Immune labs basics part 1 acute phase reactants ESR, CRP Ahmed Yehia Ismaeel, MD, Beni-Suef Erythrocyte sedimentation rate C reactive protein Cost benefit labs request

1. Laboratory Diagnosis of
Immune Diseases
(Introduction, ESR & CRP)
Ahmed Yehia Ismaeel, MD, Immunology
(Rheumatology & Allergy)
Beni-Suef University

2. Questions for
brainstorming
1. What is the most likely diagnosis
of a patient with a positive ANA?
2. What is the most common cause
of an elevated ESR >100?
3. A preferred screening lab test has
a high sensitivity or high specificity?
4. Which of the following lab tests is
most specific? ESR or CRP

3. Postulation
Rheumatic diseases can be
diagnosed only after investigations.

4. Case
• This 30-year-old lady presents with recurrent
orogenital ulcers.
• What is your diagnosis?
• What are the labs needed for this diagnosis
confirmation?

6. ICBD
Ocular lesions 2
Genital aphthosis 2
Oral aphthosis 2
Skin lesions 1
Neurological symptoms 1
Vascular manifestations 1
+ve Pathergy test
*
1
*
*Pathergy test is optional and the primary scoring system does not include pathergy testing. However, where
pathergy testing is conducted one extra point may be assigned for a positive result.
OGO (2) - BPCC (1)
All criteria are clinical.

7. A 70-year-old chronic
heavy smoker man was
admitted with left LL
acute proximal DVT.
He has 10-kg weight
loss in the last 7
months.

8. What is autoimmune
profile?
So, we requested
“autoimmune profile”.

9. !!!! I learned it from
you!!!

10. How
comes?
ANA, anti-dsDNA, ANCA (p,C), RF,
anti-CCP, S. C3, C4, ACL IgG & IgM,
anti- beta 2 GP1 IgG, IgM, LAC

11. Does he have arthritis? NO.
ANA, anti-dsDNA, ANCA (p,C), RF, anti-CCP,
S. C3, C4, ACL IgG & IgM, anti- beta 2 GP1
IgG, IgM, LAC
NO.

12. Does he have oral
ulcers, photosensitivity,
malar rash,….?
ANA, anti-dsDNA, ANCA
(p,C), RF, anti-CCP, S. C3, C4
Also, he is a male &
70 years old.
NO.

13. Does he have upper or
lower respiratory,
cutaneous or renal ,….?
ANA, anti-dsDNA, ANCA
(p,C), RF, anti-CCP, S. C3, C4
Although AAV can cause DVT,
+ve ANCA will not fulfill AAV
classification criteria.
NO.

14. What about HLA- B51?

15. HLA-B51 is more prevalent in
BD than the general population.
Due to low specificity & a
variable prevalence among
ethnicities, it is not considered
a diagnostic criterion in the
ICBD.
However, among BD patients in
this study, a significantly higher
percentage were positive for
HLA-B51 than patients in whom
BD was ruled out. This was not
the case for HLA-B5 and HLA-
B27.

16. •Because of the absence of specific biological criteria, the
diagnosis is essentially clinical. The diagnostic criteria make
it possible to establish the diagnosis with good sensitivity &
specificity.

17. •HLA-B51 does not confirm or
invalidate a diagnosis of Behçet’s
disease.

18. HVC
RECOMMENDATION 1
• An accurate history & a thorough musculoskeletal physical
examination are essential to diagnose & differentiate
inflammatory & noninflammatory symptoms & can help to
avoid unnecessary testing.

19. Although immunologic
laboratory tests can have
great utility in the diagnosis
& management of patients
with rheumatic diseases,
they can be misused.
• Improper application of these tests can
result in
• Misdiagnosis
• inappropriate therapy
• unnecessary health care expenses.

20. Antiphospholipid antibodies
may be justified by the
patient presentation, but…..
But what?

21. But remember that aPl
may be secondary to
M—Medications: most commonly
phenothiazines (chlorpromazine),
procainamide, quinidine, hydralazine,
phenytoin, α-interferon, interleukin-2, tumor
necrosis factor-α inhibitors, others.
A—Autoimmune diseases: SLE (40%–50%),
rheumatoid arthritis, dermatomyositis, Sjögren’s
syndrome, systemic sclerosis, others.
I—Infectious diseases: acute infections (bacteria,
viral, especially herpes), chronic infections (hepatitis
C, HIV).
N—Neoplasms: lymphoma most commonly.

