Transcript Rare

Rheumatic Disease
and
HIV Infection
Dr M Jokar
‫اهداف‬
‫• هدف کلی‪ :‬آشنایی با انواع عالئم روماتیسمی در جریان‬
‫‪HIV‬‬
‫• اهداف جزئی‪:‬‬
‫‪ o‬آشنایی با ‪Painful articular syndrome‬‬
‫‪ o‬آشنایی با ‪HIV–associated arthritis‬‬
‫‪ o‬آشنایی با آرتریت پسوریاتیک در مبتالیان به عفونت ‪HIV‬‬
‫‪ o‬آشنایی با ‪DILS‬‬
‫‪ o‬آشنایی با درگیری عضالت در جریان ‪HIV‬‬
HIV
• Myriad of clinical manifestations
affecting every organ system
• Rheumatic manifestations can occur
in late stages or be the first
presenting symptom
– Frequency 1-60% – varies with
ethnicity, geography, HIV stage,
antiretroviral treatment
Articular considerations in HIV
Unique to
HIV
Altered by HIV
Painful articular
syndrome
Reactive Arthritis
HIV–associated
arthritis
Psoriatic arthritis
DILS
Polymyositis
Zidovudineassociated
myopathy
Undifferentiated
spondyloarthropathy
Vasculitis
Infectious arthritis
(bacterial, fungal)
Possibly
ameliorated by HIV
Rheumatoid Arthritis
SLE
PAINFUL ARTICULAR
SYNDROME
• Severe bone and joint pain
• Self-limited syndrome
• Lasting less than 24 hours
• Few objective clinical findings
• Late stages of HIV infection
• Knee, elbow, shoulders
HIV ASSOCIATED ARTHRITIS
• Oligoarthritis
• Lower extremities
• Self-limited
• Lasting less than 6 weeks
• Knees, ankles, metatarsophalangeal joints,
wrists , elbows, metacarpophalangeal ,
interphalangeal joints
REACTIVE ARTHRITIS
PSORIATIC ARTHRITIS
• Psoriatic rash can be
extensive
• Arthritis is
predominantly
polyarticular, lower
limb, and
progressive
Diffuse infiltrative lymphocytosis syndrome
(DILS)
• Sjogren’s-like disease
– Significant, painless parotid gland
enlargement
– Sicca symptoms – xerostomia
– Anti-SSA, Anti-SSB negative
– CD8 inflammatory infiltrate
– Prominent extraglandular symptoms including
RTA, PM, lymphocytic hepatitis, lymphoma,
VII nerve palsy
Myopathies
• Myalgias – associated with viremia, FMS
• PM – with signs/symptoms similar to HIV
negative patient but ? milder;
with/without skin disease
• Zidovudine- associated myopathy
‫خالصه‬
‫در مبتالیان به عفونت ‪ HIV‬سندرمهای روماتیسمی مختلفی‬
‫دیده می شود که مهمترین آنها عبارتند از‪:‬‬
‫‪• Painful articular syndrome‬‬
‫‪• HIV–associated arthritis‬‬
‫‪• DILS‬‬
‫‪• Polymyositis‬‬
Common Rheumatologic Tests:
Evaluation and Interpretation
Dr M. Jokar
‫اهداف‬
‫هدف کلی‪ :‬آشنانی با تفسیر تست های آزمایشگاهی در‬
‫بیماریهای روماتیسمی‬
‫اهداف جزئی‪:‬‬
‫• آشنایی با تفسیر ‪ CBC‬در بیماریهای روماتیسمی‬
‫• آشنایی با تفسیر پروتئین های فاز حاد در بیماریهای‬
‫روماتیسمی‬
‫• آشنایی با تفسیر اتوآنتی بادیها در بیماریهای روماتیسمی‬
‫• آشنایی با تجزیه مایع مفصلی در بیماریهای روماتیسمی‬
indication for a test
1. Screen for a particular disease
2. Help confirm a specific diagnosis
3. Evaluate disease activity
4. Assess for target organ involvement
5. Monitor for drug toxicity
16
Before …….
