NAS Session 1 Fan Case studies in Rheumatic Disease

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes.

Case 1• Bilateral wrist pains for several years; now building a cabin— He fell on his outstretched hand a few

years ago (which hand not specified)— Bilateral wrist pain located at radial aspect— No pain during work; pain in the evening

without numbness and tingling but with stiffness at night

— Pain worse with gripping the steering wheel

— No loss of range of motion — Otherwise healthy except for mild

essential tremors

Name: KWAge: 59Occupation: Retired punch press operator

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• Naproxen sodium (OTC) taken once or twice a week completely alleviates pain for a day after each dose

• Acetaminophen did not help • He takes glucosamine/chondroitin sulfate

Treatment:

• No swelling, redness or ecchymosis• No wasting of thenar or hypothenar muscles• Normal flexion, extension, ulnar and radial deviation of the wrist

• No bony tenderness on palpation

Physical exam:

Case 17


Case 18


Case 19



Case 111

Osteoarthritis of the first carpometacarpal joint

3-4 x higher in women

Osteoarthritis of the hands is 3‐4× more prevalent in women

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Osteoarthritis:Heberden’s nodes and Bouchard’s nodes

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Genetics of osteoarthritis

Sisters of women with Heberden’s nodes were 3× as likely to have

generalized osteoarthritis as those in the general population: Stecher, 1941

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Case 2• She moved to a new home in the past

month • A lot of carrying boxes, twisting open

jars, packing• Some neck pain and tingling down the

arm• She does not play tennis, golf, or other

sports• She did not fall or injure her arm recently• She is right‐handed• She smokes 1/2 PPD × 15 years

Name: JDAge: 53Chief complaint: Right elbow pain

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•Overweight•Neck shows full ROM, slight tenderness in trapezius, no muscle spasm; no muscle weakness or sensory loss

•Right elbow full ROM, no swelling or redness, no pain on supination or pronation

•No pain with forceful extension of the elbow•Tenderness of the lateral epicondyle at full extension but not at 90‐degree flexion

•No tenderness of the proximal wrist extensor mass

•Pain with resisted wrist extension

Physical exam


Case 216

Case 2

UpToDate: 2018

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Case 2

UpToDate: 2018


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Tennis elbow (lateral epicondylitis)20

Treatment

• Activity modifications• Counterforce brace• Topical and oral NSAIDs • Passive range of motion in terminal extension and flexion with light strengthening

• Core strengthening

UpToDate: 2018

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Secondary treatment

• Corticosteroid injections

• Iontophoresis

• Platelet‐rich plasma injections1

• Autologous blood injections with ultrasound

• Acupuncture

• Botox

• Prolotherapy

UpToDate: 2018

(1) Arirachakaran A, J. Orthop Traumatol 2016;17:101

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Posterior interosseous nerve entrapment

• Weakness of finger extensors• Pain with forced extension of middle finger

• More severe – weakness in forearm supination and medial deviation of the wrist2

Nerve Entrapment Syndromes1

(1) Robert J Spinner, iKnowledge 2015. (2) Barnum M, et al. Hand Clin 1996;12:679

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Cervical radiculopathy• Neck, shoulder, or arm pain• Muscle weakness• Sensory symptoms – numbness and tingling

• Diminished deep tendon reflexes• C7 most frequent – 70%• C6 – 20%• C5, 8, T1 ‐10%• Danger signals for cervical cord compression— Lhermitte sign— Gait disturbance, usually insidious Frank Netter. Ciba‐Geigy Collection

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Pancoast tumor with brachial plexopathy

Wikipedia 2018

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Case 3• SF complains of pain and swelling in her fingers and wrists for 4 months — She has generalized stiffness for

over an hour in the morning— She sleeps poorly and has severe

fatigue— Her hands feel weak and she

cannot grip objects without pain— She denies pain in her ankles or

feet

Name: SFAge: 33Family: Three kids

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Physical examination

• Tenderness and swelling of the wrists, MCP and PIP joints

• DIP joints are not tender or swollen• She cannot make a full fist, limited flexion and extension of her wrists

• No swelling of the ankles or feet• Slight tenderness of shoulders and elbows with normal ROM


Case 327


Case 3


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Synovitis

• Swelling is confined to the area of the joint capsule

• Synovial thickening feels like a firm sponge

• Early involvement of hands and feet

• Morning stiffness lasting over 30 min

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Rheumatoid arthritis: Joint distribution

• Symmetric polyarthritis• Corresponds to the distribution of synovial lined joints

• Note absence of axial involvement except at C1‐2

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Radionuclide scan in early RA 31


Case 3Labs Normal CBC and comprehensive

metabolic panel

ESR 35 mm/hour; CRP positive at 35 mg/L

Positive IgM RF at 65 units (N 0.0 – 25.0 I.U.)

