DIAGNOSIS AND RECENT ADVANCES IN MANAGEMENT OF RHEUMATOID ARTHRITIS

1. DIAGNOSIS AND RECENT ADVANCES IN
MANAGEMENT OF RHEUMATOID ARTHRITIS
PRESENTED BY:
DR MUKESH SHUKLA , MD
SENIOR RESIDENT
MEDICINE, KGMU
LUCKNOW

2. INTRODUCTION
 Commonest inflammatory joint disease seen in clinical
practice affecting approx 1% of population.
 Chronic multisystem disease of unknown cause.
 Characterized by persistent inflammatory synovitis
leading to cartilage damage, bone erosions, joint
deformity and disability.

3. RHEUMATOID ARTHRITIS: INDIAN SCENARIO
 Prevalence of RA is around 0.5 - 1% in industrialized nations
with 5 - 50 new cases per 100,000 population annually1
 Predominantly occurs in female and elderly population1
 Prevalence of RA in Indian population is around 0.5 - 0.75%1
 It is the commonest inflammatory polyarthritis seen in clinical
practice2
1. JAPI. 2013;61.
2. JAPI. 2013;61:529.

4. ONSET
 Although Rheumatoid arthritis may present at any age, patients
most commonly are first affected in the third to sixth decades.
 Female: male 3:1
 Initial pattern of joint involvement could be:-
1) Polyarticular : most common
2) Oligoarticular
3) Monoarticular
 Morning joint stiffness > 1 hour and easing with physical activity is
characteristic.
 Small joints of hand and feet are typically involved.

5. RELATIVE INCIDENCE OF JOINT INVOLVEMENT
IN RA
 MCP and PIP joints of hands & MTP of feet 90%
 Knees, ankles & wrists- 80%
 Shoulders- 60%
 Elbows- 50%
 TM, Acromio - clavicular & SC joints- 30%

6. JOINTS INVOLVED IN RA
 Don’t forget the cervical spine!! Instability at
cervical spine can lead to impingement of the spinal cord.
 Thoracolumbar, sacroiliac, and distal interphalangeal joints
(DIP)of the hand are NOT involved.

7. SUBLUXATION OF CERVICAL SPINE

8. PIP Swelling

9. SWAN NECK DEFORMITY

12. Ulnar Deviation, MCP Swelling,
Left Wrist Swelling

14. EXTRAARTICULAR INVOLVEMENT
 Constitutional symptoms ( most common)
 Rheumatoid nodules(30%)
 Hematological-
 normocytic normochromic anemia
 leucocytosis /leucopenia
 thrombocytosis
 Felty’s syndrome-
 Chronic nodular Rheumatoid Arthritis
 Splenomegaly
 Neutropenia
o Caplan Syndrome-
• Pneumoconiosis following silica exposure
• Rheumatoid Arthritis

15. RHEUMATOID NODULE

16.  Respiratory- pleuritis ( MC ), pleural effusion, pneumonitis ,
pleuro-pulmonary nodules, ILD
 CVS-asymptomatic pericarditis , pericardial effusion,
cardiomyopathy , mitral regurgitation (mc valvular
abnormality in RA )
 Rheumatoid vasculitis- mononeuritis multiplex, cutaneous
ulceration, digital gangrene, visceral infarction
 CNS- peripheral neuropathy, cord-compression from
atlantoaxial/midcervical spine subluxation, entrapment
neuropathies
 EYE- kerato cunjunctivitis sicca, episcleritis, scleritis

17. EXTRAARTICULAR MANIFESTATIONS

18. LABORATORY INVESTIGATIONS IN RA
 CBC ( TLC, DLC, Hb )
 Acute phase reactants ( ESR, CRP )
 Rheumatoid Factor (RF).
 Anti- CCP antibodies (most specific ).

19. RHEUMATOID FACTOR (RF)
 Antibodies that recognize Fc portion of IgG.
 Can be IgM , IgG , IgA
 85% of patients with RA over the first 2 years become RF positive.
• A negative RF may be repeated 4-6 monthly for the first two year
of disease, since some patients may take 18-24 months to become
seropositive.
• PROGNISTIC VALUE- Patients with high titres of RF, in
general, tend to have POOR PROGNOSIS, MORE EXTRA
ARTICULAR MANIFESTATION.

