Rheumatoid arthritis is a chronic inflammatory disease that causes swelling and stiffness in the joints. It can also cause extra-articular manifestations affecting various organs. The document discusses the epidemiology, etiology, clinical features, extra-articular manifestations and treatment of rheumatoid arthritis. It highlights that rheumatoid arthritis predominantly affects women aged 25-55 years and can involve the lungs, heart, blood vessels and skin. Treatment involves NSAIDs, corticosteroids, conventional DMARDs like methotrexate and biological DMARDs that target cytokines like TNF-alpha if first line treatments are inadequate.

1. EXTRA ARTICULAR
MANIFESTATIONS OF RHEUMATOID
ARTHRITIS
Presenter: Dr. Asen Pongen
Moderator: Prof. Santa Naorem

2. INTRODUCTION
 A chronic inflammatory disease of unknown
etiology marked by a symmetric, peripheral
polyarthritis and systemic disease

3. EPIDEMIOLOGY
 Incidence : between 25-55 years of age after which it plateaus
until the age of 75 and then decreases.
 RA affects ~0.5–1% of the adult population worldwide
 Prevalence of RA in India is 0.20-0.75%
 RA occurs more commonly in females than in males, with a 2–3:1
ratio

4. ETIOLOGY
 Aetiology is unknown
 Autoimmune disease in which the body’s immune system
mistakenly attacks the joints

5. GENETIC FACTORS:
 Increased incidence in first degree relatives(2-20 times higher
than the general population)
 Genetic factors are estimated to account for up to 60% of
disease susceptibility
 Strong association between susceptibility to RA and certain
HLA haplotypes (HLA-DR4 & HLA-DRB1)

6. ENVIROMENT FACTORS
 Smoking tobacco increases the risk of developing
rheumatoid arthritis ( relative risk 1.5-3.5)
 Certain infections: Strains of streptococci
Epstein-Barr virus (EBV)

7. PATHOLOGY
 The pathologic hallmarks of RA are
synovial inflammation and
proliferation, focal bone erosions,
and thinning of articular cartilage
 Chronic inflammation leads to
synovial lining hyperplasia and the
formation of pannus
 Pannus destroys the articular
cartilage and subchondral bone,
producing bony erosions

8. CLINICAL FEATURES
 CONSTITUTIONAL: weight loss, fever(101°F), fatigue,
malaise, depression, cachexia
 Early morning joint stiffness lasting more than 1 h that eases
with physical activity
 RA have a higher number of tender and swollen joints

9. o Earliest involved joints - small joints of the hands & feet :
may be monoarticular, oligoarticular (≤4 joints), or
polyarticular (>5 joints)
o Wrists, MCP & PIP joints: most frequently involved joints
o Large joints involved: knees & shoulders are often affected in
established disease
o Spine usually spared except cervical spine, which may cause
compressive myelopathy & neurologic dysfunction

10. Hyperextension of PIP & flexion of
DIP joint (SWAN-NECK
DEFORMITY)
Flexion of the PIP & hyperextension
of DIP joint (BOUTONNIERE
DEFORMITY)
Subluxation of 1st MCP joint &
hyperextension of the first
interphalangeal joint lead to Z-
deformity
Ulnar deviation results from
subluxation of the MCP joints
CLASSICAL HAND SIGN IN
RHEUMATOID ARTHRITIS

11. EXTRAARTICULAR MANIFESTATIONS
Subcutaneous nodule
Subcutaneous nodules have been reported to occur
in 30–40% of patients and more commonly in those
with the highest levels of disease activity positive
test for serum RF and radiographic evidence of
joint erosions
 Firm; non tender; adherent to periosteum
&tendons on palpation
 Develop in areas of repeated trauma (E.g. :
forearm, sacral prominences, Achilles tendon)
 Also in lungs, pleura, pericardium & peritoneum
 Nodules are typically benign. Can be associated
with infection ulceration and gangrene.