Positive anti‐CCP at >100 units (N 0.0 – 6.9 units)

ANA positive at 1:320


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Rheumatoid factors

• Rheumatoid factor = antibody directed at the Fc portion of IgG

• Found in 75‐80% of RA patients

• Typical antibody detected is IgM

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RF is not a good screening test for RA

• Positive predictive value of 28%• Positive in 5% of the general population• May be negative in rheumatoid arthritis • Positive in other diseases• May be negative early and positive later

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Anti‐CCP antibody (ACPA) (antibody to cyclic‐citrullinated peptide)

Citrulline is a post-translational amino-acidConverted from arginine in the peripheral

tissues (especially in the lungs)

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Anti‐CCP antibody (cyclic‐citrullinated peptide) • A better and more specific assay than RF • Sensitivity 60‐70 (66.4)%, specificity ?100(98.3)% (active TB – 7‐39%)

• Present in early and preclinical disease (up to 14 years) IgA antibodies to enolase, fibrinogen, histone H2B

• Correlates with increased risk for progressive joint damage (contested)

• Does not correlate with fluctuation of RF Tan, YC, et al. Arth Rheum 2014;66:2706

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Rheumatoid factor, anti‐CCP and RA• 15% are persistently RF‐negative and tend to have milder disease• Anti‐citrulline antibody may be positive in RF‐negative patients• Combination of + RF and anti‐CCP in early RA predicts high risk for persistent RA— Smolen J, Aletaha D. Nature Rev Rheum 2015

• A new marker 14‐3‐3 η (eta) improves diagnostic sensitivity from 60‐91% for either RF or anti‐CCP to 72‐100 with either one of 3 markers.— Maksymowych W, et al. Arth Res Ther 2014;16:R99

• Another new diagnostic test in development is anti‐carbamylated protein antibody (anti‐CarP) — Li L, et al. PLoS One. 2016 Jul 20;11(7):e0159000

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Rheumatoid arthritis and positive ANA

• 15‐35% of RA patients have a positive ANA • Patients are clinically similar to RA patients with negative ANA

• They do not go on to develop systemic lupus erythematosus

Caspi D, et al. Rheumatol Int. 2001 Feb;20(2):43‐7.

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Rheumatoid arthritis with positive ANA

• Patients with positive rheumatoid factor and anti‐CCP are not clinically different if they also have positive ANA

• They are NOT a mixture of RA and SLE • Those who are ANA positive and RF and anti‐CCP negative have milder joint disease and better prognosis

Saudan‐Kister, A, et al. Rev Rhum Engl Ed. 1996 May;63(5):313‐20.

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Normal Joint

Difference between normal joint and joint affected by rheumatoid arthritis

Adapted from US Department of Health and Human Services Handout on Health. Publication 04-4179.

MuscleCartilage

Tendon

Bone

Joint Capsule

Synovial FluidSynovium

Cartilage Loss

Bone Loss(Generalized)

Swollen Joint Capsule

InflamedSynovium

Bone Loss/Erosion

Joint Affected by RA

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The value of x‐rays in rheumatoid arthritis

• For a Symmetric polyarthritis that satisfies ARA Criteria for rheumatoid arthritis:

• Perform X‐rays of the hands and feet

• Repeat them at 1 year or sooner if the disease is not controlled

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25% of patients in an early arthritis clinic already had erosions at the first visit

474 patients seen in an early RA clinic; 141 had definite or probable RA

0102030405060708090

<30 days <1 year

Duration of SymptomsErosions Present

Van der Horst‐Bruinsma, et al. Br. J Rheumatol 1998;37:1084

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Joint erosions occur early in rheumatoid arthritis

van der Heijde DM, et al. J Rheumatol. 1995;22:1792‐1796. Fuchs HA, et al. J Rheumatol. 1989;16:585‐591. McQueen FM, et al. Ann Rheum Dis. 1998;57:350‐356.

Year

0

10

20

30

0 1 2 3

Maxim

um Percentage of Jo

ints

Affected

Metatarsophalangeal joint

Total

Hand

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Rheumatoid arthritis

• Early erosion at the tip of the ulnar styloid

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Radiographic progression of joint erosions

6 Months 1 Year

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Rheumatoid arthritisFrequency distribution of erosions in the foot

Arthritis Care Res 2008;59:1729

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Rheumatoid arthritis

A. Soft‐tissue swelling, no erosions

B. Thinning of the cortex on the radial side and minimal joint space narrowing

C. Marginal erosion at the radial side of the metacarpal head with joint space narrowing

How fast is joint damage progressing?