20. SERUM ANTI-CCP ANTIBODIES
 The presence of serum anti-CCP antibodies has about the
same sensitivity as serum RF for the diagnosis of RA.
However, its specificity approaches 95%.
 A positive test for anti-CCP antibodies in the setting of an
early inflammatory arthritis is useful for distinguishing RA from
other forms of arthritis.
 There is some incremental value in testing for the presence
of both RF and anti-CCP, as some patients with RA are
positive for RF but negative for anti-CCP and visa versa.
 The presence of RF or anti-CCP antibodies also has
prognostic significance, with anti-CCP antibodies showing the
most value for predicting worse outcomes.

21. Other Lab Abnormalities :
Elevated APRs( ESR, CRP )
Thrombocytosis
Leukocytosis
ANA
 30-40%
Inflammatory synovial fluid
Hypoalbuminemia

22. o Radiographic Features
 Peri-articular osteopenia
 Uniform symmetric joint space narrowing
 Marginal subchondral erosions
 Joint Subluxations
 Joint destruction
 Collapse
 Ultrasound detects early soft tissue lesions.
 MRI has greatest sensitivity to detect synovitis and marrow
changes.

24. DIAGNOSIS

25. ACR CRITERIA (1987)
 1.Morning Stiffness ≥1 hour
 2.Arthritis of ≥ 3 joints observed by physician.
 3.Arthritis of hand joints-PIP,MCP,wrist
 4. Symmetric arthritis
 5. Rheumatoid nodules
 6. Positive Rheumatoid Factor
 7. Radiographic Erosions or periarticular osteopenia in hand or wrist
joints .
 Criteria 1-4 must be present for ≥6 wks
 Must have ≥4 criteria to meet diagnosis of RA

26. 2010 ACR/EULAR CLASSIFICATION CRITERIA
 a score of ≥6/10 is needed for classification of a patient as having definite RA
 A. Joint involvement SCORE
 1 large joint 0
 2−10 large joints 1
 1−3 small joints (with or without involvement of large joints) 2
 4−10 small joints (with or without involvement of large joints) 3
 >10 joints (at least 1 small joint)†† 5
 B. Serology (at least 1 test result is needed for classification)
 Negative RF and negative ACPA 0
 Low-positive RF or low-positive ACPA 2
 High-positive RF or high-positive ACP A , 3
 C. Acute-phase reactants (at least 1 test result is needed for classification)
 Normal CRP and normal ESR 0
 Abnormal CRP or abnormal ESR 1
 D. Duration of symptoms
 <6 weeks 0
 ≥6 weeks 1

27. MANAGEMENT

28. GOALS OF MANAGEMENT
 Focused on relieving pain
 Preventing damage/disability
 Patient education about the disease
 Physical Therapy for stretching and range of
motion exercises
 Occupational Therapy for splints and adaptive
devices
 Treatment should be started early and
should be individualised .
 EARLY AGGRESSIVE TREATEMNT

29. TREATMENT MODALITIES FOR RA
 NSAIDS
 Steroids
 DMARDs
 Biological therapies
 Surgery

30. NSAIDS
Non-Steroidal anti-inflammatories (NSAIDS) for symptom
control :
1) Reduce pain and swelling by inhibiting COX
2) Do not alter course of the disease.
3) Chronic use should be minimised.
4) Most common side effect related to GI tract.

31. CORTICOSTEROIDS IN RA
 Corticosteroids , both systemic and intra-articular are important
adjuncts in management of RA.
 Indications for systemic steroids are:-
 For treatment of rheumatoid flares.
 For extra-articular RA like rheumatoid vasculitis and interstitial lung
disease.
 As bridge therapy for 6-8 weeks before the action of DMARDs
begin.
 Maintainence dose of 10mg or less of predinisolone daily in patients
with active RA.
 Sometimes in pregnancy when other DMARDs cannot be used.

32. DISEASE MODIFYING ANTI-RHEUMATIC AGENTS
 Drugs that actually alter the disease course .
 Should be used as soon as diagnosis is made.
 Appearance of benefit delayed for weeks to months.
 NSAIDS must be continued with them until true remission is
achieved .
 Induction of true remission is unusual .