12. PULMONARY MANIFESTATIONS
 Pleuritis : most common pulmonary manifestation of RA
 Pleural effusions: exudative, increased monocytes and neutrophils
 Interstitial lung disease(ILD) Diagnosed by HRCT

13.  Usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP)
are the main histologic and radiologic patterns of ILD.
 UIP causes progressive scarring of the lungs that, on chest CT scan, produces
honeycomb changes in the periphery and lower portions of the lungs. NSIP are
relatively symmetric and bilateral ground-glass opacities with associated fine
reticulations, with volume loss and traction bronchiectasis.
 The presence of ILD confers a poor prognosis
 Responds better to immunosuppressive therapy .
 Pulmonary nodules are also common and may be solitary or multiple.
 Caplan’s syndrome is a rare subset of pulmonary nodulosis characterized by the
development of nodules and pneumoconiosis following silica exposure.
 Copd is also a common findings in RA

15. CARDIAC
 Pericardium is the most frequent site of cardiac involvement in RA. Clinical
manifestations occur in <10% of the affected individuals
 Myocarditis can be either granulomatous or interstitial
 Atrial fibrillation risk is increased in RA including IHD and stroke risk is also
increased.
 Rheumatoid nodules: They may develop in pericardium, myocardium and
vulvular structures
 Up to 20% of patients with RA may have asymptomatic pericardial effusions on

16. • The most common cause of death in patients with RA is cardiovascular disease
• The incidence of coronary artery disease and carotid atherosclerosis is higher in
RA patients than in the general population
• Congestive heart failure (including both systolic and diastolic dysfunction) occurs
at an approximately twofold higher rate in RA than in the general population

17. NON CARDIAC VASCULAR DISEASE
 Vasculitis
 Peripheral vascular disease
 Stroke
 Lymphatic obstruction

18. VASCULITIS
 Rheumatoid vasculitis typically occurs in patients with long-standing disease, a
positive test for serum RF or anti–cyclic citrullinated peptide (CCP) antibodies, and
hypocomplementemia
 Cutaneous vasculitis:The cutaneous signs are petechiae, nailfold lesions,
palpable purpura, digital infarcts, gangrene, livedo reticularis, and in severe cases
large, painful lower extremity ulcerations typically seen over medial or lateral
malleoli

21. PERIPHERAL VASCULAR DISEASE
 Atherosclerotic peripheral vascular disease: The risk is more
in RA then in otherwsise healthy individuals
 Venous thromboembolic disease: There is two fold increase in
patients with RA then in healthy individual

22. Sjogren’s syndrome:
Secondary Sjögren’s syndrome is defined by the presence of either
keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in association with
RA. Approximately 10% of patients with RA have secondary Sjögren’s.

23. NEUROLOGIC DISEASE
 Vasculitic neuropathy: Results from infarction of individual
peripheral nerves by vasculitis in the vasa nervorum
 Sensory neuropathy: 40% of patients have sensory
neuropathy
 20% mixed motor and sensory neuropathy
 Both mononeuritis multiplex and a distal symmetric sensory or
sensorimotor neuropathy can occur. Early in the process
nerve involvement is likely to involve one side

25. OCULAR MANIFESTATIONS
 Episcleritis
 Scleritis: Diffuse anterior scleritis is the most
common form
 Peripheral ulcerative keratitis
 Keratoconjunctivitis

29. HEMATOLOGIC
 A normochromic, normocytic anemia often develops in patients with RA and is
the most common hematological abnormality.
 The degree of anemia parallels the degree of inflammation, correlating with the
levels of serum C-reactive protein (CRP) and erythrocyte sedimentation rate
(ESR).
 Felty’s syndrome is defined by the clinical triad of neutropenia, splenomegaly
and nodular RA occurs in the late stages of severe RA
 T-cell large granular lymphocyte leukemia (T-LGL) also occurs in association
with RA which is characterized by a chronic, indolent clonal growth of LGL cells,
leading to neutropenia and splenomegaly.

30.  As opposed to Felty’s syndrome, T-LGL may develop early in the course of
RA
 Leukopenia can often be a side effect of drug therapy
 The most common histopathologic type of lymphoma is a diffuse large B-cell
lymphoma. The risk of developing lymphoma increases if the patient has high
levels of disease activity or Felty’s syndrome

31. Skeletal:
• Osteoporosis is more common in patients with RA with an
incidence rate of nearly double that of the healthy population
and a prevalence of approximately one-third in
postmenopausal women with RA
• There is also an increased risk of fragility fracture with a
greater risk among women

