RHEUMATOID ARTHRITIS2

							Rheumatoid
  Arthritis
•   INTRODUCTION
•   EPIDEMIOLOGY
•   PATHOGENESIS/PATHOLOGY
•   AETIOLOGY
•   CLINICAL FEATURES
•   INVESTIGATION
•   TREATMENT
•   PROGNOSIS
Rheumatoid arthritis (RA) is a
 chronic multisystemic
 inflammatory disease of unknown
 cause that primarily affects the
 peripheral joints in a symmetric
 pattern. It is an autoimmune
 disorder with an extremely
 variable course with associated
 nonarticular features
EPIDEMIOLOGY
 Worldwide incidence of RA is
 approximately 3 cases per 10,000
 population
 Prevalence rate ~ 1%.
 Race: RA affects all populations
  ~ higher prevalence rates (eg, 5-6% in
 some Native American groups)
  ~lower rates (eg rural sub-Saharan Africa
 & Caribbean blacks).
  ~ Urban > Rural
• Sex: M:F- 1:3 Similar after menopause
• Age: The frequency of RA ↑s with age,
  peaks btw 30-50 years. Also observed in
  both elderly persons and children.
• Familial: 1° relatives have ↑ frequency ~2-
  3%. Concordance in monozygotic twins is
  approximately 15-20%
• HLA types- ↑ - HLA-DR4 & HLA-DR1
              ↓ - HLA-DR5,-DR3,-DR7
PATHOGENESIS/PATHOLOGY
• Aetiology- unknown
• Smoking- ↑ incidence
• Possible triggers - Mycoplasma,
  Clostridia, Epstein-Barr virus, Protease
  species
• Failure to recognise self- Mistaken identity
  theory
• Molecular mimicry
All of the major immunologic
 elements play fundamental
 roles in the initiation,
 propagation, and maintenance
 of the autoimmune process of
 RA. It involves T and B
 lymphocytes, antigen-
 presenting cells (eg, B cells,
 macrophages, dendritic cells),
 and numerous cytokines.
Aberrant production and regulation of
 both pro- and anti-inflammatory
 cytokines and cytokine pathways
 are found in RA.
T cells are assumed to play a pivotal
 role in the initiation of RA, and the
 key player in this respect is
 assumed to be the Th1 CD4 cells.
 (T helper 1 cells produce IL-2 and
 interferon gamma.)
These cells may subsequently
 activate macrophages and other
 cell populations, including
 synovial fibroblasts. The latter 2
 populations are the main
 producers of the
 proinflammatory cytokines TNF-
 alpha and IL-1 that appear to be
 the major driving forces of
 inflammation.
B cells are important in the
 pathologic process because they
 may serve as antigen-presenting
 cells and activated T cells, produce
 numerous autoantibodies (eg, RF,
 to citrullinated proteins), and
 secrete cytokines. Elimination of
 populations of B cells with
 monoclonal antibodies (eg,
 rituximab) offers another effective
 therapeutic option
Early and intermediate
 molecular mediators of
 inflammation include tumor
 necrosis factor alpha (TNF-α),
 interleukins IL-1, IL-6, IL-8 and
 IL-15, transforming growth
 factor beta, fibroblast growth
 factor and platelet-derived
 growth factor.
Synovial macrophages and
 dentritic cells function as antigen
 presenting cells by expressing
 MHC class II molecules, leading
 to the production of
 immunoglobins, rheumatoid
 factors of the IgG and IgM class
 and complement components by
 B-Lymphocytes
Once triggered, the immune
 response causes inflammation of
 the synovium, leading to edema,
 vasodilation and infiltration by
 activated T-cells (mainly CD4 in
 nodular aggregates and CD8 in
 diffuse infiltrates).
The disease progresses in
 concert with formation of
 granulation tissue at the
 edges of the synovial lining
 (pannus) with extensive
 angiogenesis and
 production of enzymes that
 cause tissue damage
Once the inflammatory reaction is
