% C: 20% D: 50% Rheumatoid arthritis has a prevalence of 1% in the USA, less than gout and OA, but more than lupus and other connective tissue disorders. Question 2 What co-morbidity has a high likelihood ratio with psoriatic arthritis? A: Lymphoma B: Meningitis C: Cardiovascular Disease D: Melanoma 14
Question 2 What co-morbidity has a high likelihood ratio with psoriatic arthritis? A: Lymphoma B: Meningitis C: Cardiovascular Disease D: Melanoma Risk of major adverse cardiovascular events has a LR of 1.2 in patients with psoriatic arthritis, and is even higher in RA patients Question 3 What has the lowest likelihood ratio of biopsy proven giant cell arteritis? A: Presence of jaw claudication B: Absence of fever C: Normal hemoglobin D: Normal sedimentation rate Question 3 What has the lowest likelihood ratio of biopsy proven giant cell arteritis? A: B: C: D: Presence of jaw claudication Absence of fever Normal hemoglobin Normal sedimentation rate The likelihood ratio of biopsy proven giant cell arteritis is 0.4 in patients with a normal ESR 15
Question 4 A patient has a positive ANA, titer 1:160. In which scenario is the diagnosis of lupus most likely to be made? A: B: Patient has fatigue and anemia only. Patient has joint pain with synovitis, photosensitive rash, and proteinuria. C: Patient has hemoptysis, proteinuria, and positive ANCA. D: Patient has full body pain, poor sleep, and recent infection with EBV. Question 4 A patient has a positive ANA, titer 1:160. In which scenario is the diagnosis of lupus most likely to be made? A: B: C: D: Patient has fatigue and anemia only. Patient has joint pain with synovitis, photosensitive rash, and proteinuria. Patient has hemoptysis, proteinuria, and positive ANCA. Patient has full body pain, poor sleep, and recent infection with EBV. Only B meets the criteria for a diagnosis of lupus, while the other cases are all possible causes of positive ANA. Thank You jlacontimd@gmail.com 16