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 RHEUM UPDATE 2016--II Laboratory Update  RHEUM UPDATE 2016--II Laboratory Update

RHEUM UPDATE 2016--II Laboratory Update - PowerPoint Presentation

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RHEUM UPDATE 2016--II Laboratory Update - PPT Presentation

Mark A McQuillan MD FACP SFHM June 15 2016 DISCLOSURES None Blake Roessler MD David A Fox Division Chief W Joseph McCune Ruba Kado MD Josef Holoshitz MD UMHS Rheumatology William Repaskey ID: 774722

anca wegener update vasculitis anca wegener update vasculitis disease pattern sle antibodies granulomatosis ena pr3 syndrome panel patterns patients

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Slide1

Slide2

RHEUM UPDATE 2016--II

Laboratory Update

Mark A. McQuillan MD FACP SFHM

June 15, 2016

Slide3

DISCLOSURES

None

Slide4

Blake Roessler MDDavid A. Fox, Division ChiefW. Joseph McCuneRuba Kado MDJosef Holoshitz MDUMHS RheumatologyWilliam Repaskey MD MFH

Acknowledgements

Slide5

Goals

Rheumatology Labs: how much is reasonable?

What rheum labs are pathognomonic?

(audience top 2 choices)

Costs

How often should the key tests be obtained? Repeated?

What tests are helpful before referral?

What tests are helpful for monitoring?

Local tips for your EMR?

Slide6

Update in LABS

Slide7

Slide8

WESR—sick or not sick?

Causes of falsely Low WESR

Vibration

Timing (RBC alignment and hydrostatic bonds do not necessarily follow a linear response curve)

Anemia (? All types)

Hypofibrinogenemia

Coagulopathy (esp. DIC)

Hemoglobinopathy (Hgb S or S-C)

Muscle Diseases (?mechanism)

Slide9

Can you always follow the WESR?

Certain diseases classically do not have WESR elevation associated with flares…

PM/DM

RA

OA

SD

SSA

PMR ?

Slide10

“Sedimentation” (historic perspective)

ESR described in writings of British Surgeon and Anatomist John Hunter (1728-1793).

Famous for experimental self-inoculation with GC which led to his subsequent fatal co-infection by syphilis

Whose home was supposedly model for “Dr. Jekyll and Mr. Hyde”

Book entitled, “Treatise on the Blood, Inflammation, and Gun-Shot Wounds”

Slide11

Dr. Hunter’s observation on sedimentation:

“…The red globules subsided much faster in the inflammatory blood than in the other…”

Subsequent distinction between “inflammatory fevers” and “symptomatic fevers”

Slide12

ESR measurement

Described by Polish physician Edmund F.

Biernacki

(1866-1911)

Designed glass cylinders

Correlated with fibrinogen level

1897

His studies later associated ESR with RA, TB, fevers, nephritis, hepatic disorders

Slide13

ESR early investigators

1917

Ludwik

Hirszfeld

, Polish microbiologist (malaria)

1918 Robert

Fahraeus

, Swedish hematologist, ESR elevation in pregnancy

Alf

Westergren

, Swedish internist, used sodium citrate as anticoagulant, helpful in prognostication for TB patients

1973, J

Clin

Pathology established

Westergren

method as preferred

Slide14

ENA

Sm, Ro, La, RNP

Centromere

Histone

Others

ANA PATTERNS—diffuse, rim, speckled, homogeneous, nucleolar, centromere

?? Significance ??

Slide15

Advances in ENA testing

ENA-5

ENA-11

Paraneoplastic panel

Unusual markers

?significance

Slide16

ENA staining patterns

Slide17

Antinuclear antibody staining patterns on mouse liver by immunofluorescence.

(Top left panel) There is homogeneous or diffuse staining of the nuclei. The pattern is strongly associated with antibodies to nucleosomes. It is seen in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and drug-induced lupus.

(Top right panel) The peripheral (also called rim) pattern, in which the periphery of the nucleus reacts with the patient's serum. This pattern correlates with antibodies to double-stranded DNA (dsDNA) and nuclear envelope proteins and is suggestive of SLE.

(Bottom left panel) The speckled pattern in which there may be few or many speckles, and small or large speckles. The pattern represents antibodies to the components of extractable nuclear antigens, eg, Smith (SM), ribonucleoprotein (RNP), Ro (SSA), La (SSB) and probably other nuclear antigens. The pattern may be seen in patients with SLE, Sjögren's syndrome, scleroderma, infectious mononucleosis and other conditions, and in normal subjects (especially in low titer).