ACR Clinical Slide Collection, 1997.

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Magnetic resonance imaging as a diagnostic tool

McQueen FM, et al. Ann Rheum Dis. 1999;58:156–163; McQueen FM, et al. Ann Rheum Dis. 1998;57:350–356.

X‐ray MRI

Erosions Detected:X‐rays vs MRI

14

4550

0

Percen

t of Erosions

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MRI scan of the MCP joints as an index of disease progression in RA

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MRI scan of the feet in Early RA

Erosions at 5th MTP

Tenosynovitis between toes

High sensitivity: 97% synovitis, 80% erosions

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Diagnosis of RA: Utility of UltrasonographyHealthy Subject

RA Patient

* *

*Erosion; mc = metacarpal head; ph = phalanx.Grassi W, et al. Ann Rheum Dis. 2001;60:98–103.

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Diagnosis of RA: Utility of ultrasonography:Power doppler measures vascularity

AOM: Area of measurementAOC: Area of calibration

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Ultrasonography detects more erosions in early RA

Wakefield RJ, et al. Arthritis Rheum. 2000;43:2762–2770.

0

10

20

30

40

50

60

Thumb 2nd 3rd 4th 5th

No. of E

rosion

s

MCP Joints

X‐ray

Sonography

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ACR recommendations: Early aggressive treatment of RA

50% to 70% of patients have radiographic damage within the first

2 years of disease onset2,3

Critical window of opportunity

Early Established End Stage

Disease onset

1. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:328‐346.

2. van der Heijde DM. Br J Rheumatol.1995:34(suppl 2):74‐78.3. Sundy SS, St Clair EW. J Musculoskel Med. 2002;19:395‐403.

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Altering the Natural Course of RA

Popu

latio

n x-

ray

scor

e

Disease duration (time)

Prevents progression

Natural course

RA untreated

Intervention

StructuralDamage

Progression

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NSAIDs are useful earlier on to relieve symptoms

Patie

nts (%) 29

40*44*

36*

0

10

20

30

40

50

Placebo (n=231)

Celecoxib 100 mg bid(n=240)

Celecoxib 200 mg bid(n=235)

Naproxen 500 mg bid(n=225)

*P<.05 vs placebo.RA=rheumatoid arthritis; ACR=American College of Rheumatology.Simon et al. JAMA. 1999;282:1921‐1928.

All NSAIDs and COX-2 inhibitors perform equally

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Managing RA • Methotrexate is the drug of choice

— Start when RA is confirmed— 7.5mg weekly for first week and then 15mg weekly for a

month and then 20mg weekly; maximum dose may be 25mg — SQ may work when oral MTX is not too effective –

auto‐injectors available— Folic acid 1mg daily but skip it on the day that the patient

takes methotrexate: reduces nausea, GI distress, fatigue and oral ulcers. Leucovorin may work for more sensitive patients

— Liver function tests every 4 weeks and after 6 months every 6 weeks

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Managing RA • Methotrexate is the drug of choice

— Restrict alcohol to 3 drinks a week?•No ↑ LFT in Bri sh study (under 14 units a week) (1 unit = 10ml or 8g)

— MTX has a slow onset but rapid loss of effect upon withdrawal

— 3 months may be needed for adequate trial— RBC MTX polyglutamates may monitor tissue levels

but not efficacy— Liver biopsy is not needed at 1500mg total dose— Induces remission in about 1/3 of patients with early

RA

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Managing RA • Sulfasalazine

— Alternative in hepatitis B and hepatitis C positive patients

— Start with 500mg twice a day and build up to max 4 g daily

—May take 2 months to show a benefit— Follow CBC in 4 weeks and liver function tests and

then every 3 months— Severe neutropenia may occur within 1 month and

also years later*—May cause reduced sperm count

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Managing RA

Hydroxychloroquine• May be useful in RF‐ and anti‐CCP – patients

• Eye examination baseline then after 5 years

• Reduce dosage to 5mg/kg/d actual body weight at 5 years

• May show efficacy combined with MTX and SSZ

Leflunomide• An alternative to MTX; may have synergistic benefit combined with MTX

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HCQ retinal toxicity

“Bull’s eye retinopathy”

SD‐OCT: thinning of retina Alternative is mfERGCumulative risk is >1000 grams; >1% risk after 5‐7 years

10% risk at 10 years!New guidelines: use 5mg/kg/d of actual weight after 5 years

Marmor M. J Curr Ophthalmol. 2017 Sep; 29(3): 143–144

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Managing RA • Corticosteroids

— Intra‐articular or tendon injections useful any time during course of disease

— High dose prednisone with rapid taper may be effective but controversial

— Low‐dose prednisone may be disease modifying (5mg daily)— Slow taper with improvement is reasonable— Long term treatment with low‐dose prednisone show higher

mortality at 10 years: infections and amyloidosis (Finland study 2006)

— Use a bisphosphonate to prevent GIO

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Ann Intern Med. 2012;156(5):329‐339.

