Rheumatoid arthritis Part 1, case based approach with application of the latest guidelines Ahmed Yehia Ismaeel, MD, Beni-Suef

1. Rheumatoid arthritis
Ahmed Yehia, MD
Internal Medicine, Immunology
(Allergy & Rheumatology), Beni-Suef

2. 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?

3. Approach to
arthritis can be
classified into 8
steps :
1. Articular or non-articular pain
2. Is it arthralgia or arthritis?
3. Acute or chronic (Duration)
4. Inflammatory or non-inflammatory
5. Mono, oligo or polyarticular (Number)
6. Distribution: Symmetrical or
asymmetrical; with or without axial
involvement
7. Extraarticular manifestations present or
absent
8. The patient as a whole (demographics)

4. 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.

5. Feature STR (Soft tissue
rheumatism)
Articular pain
Pain Superficial,
sharply localized
Deep, diffuse
circumferential
Tenderness Localized Circumferential, along joint
line
Active
movement
Painful in
some directions
Painful in
all directions
Passive
movement
No pain Painful
Synovitis/Effusion Nil Present
Crepitus/Instability/
Deformity/Locking
Absent Often present

6. •She has morning stiffness that
usually lasts a few hours & is
accompanied by polyarticular
pain & swelling.

7. 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).

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

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

10. 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

11. 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

13. X-ray hands

14. RA ACR
classification
criteria 1987

15. So, imaging has regressed in
RA early detection.
No, here is the newcomer.

16. Ultrasound shows inflammation in
both hands. In her dominant hand,
there is significant synovitis (swelling
& tenderness) across her PIP & MCP
joints, & carpal bones & wrist.
The findings are similar in her
nondominant hand, but the
inflammation is not quite as severe.

20. Should I start
treatment Dr or is it
enough to adjust diet
& do physiotherapy?
?????

21. Let’s search web for
guidelines.

23. 1. Therapy with DMARDs
should be started as soon
as the diagnosis of RA is
made. (1a A 9.9±0.2 100)

26. ‫هابدأ‬
‫بإيه‬
‫يا‬
‫دكتور؟‬
?????

27. When should a patient with
RA be started on a DMARD?
• Once RA diagnosis is
established, all patients (with
rare exception) should begin
DMARD therapy.
• Bone erosions & joint space
narrowing develop within the
first 2 years of disease in most
patients & are progressive from
that point onward.
• Therefore, early, aggressive
treatment with DMARDs is
warranted.

28. What is meant
by a DMARD?
?????

29. To be designated a DMARD, a drug must change the course of the
disease for at least 1 year as evidenced by 1 of the following
sustained improvement
in physical function
decreased inflammatory
synovitis
slowing or prevention of
structural joint damage.
DMARDs are drugs having some ability to do this.
Because there is no cure for most rheumatic diseases such as RA or
SLE, the goal of treatment is to put the disease into remission.

30. There are three general classes of
DMARDs in rheumatology
Conventional
synthetic DMARDs
(csDMARDs)
Target synthetic
DMARDs: apremilast,
JAK inhibitors
Biologic DMARDs
(bDMARDs):

31. US-FDA approved drugs for treatment
of RA
csDMARDs
• Hydroxychloroquine
• Sulfasalazine
• methotrexate
• leflunomide
bDMARDs
• TNF inhibitors
•Etanercept
•Adalimumab
•infliximab,
•Golimumab
•certolizumab pegol
• T cell costimulatory inhibitor
•abatacept
• IL-6 receptor inhibitors
•Tocilizumab
•sarilumab
• Anti-CD20 antibody
•rituximab
tsDMARDs: JAK inhibitors
• Tofacitinib
• Baricitinib
• upadacitinib

32. 4. MTX should be part of the first
treatment strategy. (1a A 9.6±0.8
96)

33. ‫بدأ‬ ‫الدكتور‬ ‫زميلة‬ ‫لي‬
‫لها‬
‫أبيتويد‬
20
.
‫هل‬
‫بيه؟؟‬ ‫أبدأ‬ ‫ممكن‬
‫نبد‬ ‫األفضل‬
‫أ‬
‫بميثوتريك‬
‫سات‬

34. ‫إيه‬ ‫طب‬
‫نبدأ‬ ‫رأيك‬
‫بالبيولوجي‬
‫؟‬
‫سمعت‬
‫ممتاز‬ ‫أنه‬
.
‫جدا‬ ‫غالي‬
.