22. Respect the patient
demographics (age, sex,
geography….
Would we
screen for
hereditary
thrombophilia?

23. In an elderly chronic heavy
smoker with unptovoked DVT,
don’t forget malignancy.
I’ll revise history
& examination to
narrow the D.D.
‫خيرا‬ ‫هللا‬ ‫جزاكم‬
‫أستاذي‬
.

24. • Thrombophilia testing is costly and can result in harm to
patients if the duration of anticoagulation is inappropriately
prolonged or if patients are incorrectly labeled as thrombophilic.
• Thrombophilia testing does not change the management of
venous thromboembolisms (VTEs) occurring in the setting of
major transient VTE risk factors. When VTE occurs in the
setting of pregnancy or hormonal therapy, or when there is a
strong family history plus a major transient risk factor, the role of
thrombophilia testing is complex & patients & clinicians are
advised to seek guidance from an expert in VTE.

25. So, “autoimmune
profile” screening for
every patient is a
myth.

26. Case
Her GP requested her labs which revealed the
following:
CBC,
chemistry:
normal.
ESR: 8.
ANA, +ve,
1/40.
How to
assess?
A 40-year-old female patient presents with a 2
weeks history of diffuse bony pains. No other
signs or symptoms.

27. Pretest probability

28. While the absence of an ANA virtually
excludes a diagnosis of SLE, the presence
of ANAs does not establish the
diagnosis.
So, is it sensitive or
specific?

29. A good clinician is a
good observer.
A careful history provides 80% of the
diagnostic information.
Physical examination adds another
15%.
While Imaging and laboratory
together contribute only 5%.

30. So, this postulation is wrong.
Rheumatic diseases can be
diagnosed only after
investigations.

31. • So , don’t request an investigation unless:
1. You have done a thorough history and
examination.
2. A D.D. exists in your mind ,
3. It will change the plan of management
and
4. You know how to interpret it.

32. Laboratory tests may play an
important role in the diagnosis of
patients with rheumatic diseases.
Improper use of these tests may result
in misdiagnosis, needless additional
testing or even inappropriate therapy.
False positives

33. What do False positives mean?
Immunology doctor

34. Just today, a 17-year-old female with epistaxis referred to me!!!!!!

35. Unnecessary investigation= false positive

36. ‫قصدك‬ ‫حضرتك‬
‫جنبي‬ ‫اللي‬ ‫المطعم‬
.
‫دكتور‬ ‫يا‬
,
‫تأمين‬ ‫لي‬ ‫أنا‬
.
‫كل‬ ‫لي‬ ‫تطلب‬ ‫ممكن‬
‫و‬ ‫تحاليل‬
‫اتوصى‬
‫بالمناعة‬
.

37. Key points when using
rheumatologic laboratory tests
1) Order tests that help to confirm a
clinical impression or to sort out a
differential diagnosis.
2) Most immunologic laboratory
tests are not useful as screening
tests for healthy subjects, since
all tests have a false positive rate.
3) A positive test may or may not be
associated with a disease state
(the pretest probability of the
disease is essential).

38. Common Misperceptions
•Positive result = Disease
•These tests are free, so order
as many as you want.
•“Money grows on trees”.

39. Because of limited
specificity, results
of these tests
should always be
• interpreted in the context of
the clinical history & physical
examination
• applied with great caution, if
at all, in the setting of low
pretest probability
ANA positive, 1/80
For clinical correlation

40. Role of investigations in rheumatology
Diagnosis
& Exclude other
differentials
Prognosis
Determine
disease
extent Severity
Follow up
Disease state
(flare, remission,
stable)
Treatment
Response to
treatment
Drug side effect

41. Erythrocyte
Sedimentation
Rate (ESR)
ESR is an indirect measure of alterations
in acute phase reactants.

42. ++Proteins neutralize
RBCs' surface
charges, promoting
their ability to settle at
a faster rate.
Fibrinogen & other acute
phase reactants
Hypergammaglobulinemia
• Polyclonal
• monoclonal

43. Acute Phase Proteins
•Proteins that show an increase >25% with inflammation
•Synthesized in the liver.

44. Erythrocyte
Sedimentation
Rate (ESR)
The ESR is a sensitive
but non-specific
indicator of the
presence of disease.

45. Laboratory Assessment
 ESR is a measurement of the
distance that RBCs fall within a
specified anticoagulated tube
(Westergren) over 1 hour.
• Whole blood is allowed to stand
for 1 hr.
• The distance between the RBC
sediment and top of the tube in
mm is the ESR.
• The presence of APRs makes the
cells fall faster and raises that
distance.