33. DMARDS
Commonly used Less commonly used
Methotrexate Chloroquine
Hydroxychloroquine Gold(parenteral &oral)
Sulphasalazine CyclosporineA
Leflunomide D-penicillamine/bucillamine
Minocycline/Doxycycline
Levamisole
Azathioprine,cyclophosphamid
e, chlorambucil

34. CLINICAL INFORMATION ABOUT DMARDS
NAME DOSE SIDE EFFECTS MONITORING ONSET OF
ACTION
1) Hydroxyclor
oquine
200mg twice
daily x 3
months, then
once daily
Skin
pigmentation ,
retinopahy
,nausea,
psychosis,
myopathy
Fundoscopy&
perimetry yearly
2-4 months
2) Methotrexate 7.5-25 mg once
a week
orally,s/c or i/m
GI upset,
hepatotoxicity,
Bone marrow
suppression,
pulmonary
fibrosis
Blood
counts,LFT 6-8
weekly,Chest x-
ray annually,
urea/creatinine
3 monthly;
Liver biopsy
1-2 months

35. CLINICAL INFORMATION ABOUT DMARDS
CONTND..
NAME DOSE SIDE EFFECTS MONITORING ONSET OF
ACTION
3)Sulphasalazin
e
2gm daily p.o Rash,
myelosuppressi
on, may reduce
sperm count
Blood counts
,LFT 6-8 weekly
1-2 months
4)Leflunomide Loading 100 mg
daily x 3 days,
then 10-20 mg
daily p.o
Nausea,diarrho
ea,alopecia,
hepatotoxicity
LFT 6-8 weekly 1-2 months

36. WHEN TO START DMARDS?
 DMARDs are indicated in all patients with RA who continue
to have active disease even after 3 months of NSAIDS use.
 The period of 3 months is arbitary & has been chosen since a
small percentage of patients may go in spontaneous
remission.
 The vast majority , however , need DMARDs and many
rheumatologists start DMARDs from Day 1.

37. HOW TO SELECT DMARDS?
 There are no strict guidelines about which DMARDs to start first
in an individual.
 Methotrexate has rapid onset of action than other DMARD.
 Taking in account patient tolerance, cost considerations and
ease of once weekly oral administration METHOTREXATE is
the DMARD of choice, most widely prescribed in the world.

38. SHOULD DMARDS BE USED SINGLY
OR IN COMBINATION?
 Since single DMARD therapy (in conjunction with NSAIDS) is
often only modestly effective , combination therapy has an
inherent approach .
 DMARD combination is specially effective if they include
methotrexate as an anchor drug.
 Combination of methotrexate with leflunamide are
synergestic since there mode of action is different.

39. LIMITATIONS OF CONVENTIONAL DMARDS
1) The onset of action takes several months.
2) The remission induced in many cases is partial.
3) There may be substantial toxicity which requires
careful monitoring.
4) DMARDs have a tendency to lose effectiveness
with time-(slip out).
 These drawbacks have made researchers look for
alternative treatment strategies for RA- The
Biologic Response Modifiers.

40. BIOLOGICS IN RA
 Cytokines such as TNF-α ,IL-1,IL-10 etc. are key mediators
of immune function in RA and have been major targets of
therapeutic manipulations in RA.
 Of the various cytokines,TNF-α has attaracted maximum
attention.
 Various biologicals approved in RA are:-
1) Anti TNF agents : Infliximab Etanercept Adalimumab
2) IL-1 receptor antagonist : Anakinra
3) IL-6 receptor antagonist : Tocilizumab
4) Anti CD20 antibody : Rituximab
5) T cell costimulatory inhibitor : Abatacept

41. Agent Usual dose/route Side effects Contraindications
Infliximab
(Anti-TNF)
3 mg/kg i.v infusion
at wks 0,2 and 6
followed by
maintainence dosing
every 8 wks
Has to be combined
with MTX.
Infusion reactions,
increased risk of
infection,
reactivation of TB
,etc
Active
infections,uncontrolled
DM,surgery(with hold for
2 wks post op)
Etanercept
(Anti-TNF)
Active
infections,uncontrolled
DM,surgery(with hold for
2 wks post op)
Adalimumab
(Anti-TNF)
40 mg s/c every 2
wks(fornightly)
May be given with
MTX or as
Same as that of
infliximab
Active infections
.
25 mg s/c twice a wk
May be given with
MTX or as
monotherapy.
Injection site
reaction,URTI ,
reactivation of
TB,development
of
ANA,exacerbation
of demyelenating
disease.