35. ‫التكلفة‬ ‫مهم‬ ‫مش‬
‫لي‬ ‫بالنسبة‬
.
‫العالم‬ ‫التوصيات‬
‫ية‬
‫نبدأ‬ ‫األفضل‬ ‫أنه‬
‫بميثوتريكسات‬

37. In ACR 2021,
triple therapy
refers to
Hydroxychloroquine Sulfasalazine
either methotrexate
or leflunomide.

38. Methotrexate
monotherapy is
conditionally
recommended over dual
or triple csDMARD therapy
for DMARD-naïve patients
with moderate-to-high
disease activity.
• Because the higher burden of
combination therapy (e.g., multiple
drugs, higher cost) outweighs the
moderate-quality evidence
suggesting greater improvements
in disease activity associated with
combination csDMARDs.
• The recommendation is conditional
because some patients may
choose csDMARD combination
therapy for an increased probability
of obtaining a better response
despite the added burden of taking
multiple medications.

39. Methotrexate monotherapy is conditionally
recommended over methotrexate plus a TNF inhibitor for
DMARD-naïve patients with moderate-to-high disease
activity.
• Despite low-certainty evidence supporting greater
improvement in disease activity with MTX plus a TNFi,
MTX monotherapy is preferred over the combination
because many patients will reach their goal on MTX
monotherapy & because of the additional risks of toxicity &
higher costs associated with TNFis.
• The recommendation is conditional because some
patients, especially those with poor prognostic
factors, may prioritize more rapid onset of action &
greater chance of improvement associated with
combination therapy over the additional risks & costs
associated with initial use of MTX in combination with a
TNFi.

40. • 6. Short-term glucocorticoids should be considered when initiating
or changing csDMARDs, in different dose regimens & routes of
administration, but should be tapered & discontinued as rapidly as
clinically feasible. (1a A 9.3±1.2 92)

41. Low dose glucocorticoids
<7.5 mg/day prednisone
equivalent
Short-term
Up to 3 months

42. Initiation of a csDMARD without short-term (<3 months) glucocorticoids is
conditionally recommended over initiation of a csDMARD with short-term
glucocorticoids for DMARD-naïve patients with moderate-to- high disease
activity.
Initiation of a csDMARD without longer term (≥3 months) glucocorticoids is
strongly recommended over initiation of a csDMARD with longer-term
glucocorticoids for DMARD-naïve patients with moderate-to-high disease
activity

43. Initiation of a csDMARD without short-term (<3
months) glucocorticoids is conditionally
recommended over initiation of a csDMARD with
short-term glucocorticoids for DMARD-naïve
patients with moderate-to-high disease activity.
• While the voting panel agreed that
glucocorticoids should not be systematically
prescribed, the recommendation is conditional
because all members acknowledged that short-
term glucocorticoids are frequently necessary to
alleviate symptoms prior to the onset of action of
DMARDs. Treatment with glucocorticoids should
be limited to the lowest effective dose for the
shortest duration possible. The toxicity
associated with glucocorticoids was judged to
outweigh potential benefits.

44. DMARDs
Usual Time
to Effect
• as early as 4 to 6 weeks
MTX
• relatively rapid within 4-8 weeks
Leflunamide
• It may take 6 weeks to 3 months to see the effects.
Sulfasalazine
• A period of 2 to 4 months is usual. Most agree that
if no response after 5-6 months,this should
be considered a drug failure.
Hydroxychloroquine
• rapid onset of action sometimes with
improvements seen within 2 to 4 weeks
TNF inhibitors

45. ‫المواطن‬
‫المصري‬
‫األصيل‬
‫ورأيه‬
‫في‬
‫الكورتيزون‬
‫مهما‬
‫كان‬
‫عليل‬

46. ‫ميثوتريكسات‬
‫أم‬ ‫حقن‬
‫أقراص؟‬
‫؟؟؟؟‬

47. Oral methotrexate is conditionally recommended over subcutaneous
methotrexate for patients initiating methotrexate.
Oral administration is preferred, despite moderate evidence suggesting
superior efficacy of subcutaneous injections, due to the ease of oral
administration & similar bioavailability at typical starting doses.

48. ‫جرعة‬
‫ميثوتريكسات‬
‫كام؟‬
‫؟؟؟؟‬

49. Initiation/titration of methotrexate to a weekly dose of at least 15 mg
within 4 to 6 weeks is conditionally recommended over initiation/
titration to a weekly dose of <15 mg.
This recommendation refers only to the initial prescribing of
methotrexate & is not meant to limit further dose escalation, which
often provides additional efficacy.