47. Case
A family which is under the cover of health insurance underwent
routine lab. investigations. Their ESR came back as follows:
The 70-year-old grandpa: 1st h.: 30mm,2nd h.: 50mm.
The 68-year-old grandma: 1st h.: 38mm, 2nd h.: 70mm
The 40-year-old mother: 1st h.: 22mm, 2nd h.: 40mm
The 7-year-old child: 1st h.: 20mm, 2nd h.: 36mm
• The Lab. Range : <15 mm/hr for men <20mm/hr for women

48. •How to assess?

49. The ESR is affected by age & sex.
• The normal ESR
• increases with age
• usually higher in women.

50.  Range :
<15 mm/hr for men
<20mm/hr for women
Age adjusted (A well accepted rule of thumb is to
adjust the upper limit of normal as):
(Males) Age
2
(Females) (Age + 10)
2
1st , 2nd hour or both?

51. Case
A family which is under the cover of health insurance underwent
routine lab. investigations. Their ESR came back as follows:
The 70-year-old grandpa: 1st h.: 30mm,2nd h.: 50mm.
The 68-year-old grandma: 1st h.: 38mm, 2nd h.: 70mm
The 40-year-old mother: 1st h.: 22mm, 2nd h.: 40mm
The 7-year-old child: 1st h.: 20mm, 2nd h.: 36mm
• The Lab. Range : <15 mm/hr for men <20mm/hr for women

52. Case
His ESR is 30.
How to assess?
A 40-year-old gentleman presents
with slight fatigue and bony pains.

53. Slightly raised ESR??!
• In those with a slightly raised
ESR, the best plan is probably
to wait a month and repeat
it.
• There is a group of patients
whose vague symptoms
would have prompted
nothing more than
reassurance.

54. Causes of elevated ESR
Inflammatory
• Infectious
• Non-infectious
Autoimmune
Malignancy
Non-inflammatory
• Anemia
• Ageing
• Pregnancy
• CKD (ESKD, nephrotic syndrome, GN)
• Cholesterol++
• Diabetes mellitus
• Drugs: OCPs
• Ethnicity
• Female sex
• Obesity

55. Markedly elevated ESR
(>100 mm/hr)
• Infections, bacterial (35%)
e.g. TB.
• Connective tissue diseases
(25%): e.g. GCA
• Malignancy : lymphoma ,
myeloma, metastatic
cancer (15%)
• Other causes (22%)
• Unknown (3%).

56. Among the rheumatologic conditions those
most likely to cause markedly elevated ESR
Giant cell arteritis
ANCA (antineutrophil
cytoplasmic
autoantibody)-
associated vasculitis
Polymyalgia
rheumatica
Adult-onset Still
disease

57. Workup for markedly
elevated ESR
•Therefore, it would be wise
(after history and
examination) to consider
these tests: FBC, plasma
electrophoresis, U&E, PSA,
chest and abdominal
imaging, ± biopsy of bone
marrow or temporal artery.
Hard work

58. Excessively
Low ESR
Low proteins
• Low-fibrinogen states
• Afibrinogenemia
• dysfibrinogenemia
• Liver failure
• Heart failure
• Agammaglobulinemia
• High dose steroid use
RBCs conditions
• Conditions promoting
rouleaux formation
(e.g., polycythemia
vera).
• Sickle cell disease
• Microcytosis
(including
spherocytosis)
• Anisocytosis

59. Excessively
Low ESR •Even a slightly raised ESR in these
patients should prompt one to ask:
“What else is the matter?"

61. Case
A 10 years old SLE patient presents
with fever , flare of arthritis and skin
rash. No other manifestations.
ESR 4. CRP 96.
HGB 8. PLT 40. WBC 3.
She is on hydroxychloroquine 200 x 2
, prednisone 10 mg / day.
How to proceed?

62. Macrophage
activation
syndrome

63. Anyone WHO ISN’t Confused
Really Doesn’t Understand The Situation.
Edward R. Murrow

64. Case
A 33 years old male patient was diagnosed by
Duke’s criteria as infective endocarditis and was
initiated on antibiotics.
Initial ESR was 120.
Follow up ESR 1 week later was still high, 116.
What is your plan & how to
manage his antibiotics?