• Interpret a test result
1.Sensitivity
2.Specificity
3.positive and negative
predictive values
17
• Sensitivity
– Proportion of patients with a disease who
have a positive test result
• Specificity
– Proportion of persons without a disease who
have a negative test result
• Predictive value
– likelihood or lack of the disease based on a
positive or negative test result
– Negative predictive value (NPV)
• True negative/(true negative + false negative)
– Positive predictive value (PPV)
• True positive/(true positive + false positive)
CBC
• Leukocytosis
• Leukopenia
• Lymphocytosis
• Lymphopenia
CBC
• Anemia
1. Anemia of chronic di.
2. Hemolytic anemia
3. Iron de.
4. Megaloblastic anemia
CBC
• Thrombocytosis
• Thrombocytopenia
Acute phase reactants
• Heterogeneous group of proteins
synthesized in liver in response to
inflammation
– Fibrinogen
– Serum Amyloid A
– Haptoglobin
– C-reactive protein
– Alpha-1-antitrypsin
Acute phase protein response
Adapted from Gitlin JD, Colten HR in Pick E, Landy M [eds]: Lymphokines.14;123,1987.
Common markers of inflammation
• ESR
– Indirect measure of changes in acutephase reactants and quantitative Igs
Mechanism of elevated ESR
• If higher concentration of asymmetrically
charged acute-phase protein or
hypergammaglobulinemia occurs,
dielectric constant of plasma increases and
dissipates inter-RBC repulsive forces, leads
to closer aggregation of RBCs, so they fall
faster, and cause ESR elevation
Noninflammatory conditions with
elevated ESR
• Aging
• Female sex
• Obesity
• Pregnancy
Rule of thumb
• Age-adjusted upper limit normal for ESR
– Male: age/2
– Female: (age + 10)/2
Causes of markedly elevated
ESR
• ESR >100
– Infection, bacterial
– CTD (GCA, PMR, SLE, vasculitides
– Malignancy: lymphomas, myeloma, etc
– Other causes
Causes of extremely low
ESR
• ESR ~ 0mm/hr
– Agammaglobulinemia
– Afibrinogenemia/dysfibrinogemia
– Extreme polycythemia (Hematocrit
>65%)
– Increased plasma viscosity
C-reactive protein (CRP)
• Acute phase reactant produced by liver
– Response to IL-6, other cytokines
• Rises and falls quickly
– Elevation within 4 hr of tissue injury
– Peak at 24-72 hr
– Half-life ~18 hr
Rule of thumb
• CRP <0.2 mg/dL: normal
• CRP 0.2-1.0 mg/dL: indeterminate
(may be seen in smoking, DM)
• CRP >1.0 mg/dL: inflammatory
• Levels > 10mg/dL suggest bacterial
infection (up to 85%), or possibly
systemic vasculitis, metastatic cancer
Antinuclear antibodies
(ANA)
Current ANA measurement
• Fluorescence microscopy
– HEp-2 cells (derived from human epithelial
tumor cell line) incubated with pt’s serum
– Fluoresceinated Ab added, binds to pt’s Abs
bound to nucleus
ANA
• High sensitivity in SLE, but poor specificity
• Positive ANA has predictive value of only
11%
• ANA found in 5-10% of pts without CTD
– Healthy pts, chronic infections (e.g., Hep C),
multiple meds, etc.
ANA
• Condition
–
–
–
–
–
–
–
SLE
Drug induced lupus
MCTD
Autoimmune liver dz
Sjogren’s syndrome
Polymyositis
RA
• % ANA-positive
–
–
–
–
–
–
–
99%
95-100%
95-100%
60-100%
75-90%
30-80%
30-50%
ANA
• Condition
– Multiple sclerosis
– Pts with silicone breast
implants
– Healthy relatives of pts
with SLE
– Neoplasms
– Normal elderly (>70
yrs)
• % ANA-positive
– 25%
– 15-25%
– 20%
ANA
• Is the ANA a good screening test for
SLE?