51. •Based on these findings, a diagnosis
of rheumatoid arthritis (RA) is made.
She is started on
• Oral methotrexate, 15 mg weekly.

52. 2 weeks later,
she came with 2
days of nausea,
vomiting &
severe epigastric
pain.
What is the best next step?
Revise dosing.
Some patients mistakenly
take MTX daily not weekly!!!

53. The importance of basics
• MTX is a structural analogue of folic acid that can
competitively inhibit the binding of dihydrofolic acid
(FH2) to the enzyme dihydrofolate reductase (DHFR).
DHFR is responsible for reducing FH2 to folinic acid
(5-formyltetrahydrofolate [FH4]; also termed
leucovorin), the active intracellular metabolite.
• Therefore, MTX interferes with DNA
synthesis, repair & cellular replication.
• Actively proliferating tissues that have a
high rate of cellular metabolism such as
malignant cells, bone marrow, fetal cells,
hair follicles, buccal & intestinal mucosa
&urinary bladder cells are generally more
sensitive to MTX.

54. So, don’t forget folic acid supplement with MTX.
FA 1 mg/day should always
be given with MTX.
FA (1 mg daily): FA can be
taken daily, including the day
of MTX, because it is
passively taken up by the cell
& does not compete with
MTX for uptake by the
reduced folate carrier.
5–10mg once weekly by
mouth given morning after
MTX dose

55. Despite ensuring the right dose
& adding FA supplement, she still
has gastrointestinal symptoms.
What is the best next
step?

56. According to ACR
2021
recommendations,
for patients not
tolerating oral weekly
methotrexate, all the
following are
preferred options
except
a split dose of oral MTX over 24
hours
weekly subcutaneous MTX
an increased dose of folic/folinic
acid
switching to alternative DMARD(s)

57. A split dose of oral MTX over 24 hours or weekly
subcutaneous injections, and/or an increased dose of
folic/folinic acid, is conditionally recommended over switching
to alternative DMARD(s) for patients not tolerating oral
weekly methotrexate.

58. Patient preferences
The recommendation is
conditional because
patient preferences play
an important role in the
decision whether to
continue MTX or switch
to other DMARDs.

59. Despite its effectiveness as a disease-
modifying agent in RA, the probability of
MTX discontinuation 1 year after therapy
is initiated is 30%.
Alarcon GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis.
Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum
1989;32:671–6.

60. FA 1 mg/day should always
be given with MTX & the
dose can be increased to 2
to 5 mg/day if symptoms of
toxicity (mouth sores)
develop.
The dose may be increased
to 5 mg/day as needed,
based upon reporting of
residual symptoms.

61. She is currently suffering from a
urinary tract infection.
What antibiotic should be
avoided for this patient?
A. Amoxicillin
B. Ciprofloxacin
C. Co- amoxiclav
D. Nitrofurantoin
E. Trimethoprim

62. Answer: E. Trimethoprim
• Both methotrexate & trimethoprim interfere with folic acid
biochemistry & if the two drugs are taken concurrently there is
an increased risk of abrupt severe bone marrow suppression &
potential fatality.
• Reference:
• Clinical Pharmacology Bulletin. Drug interactions with
methotrexate. Available at: http:// www.
• druginformation.co.nz/ Bulletins/ 2012/ 004_ 12_
Drug%20Interactions%20with%20Methotrexate.pdf

63. MTX with trimethoprim-
sulfamethoxazole combination
Usually well tolerated in patients taking
prophylaxis(usually as one double-strength tablet three
times weekly, such as on a Monday-Wednesday-Friday
regimen)
Should be avoided when the antibiotic is used in a twice-
daily regimen for treatment of an active infection.
Significant bone marrow & other toxicities have been
observed with use of a daily sulfa antibiotic regimen.

64. Drug interaction
checker

65. Based on her presentation, medical history, and
physical examination findings, which of the
following best describes her prognostic outlook?
Improved prognosis
Worse prognosis
Neither improved nor worse prognosis
Not enough information provided to make the
determination

66. Prognostic Factors in RA
•There are no uniform criteria defining poor
prognostic factors in patients with RA, and a
variety of factors have been associated with
worse outcomes, including
•higher likelihood of radiographic progression
•absence of remission
•functional limitations.

67. Poor prognostic factors (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

68. 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

69. •Both RF & ACPA positivity
have been individually
associated with negative
effects; however, these
effects appear to be
amplified in patients with
double autoantibody
positivity.