32. • The inflammatory milieu of the joint probably spills over into
the rest of the body and promotes generalized bone loss by
activating osteoclasts
• Both trabecular and cortical bone are affected by the
inflammatory response, with cortical sites more susceptible
to bone loss
• Chronic use of glucocorticoids and disability-related
immobility also contribute to osteoporosis
• Hip fractures are more likely to occur in patients with RA and
are significant predictors of increased disability and mortality

33. Neurological and psychiatric manifestatioin :
Central nervous system:
Cervical myelopathy- Cervical myelopathy resulting from atlantoaxial
subluxation, atlantoaxial impaction
Central nervous system vasculitis:
Clinical manifestations- Headache and mental status changes with seizure
cranial nerve palsies blindness, paralysis,dementia ,aphasia, gait disorders
and intracranial hemorrhage.

34. Rheumatoid nodules:
Rheumatoid nodules have been reported in patients with cerebral
leptomeninges and within the choroid plexus
Extra dural nodules in the spinal canal may cause compression and spinal
stenosis
Rheumatoid meningitis:
Characterized by inflammatory infiltrate of the meninges or aseptic
meningitis
Progressive multifocal leukoencephalopathy: PML, associated with
polyoma John Cunningham (JC) virus has been reported although risk is
very small.

35. PERIPHERAL NERVOUS SYSTEM
 Carpal tunnel syndrome due to
compression of the median nerve
commonly associated with pain and
paraesthesia and less commonly with
weakness
 Tarsal tunnel syndrome: Due to
compression of the tibial nerve. It may
result from tenosynovitis, inflammation
of FR or valgus deformities. Atrophy and
weakness of intrinsic foot muscles occur
in advance disease.
 Distal sensory neuropathy: Symmetric
paresthesias and burning sensations
tend to be worse in the feet than in the
hands. Decreased or absent deep
tendon reflexes.
 Combined sensorimotor neuropathy:
Due to ischemic neuropathy. Both
symmetric and asymmetric mononeuritis
multiplex have been described.
Compressive neuropathy
Non compressive
neuropathy

36. PSYCHIATRIC DISEASE
 Depression is common in patients with RA and symptoms of
depression are associated with increased pain, fatigue and
disability

37. RENAL
• Direct effects of RA on kidney are rare and include focal
glomerulonephritis usually of mesangioproliferative type or
membranous type without rapid progression of renal
dysfunction
• Patients with long standing inflammatory disease may
develop secondary amyloidosis

38. MUSCLE DISORDERS
 Myopathy:
1. Disuse atrophy: Sarcopenia low muscle mass and low skeletal
muscle strength or low physical performance. Occurs frequently in
older adults
2. Glucocorticoid induced myopathy- proximal muscle weakness
without significant serum muscle enzyme elevations
3. Myositis :Inflammatory myositis

39. DIAGNOSIS
 Clinical diagnosis of RA is largely based on signs and
symptoms
 Laboratory diagnosis
 Radiographic imaging

40. LABORATORY FEATURES
 Elevated ESR or CRP
 Detection of serum RF and anti-CCP antibody
Serum IgM RF has been found in 75–80% of patients with RA
Anti-CCP antibody : specificity 95%
helps distinguishing RA from other
Arthritis

41. SYNOVIAL FLUID ANALYSIS
 Reflects an acute inflammatory state
 Synovial fluid white blood cell (WBC):5000 and 50,000
wbc/μL
 Synovial fluid analysis:
 Most useful for confirming an inflammatory arthritis (as
opposed to osteoarthritis)
 To exclude infection or a crystal-induced arthritis such as
gout or pseudogout

42. IMAGING
Plain x-ray:
 Periarticular osteopenia
 Soft tissue swelling
 Symmetric joint space
loss
 Subchondral erosions

43. MRI
Detecting changes in the soft tissues such as synovitis,
tenosynovitis, and effusion
ULTRASOUND INCLUDING POWER COLOUR
DOPPLER
It can also reliably detect synovitis, including increased joint
vascularity indicative of inflammation

44. IMAGING

45. TREATMENT
Primary Objectives –
Target is low disease activity or remission
Reduction of inflammation and pain
Preservation of function
Prevention of deformity

46. DRUGS USED
NSAIDs
CORTICOSTEROIDS
DMARDs
CONVENTIONAL
BIOLOGICAL

47. NSAIDS
NSAIDs exhibit both analgesic and anti-inflammatory properties
 Symptomatic relief in RA
 Do not prevent erosions/alter disease progression
 Not appropriate for monotherapy
 Used in conjunction with DMARDs
S/E: Gastritis and PUD as well as impairment of renal function