42. Abatacept
(CTLA-4-IgG1
Fusion protien)
Co-stimulation
inhibitor
10 mg/ kg body
wt.
At 0, 2 , 4 wks &
then 4wkly
Infections, infusion
reactions
Active infection
TB
Concomittant with other
anti-TNF-α
Rituximab
(Anti CD20)
1000 mg iv at
0, 2, 24 wks
Infusion reactions,
Infections
Same as above
Tocilizumab
( Anti IL-6)
4-8 mg/kg
8 mg/kg iv
monthly
Infections, infusion
reactions,dyslipide
mia
Active infections
Agent
Usual
dose/route
Side effects
.
Anakinra 100 mg s/c once
daily
May be given
with MTX or as
monotherapy.
Injection site
pain,infections,
neutropenia
Active infections
Contraindication
s
IL – 1
receptor
antagonis
t

43. 2012 ACR UPDATE

45. HOW TO MONITOR TT IN RA?
 Disease activity is assesed by several parameters…
duration of morning stiffness,tender joint count,swollen joint
count, visual analogue scale for pain, health assessment
questionnaire,ESR,NSAID pill count,DAS score etc..
• Patient on MTX,SSZ or leflunamide show clinical improvement
in 6-8 wks.
• Patient should be observed for 6 months before declaring a
DMARD ineffective.

46. HOW LONG SHOULD TT. BE CONTINUED?
 Once remission is achieved , maintenance dose for long period
is recommended.
 Relapse occurs in 3-5 months (1-2 months in case of MTX) if
drug is discontinued in most instances.
 DMARDs are discontinued by patients because of toxicity or
secondary failure(common after 1-2 yrs) and such patients
might have to shift over different DMARDs over 5-10 yrs.
 Disease flare may require escalation of DMARD dose with short
course of steroids.

47. SURGICAL APPROACHES
 Synovectomy is ordinarily not recommended for
patients with rheumatoid arthritis, primarily because
relief is only transient.
 However, an exception is synovectomy of the wrist,
which is recommended if intense synovitis is persistent
despite medical treatment over 6 to 12 months.
 Total joint arthroplasties , particularly of the knee, hip,
wrist, and elbow, are highly successful.
 Other operations include release of nerve
entrapments (e.g., carpal tunnel syndrome),
arthroscopic procedures, and, occasionally, removal of
a symptomatic rheumatoid nodule.

48. RHEUMATOID ARTHRITIS IN PREGNANCY
 Most patients with RA go into remission during pregnancy.
 Methotrexate and leflunomide should be discontinued for at least 3
months before trying to conceive.
 Paracetamol is the oral analgesic of choice during pregnancy.
 Corticosteroids may be used to control disease flares
 DMARDs that may be used: sulfasalazine, hydroxychloroquine,
azathioprine or ciclosporin if required to control inflammation.
 DMARDs that must be avoided: methotrexate,
leflunomide,cyclophosphamide, gold and penicillamine.
 Biological therapies: safety during pregnancy is currently
unclear.

49. RHEUMATOID ARTHRITIS IN ELDERLY
 Older individuals may receive less aggressive treatment due to
concerns about increased risks of drug toxicity.
 Conventional DMARDs and biologic agents are equally effective
and safe in younger and older patients.
 Due to comorbidities,many elderly patients have an increased
risk of infection.
 Aging also leads to a gradual decline in renal function that may
raise the risk for side effects from NSAIDs and some DMARDS,
such as methotrexate.
 Renal function must be taken into consideration before
prescribing methotrexate, which is mostly cleared by the
kidneys.

50. RHEUMATOID ARTHRITIS IN 2017
 There is considerable interest in picking up RA in
its preclinical state when disease is immunologically
nascent, the concept of preclinical RA .
 Pre- clinical RA is an exiting concept that stimulates
identification of pre – clinical didease .
 Research is currently focused on genetic
predisposition and environmental risk factors in
rheumatoid arthritis.
 Genome wide association study analyses have
identified various RA associated genes such as
HLA- DRB1, PTPN22, TNFAIP3,STAT4 and CCR6.

51.  The next decade is likely to witness a better price
rationalization due to variety of factors making biologics
accessible to many.
 Enormous amount of research is going on small
molecules targeting various intracellular pathways like
janus associated kinases (JAKs), spleen tyrosine kinase
(SYK) and brutons tyrosine kinase (BTK) .
 Tofacitinib, a small molecule inhibitor has shown
excellent efficacy in management of RA.

52.  Currently we have choices of synthetic (s DMARD)
and biological disease modifying antirheumatoid
drugs (b DMARD) that can enable us to achieve
remarkable improvement in clinical outcome
including remission.
 The future seems promising with our better
understanding of RA pathogenesis, better
strategies and newer molecules .

53. TAKE HOME MESSAGE
 The earlier we control of inflammation in RA, the better is
the outcome.
 The current treatment strategy should be to make
diagnosis early, be aggressive with therapy after
diagnosis and aim should be to reach clinical remission.
 ‘Hit early and hit hard’ should be the motto .