– If entire population was screened, more
normal individuals would be detected with
positive ANA than SLE pts. by ~50:1
ANA
• Clinical value of ordering an ANA test can
be dramatically enhanced when there is a
reasonable pre-test probability of an
autoimmune disease
ANA patterns
• Homogeneous (diffuse)
– SLE, drug-induced SLE, other diseases
ANA patterns
• Rim (peripheral)
– SLE, autoimmune hepatitis
ANA patterns
• Speckled
– SLE, MCTD, Sjogren’s, Scleroderma, other dz
ANA patterns
• Nucleolar
– Scleroderma, hepatocellular carcinoma
ANA profile
• If screening ANA is positive and additional
info needed to further delineate type of
autoimmune disease
• In extremely rare instances, ANA may be
negative but SS-A antibodies may be
detected in pts. with an SS-A associated
disease
ANA Profile
dsDN
A
RNP
Sm
SS-A
SS-B
CENTROMERE
SLE
60%
30%
30%
30%
15%
Rare
RA
(-)
(-)
(-)
Rare
Rare
(-)
MCTD
(-)
>95% (-)
Rare
Rare
Rare
Scleroder
ma
(-)
Low
titer
(-)
Rare
Rare
10-15%
CREST
(-)
(-)
(-)
(-)
(-)
60-90%
Sjogren’s
(-)
Rare
(-)
70%
60%
(-)
Antiphospholipid antibodies
• Heterogeneous group of Ab that bind to
plasma proteins, have affinity for
phospholipid surfaces
– Anticardiolipin Ab (ACL)
– Lupus anticoagulant (LAC)
– Beta 2-glycoprotein I
Antiphospholipid antibodies
• ACL measured by ELISA assay for IgG,
IgM, and IgA isotypes
• LAC measured by phospholipid-dependent
screening test, if prolonged, add 1:1 mix
with normal plasma - if no correction, LAC
present
• Beta 2-glycoprotein I measured by ELISA
Antiphospholipid antibodies
• Conditions with positive aPL
– ~8% normal population
– chronic infections e.g., HIV, Hep C
– Medications e.g., phenothiazines, hydralazine,
phenytoin, procainamide, quinidine
– ~20% pts. with systemic vasculitis
– ~15% pts. with recurrent miscarriage
– ~50% pts. with SLE
Antiphospholipid antibodies
• ~50% pts. with SLE and aPL will develop
a thrombotic event
• ~3-7% pts. per year who have aPL will
experience a new thrombotic event
• Overall positive predictive value of an aPL
for future CVA, venous thrombosis, or
recurrent MC is between 10-25%
Anticytoplasmic Antibodies
• Often more helpful in diagnosis than
antibodies against nuclear antigens
• Seen with multiple autoimmune diseases
and several forms of vasculitis
Anticytoplasmic antibodies
Disease
Cytoplasmic
Antigen
Frequency
Polymyositis
tRNA synthetase
(anti-Jo-1, etc)
20-30%
SLE
Ribosomal P
5-10%
Wegener’s
granulomatosis
Serine
proteinase-3
(in neutrophils)
Myeloperoxidase
(in neutrophils)
Mitochondria
90%
Microscopic
polyarteritis
Primary biliary
cirrhosis
70%
80%
Anti-neutrophil cytoplasmic
Antibodies (ANCA)
• C-ANCA
– Most commonly seen in Wegener’s
granulomatosis, microscopic polyarteritis,
rarely Churg-Strauss vasculitis
ANCA
• P-ANCA
– seen in multiple diseases as well as vasculitis
P-ANCA
• MPO positive
– Microscopic
polyarteritis
– Pauci-immune GN
– Churg-Strauss
vasculitis
– Drug-induced
syndromes
• MPO negative
–
–
–
–
Ulcerative colitis
Autoimmune disease
HIV
Chronic infections or
neoplasms (rare)
ANCA
• If pt. tests positive to ANCA, evaluation of
specific antigen testing for MPO and PR3
should be undertaken
• If C-ANCA is not against PR3 or P-ANCA is
not against MPO, must consider causes
other than vasculitis
Rheumatoid factor (RF)
• Autoantibody directed against the Fc
(constant) region of an IgG molecule
– Multiple isotypes, including IgM, IgG, IgA, and
IgE
– IgM RF is routinely measured using latex
