• Extraarticular involvement,
including rheumatoid nodules, vasculitis, eye inflammation, neurologic dysfunction,
cardiopulmonary disease, lymphadenopathy, and splenomegaly, can be
manifestations of the disease

• Although the usual disease course is
chronic, some patients will enter a remission spontaneously

EPIDEMIOLOGY OF RHEUMATOID ARTHRITIS

• Rheumatoid arthritis is estimated to
have a prevalence of 1% and does not have any racial predilections

• It can occur at any age, with
increasing prevalence up to the seventh decade of life

• The disease is 3 times more common
in women

• In people ages 15 to 45 years, women
predominate by a ratio of 6:1; the sex ratio is approximately equal among
patients in the first decade of life and in those older than age 60 years

• Epidemiologic data suggest that a
genetic predisposition and exposure to unknown environmental factors may be
necessary for expression of the disease

• The major histocompatibility complex
molecules, located on T lymphocytes, appear to have an important role in most
patients with RA

• These molecules can be characterized
using human lymphocyte antigen (HLA) typing

• A majority of patients with RA have
HLA-DR4, HLA-DR1, or both antigens in the major histocompatibility complex
region

• Patients with HLA-DR4 antigen are
3.5 times more likely to develop RA than those patients who have other HLA-DR
antigens

• Although the major histocompatibility complex
region is important, it is not the sole determinant, because patients can have
the disease without these HLA types

PATHOPHYSIOLOGY OF RHEUMATOID ARTHRITIS

• Chronic
inflammation of the synovial tissue lining the joint results in the
proliferation of this tissue

• The
inflamed, proliferating synovium is characteristic of rheumatoid arthritis is
called pannus

• This
pannus invades the cartilage and eventually the bone surface, producing
erosions of bone and cartilage and leading to destruction of the joint

• Rheumatoid
arthritis is considered to be an immune response to an unknown antigen and the
antibody formed against rheumatoid arthritis is (rheumatoid factor), which is
Immunoglobulin M (IgM).

• In
rheumatoid arthritis immune system can no longer differentiate self from
nonself tissues and attacks the synovial tissue and other connective tissues

• The
immune system has both

• humoral
(B -Lymphocytes) and

• cell-mediated
(T-lymphocytes) functions.

• The
humoral component is necessary for the formation of antibodies.

• Most
patients with rheumatoid arthritis form antibodies called rheumatoid
factors.

• Immunoglobulins
(IgM) can activate the complement system

• The
complement system encourages chemotaxis, phagocytosis, and the release of
lymphokines by mononuclear cells, which are then presented to T lymphocytes.

• The
processed antigen is recognized by MHC proteins on the lymphocyte, which
activates it to stimulate the production of T and B cells.

• The
proinflammatory cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1),
and interleukin-6 (IL-6) are key substances in the initiation and continuance
of rheumatoid inflammation

• Activated
T cells produce cytotoxins, which are directly toxic to tissues, and cytokines,
which stimulate further activation of inflammatory processes and attract cells
to areas of inflammation

• Rheumatoid
arthritis progresses in 3 stages:-

1 st Stage – Swelling of the synovial lining, causing, pain,
warmth,stiffness, redness ,swelling around the joint

2 nd Stage – Rapid division and growth of cells, or pannus, which causes
the synovium to thicken

3 rd Stage – The inflamed cells release enzymes that might damage, bone
& cartilage, often causing the involved joint to loose its shape and
alignment, causing more pain and loss of movement

• Vasoactive
substances also play a role in the inflammatory process.

• Histamine,
kinins, and prostaglandins are released at the site of inflammation.

• These
substances increase both blood flow to the site of inflammation and the
permeability of blood vessels.

• These
substances cause the edema, warmth, erythema and pain

• Loss
of cartilage may result in a loss of the joint space

• The
formation of chronic granulation or scar tissue can lead to loss of joint
motion or bony fusion (called ankylosis)

• This
results in a loss of support to the affected joint leading to chronic deformity

• CD8 + killer T cells have a
regulatory effect on the immune process by suppressing activity of CD4 + cells
through release of antiinflammatory cytokines and promoting apoptosis (cell
death)

• Activated T cells produce cytotoxins, which
are directly toxic to tissues, and cytokines, which stimulate further
activation of inflammatory processes and attract cells to areas of inflammation

• Macrophages are stimulated to
release prostaglandins and cytotoxins

• T-cell activation requires both
stimulation by proinflammatory cytokines as well as interaction between cell
surface receptors, called co-stimulation

• One of these costimulation
interactions is between CD28 and CD80/86

• The binding of the CD80/86 receptor
by abatacept has proved to be an effective treatment for RA but preventing
costimulation interactions between T cells

• Although it has been suggested that
T cells play a key role in the pathogenesis of RA, B cells clearly have an
equally important role