 established, the synovium
 thickens, the cartilage and the
 underlying bone begins to
 disintegrate and evidence of joint
 destruction accrues. Although the
 articular structures are the
 primary sites, other tissues are
 also affected.
CLINICAL FEATURES
Most patients with the disease
 have an insidious onset. It may
 begin with systemic features,
 such as fever, malaise,
 arthralgias, and weakness,
 before the appearance of overt
 joint inflammation and
 swelling.
A small percentage of patients
 (approximately 10%) have an
 abrupt onset with the acute
 development of synovitis and
 extra-articular manifestations.
 Spontaneous remission is
 uncommon, especially after the
 first 3-6 months.
Joint involvement is the
 characteristic feature of patients
 with RA. In general, the small
 joints of the hands and feet are
 affected in a relatively symmetric
 distribution. Joints show
 inflammation with swelling,
 tenderness, warmth, and
 decreased range of motion.
Atrophy of the interosseous muscles of the
  hands is a typical early finding.
Joint and tendon destruction may lead to
  ~ulnar deviation
  ~boutonnière
  ~swan-neck deformities
  ~hammer toes, and occasionally joint
  ankylosis.
Other musculoskeletal manifestations
* Tenosynovitis
* Tendon rupture commonly involving the
  4th and 5th digital extensor tendons at the
  wrist)
* Periarticular osteoporosis & generalized
  osteoporosis ~ systemic chronic
  inflammation, immobilization-related
  changes or corticosteroid therapy
* Carpal tunnel syndrome
* Muscle atrophy from disuse
Most commonly affected joints, in
  decreasing frequency
* MCP
* Wrist
* PIP
* Knee
* MTP
* Shoulder
* Ankle
* Cervical spine
* Hip
* Elbow
* Temporomandibular
Extra-articular
Skin: Subcutaneous nodules &
 vasculitic lesions~ palpable
 purpura or skin ulceration
Cardiac: Myocardial infarction, &
 asymptomatic pericardial
 effusions are common;
  Rarely-pericarditis, constrictive
 pericarditis. Myocarditis, coronary
 vasculitis, valvular dx, and
 conduction defects
•Pulmonary: pleural effusions,
  interstitial fibrosis, nodules
  (Caplan syndrome), and
  bronchiolitis obliterans-organizing
  pneumonia.
• Renal – amyloidosis,also 2° effect
  of drugs
• GI: Felty syndrome (ie, RA,
  splenomegaly, and neutropenia)
  & 2° effects of drugs
• Hematologic: anemia, thrombocytosis, and
  eosinophilia. Leukopenia in patients with Felty
  syndrome.
• Neurologic: nerve entrapment, carpal tunnel
  syndrome, mononeuritis multiplex, and
  cervical myelopathy.
• Ocular: Keratoconjunctivitis sicca is common
  in RA and is often the initial manifestation of
  secondary Sjögren syndrome. The eye may
  also have episcleritis, uveitis, and nodular
  scleritis that may lead to scleromalacia.
DIAGNOSIS
• ARA Diagnostic Criteria
• 1. Joint morning stiffness > 1 hour
• 2. Arthritis of 3 or more joints
• 3. Arthritis of hand joints
• 4. Symmetrical Arthritis
• 5. Rheumatoid nodules
• 6. Seropositivity for RF
• 7 Radiographic changes
COMPLICATIONS
• Ruptured tendons
• Joint infection
• Ruptured joint (e.g Baker’s cysts)
• Spinal cord compression
• Amyloidosis
• Side effect of therapy
               Differentials
• Postviral arthritis - rubella, hepatitis B or
  parvovirus
• Seronegative spondyloarthropathies
• Polymyalgia rheumatica
• Acute nodal osteoarthritis
• Autoimmune connective tissue diseases
  e.g SLE
• Hemoglobinopathies
INVESTIGATION
HAEMATOLOC PARAMETERS
• FBC +ESR → *Anaemia
            ↑Wbc (↓ in Felty’s)
            ↑Platelet ( ↓ in Felty’s)
            ↑ESR

