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Joseph LaConti, M.D., Ph.D.Center for Arthritis and Rheumatic Diseases

Miami, FL

June 29, 2018

Manifestations and Presentations of Collagen Vascular Diseases

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

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• 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.

Reviews and References

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?

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

Female to male ratio

Who Presents With Rheumatologic Problems?

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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.

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Acute or subacute cutaneous lupus - 60-70%

Malar rash and alopecia - 50-60%

Discoid or chronic lupus -30%

Oral ulcers - 15-45%

Of the 11 classification criteria for SLE from ACR guidelines, four are skin related.

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.

Lupus and The Skin

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)

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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 Non-inflammatory

Swelling Minor swelling

Worse in morning Worse after work or with use

Better with movement Worse with movement

Morning stiffness over 1 hour Stiffness less than one hour

Associated with systemic symptoms Associated with metabolic syndrome

Non-weight bearing joints Most load bearing joints

Dramatic response to NSAIDs or steroids Blunted response to NSAIDs or steroids

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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...

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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.

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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

• 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?

The Constitutional Symptoms

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• Lymphoma

• Infection

• When I have satisfied these are not present beyond a reasonable doubt:● Polymyalgia rheumatica

● Gout or pseudo gout

●Vasculitis

The Differential

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?

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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

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The Anti-nuclear Antigen

Classification of Human Epithelial Type 2 Cell Indirect Immunofluoresence Images via Codebook Based DescriptorsArnold Wiliem, http://www.uq.id.au/a.wiliem/datasets/snphep2/index.html

● Can be either ELISA or immuno-fluorescence 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

Sensitivity and Specificity

● The ANA test is best performed with ahigh 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

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An Example

● Positive ANA

● Positive Sm, Chromatin, and RNP: specific for lupus

● Positive DsDNA: specific fornephritis

● Low C3 and C4: specific forantibody-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, andRNP: 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

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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

?

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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

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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: Presence of jaw claudication• B: Absence of fever• C: Normal hemoglobin• D: Normal sedimentation rate

• The likelihood ratio of biopsy proven giant cell arteritis is 0.4 in patients with a normal ESR

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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: Patient has fatigue and anemia only.• B: 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: Patient has fatigue and anemia only.• B: Patient has joint pain with synovitis, photosensiti ve rash, and

proteinuria.• C: Patient has hemoptysis, proteinuria, and positive ANCA.• D: 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