70. • In an observational study of patients with established
RA, tender joint counts were found to strongly
correlate only with subjective measures, including the
Clinical Disease Activity Index (CDAI) & Simplified
Disease Activity Index (SDAI) & patient-reported
outcome (PRO) measures, and were weakly associated
with objective assessments of inflammatory activity,
such ultrasonography findings.

71. Prospective studies in patients with early RA suggest that
~75% have joint erosions, with the majority developing them
during the first 2 years following their diagnosis.
In a study assessing predictors of radiographic damage in
patients with early RA, RF positivity was found to be a
significant predictor of both erosions & joint space narrowing.
Whereas ACPA positivity was predictive only of erosions.
Smoking & high baseline disease activity (Disease Activity
Score with 28-Joint Counts [DAS28] > 5.1) were also predictive
of radiographic progression.

72. CASE CONTINUED
• One month after starting
treatment, she has a
follow-up appointment
with you to assess
whether the treatment is
working.

73. ‫هلل‬ ‫الحمد‬ ‫كويس‬
.
‫أخبار‬
‫الروماتويد‬
‫إي‬
‫ه؟‬
‫أم‬ ‫العالج‬ ‫نفس‬ ‫نكمل‬
‫العالج؟‬ ‫نقلل‬
!!

74. ‫كده‬ ‫أد‬ ‫مش‬
.
‫أخبار‬
‫الروماتويد‬
‫إي‬
‫ه؟‬
‫أم‬ ‫العالج‬ ‫نفس‬ ‫نكمل‬
‫العالج؟‬ ‫في‬ ‫نزيد‬
!!

75. ‫نص‬
‫نص‬
‫أخبار‬
‫الروماتويد‬
‫إي‬
‫ه؟‬
‫أم‬ ‫العالج‬ ‫نفس‬ ‫نكمل‬
‫العالج؟‬ ‫في‬ ‫نزيد‬
!!

76. •Which of the following would best determine the
patient's level of disease activity during this visit?
• 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)

77. 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.

78. • A challenge with monitoring patients has been an abundance of
disease activity measures, with an ACR Working Group
identifying 63 such measures during a systematic literature
review in 2012. The ACR Working Group reviewed these
measures for validity, feasibility, & acceptability & recommended
6 instruments, which were revised to 5 preferred instruments in
2019. The group selected these measures because they
provided an accurate picture of disease activity, were sensitive
to change, discriminated well between disease activity states
(ie, low, moderate, high), included remission criteria, & were
feasible to perform in most clinical settings.

79. Notably, the updated ACR
recommendations maintain several
patient-driven composite tools that
exclude tender & swollen joint
counts, whereas EULAR
recommendations do not endorse
scoring systems that exclude these
counts.

80. 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

82. Overview of ACR's
Recommended
Disease Activity
Measures
(Other Measures
Meeting Minimum
Standard for Regular
Use)
MBDA score, VECTRA DA
PAS or PAS-II
RADAI
Rheumatoid Arthritis Disease
Activity Index 5 (RADAI-5)
Routine Assessment of Patient
Index Data 5 (RAPID5)

83. Among the
measures meeting
the minimum
criteria for regular
use is MBDA
score (including 12
serum biomarkers)
CRP
Epidermal growth factor
Interleukin-6
Leptin
Matrix metalloproteinase (MMP)-1
MMP-3
Resistin
Serum amyloid A
Tumor necrosis factor (TNF) receptor 1
Vascular cell adhesion molecule 1
Vascular endothelial growth factor A,
YKL-40

84. She is found to have
an SDAI score of 22.0.
What does this
mean?

85. Assessing Disease Activity in Patients
Being Treated for RA
• Knowing patients' level of disease activity is essential for treatment
decision-making & is included in treat-to-target, an approach
endorsed by the ACR, EULAR, & other medical organizations
because it has been shown to yield superior outcomes to standard
care.
• Treat-to-target is a systematic approach that involves frequent
monitoring of disease activity using validated instruments & modifying
treatment as needed to minimize disease activity, with the goal of
reaching a predefined target, typically remission or low disease
activity. During periods of active disease, it is recommended that
monitoring occur every 1 to 3 months, with monthly monitoring
recommended for patients with high or moderate disease

86. TTT
or
T2T

88. Dr, what is the
treatment
target?
‫؟؟؟؟‬

89. • A TTT approach is strongly recommended over usual care for
patients who have not been previously treated with bDMARDs
or tsDMARDs.
• A TTT approach is conditionally recommended over usual
care for patients who have had an inadequate response to
bDMARDs or tsDMARDs.
• A minimal initial treatment goal of low disease activity is
conditionally recommended over a goal of remission.

