Rheumatoid arthritis

1. RHEUMATOID ARTHRITIS
DR ANEES KURIKKAL
MD Internal medicine resident
2020/9/22

2. INTRODUCTION
 Rheumatoid arthritis (RA) : the most common inflammatory arthritis, affecting from 0.5% to 1% of
the general population worldwide.
 RA, a systemic disease, may also lead to a variety of extraarticular manifestations, including
fatigue,subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and
hematologic abnormalities
 Early diagnosis of RA is pivotal to prevent damage and complications

3. CLINICAL FEATURES
The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the
age of 75 and then decreases
 C/O early morning joint stiffness lasting more than 1 h that eases with physical activity.
Small joints of hand and feet are the earliest involved joints
The initial pattern of joint involvement may be monoarticular, oligoarticular (≤4 joints), or
polyarticular (>5 joints), usually in a symmetric distribution.
the wrists, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints are the most
frequently involved joints
DIP also can be involved , but is usually a manifestation of coexistant osteoarthritis
Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion,
reduced grip strength, and “trigger” fingers.

4. Ulnar deviation results from subluxation of the MCP
joints,
Hyperextension of the PIP joint with flexion of the
DIP joint (“swan-neck deformity”)
flexion of the PIP joint with hyperextension of the DIP
joint (“boutonnière deformity”)
Subluxation of the first MCP joint with
hyperextension of the first interphalangeal (IP) joint
(“Z-line deformity”)

5. Inflammation about the ulnar styloid and
tenosynovitis of the extensor carpi ulnaris
may cause subluxation of the distal ulna,
resulting in a “piano-key movement” of
the ulnar styloid.

6. MTP joint involt is an early feature of RA , but chronic inflammation of ankle and midtarsal areas
come later and may lead to pes planovalgus (flat feet )
Atlantoaxial involvement of the cervical spine may cause compressive myelopathy and
neurologic dysfunction.
RA rarely affects the thoracic and lumbar spine.
Extraarticular manifestations may develop during the clinical course of RA in up to 40% of
patients, even prior to the onset of arthritis
Subcutaneous nodules, secondary Sjögren’s syndrome, interstitial lung disease (ILD),
pulmonary nodules, and anemia are among the most frequently observed extraarticular
manifestations.

7. CONSTITUTIONAL SIGNS AND SYMPTOMS
 include weight loss, fever, fatigue, malaise, depression, and in the most severe cases,
cachexia
the presence of a fever of >38.3°C (101°F) at any time during the clinical course should
raise suspicion of systemic vasculitis or infection.

8. NODULES
 Subcutaneous nodules have been reported to occur in 30–40% of patients and more commonly in
those with the highest levels of disease activity
When palpated, the nodules are generally firm; nontender; and adherent to periosteum, tendons, or
bursae; developing in areas of the skeleton subject to repeated trauma or irritation such as the
forearm, sacral prominences, and Achilles tendon
may also occur in the lungs, pleura, pericardium, and peritoneum
Are usually benign

10. PULMONARY INVOLVEMENT
Pleuritis, the most common pulmonary manifestation of RA, may produce pleuritic chest pain
and dyspnea, as well as a pleural friction rub and effusion
Pleural effusions : exudative with increased numbers of monocytes and neutrophils
ILD may also occur and can be a/w cigarette smoking
Recent studies have shown the overall prevalence of ILD in RA to be as high as 12%
Usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) are the
main histological and radiologic patterns of ILD
PFT : restrictive pattern with reduced DLCO
 Caplan’s syndrome is a rare subset of pulmonary nodulosis characterized by the development of
nodules and pneumoconiosis following silica exposure

11. CARDIAC INVOLVEMENT
 The most frequent site of cardiac involvement in RA is the pericardium
But clinical manifestations of pericarditis occur in <10% of patients with RA
Cardiomyopathy, may result from necrotizing or granulomatous myocarditis, coronary artery
disease, or diastolic dysfunction.
This also may be subclinical and only identified by echo or cardiac MRI
 Rarely, the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid.
Mitral regurgitation is the most common valvular abnormality in RA

12. HAEMATOLOGIC
A normochromic, normocytic anemia often develops in patients with RA and is the most common
hematologic abnormality
ESR, CRP and platelet levels may be elevated
Felty’s syndrome is defined by the clinical triad of neutropenia, splenomegaly, and nodular RA
and is seen in <1% of patients
Occurs in late stages of RA
 T cell large granular lymphocyte leukemia (T-LGL) may have a similar clinical presentation and
often occurs in association with RA., but it presents early
The most common histopathologic type of lymphoma is a diffuse large B cell lymphoma (DLBCL)
The risk of developing lymphoma increases if the patient has high levels of disease activity or Felty’s
syndrome.