65. C Reactive Protein (CRP)
• What does the C stand for?
• C-polysaccharide from the pneumococcus cell walls
• Acute phase protein- Group 3
• Exclusively produced by hepatocytes
• Direct measure of inflammation

66. • CRP is an annular pentameric
protein (pentraxin)mproduced by the
liver in response to interleukin-6.
Normally present in the serum in
trace amounts,
• CRP concentrations rapidly
increase during inflammation
within 4 to 6 hours, peak at 2 to 3
days, and normalize over a week.
• CRP is induced by pro-inflammatory
interleukin (IL)-6 along with IL-1β &
tumor necrosis factor α (TNF α), to a
lesser extent.

67. • CRP is a component of the
innate immune response
whose major function is to
recognize foreign pathogens
and damaged cells by binding
to phosphocholine surfaces, as
well as to exposed endogenous
ligands including
ribonucleoproteins, histones,
chromatin &
lysophosphatidylcholine.
Clearance via activation of
complement proteins or
phagocytic cells follows.

68. C Reactive Protein
(CRP)
Normal Levels <1
Moderate elevation 1-10
• Seen in most of the rheumatic
conditions- RA, SLE, Sjogren’s
Marked elevation >10
• Seen in serious bacterial infections,
severe RA, Vasculitis, PMR

69. Does age or sex affect CRP levels?
CRP ULN, mg/dl
Male
Age/50
Female
(Age/50)+0.6

70. The age-adjusted
upper limit of normal
for CRP
• Male = age in years/50
• Female = (age in years/50) + 0.6

71. Age & obesity adjusted upper limit of normal for CRP

72. C Reactive
Protein
(CRP)
Levels rise within
4 hours of
stimulus
Peaks within 2-3
days.
Half life 8 hours
With effective
treatment of the
underlying cause,
levels can
normalize within
24-48 hours

73. CRP vs. ESR
CRP
• Rises quickly
• Falls quickly
• Direct marker of inflammation
• Narrow range of results
• High sensitivity
• High specificity
• High reproducibility
• NOT affected by factors (age, gender,
anemia, RBC shape, plasma proteins)
ESR
• Rises slowly
• Falls slowly
• Indirect marker of inflammation
• Wide range of results
• Moderate sensitivity
• Moderate specificity
• Moderate reproducibility
• Affected by many factors

74. Due to CRP
advantages over ESR
It is better for follow up &
monitoring of response to
treatment.

75. Case
• A 28-year-old lady presented
with 2 months history of LBP.
• It is aggravated by exertion & is
relieved by rest.
• She had unremarkable labs
apart from mildly elevated CRP.

76. What is the most
likely diagnosis?

77. Would you request HLA-B27?
No, low pretest probability.
•mechanical in character
•Duration < 3 months.
This LBP

78. Causes of low
back pain
• Lumbar spondylosis
• Disk herniation
• Spondylolisthesis
• Spinal stenosis
• Fracture (mostly osteoporotic)
• Nonspecific (idiopathic)
Mechanical
• Primary
• Metastatic
Neoplastic
• Spondyloarthritis
Inflammatory

79. Causes of low back pain
Infectious
• Vertebral
osteomyelitis
• Epidural
abscess
• Septic diskitis
• Herpes zoster
Metabolic
• Osteoporotic
compression
fractures
• Paget disease
Referred pain to
spine
• From major
viscera,
retroperitoneal
structures,
urogenital
system, aorta,
or hip

80. 80% of individuals have
a LBP episode at some
point throughout life.
• The incidence of SpA varies,
depending on the examined
populations, from 0.2% to 1.9%.
Mechanical
LBP
IBP
Uncommon presentation of a
common disease is more
common than a common
presentation of an uncommon
disease
Epidemiology

81. Recommendation 2
•Don’t order an HLA-B27 unless
spondyloarthritis is suspected based on specific
signs or symptoms.
Canadian Rheumatology Association, September 30, 2022

82. Recommendation 2
• HLA-B27 testing is not useful as a single diagnostic test in a patient with LBP without further SpA signs
or symptoms (e.g., IBP: 3 months duration with age of onset <45 years, peripheral synovitis, enthesitis,
dactylitis, psoriasis or uveitis) because the diagnosis of SPA in these patients is of low probability.
• If HLA-B27 is used, at least two SpA signs or symptoms, or the presence of positive imaging findings,
need to be present to classify a patient as having axial SpA. There is no clinical utility to ordering an
HLA-B27 in the absence of positive imaging or the minimally required SpA signs or symptoms.
Canadian Rheumatology Association, September 30, 2022

84. In rheumatologic conditions,
CRP is typically elevated 2 to
l0 times the normal level.
• A higher level (especially >10 mg/dl [tOO
mg/L]) should prompt consideration of an
alternative diagnosis, such as infection.

