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
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Slide1
Slide2RHEUM UPDATE 2016--II
Laboratory Update
Mark A. McQuillan MD FACP SFHM
June 15, 2016
Slide3DISCLOSURES
None
Slide4Blake Roessler MDDavid A. Fox, Division ChiefW. Joseph McCuneRuba Kado MDJosef Holoshitz MDUMHS RheumatologyWilliam Repaskey MD MFH
Acknowledgements
Slide5Goals
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?
Slide6Update in LABS
Slide7Slide8WESR—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)
Slide9Can 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”
Slide11Dr. 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”
Slide12ESR 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
Slide13ESR 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
Slide14ENA
Sm, Ro, La, RNP
Centromere
Histone
Others
ANA PATTERNS—diffuse, rim, speckled, homogeneous, nucleolar, centromere
?? Significance ??
Slide15Advances in ENA testing
ENA-5
ENA-11
Paraneoplastic panel
Unusual markers
?significance
Slide16ENA staining patterns
Slide17Antinuclear 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
Slide18ENA 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)
Anti-CCP
Antibodies to citrullinated cyclic polypeptides
Early and sensitive indicator of RA
Specificity ?
Confounders:
MCTD
Other Overlap syndromes
Slide20WESR 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
Slide22Vasculitis Update June 2016
William Repaskey MD
Mark A. McQuillan MD FACP SFHM
Slide23OBJECTIVES
Update in classification of Vasculitis
Update in nomenclature
Update in Diagnostic testing interpretation
Case-based
Invitation to question
Slide24Why update classification?
Pathophysiology
Testing
Treatment advantage
Slide25Nomenclature update
Eponymous expungement
Examples
Reactive arthritis
Micro-angiitis
others
Slide26Rheumatology Labs:
C3 normal
CH50 220(H)
P-ANCA positive (1:80)
MPO 1.0 (upper limit of normal 0.9); PR3 negative
Slide27Other Rheum Labs
Slide28Bronchoscopy
Slide29BAL 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…”
Slide31CXR
Slide32Tale 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
Slide33DAH
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
Slide34DAH Causes
Slide35BAL in DAH
Slide36Clinical Classification of Systemic Vasculitis
Slide37Slide38Pauci-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)
Slide39What 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
Slide40ANCA 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
Slide41Three patterns of ANCA
Slide42Slide43Applications of ANCA
Churg-Strauss SyndromeWegener's GranulomatosisMicroscopic PolyangiitisANCA10%80%40 %PR3-ANCA60%20%50%MPO-ANCA30%5%10%Negative
Slide44Microscopic 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
Slide46Churg-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
Slide47References
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.
Slide48Development 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
Slide49Friedrich 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]
Slide50Wegener (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."
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