(Bottom right panel) There is a nucleolar pattern, in which the patient's serum only reacts with the nucleoli. This pattern represents antibodies to nucleolar RNA associated proteins or complexes, and is primarily seen in scleroderma.

Courtesy of Peter H Schur, MD.

Graphic 53431 Version 8.0

Slide18

ENA patterns and associations

Patterns

HomogeneousRimSpeckledNucleolar

Possible Disease Associations

RA, SLE, drug-induced SLE

dsDNA, SLE

Non-specific*

Scleroderma, MCTD

* Smith, Ro, La, RNP

SLE, Sjogren’s, SD, mono,

Normals (low titer)

Slide19

Anti-CCP

Antibodies to citrullinated cyclic polypeptides

Early and sensitive indicator of RA

Specificity ?

Confounders:

MCTD

Other Overlap syndromes

Slide20

WESR vs CRP

CheapTurnaround timeSensitivityPoor specificityFalse low WESRLab interference? Serial values

CRP more costly

More sensitive w IBD

?Serial values

? Less sensitive vs more sensitive

Slide21

“ANCA positive Vasculitis”

MPO

PR3

Slide22

Vasculitis Update June 2016

William Repaskey MD

Mark A. McQuillan MD FACP SFHM

Slide23

OBJECTIVES

Update in classification of Vasculitis

Update in nomenclature

Update in Diagnostic testing interpretation

Case-based

Invitation to question

Slide24

Why update classification?

Pathophysiology

Testing

Treatment advantage

Slide25

Nomenclature update

Eponymous expungement

Examples

Reactive arthritis

Micro-angiitis

others

Slide26

Rheumatology Labs:

C3 normal

CH50 220(H)

P-ANCA positive (1:80)

MPO 1.0 (upper limit of normal 0.9); PR3 negative

Slide27

Other Rheum Labs

Slide28

Bronchoscopy

Slide29

BAL Findings

Slide30

…Encore

ICU Admit 1 week later: “…87

year old male with a recent admission for hemoptysis found to have pseudomonas

on

bronch, who is readmitted with worsened SOB, hemoptysis, and interval worsening of b/l airspace disease on CT concerning for

DAH…”

Slide31

CXR

Slide32

Tale of the Soup

AEC (nl 0-500) 900 on 5/6<-- 1100 in March 2013<-- 1200 in August 2012ENA11 negNAB negANCA neg<---1:80MPO + 4.3<--1.0PR3 neg<--negAnti-GBM negCAB negB2GP1RF 33<---10hep C neganti ccp 5ck 54esr 100 <--75crp 22 <--4.5c3 116c4 22UA no blood, no protein. initial UA 6-10 RBC

Slide33

DAH

Not

a specific disorder, but a

syndrome

Persistent

or recurrent pulmonary hemorrhage. A

utoimmune

disorders

most

common.

dyspnea

, cough, hemoptysis, and new alveolar infiltrates on chest

imaging

Hemoptysis absent

in up to one third of

patients

(most w/ anemia, dropping hct)

Symptoms

, signs, and chest-x-ray findings are not

specific

BAL shows

persistent/increasing

 hemorrhage with sequential lavage

samples

and

hemosiderin-laden macrophages

Slide34

DAH Causes

Slide35

BAL in DAH

Slide36

Clinical Classification of Systemic Vasculitis

Slide37

Slide38

Pauci-Immune Small Vessel Vasculitides (name changes)

Microscopic polyangiitis (MPA

) aka PAN

Granulomatosis

with polyangiitis (GPA, formerly known as Wegener

granulomatosis), as of 2011 ACCP editorial;

(in 2000 WG had been renamed “ANCA-associated Granulomatous Vasculitis” when ACCP identified Wegener’s Nazi past and rescinded the “master clinician” award bestowed in 1989

Eosinophilic

granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss

syndrome)

Slide39

What are ANCAs?

Anti-neutrophil cytoplasmic antibodiesAntibodies against myeloperoxidase (MPO-ANCA) and Proteinase 3 (PR3-ANCA)MPO & PR3 are found in the azurophilic granules of neutrophils and the lysosomes of monocytes.ANCAs are autoantibodies Therefore ANCA-associated vasculitis is an autoimmune disease

John H. Stone, MD, MPH

Slide40

ANCA testing

Although particular ANCAs are linked with particular diseases, it is possible to be ANCA + without manifesting a disease syndrome, and it is possible to manifest a traditional ANCA-associated vasculitis without + ANCAs

Any of the ANCA-associated vasculitides can be associated with either type of ANCA or no ANCAs at all.