54. Thank
you.

55. INSTRUMENTS TO MEASURE DISEASE ACTIVITY AND TO
DEFINE REMISSION

58. HOW TO CALCULATE DAS28 SCORE

59. ACR/EULAR PROVISIONAL DEFINITION OF REMISSION IN
RHEUMATOID ARTHRITIS

60. MCQ

61. MCQ : 1
 A 45 year old women presents to the rheumatology
opd clinic with a three months history of stiff hands
and wrists. She mentions that the pain is
particularly bad in the morning. On examination ,
the wrist , MCP joints and PIP joints are swollen and
warm . A diagnosis of rheumatoid arthritis is
suspected. Which of the following is most specific
for confirming the diagnosis-
A. X – rays
B. Rheumatoid factor levels
C. Anti-CCP levels
D. Erythrocyte sedimentation rate

62. MCQ : 2
 A 50 year old women , who has received a
recent diagnosis of rheumatoid arthritis
,presents to her GP with ongoing pain and
stiffness in her hands and feet . Which joints
are usually spared at onset of rheumatoid
arthritis ?
A. Proximal interphalangeal joints
B. Distal interphalangeal joints
C. Wrist
D. Metacarpophalangeal joint

63. MCQ : 3
Which of the following is not a criterion
for remission in rheumatoid arthritis (RA)
according to the ACR/EULAR 2011
criteria?
A. C-reactive protein (CRP) ≤1 mg/dL
B. Swollen joint count ≤1
C. Tender joint count ≤1
D. Physician global assessment ≤1

64. MCQ : 4
 . Which of the following regarding Infliximab is most
true?
A. Is a monoclonal antibody to the glycoprotein IIb-
IIIa receptor
B. Is authorized for the treatment of severe ulcerative
colitis
C. Is licensed for the treatment of RA
D. It prevents relapse of Crohn’s disease in patients
who are in remission
E. Must not be used in combination with
methotrexate due to increased toxicity

65. MCQ : 5
 A 45-year-old female teacher presents complaining of
severe left knee pain. She has a long-term history of
rheumatoid arthritis, which has been well controlled for
several years on a multidrug regimen of methotrexate,
hydroxychloroquine, and a nonsteroidal anti-inflammatory
drug (NSAID). Which of the following symptoms suggests
secondary degenerative joint disease (rather than
rheumatoid arthritis) as a cause of her knee pain?
A. Prolonged morning stiffness
B. Pain that is exacerbated by activity
C. Increased fatigue
D. Multiple joint complaints
E. Weight loss

66. MCQ- 6
 A 33-year-old female accountant with rheumatoid arthritis
has severe neck pain and occipital headaches. A flexion-
extension radiograph of her neck shows minimal widening
of the preodontoid space. Which of the following is the most
appropriate course for this patient?
A. Refer the patient to a neurologist for treatment of chronic
headache
B. Change the patient’s current NSAID to another class
C. Obtain a cervical spine magnetic resonance image (MRI)
with gadolinium
D. Check the patient’s erythrocyte sedimentation rate and RF
levels
E. Initiate use of a soft collar for 2 weeks

67. MCQ- 7
 A 22-year-old male automobile mechanic who was
recently diagnosed with rheumatoid arthritis presents
complaining of difficulty holding his wrench and other
tools. He also notes an occasional “electric shock”
sensation in his right index and middle fingers. Physical
examination reveals bilateral (right greater than left)
wrist synovitis. He has a solid handgrip and no muscle
atrophy. Which of the following is the most likely cause
of his symptoms?
A. Tendonitis of the abductor pollicis brevis
B. Keinbock’s syndrome
C. DeQuervain’s tenosynovitis
D. Rupture of the fourth and fifth extensor tendons
E. Carpal tunnel syndrome

68. MCQ- 8
 A 37-year-old female bus driver is referred by her primary care
physician for evaluation of a polyarthritis of 3 months’ duration. On
examination, she has a symmetrical distribution of synovitis that is
consistent with rheumatoid arthritis; radiographs show periarticular
demineralization and soft-tissue swelling. Which of the following is
the most appropriate course of therapy for this patient?
A.Methotrexate (12.5 mg/wk) and prednisone (7.5 mg/day)
B.Pulse methylprednisolone sodium succinate
C.Six week course of NSAIDs followed by reevaluation Cyclosporine
(1.5 mg/kg/day)
D.Tumor-necrosis factor (TNF) α-inhibitor (25 units subcutaneously,
biweekly

69. ANSWERS
1. C
2. B
3. D
4. C
5. B
6. C
7. E
8. A