90. Overview of ACR's
Recommended Disease Activity
Measures
Measure Scoring Cutoffs
SDAI Remission: ≤ 3.3
Low activity: > 3.3 to ≤ 11.0
Moderate activity: > 11.0 to ≤ 26.0
High activity: > 26.0 to 86.0
CDAI Remission: ≤ 2.8
Low activity: > 2.8 to 10.0
Moderate activity: > 10.0 to 22.0
High activity: > 22.0 to 76.0
DAS28-ESR or DAS28-CRP Remission: < 2.6
Low activity: 2.6 to < 3.2
Moderate activity: 3.2 to ≤ 5.1
High activity: > 5.1 to 9.4
RAPID-3 Remission: 0 to 1.0
Low activity: > 1.0 to 2.0
Moderate activity: > 2.0 to 4.0
High activity: > 4.0 to 10.0
Our patient
after 1 month

91. ACR 2021 Guiding principles
RA requires early evaluation, diagnosis &
management.
Treatment decisions should follow a shared
decision-making process.
Treatment decisions should be reevaluated
within a minimum of 3 months based on
efficacy & tolerability of the DMARD(s) chosen.
Disease activity levels refer to those calculated
using RA disease activity measures endorsed by

92. • The MTX dose is increased as tolerated & as needed to control
symptoms & signs of arthritis.
• The author's usual approach is to increase the dose after 4 weeks at a
rate of 2.5mg (one tablet)/week as indicated by disease activity & as
tolerated.
• In patients with continued high disease activity, the author may
increase by up to 5 mg/week if few comorbidities are present & the
increase in the dose continues to be well tolerated.

93. So, you told her to increase MTX
dose gradually (2.5 mg/week) to
the maximal dose of 25 mg/week.
Do you need investigations for
follow up?

94. Monitoring
Before starting MTX
• CBC with platelets
• Hepatitis B & C serologies
• AST, ALT, albumin
• S. creatinine (CrCl)
• A chest x-ray should be
performed if the patient has not
had one in the past year.
Monitor /2:4 weeks for the first 3
months, then /8:12 weeks for the
next 3:6 months, then /12 weeks.
• CBC
• S. creatinine
• ALT, AST

95. MTX renal adjustment according to eGFR
Dose reduction
by 25% for CrCl
<80 mL/minute
by50% for CrCl
<50 mL/minute.
MTX should not
be used in
patients
on dialysis or
who have a CrCl
<30 mL/minute.

97. EULAR RA
recommendations
2022

98. RF is a series of
antibodies against
the IgG.

99. •RF is an antibody
directed against the
Fc fragment of
immunoglobulin G
(IgG).
•It may be of any
isotype: IgG, IgA,
IgE, and IgM.
•RF-IgM is the only
one measured in
clinical practice.

100. Case
A 22
years old
female
patient
with RA
comes to
you for
follow up.
Her joints
are not
tender or
swollen.
Her ESR is
19.
CRP is 4.
RF is 32
(baseline
was 16).
What is
your plan
in her
current
situation?

101. Rheumatoid factor is not consistent in follow
up of disease activity.

102. Case
RF, anti-CCP, ANA, HCV AB, HBsAg: -ve.
What is the likely diagnosis?
CRP is 48.
Her ESR is 80.
A 22 years old female patient comes to you with 4 months of diffuse symmetrical
peripheral (bilateral MCP, PIP, wrists) arthritis, no other manifestations.

104. Clinical use
of the test
A negative RF does not exclude the
diagnosis of RA (seronegative RA).
RA patients with high RF titer tend to
have more severe disease (prognostic
value).
Poor correlation with disease activity.
(no use to repeatedly measure RF).

105. Case
A 30 years old male patient presents with bilateral
symmetrical peripheral small arthritis.
ESR 120
CRP: 96
Rheumatoid factor: +ve, 512.
C3: normal.
C4: 2 (20 – 40)
How to proceed?

106. How to
proceed?
ANA,
anti-
CCP: -ve.

107. •HCV AB +ve ( PCR 2000000 ).
•How to proceed?

108. •S. cryoglobulins:
negative !!!!!!!!!!!!!!!