13. SECONDARY SJÖGREN’S SYNDROME
 is defined by the presence of either keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in
association with another connective tissue disease, such as RA.
Approximately 10% of patients with RA have secondary Sjögren’s syndrome.
RHEUMATOID VASCULITIS
typically occurs in patients with long-standing disease, a positive test for serum RF or anti-CCP
antibodies, and hypocomplementemia
The cutaneous signs vary and include petechiae, purpura, digital infarcts, gangrene, livedo reticularis,
and in severe cases large, painful lower extremity ulcerations.
Vasculitic ulcers may be treated successfully with immunosuppressive agents
Sensorimotor polyneuropathies, such as mononeuritis multiplex, may occur in association with
systemic rheumatoid vasculitis.

14. ASSOCIATED CONDITIONS
 CARDIOVASCULAR DISEASE
The most common cause of death in patients with RA is cardiovascular disease.
Incidence of CAD and carotid atherosclerosis is higher in RA pts
CCF occurs at 2 fold higher rate than in general population
OSTEOPOROSIS
Osteoporosis is more common in patients with RA than an age- and sex-matched population, with
prevalence rates of 20–30%.
Inflammation spill over to bone osteoclast activation  generalized bone loss
Hip fractures are more likely to occur in patients with RA

15.  HYPOANDROGENISM
Men and postmenopausal women with RA have lower mean serum testosterone, luteinizing
hormone (LH), and dehydroepiandrosterone (DHEA) levels than control populations.
Patients receiving chronic glucocorticoid therapy may develop hypoandrogenism owing to inhibition
of LH and follicle-stimulating hormone (FSH) secretion from the pituitary gland.
Men with hypoandrogenism should be considered for androgen replacement therapy, since they are
prone to osteoporosis

17. EPIDEMIOLOGY
RA affects ~0.5–1% of the adult population worldwide.
Incidence has decreased due to proper treatment , but prevalence remains the same
RA occurs more commonly in females than in males, with a 2–3:1 ratio
Studies hypothesize that estrogen can stimulate production of tumor necrosis factor α (TNF-α), a
major cytokine in the pathogenesis of RA.

18. GENETIC CONSIDERATIONS
first-degree relative of a patient : risk of RA is 2–10 times greater than in the general population
Risk is a/w allelic variation in the HLA-DRB1 gene, which encodes the MHC II β-chain molecule
 Carriership of the SE alleles ( shared epitope) is associated with production of anti-CCP antibodies
and worse disease outcomes.
non-MHC genes contributing to the risk of RA  gene encoding protein tyrosine phosphatase non-
receptor 22 (PTPN22)
Others PAD14, APOM

19. ENVIRONMENTAL FACTORS
Most important : cigarette smoking ( relative risk of getting RA 1.5-3.5)
Women who smoke (2.5)
Risk from smoking related to RF and antiCCP antibody positive disease
Periodontitis due to Porphyromonas gingivalis may predispose to RA (citrullination of
arginine by peptidyl arginine deiminase (PAD) leads to anti CCP antibody production


20. PATHOPHYSIOLOGY
RA is characterised by infiltration of the synovial membrane with lymphocytes, plasma cells,
dendritic cells and macrophages.
In Lymphoid follicles in synovial membrane , T- and B-cell interactions occur  cytokine release
 activate B cells to produce autoantibodies (RF and ACPA)
Synovial macrophages : activated by TNF and interferon gamma (IFN-γ)
Macrophages  pro-inflammatory cytokines, including TNF, IL-1 and IL-6
Synovial fibroblasts proliferate, causing synovial hypertrophy and producing matrix
metalloproteinases and the proteinase ADAMTS-5, which degrade soft tissues and cartilage
Prostaglandins and Nitric Oxide in inflamed synovium  vasodilatation  pain and swelling
Systemic release of IL-6 triggers production of acute phase proteins by the liver.