85. CRP is thought to be a better marker
than ESR for measuring inflammation
in spondylarthritis.

87. SpA features
(Ahmed Yehia
mnemonics)
•Arthritis
•Psoriasis
•CRP ++
•Crohn’s / Colitis
•Dactylitis
•Enthesitis
•Eye (uveitis)
•Family history of SpA
•Good response to NSAIDs
•HLA B27
•Inflammatory back pain

88. But how to assess
response?
1.Clinically
2.Acute phase reactants
3.BASDAI
4.ASDAS CRP
5.ASDAS ESR
6.MRI sacroiliac joints
7.MRI spine

89. ASAS-EULAR
recommendations
(axSpA: 2022 update)
In the last decade, the Ankylosing
Spondylitis Disease Activity Score
(ASDAS) has emerged as the most
appropriate instrument for disease
activity assessment, so
recommended for monitoring.
ASDAS, preferably calculated using
CRP, is a well-balanced index without
redundancy across its items, in
contrast to the historically more
widely used Bath Ankylosing
Spondylitis Disease Activity Index
(BASDAI).

90. ASDAS-CRP vs BASDAI
ASDAS-CRP BASDAI
longitudinally associated with syndesmophyte formation No
Subjective (patient perspective) + objective (CRP) Subjective only

91. What is the difference?

92. Case
An SLE patient presents with fever , flare of arthritis and
skin rash. No other manifestations.
ESR 120
CRP 96
HGB 8 PLT 420 WBC 11.
She is on hydroxychloroquine 200 x 2 , prednisone 10
mg / day.

94. Case
An SLE patient presents with fever , flare of arthritis and
skin rash. No other manifestations.
ESR 120
CRP 96
HGB 8 PLT 420 WBC 11.
She is on hydroxychloroquine 200 x 2 , prednisone 10
mg / day.

95. This is mostly an
infection.
• So, do cultures and investigate for
infections.

96. Case
An SLE patient presents with fever , flare of arthritis and skin rash.
Examination revealed pericardial rub.
No other manifestations.
ESR 120
CRP 96
She is on hydroxychloroquine 200 x 2 , prednisone 10 mg / day.
Disease activity vs infection

97. In SLE patients with fever in whom synovitis or
serositis can be excluded, elevated CRP levels
suggest a bacterial source of inflammation & fever.
CRP levels are usually normal in active SLE except
in chronic synovitis or acute serositis.

98. High-sensitivity CRP (hsCRP)
• High-sensitivity CRP (hsCRP) allows for the detection of low-grade
systemic inflammation, down to levels of 0.3 mg/L compared with the 3
to 5 mg/L range of the regular CRP assay, which can be associated
with disease activity.

99. • An elevated ESR observed together with a
normal CRP is often a false-positive value for the
ESR; this may reflect the effects of blood
constituents, such as monoclonal
immunoglobulins, that are not related to
inflammation but that can influence the ESR.
• However, this conclusion is not always valid. As
an example, the ESR may be markedly elevated
in patients with active SLE, while the CRP
response is muted.
• These variations may be explained by differences
in the production of specific cytokines or their
modulators in different diseases.

100. • We have identified a group of children with IBD in remission taking AZA or 6-MP with persistently elevated ESR but normal
CRP levels. Discordance between ESR and CRP has been observed in from 28% to 55% of adult patients with rheumatoid
arthritis. In most of these cases, the ESR is elevated in the face of a normal CRP. In many of these patients the discordance can
be partly attributed to elevations in serum immunoglobulin G and A or a low hemoglobin level (18). In none of these reports
have authors examined the potential impact of medications on ESR.
• A possible explanation for the persistent elevation of ESR in the face of normal CRP seen in this study may be changes in red
cell volume. Chronic use of AZA and 6-MP is associated with macrocytosis, presumably secondary to alterations in folate
metabolism. The ESR may be increased because of the anemia commonly observed in children with IBD. We did not find any
difference in the mean hematocrit of the group with chronically elevated ESR compared with that of the group with normal
ESR. We did note a higher mean MCV in the children with elevated ESR than in those with concordant ESR and CRP. However,
this difference was small, and in both groups the MCV was within the normal range. Hyperglobulinemia and
hyperfibrinogenemia have been associated with increased ESR. Although we did not routinely measure serum fibrinogen or
serum immunoglobulin G in our patients, serum total protein, serum albumin, and estimated serum globulin were not
significantly different in the group of children with persistently elevated ESR and the group with normal ESR.
• We have observed persistent discordance between ESR and CRP only in patients taking AZA or 6-MP. It is conceivable that
differences in the metabolism of AZA or 6-MP could affect ESR in certain individuals. We do not routinely measure these
metabolites, so it is not possible to test this hypothesis with our current data; however, the lack of any association between
serum albumin, transaminases, MCV, white blood cell count, or total neutrophil count and persistently elevated ESR does not
favor the theory that accumulation of metabolites is the source of this disparity.