109. Rheumatic Conditions Infections Pulmonary
Disease
Miscellineous
RA (70-80%) SBE Silicosis Aging
SLE (15-35%)
MCTD (50-60%)
TB
Leprosy
Sarcoidosis Leukemia
Sjogren’s Syndrome
(75-95%)
Syphilis IPF Colon Cancer
Systemic Sclerosis Viral
infections
Asbestosis Cirrhosis- Hep C/PBC
Cryoglobulinemia
(40-100%)
Parasitic
Disease
Sarcoidosis
RF positive disease states

110. Frequency of a positive RF increases with age
Age 20-60
2-4%
Age 60-70
5%
Age >70
10-25%

111. Rheumatoid Arthritis
RA
100 patients
RF +
At diagnosis
60 patients
Initially RF-, becomes
RF+
during course of disease
20 patients
RF –
Seronegative RA
20 patients

112. Case
A 40 years old patient presents
for routine clinical follow up.
History and examination are
unremarkable.
Investigations returned back
normal except a positive anti-
CCP.
What is the best next step?

114. • Anti-CCP antibodies
have been detected in
sera of patients with RA
up to 10 years prior to
the onset of disease.
About one-third of
patients with RA will be
positive for these
antibodies, but RF
negative, on
presentation.

115. RA serology
Up to 80% of patients with RA test positive for RF,
whereas ~66% test positive for ACPA. RF's diagnostic
specificity ranges from 48% to 92%, whereas ACPA's
specificity reaches 98%. A challenge with RF is that
healthy patients and those with other conditions, such
as liver disease, may also test positive for this marker.
Because both RF & ACPA have been isolated
from the serum of healthy patients, sometimes
> a decade before their RA diagnosis, these
markers may help identify people at high risk for
developing RA, potentially enabling closer
monitoring & earlier diagnosis.

116. Cyclic citrullinated
peptide antibodies
(Anti-CCP)
or Anti-citrullinated
protein antibody
(ACPA)
 More recently discovered RA specific
antibodies with sensitivity similar to RF
and a very good specificity.
ACPAs are sensitive (70%) and highly specific
(95%) for RA.
This test is valuable in confirming the
diagnosis of early RA.
Anti-CCP antibodies can predict the
development of rheumatoid arthritis.
High titre of anti-CCP are prognostic for
erosive disease.
(Nielen MMJ ,
Arthritis Rheum 2004)

117. Recommendation 9
Don’t order Rheumatoid factor (RF) & Anti-
Citrullinated Protein Antibody (ACPA) unless patients
have clinically suspicious arthralgia (CSA) or arthritis
on exam.
Canadian Rheumatology Association, September 30, 2022

118. EULAR defined
characteristics
describing arthralgia at
risk for RA
• To be used in patients with
arthralgia without clinical
arthritis & without other
diagnosis or other explanation
for the arthralgia.

119. EULAR defined
characteristics
describing
arthralgia at
risk for RA
• Joint symptoms of recent onset (duration
<1 year)
• Symptoms located in MCP joints
• Duration of morning stiffness ≥60 min
• Most severe symptoms present in the early
morning
• Presence of a first-degree relative with RA
History taking
• Difficulty with making a fist
• Positive squeeze test of MCP joints
Physical examination

120. Recommendation 9
justification
Avoid ordering these autoantibodies in patients with arthralgia who do not meet
the CSA criteria or have arthritis (>1 swollen joint) on physical exam.
EULAR defines CSA at risk for developing RA as having 3 or more parameters.
Even in CSA with positive RF & ACPA, > 30%-60% of patients will not develop RA
over the next 2 years.
Most musculoskeletal pain causing global disability is not related to RA.
Inappropriate testing of RF serology in patients with low likelihood of RA is
associated with low positive predictive value (PPV) & increased cost.
Canadian Rheumatology Association, September 30, 2022

122. Case
• A 22-year-old female presented with
polyarthritis, malar rash, photosensitivity &
polyarthritis of small MCPs & PIPs for 3
months.
• ESR: 100 mm (1st hour)
• Her rheumatoid factor is positive, 48.
• What is your diagnosis?

124. SLE.
Could she have
rhupus (RF +ve,
arthritis)?
ANA (IF):
positive, 1/
160, speckled
Anti-dsDNA:
highly positive
S. C3, C4:
consumed
Anti-CCP:
negative
X-ray hands:
normal
What is your
diagnosis?

125. RhS
(Rhupus
syndrome)
is defined
as
A deforming & erosive symmetric
polyarthritis
Symptoms of SLE
Antibodies of high diagnostic specificity,
such as anti-double stranded DNA, anti-
Smith & anti CCP antibodies.

126. Meeting in RA part 2
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