Low‐dose prednisone inclusion in a methotrexate‐based, tight control strategy for early rheumatoid arthritis: A randomized trial

1

2

3

4

5

6

7

10

20

30

40

50

60

0.2

0.4

0.6

0.8

1.0

1.2

1.4

5

10

15

20

25

30

35

40

0 4 8 12 16 20

0 4 8 12 16 200 4 8 12 16 20

0 4 8 12 16 20

Mea

n DA

S28

Mea

n VA

S for P

ain, m

m

Mea

n HAQ

Mea

n ESR, m

m/h

Time, mo Time, mo

MTXPlacebo

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Date of download: 12/22/2014

Ann Intern Med. 2012;156(5):329-339. doi:10.7326/0003-4819-156-5-201203060-00004

Individual patients' erosion scores.

Totals of 112 and 110 patients were analyzed for the MTX and prednisone group and the MTX and

placebo group, respectively. Arrows with percentages show the proportion of patients

within each treatment strategy with no erosions at 2 y. MTX = methotrexate.

Copyright © American College of Physicians. All rights reserved.

Low‐Dose prednisone inclusion in a methotrexate‐based, tight control strategy for early rheumatoid arthritis: A Randomized Trial

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Managing RA

• Corticosteroids —Major risk for osteoporotic spine fractures early in

treatment — Higher risk for infection, herpes zoster, tuberculosis— Never use it alone, claims that it is disease‐modifying

are weak and confined to slight reduction in erosions on X‐rays over 4 years

— Most low‐dose data do not show benefit beyond one year

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Diet and RA

• 24% of 217 patients with RA (disease duration 17 years) reported that certain foods affect disease activity— Improved symptoms: blueberries, fish, spinach— Exacerbated symptoms: desserts, soda with sugar

• Improved symptoms: younger age, sleep, warmer room temperatures, vitamin / mineral supplements

• DAS and medications used had no effect• 58% using a biologic agentTedeschi SK, et al. Arth Care Res February 19, 2017

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RA MANAGEMENT: The biologic response modifiers


Synoviocytes

The integrated immune response and pathogenesis of RA

B cell

MΦ

Immune complexesComplement fixationAttract inflammatory

cell infiltrates

Cytokines

Pannus

Articularcartilage

CytokinesMetalloproteinases

IL‐6and other cytokines

IL‐6 and other cytokines Plasma cell

Antigen‐presentingcells (APCs)– B cells– Dendritic cells– Macrophages

OsteoclastChondrocytes

Production of metalloproteinases and other effector moleculesMigration of polymorphonuclear cells

Erosion of bone and cartilage

Rheumatoid factor (RF),anti–cyclic citrullinated peptide

(anti‐CCP) antibodies

T cellAPC

Adapted from Smolen and Steiner. Nature Rev Drug Discov. 2003;2:473; Choy and Panayi. N Engl J Med. 2001;344:907; Silverman and Carson. Arthritis Res Ther. 2003;5(suppl 4):S1.

Biological Agents in RA

Anti‐TNF • Etanercept • Infliximab • Adalimumab • Certolizumab • Golimumab

IL‐1 blockade• Anakinra

T cell modulation• Abatacept

B cell depletion• Rituximab

IL‐6 inhibition• Tocilizumab• Sarilumab

JAK inhibition• Tofacitinib• Baricitinib

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Anti‐TNF in RA • Works best in combination with MTX even in MTX failures: don’t stop MTX when you add a TNF inhibitor

• The earlier you treat the better the outcome• Always perform a screen for latent TB before starting treatment: PPD skin test, Quantiferon‐Gold, chest X‐rays

• Give INH for 4 weeks before starting anti‐TNF agent and continue for 9 months

• Consider Rifampin for recent immigrants from INH‐resistant countries: Vietnam, Peru

• Watch out for serious infections, the clinical picture may be much subdued

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NAS Session 1 Fan Case studies in Rheumatic Disease

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