48. CORTICOSTEROIDS
 Anti-inflammatory effect in RA & slow rate of erosion
 Low-dose corticosteroids – as a bridge to reduce disease
activity until the slower acting DMARDs take effect
 Adjunctive therapy for active disease that persists despite
treatment with DMARDs
10 mg of prednisone or equivalent per day is appropriate for
articular disease

49. CORTICOSTEROIDS
Higher doses use : to manage extra-articular manifestations –
eg: pericarditis, necrotizing scleritis
Intra-articular corticosteroids – if one or two joints are highly
inflamed. – Triamcinolone, 10–40 mg
S/E: Osteoporosis and PUD

50. DMARDS
 Ability to slow or prevent structural progression of RA
 The conventional DMARDs include
Hydroxychloroquine
Sulfasalazine
Methotrexate
Leflunomide
 They exhibit a delayed onset of action of ~6–12 weeks

52. BIOLOGICS DMARDS
 Biologics are genetically engineered from a living
organism, such as a virus, gene or protein, to simulate the
body’s natural response to infection and disease
 Biologics are typically reserved for people whose arthritis
has not responded adequately to traditional disease-
modifying anti rheumatic drugs (DMARDs)

53. IMPORTANT POINTS
 Biologics are effective
 Biologics may increase risk of infection
(Patients should be screened for tuberculosis and other
infections before starting a biologic)
 Biologics are usually given by Injection or IV
 Biologics require a strict follow-up schedule
 Biologics are expensive

54. HOW DO BIOLOGICS TREAT RHEUMATOID ARTHRITIS
 Inhibit specific components of the immune system that
play pivotal roles in inflammation
 To treat moderate to severe rheumatoid arthritis that has
not responded adequately to other treatments
 Slow down the progression of rheumatoid arthritis when
1st line drugs have failed

55. BIOLOGICS IN RA
Cytokines such as TNF-α ,IL-1,IL-6 etc. are key mediators of
immune function in RA and have been major targets of
therapeutic manipulations in RA

56. Various biologicals approved in RA are:-
 Anti TNF agents : Infliximab, Etanercept, Adalimumab
 IL-1 receptor antagonist : Anakinra
 IL-6 receptor antagonist : Tocilizumab
 Anti CD20 antibody : Rituximab
 T cell co-stimulatory inhibitor : Abatacept
 JAK lnhibitor : Tofacitinib

58. SIDE EFFECTS:
 ↑ Risk bacterial, fungal infections
 Reactivation of latent TB
 ↑ Lymphoma risk (controversial)
 Drug-induced lupus
 Infusion/ injection reaction
 ↑ LFTs

59. IL-1 RECEPTOR ANTAGONIST
Anakinra
 It is recombinant human IL-1 receptor antagonist
Used in cases who have failed on others drugs

61. IL-6 RECEPTOR ANTAGONIST
TOCILIZUMAB
 Humanized anti IL-6 monoclonal Ab that specifically inhibits
the action of 1L-6
 It is reserved for Resistant RA
 CBC should be monitoring
at regular interval

62. T-CELL CO-STIMULATION INHIBITOR
ABATACEPT
 It is recombinant fusion protein
 MOA: inhibits activation of T cell
 Used when there is inadequate response to DMARDS or in
combination with MTX or LEFLUNOMIDE

63. RITUXIMAB -B CELL DEPLETION THERAPY
Monoclonal antibody directed against CD20
 MOA: It works by depleting B cells, which in turn, leads
to a reduction in the inflammatory response by unknown
mechanisms. These mechanisms may include a reduction
in autoantibodies, inhibition of T cell activation, and
alteration of cytokine production

64.  Used in resistant RA in Combination therapy with
Methotrexate

65. JANUS KINASE ENZYME INHIBITOR
Tofacitinib
MOA: Targets inflammation signaling pathway that transduce
the positive signals of cytokines and other inflammatory
mediators