• Renal Function test

• Liver Function Test
•   Immunologic parameters
        ~ RF- +ve in 60-80% of RA
        ~ Found in other conditions & N ppl
        ~ Antinuclear antibody
        ~ Newer Ab- anti-RA 33
                      anti-CCP(Anti Cyclic Citrullinated
      peptide)
                       -sensitivity & specificity ≥ RF
                       ↑ frequency of +ve results in
      early RA.
         Anti-CCP antibodies + RF → highly specific
      for RA.
         Anti-CCP antibodies, as do RF → worse
      prognosis
Conditions with RF in the serum
• Autoimmune rheumatic diseases RF
  (IgM) %
• Rheumatoid arthritis 70
• Systemic lupus erythematosus 25
• Sjdgren's syndrome 90
• Systemic sclerosis 30
• Polymyositis/dermatomyositis 50
• Juvenile idiopathic arthritis Variable
• Viral infections
  Hepatitis
  Infectious mononucleosis
Chronic infections
  Tuberculosis
  Leprosy
  Infective endocarditis
• Syphilis
Hyperglobulinaemia
CLD
Sarcoidosis
Cryglobulinaemia

• Normal population
   Elderly
   Relatives of patient with RA
Synovial fluid analysis
• An inflammatory synovial fluid (WBC count
  >2000/mL) is present with counts
  generally from 5,000-50,000/mL.
• Usually, neutrophil predominance (60-
  80%) is observed in the synovial fluid (in
  contrast with mononuclear cell
  predominance in the synovium)
Imaging Studies:
  X-Ray
  ~ Features- ↑ soft tissue, juxta-articular
  osteoporosis, ↓ joint space. Later bony
  erosions ± subluxation ± carpal destruction
   ~ Extremities - Hands, wrists, knees, feet,
    elbows, shoulders, hips, cervical spine
   MRI: used in patients with abnormalities
    of the cervical spine
   Bone scanning: Findings may help to
    distinguish inflammatory from non-
    inflammatory changes in patients with
    minimal swelling.
Principles of Treatment
• Relief of pain
• Reduction of inflammation
• Protection of articular structures
• Maintenance of function
• Control of systemic involvement
• Nonpharmacologic
  ~ Education
  ~ Physiotherapy and physical therapy to help
    improve and sustain range of motion, ↑
    muscle strength, and ↓ pain.
  ~ Occupational therapy
  ~ Orthopedic measures include reconstructive
    and replacement-type surgical measures
         * Synovectomy
         * Tendon corrections,
         * Joint replacements
Pharmacologic
• DMARDs
    ~ Xenobiotics
    ~ Biological agents
• Anti-inflammatry agents
    ~ Glucocorticoids
    ~ NSAIDs
• Analgesics
Disease Modifying Anti-rheumatic Drugs
  (DMARDs)
    ~ Produce durable remissions and delay
  or halt disease progression.
    ~ Prevent bone and joint damage from
  occurring secondary to the uncontrolled
  inflammation
    ~ Effective reduction in symptoms and
  signs
            DMARDs - Xenobiotics

•   azathioprine
•   ciclosporin (cyclosporine A)
•   D-penicillamine
•   gold salts
•   hydroxychloroquine
•   leflunomide
•   methotrexate (MTX)
•   minocycline
•   sulfasalazine (SSZ)
         DMARDs – Biological Agents

• tumor necrosis factor (TNFα) blockers -
     ~ etanercept (Enbrel)
     ~ infliximab (Remicade)
     ~ adalimumab (Humira)
• interleukin-1 blockers - anakinra
• anti-B cell (CD20) antibody - rituximab
  (Rituxan)[17]
• blockers of T cell activation - abatacept
  (Orencia)
Side Effect of DMARDs
  ~ Liver - (MTX, SSZ, leflunomide, azathioprine,
  gold compounds, D-penicillamine)
  ~ Bone marrow toxicity (MTX, SSZ, leflunomide,
  azathioprine, gold compounds, D-penicillamine)
  ~ Renal toxicity (cyclosporine A, parenteral gold
  salts, D-penicillamine)
  ~ Pneumonitis (MTX)
  ~ Allergic skin reactions (gold compounds, SSZ)
  ~ Autoimmunity (D-penicillamine, SSZ,
  minocycline)
  ~ Infections (azathioprine, cyclosporine A).
  ~ Ocular toxicity- Hydroxychloroquine
      Anti-inflammatry agents
Glucocorticoids
 ~ used to bridge the time until
 DMARDs are effective.
 ~ they do not halt or retard bone
 destruction
 ~ timely dose reductions and
 cessation are important because of
 the adverse effects associated with
 long-term steroid use.
Nonsteroidal anti-inflammatory
 drugs
~ NSAIDs interfere with prostaglandin
 synthesis through inhibition of the
 enzyme cyclooxygenase (COX), thus
 reducing swelling and pain.
~ they do not retard joint destruction.
~ Commonly used NSAIDs include
 ibuprofen, naproxen, ketoprofen,
 piroxicam, and diclofenac.
The coxibs (COX-2 inhibitors)- have
 selectivity for COX-2
  E.g – Celecoxib, Rofecoxib
  ~ have been shown to be clinically
 efficacious
  ~ accompanied by significantly reduced
 GI toxicity
  ~ Other adverse effects, such as water
 retention, hypertension, and abnormal
 transaminase levels, are observed with
 both nonselective and COX-2–selective
 drugs.
Analgesics include:
• acetaminophen
• opiates
• diproqualone
• lidocaine topical
Prognostic factors
• Persistent synovitis
• Early erosive disease
• Extra-articular findings (including subcutaneous
  rheumatoid nodules)
• Positive serum RF findings
• Positive serum anti-CCP autoantibodies
• Carriership of HLA-DR4 "Shared Epitope" alleles
• Family history of RA
• Poor functional status
• Socioeconomic factors
• Elevated acute phase response (erythrocyte
  sedimentation rate [ESR],
• C-reactive protein [CRP])
• Increased clinical severity
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