agglutination titers, nephelometry, and ELISA
Rheumatoid factor
• Very low levels normal, but higher
production secondary to chronic immune
stimulation
• RF positive in ~80% of patients with RA
• Multiple other causes of positive RF
Conditions associated with a
positive RF
• Rheumatologic diseases • Non-rheumatologic
–
–
–
–
–
–
RA (80-85%)
Sjogren’s (75-95%)
MCTD (50-60%)
Scleroderma (20-30%)
Sarcoidosis (15%)
Polymyositis (5-10%)
conditions
–
–
–
–
–
Chronic hepatitis
Pulmonary disease
Neoplasms
Aging
Cryoglobulinemia
(40-100%)
– Infections
• AIDS, Mono, TB, syphilis,
parasites, endocarditis
Frequency of RF positivity in
normal population
• AGE
• Frequency of +RF
– 20-60 years
– 2-4%
– 60-70 years
– 5%
– >70 years
– 10-25%
Anti-CCP antibodies
• High specificity and moderate
sensitivity for RA
Anti-CCP antibodies
• Sensitivity 68% for RA
• Specificity 98% for RA
• Can be seen in active TB, other CTD
• Clinical implications
– Predictive of more aggressive disease with
more progressive joint damage
Complement
• Cascade of proteins activated by many
agents, including immune or antigenantibody complexes
• May be decreased due to
– Increased consumption (proteolysis)
• Increased levels of circulating immune complexes
activate classical pathway
– Decreased production
• Hereditary deficiency or liver disease
Hereditary complement
deficiencies
• May see SLE-like disease with deficiencies
in C1-C4
• Terminal complement (C5-9) deficiencies
lead to recurrent infections
• Deficiency in C1 INH leads to angioedema
(hereditary or acquired)
Diseases associated with low
complement levels
• Rheumatic diseases
– SLE, systemic vasculitis, cryoglobulinemia,
RA (rare)
• Glomerulonephritis
– Post streptococcal and membranoproliferative
• Infectious diseases
– Bacterial sepsis, SBE, Hepatitis B, other
viremias, parasitemias
Complement level
assessment
• C3 and C4 generally decreased with
increased disease activity in SLE
• Decreased levels may predict impending
disease flares
– C4 lowers before C3 and remains lower longer
• CH50 not useful as disease activity marker
HLA-B27
• Sensitivity
– ~95% for AS
– ~80% for Reactive Arthritis
– ~70% for SpA associated with psoriasis
– ~50% for SpA associated with IBD
– ~70-84% for uSpA
HLA-B27
• Specificity
– Low given prevalence is ~8% in Caucasian
population
• In patients with inflammatory back pain,
HLA-B27 positivity yields
– 20-fold increased risk of SpA
Synovial fluid analysis
• Studies to perform
– Gram stain and culture
– Total leukocyte count with differential
– Polarized microscopy
Synovial fluid analysis
Fluid type
Appearance Total WBC %PMNs
Count/mm3
Normal
Clear,
viscous
0-200
<10%
NonClear to sl.
inflammatory turbid
200-2000
<20%
Inflammatory Slightly
turbid
200050,000
20-70%
Septic
>50,000
>70%
Turbid
)String test( ‫نخي شكل شدن‬
Synovial fluid analysis
• Noninflammatory joint effusions
– OA, joint trauma, mechanical derangement, AVN
• Inflammatory synovial fluid
– Multiple rheumatic disorders
– Infectious arthritis
• Septic
– Joint sepsis
– Pseudosepsis in gout, reactive arthritis or RA
Polarized light microscopy
Gout
Pseudogout
Crystal
Monosodium
urate (MSU)
Shape
Needle
Birefringence
Negative
Calcium
pyrophosphate
dihydrate
(CPPD)
Rhomboid or
rectangular
Positive
Crystal color
Yellow
parallel to axis
Blue
CPPD and MSU crystals
‫خالصه‬
‫تست های آزمایشگاهی در تشخیص و پیگیری بیماران‬
‫روماتیسمی از اهمیت زیادی برخودارند بهر حال عالئم‬
‫آزمایشگاهی همیشه در کنار عالئم بالینی باید تفسیر شوند‬