Other autoimmune disease can be ANCA positive, at least on immunofluorescence

Slide41

Three patterns of ANCA

Slide42

Slide43

Applications of ANCA

Churg-Strauss SyndromeWegener's GranulomatosisMicroscopic PolyangiitisANCA10%80%40 %PR3-ANCA60%20%50%MPO-ANCA30%5%10%Negative

Slide44

Microscopic Polyangiitis

Most common ANCA vasculitis (though rare:

13 to 19

cases/million)

Median age ~ 50s

Vasculitis of small and medium sized arteries

No granulomas.

60% of patients are ANCA-positive, usually perinuclear ANCA (p-ANCA) with antibodies against

myeloperoxidase but

can be PR3-ANCA and, rarely, ANCA negative

Slide45

“Pauci-immune” (ie, immune globulin deposition is not seen on tissue biopsy)Differentiates from immune complex-mediated small-vessel vasculitides (eg, immunoglobulin A–associated vasculitis—formerly known as Henoch-Schönlein purpura)Older literature (ie, before 1994) did not adequately distinguish between polyarteritis nodosa and MPA―alveolar hemorrhage and glomerulonephritis can occur in MPA but not in polyarteritis nodosa.

More MPA

Slide46

Churg-Strauss Syndrome

Allergic Granulomatosis and angiitisVasculitis of small and medium sized arteriesNecrotizing vasculitisBuilds over years until full presentation as it progresses through the following phases:Prodromal Phase- teens-20sAllergic rhinitisAsthmaEosinophilic phaseVasculitic phase as early as 20s-30s, but mean age is 50s

Curr Opin Rheumatol. 2010;22(1):21-8

Slide47

References

Al-Saadi, A. In

: Clinical immunology principles and practice RICH, 2nd

edition Methodological

update

ANCA.mht, 2008

Schrier, P. In:

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis and Anti-Glomerular Basement Membrane Antibody

Glomerulonephritis, PPT, 2011

Gota, C. In : The Merck Manual, 2012

Stone, J. In: UpToDate, 2013.

Slide48

Development of ANCA

Theory of molecular mimicry.Superantigens have the power to stimulate a strong immune response . THEY have regions that resemble self-antigens – this is the theory of molecular mimicry.classical example in post group A streptococcal rheumatic heart disease, where there is similarity between M proteins of Streptococcus pyogenes to cardiac myosin and laminin.

Theory of defective apoptosis.ANCA may be developed either via ineffective apoptosis or ineffective removal of apoptotic cell fragments, leading to the exposure of the immune system to molecules normally sequestered inside the cells. This theory solves the paradox of how it could be possible for antibodies to be raised against the intracellular antigenic targets of ANCA.[4]

Methodological update ANCA.mht

Slide49

Friedrich Wegener

Friedrich Wegener (born 1907 in Varel – July 9, 1990, Lübeck) was a German pathologist who is notable for his description of a rare disease. Although this disease was known before Wegener's description, since the 1950s it has been called by the name Wegener's granulomatosis.[1]

Wegener joined the Nazi Party in 1932.[1] As a relatively high-ranking military doctor, he spent some of World War II in a medical office three blocks from the Łódź Ghetto, a Jewish ghetto in Łódź, Poland.[1] There is speculation that he participated in experiments on concentration camp inmates.[1]

The American College of Chest Physicians (ACCP) awarded Wegener a “master clinician” prize in 1989.[1] After his Nazi past was discovered in 2000, the ACCP rescinded the prize and, separately, a campaign was begun to rename Wegener's granulomatosis to ANCA-associated granulomatous vasculitis.[1] More recently, several journals proposed the name 'granulomatosis with polyangiitis' in a 2011 editorial.[2]

Slide50

Wegener (cont’d.)

"The facts we have uncovered do not prove Dr Friedrich Wegener guilty of war crimes. However, the evidence suggests that Dr Wegener was, at least at some point of his career, a follower of the Nazi regime. Dr Wegener’s mentor, Martin Staemmler, was an ardent supporter of the racial hygiene. In addition, our data indicate that Dr Wegener was wanted by Polish authorities and that his files were forwarded to the United Nations War Crimes Commission. Finally, Dr Wegener worked in close proximity to the genocide machinery in Lodz."

[8

]

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