21. At the joint margin, the inflamed synovium (pannus) directly invades bone and cartilage to cause
joint erosions.
Bone erosion is due to osteoclast activation by RANKL
Angiogenesis  highly vascular synovium  proinflammatory cytokines  recruit more
leukocytes  more inflammation
Later, fibrous or bony ankylosis may occur
Muscles adjacent to inflamed joints atrophy and may be infiltrated with lymphocytes 
progressive biomechanical dysfunction and may further amplify destruction

23. DIAGNOSIS
Based on signs, symptoms
of chronic arthritis + lab and
radiographic evidence
ACR- EULAR score >= 6 :
definite RA

24. LAB FEATURES
Raised ESR,CRP
Serum IgM RF : 75–80% of patients with RA;
 Anti CCP antibody : diagnostic specificity 95%, has significance for worse prognosis
SYNOVIAL FLUID ANALYSIS
WBC: 5000 and 50,000 /μL (<2000 WBC/μL in osteoarthritis)
Predominant cell : Neutrophil
Can confirm inflammation and exclude infection, crystal induced arthritis

25. JOINT IMAGING
Useful for diagnosis and for tracking progression of joint damage
Plain X Ray : most widely used – shows joint space narrowing
“Periarticular osteopenia”
 other findings on X ray : soft tissue swelling, symmetric joint space loss, and subchondral
erosions, most frequently in the wrists and hands (MCPs and PIPs) and the feet (MTPs).
MRI and USG can detect synovitis, tenosynovitis, and effusions and has greater sensitivity for
identifying bony abnormalities.
Power color doppler is an USG based investigation which ca detect erosions

26. CLINICAL COURSE
The natural history of RA is complex and affected by a number of factors including age of onset,
gender, genotype and comorbid conditions
10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will
undergo a spontaneous remission within 6 months
But majority show a pattern of persistent and progressive disease activity that waxes and wanes in
intensity over time
More than one-half of patients with RA are unable to work 10 years after the onset of their disease
The overall mortality rate in RA is two times greater than the general population, with ischemic
heart disease being the most common cause of death followed by infection
 Median life expectancy is shortened by an average of 7 years for men and 3 years for women
compared to control populations

27. TREATMENT
The treatment goal is to suppress inflammation, control symptoms and prevent joint damage.
This involves a combination of pharmacological and non-pharmacological therapies
Various disease activity scores are employed : Disease Activity Score (DAS), Simplified Disease
Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of
Patient Index Data 3 (RAPID3)
The medications used for the treatment of RA may be divided into broad categories
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Glucocorticoids (prednisone and methylprednisolone)
• Conventional DMARDs
• Biologic DMARDs

29. GLUCOCORTICOIDS
They may be administered in low to moderate doses to achieve rapid disease control before the
onset of fully effective DMARD therapy, which often takes several weeks or even months.
1- to 2-week burst of glucocorticoids may be prescribed for the management of acute disease flares
Chronic administration of low doses (5–10 mg/d) of prednisone  control disease activity in
patients with an inadequate response to DMARD therapy.
 High-dose : for severe extraarticular manifestations of RA, such as ILD
intraarticular injection of triamcinolone acetonide : limited no of affected joints
Bisphosphonates to prevent osteoporosis

30. CONVENTIONAL DMARDS
DMARDs are so named because of their ability to slow or prevent structural progression of RA.
Include : hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide
Has delayed onset of action of ~6–12 weeks
Methotrexate is the pioneer and can stimulate adenosine release from cells, producing an anti-
inflammatory effect
Leflunomide, an inhibitor of pyrimidine synthesis : efficacy similar to methotrexate
Hydroxychloroquine has not been shown to delay radiographic progression of disease and thus is
not considered to be a true DMARD
Sulfasalazine can reduce radiographic progression of disease

31. BIOLOGIC DMARDS
They are protein therapeutics which target cytokines and cell-surface molecules.
TNF inhibitors :
• first approved biologicals
• include Infliximab ,Adalimumab ,Golimumab , Certolizumab and Etanercept
• Anti-TNF agents avoid in active infection or a history of hypersensitivity
• contraindicated in patients with chronic hepatitis B infection or class III/IV congestive heart
failure
• Screen for TB before starting the drug
• Never combine with anakinra  severe infections
Anakinra, an IL-1 receptor antagonist: came later , rarely used now
Abatacept, rituximab, and tocilizumab are the newest members of this class

35. YAHT K ON U