66. DAS28 is a simplified version of DAS44 that evaluates just 28 joints. It does not include the
ankles or joints in the feet.
The DAS28 score is arrived at using:
1.The number of swollen joints (out of the 28),
2.The number of tender joints (out of the 28),
3.The C reactive protein (CRP) or erythrocyte sedimentation rate (ESR) lab test results
4.Answers to a patient health assessment questionnaire
A mathematical formula is used to calculate the overall score. DAS28 can range from 0 to
9.4.
Generally, a DAS28 score of 1 :
•More than 5.1 indicates high disease activity
•Between 3.2 and 5.1 indicates moderate disease activity
•Between 2.6 and less than 3.2 indicates low disease activity
•Lower than 2.6 indicates disease remission

67. •Sternoclavicular joints (2), which connect the collarbone and
the breastbone
•Acromioclavicular joints (2), which connect the acromion to
the clavicle
•Shoulders (2)
•Elbows (2)
•Wrists (2)
•Large knuckles (10) also called the
metacarpophalangeal (MCP) joints
•Middle knuckles (10), also called proximal interphalangeal
(PIP) joints
•Knee (2)

68. 2021 American College of Rheumatology Guideline for
the Treatment of Rheumatoid Arthritis

69. RECOMMENDATIONS FOR DMARD-NAIVE PATIENTS
WITH MODERATE-TO-HIGH DISEASE ACTIVITY
 DMARD monotherapy Methotrexate is strongly recommended over
hydroxychloroquine or sulfasalazine for DMARD naive patients with
moderate-to-high disease activity
 Methotrexate is conditionally recommended over leflunomide for DMARD-
naive patients with moderate-to-high disease activity
 Methotrexate monotherapy is strongly recommended over bDMARD or
tsDMARD monotherapy for DMARD-naive patients with moderate-to-high
disease activity

70. • Methotrexate monotherapy is conditionally recommended
over dual or triple csDMARD therapy for DMARD-naive
patients with moderate-to-high disease activity
• Methotrexate monotherapy is conditionally recommended
over methotrexate plus a tumor necrosis factor (TNF)
inhibitor for DMARD-naive patients with moderate-to-high
disease activity
• Initiation of a csDMARD without short-term glucocorticoids is
conditionally recommended over initiation of a csDMARD
with short-term glucocorticoids for DMARD-naive patients
with moderate-to-high disease activity

71. Initiation of a csDMARD without longerterm (≥3 months)
glucocorticoids is strongly recommended over initiation of a
csDMARD with longer-term glucocorticoids for DMARD-naive
patients with moderate-to-high disease activity

72. RECOMMENDATIONS FOR ADMINISTRATION OF
METHOTREXATE
 Oral methotrexate is conditionally recommended over subcutaneous
methotrexate for patients initiating methotrexate
 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 <15mg
 A split dose of oral methotrexate 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

73.  Switching to subcutaneous methotrexate is conditionally
recommended over the addition of/ switching to alternative
DMARD(s) for patients taking oral methotrexate who are not
at target

74. Recommendations for specific patient
populations

75. Subcutaneous nodules
Methotrexate is conditionally recommended over alternative DMARDs for patients with subcutaneous
nodules who have moderate-to-high disease activity. Switching to a non-methotrexate DMARD is
conditionally recommended over continuation of methotrexate for patients taking methotrexate with
progressive subcutaneous nodules.
Pulmonary disease
Methotrexate is conditionally recommended over alternative DMARDs for the treatment of inflammatory
arthritis for patients with clinically diagnosed mild and stable airway or parenchymal lung disease who have
moderate-to-high disease activity.
Heart failure
Addition of a non–TNF inhibitor bDMARD or tsDMARD is conditionally recommended over addition of a
TNF inhibitor for patients with NYHA class III or IV heart failure and an inadequate response to
csDMARDs. Switching to a non–TNF inhibitor bDMARD or tsDMARD is conditionally recommended over
continuation of a TNF inhibitor for patients taking a TNF inhibitor who develop heart failure.

76. Lymphoproliferative disorder
Rituximab is conditionally recommended over other DMARDs for
patients who have a previous lymphoproliferative disorder for which
rituximab is an approved treatment and who have moderate-to-high
disease activity.

77. SURGERY
 Synovectomy of wrist or finger tendon sheaths for pain relief or to prevent
tendon rupture when medical interventions have failed
 Osteotomy
 Athroplasty

78. REFERENCES
 Harrison’s Principles of Internal Medicine 21st
edition
 Upto date
 Kelly and Firestein’s