101. • Infection, renal insufficiency, and low
albumin were associated with having
elevated ESR/low CRP; low albumin
predicted elevated CRP/low ESR and
elevated ESR/low CRP discordance. RA
patients were less likely to have elevated
ESR/depressed CRP. ESR as a measure
inflammation in systemic rheumatic disease
may be limited in settings of infection, renal
insufficiency, and low albumin.

102. • When an elevated ESR Is identified without an obvious etiology,
measuring the C-reactive protein can provide information to guide
further evaluation
• Discordances in which the ESR Is disproportionally higher than the C-
reactive protein are generally more indicative of malignancy and
autoimmune disease
• Discordances in which the C-reactive protein is disproportionally higher
than the ESR are generally more Indicative of infection

103. Effect of anemia on ESR. Can it be estimated?
• (a mild anemia will not change ESR to a clinically significant degree) > Use
the Fabry equation: corrected ESR = Westergren sed rate * 15 / (55-
hematocrit) • Use the ESR in combination with C reactive protein and platelet
count o If all 3 are in the same direction (e.g. all elevated), then sensitivity and
specificity of ESR is increased o If ESR is elevated, CRP is normal, and
platelet count is normal, ESR could be elevated due to some other globulin or
some other reason to have fibrinogen increase other than temporal arteritis.

104. Effect of anemia on ESR. Can it be estimated?
• Use the Fabry equation: corrected ESR = Westergren sed rate * 15 / (55-
hematocrit).

105. Effect of anemia on ESR. Can it be estimated?
• The general formula for calculating the corrected ESR in the
presence of anemia is:
• Corrected ESR=Observed ESR/Correction Factor
• The correction factor is calculated based on the patient's hematocrit
(Hct) & hemoglobin (Hb) levels. The specific correction factor may
vary slightly depending on the laboratory & the method used.
However, a commonly used formula is:
• Correction Factor=(Hct/2)+1
• Here, Hct is the hematocrit measured as a decimal (e.g., 0.36 for a
36% hematocrit). The correction factor is usually added to the
formula to account for the dilution effect of anemia on the
sedimentation rate.

106. Effect of anemia on ESR. Can it be estimated?
• Use the ESR in combination with C reactive protein and platelet count o If all 3
are in the same direction (e.g. all elevated), then sensitivity and specificity of
ESR is increased o If ESR is elevated, CRP is normal, and platelet count is
normal, ESR could be elevated due to some other globulin or some other
reason to have fibrinogen increase other than temporal arteritis.

107. Causes of elevated CRP
Marked elevation
• Bacterial infection
• Abscess
• Crohn’s disease
• Connective tissue diseases
(except SLE)
• Neoplasia
• Trauma
• Necrosis (eg MI)
Normal-to-slight elevation
• Viral infection
• Steroids/oestrogens
• Ulcerative colitis
• SLE
• Morbid obesity
• Atherosclerosis
• Diabetes mellitus

108. CRP response may be less
pronounced in patients
suffering from liver disease.

109. Levels >8–10
mg/dL (> 80-
100 mg/L)
should
suggest
bacterial infection,
systemic vasculitis
acute polyarticular crystal
disease
widely metastatic cancer.

110. Case
• An SLE patient comes for follow up,
no flare of arthritis , skin rash or ….
• ESR 20
• CRP 5
• HGB 10
• PLT 420
• WBC 16.
• She is on hydroxychloroquine 200 x 2 ,
prednisone 10 mg / day.
• How to manage her leukocytosis?

111. So, do a differential &blood film+/-
cultures according to clinical suspicion.
• Leukocytosis may reflect :
1. inflammation or
2. infection, and
3. glucocorticoid also elevates the neutrophil cell count by
demarginalization , so they are mature with no shift to
the left or toxic granulation.

113. •Changes in levels of APR largely result
from the effects of cytokines, including
interleukin (IL)-6, IL-1 beta, tumor
necrosis factor-alpha (TNF-alpha), and
interferon gamma.

114. Acute phase
reactants
• CRP, Ceruloplasmin,
Complement, Cytosis (WBC,PLT)
• Fibrinogen , Ferritin
• Alpha 1 antitrypsin , Amyloid A
• Haptoglobin

116. The assessment of APR may
be most helpful in patients
with (& are included in the
criteria)
•RA
•Polymyalgia
rheumatica
•Giant cell arteritis.

117. • APRs are only part of the diagnostic criteria for RA, polymyalgia rheumatica (PMR) and giant cell
arteritis (GCA); so, normal values do not exclude disease in the setting of strong clinical suspicion.

119. Classification criteria of PMR

121. Case
• A 60-year-old female presented to the ER
with acute severe right temporal headache
for 1 day. She has long history of neck &
both shoulder pain, more when arising from
bed in the morning with stiff shoulders for
about 1 hour. By examination, you find only
scalp tenderness.
• How to proceed?
• CT brain & ESR
• CT brain is normal .
• ESR: 25 mm (1st hour)
• Are there other examinations that may
help?

122. • Eye examination
• Temporal artery duplex
Halo sign

123. 2 + 2 + 2 + 2
= 8

124. • So, take care. It is not mandatory to have elevated APRs in
autoimmune diseases.

125. How to manage this case?
•GCA is an emergency that may cause vision loss.
•We will manage according to the latest guidelines.

126. CASE 1:
PATIENT
HISTORY
AND
PRESENTATI
ON
•A.S.M is a 25-year-old female who
presents to you after a 1-month
history of pain in the joints.
•How to approach?

127. APRs can be used in differentiating inflammatory
from non-inflammatory arthritis.

128. Inflammatory Non-inflammatory
Stiffness (Morning
stiffness)
> 60 min. Brief
Swelling, redness,
hotness (Synovitis)
++++ -
Systemic
manifestations
+++ -
Symptoms worsen by Rest (immobility) Use &
weight bearing
Spontaneous flares Common Uncommon

129. Inflammatory Non-inflammatory
Symmetry (bilateral) Occasional Common
Sedimentation rate
(ESR) & CRP
+++ Normal
Serology (RF, Anti-
CCP, ANA,…)
Usually positive Negative
Synovial fluid
WBCs
>2000/pL mainly neutrophils
in acute inflammation
& monocytes in chronic
inflammation
200-2000/pL ,
mainly
monocytes
Locking or
instability
Implies loose body, internal
derangement, or weakness
Uncommon

130. CASE 1:
PATIENT
HISTORY
AND
PRESENTATI
ON
•A.S.M is a 25-year-old female who
presents to you after a 1-month
history of pain in the joints.
•How to approach?

131. PATIENT
HISTORY &
PRESENTATION
She has 1-month history of pain in the joints of
her fingers, particularly in her dominant hand.
The pain is deep & diffuse along the joint lines.
Tenderness is present with active & passive
movements.
She reports some fatigue but no other symptoms
& has no significant medical or family history.

132. Laboratory studies are significant
for
Erythrocyte sedimentation rate (ESR) of 48
mm/h (normal range, 0-20 mm/h)
C-reactive protein (CRP) of 7 mg/dL (normal
range, 0.08-3.1 mg/dL)
Positive rheumatoid factor (RF) &
anticitrullinated protein antibodies (ACPA).

133. Is RF or
Anti-CCP titre
significant?
In classification criteria
In prognosis

134. Her RF is positive, 48
(Reference: Negative, < 8)
Her anti-CCP is positive, 200
(Reference: Negative, < 5)

135. • However, both ESR & CRP are elevated in only 40% of RA
patients.

136. She failed initial
treatment with escalating
MTX doses.
What is the next step?

137. What is the prognosis of our patient?
Improved prognosis
Worse prognosis
Neither improved nor worse prognosis
Not enough information provided to make the
determination
Determine patient prognosis.

138. Elevated APRs are 1 of the Poor
prognostic factors in RA (EULAR 2022)
Persistently moderate or high disease activity (after csDMARD therapy) according to composite
measures including joint counts despite csDMARD therapy
High acute phase reactant levels
High swollen joint count
Presence of RF &/or ACPA, especially at high levels
Presence of early erosions
Failure of 2 or more csDMARDs

139. Prognostic Factors Associated With a Worse Prognosis in Patients With RA
Demographi
c Features
•Age < 30 y >Female sex
•Positive smoking status
Laborator
y
Findings
•RF positivity >ACPA positivity
•Elevated ESR >Elevated CRP level
•High MBDA scores
Genetics •Presence of HLA-DRB1*04 genotype
Clinical
&
Imaging
Findings
•Insidious onset
•Presence of systemic symptoms >Extraarticular
disease
•Higher number of involved joints
•Presence of erosions at baseline
•Bone edema on MRI
Our patient

141. In patients with RA, a persistently
elevated CRP level may be associated
with
radiographic
progression of
joint disease
long-term
disability.

142. How to follow
up & assess
response?

143. •Which of the following would best determine RA patient's
level of disease activity during follow up?
• Acute phase reactants: ESR & CRP
• Order repeat x-rays to assess progression of
radiographic damage of involved joints
• Order a test for antinuclear antibodies (ANA)
• Complete a Simplified Disease Activity Index (SDAI) or
Clinical Disease Activity Index (CDAI)

144. Measuring a heterogeneous disease is complex & requires
considering a variety of factors, making use of validated
composite disease activity assessments the best option
for determining a patient's level of disease activity.
The SDAI, which is a provider, patient & laboratory
composite tool, is 1 of the 5 disease activity assessments
recommended by the American College of Rheumatology
(ACR).
The CDAI includes the same components as the SDAI but
omits an acute-phase reactant measure.

145. ESR is sometimes used to monitor the activity of inflammatory conditions
such as SLE & RA, although other markers of disease activity such as clinical
signs and symptoms and lab indicators of organ function are more useful.
Use validated composite indices to assess disease activity & follow up.

146. Overview of ACR's Recommended Disease Activity
Measures
Measur
e
Description
SDAI •Provider, patient, and laboratory composite tool
• Includes 28 swollen joint count, 28 tender joint count, provider global assessment of disease activity,
patient global assessment of disease activity, & CRP level
•Uses simpler numerical addition of individual components that are weighted evenly
CDAI •Provider and patient composite tool
• Includes 28 swollen joint count, 28 tender joint count, provider global assessment of disease activity, and
patient global assessment of disease activity
•Uses simple numerical addition of component scores, and because it omits an acute-phase reactant (ie, ESR
or CRP), results can be provided in real time
DAS
28-
ESR
or
DAS
28-
CRP
•Provider, patient, and laboratory composite tool
• Includes 28 swollen joint count, 28 tender joint count, patient global assessment of disease activity &
ESR or CRP level
•Uses a complex calculation that places different weights on individual indices (eg, tender joint counts are
weighted more heavily than swollen joint counts)
RAPI
D-3
•Patient-driven composite tool
• Includes visual analog scale patient pain score, patient global assessment of disease activity, and

147. • She was initiated on Tocilizumab due to associated ILD.
• You follow up her response by composite indices.
• SDAI: low
• CDAI: moderate
• Which is more accurate here?
• Patients taking tocilizumab (IL-6 inhibitor) experience
impaired hepatic production of CRP but may still have
active disease. Alternative measures of outcome or
disease activity should be considered in these patients.

149. Laboratory Assessment
• Nephelometry and enzyme-linked immunosorbent assays (ELISAs) are
• used to measure CRP.

150. Case
• An SLE patient comes for follow up,
with flare of arthritis and skin rash.
• ESR 120
• CRP 5
• HGB 10
• PLT 420
• WBC 16.
• S. albumin: 2.9
• How to assess her hypoalbuminemia?

151. Urine: NAD
Can we exclude
proteinuria in this way?

152. 24 hour urinary proteins:
20 mg
Urine protein/ creatinine
ratio: 20 mg/gm
How to interprete her
hypoalbuminemia?

153. Negative APR • A concomitant
reduction in
albumin level, is
characteristic of
conditions such
as infection,
malignancy ,
trauma, surgery,
and
inflammatory
disease.

154. ‫جزاكم‬
‫هللا‬
‫خيرا‬
‫رب‬ ‫هلل‬ ‫والحمد‬
‫العالمين‬