• Evidence for this importance may be
found in the effectiveness of B-cell depletion using rituximab in controlling
rheumatoid inflammation

• Activated B cells produce plasma
cells, which form antibodies

• These antibodies in combination with
complement result in the accumulation of polymorphonuclear leukocytes, which
release cytotoxins, oxygen free radicals, and hydroxyl radicals that promote
cellular damage to synovium and bone

• The benefits of B-cell depletion occur even
though antibody formation is not suppressed with rituximab therapy suggesting
other mechanisms play a role in reducing RA activity

• B cells produce cytokines that may
alter the function of other immune cells

• They also have the ability to
process antigens and act as antigen presenting cells, which interact with T
cells to activate the immune process

• In the synovial membrane, CD4 + T
cells are abundant and communicate with macrophages, osteoclasts, fibroblasts
and chondrocytes either through direct cell–cell interactions using cell
surface receptors or through proinflammatory cytokines such as TNF-α, IL-1,
and IL-6

• These cells produce
metalloproteinases and other cytotoxic substances, which lead to the erosion of
bone and cartilage

• They also release substances
promoting growth of blood vessels and adhesion molecules, which assists in
proinflammatory cell trafficking and attachment of fibroblasts to cartilage and
eventual synovial invasion and destruction

• Vasoactive substances also play a
role in the inflammatory process

• Histamine, kinins, and
prostaglandins are released at the site of inflammation

• These substances increase both blood
flow to the site of inflammation and the permeability of blood vessels

• These substances cause -granulocytes
to pass from blood vessels to the site of inflammation

• The end results of the chronic
inflammatory changes are variable. Loss of cartilage may result in a loss of
the joint space

• The formation of chronic granulation
or scar tissue can lead to loss of joint motion or bony fusion (called ankylosis
)

• Laxity of tendon structures can result in a loss of
support to the affected joint, leading to instability or subluxation

Clinical Presentation

SYMPTOMS OF RHEUMATOID ARTHRITIS

• Joint
pain and stiffness of more than 6 weeks’ duration

• May
also experience fatigue, weakness, low-grade fever, and loss of appetite

• Muscle
pain and afternoon fatigue may also be present

• Joint
deformity is generally seen late in the disease

SIGNS OF RHEUMATOID ARTHRITIS

• Tenderness
with warmth and swelling over affected joints usually involving hands and feet

• Distribution
of joint involvement is frequently symmetrical

• Rheumatoid
nodules may also be present

LABORATORY
TESTS FOR RHEUMATOID ARTHRITIS

• Rheumatoid
factor detectable in 60% to 70%.

• Elevated
erythrocyte sedimentation rate (ESR)and

• C-reactive
protein are markers for inflammation.

• Normocytic
normochromic anemia is common, as is thrombocytosis.

OTHER
DIAGNOSTIC TESTS FOR RHEUMATOID ARTHRITIS

• Joint
fluid aspiration may show increased white blood cell counts without infection,
and crystals.

• Joint
radiographs may show periarticular osteoporosis, joint space narrowing, or
erosions.

ü The
symptoms of rheumatoid arthritis usually develop over the course of several
weeks to months

ü symptoms
include fatigue, weakness, low-grade fever, loss of appetite, and joint pain

ü Stiffness
and muscle aches (myalgias) may precede the development of joint swelling
(synovitis)

ü Fatigue
may be more of a problem in the afternoon

ü During
disease flares, the onset of fatigue begins earlier in the day and subsides as
disease activity lessens

Joint Involvement

• Joint
involvement tends to be symmetrical; however, early in the disease some
patients present with an asymmetrical pattern involving one or a few joints
that eventually develops into the more classic presentation

• About
20% of patients develop an abrupt onset of their illness with fevers,
polyarthritis, and constitutional symptoms (e.g., depression, anxiety, fatigue,
anorexia, and weight loss

• No
single test or physical finding can be used to make the diagnosis of
rheumatoid arthritis

• The
joints affected most frequently by rheumatoid arthritis are the small joints of
the hands, wrists, and feet

• In addition, elbows, shoulders, hips, knees,
and ankles may be involved

• Patients
usually experience joint stiffness that typically is worse in the morning

• Chronic
inflammation with lack of adequate exercise program results in loss of range of
motion, atrophy of muscles, weakness, and deformity

• On
examination, the swelling of the joints may be visible or may be apparent only
by palpation

• The
swelling feels soft and spongy because it is caused by proliferation of soft
tissues or fluid accumulation within the joint capsule

• The
swollen joint may appear erythematous and feel warmer than nearby skin
surfaces, especially early in the course of the disease

• Deformity
of the hand may be seen with chronic inflammation

• These
changes may alter the mechanics of hand function, reducing grip strength and
making it difficult to perform usual daily activities

• Swelling
at the elbow is most evident at the radiohumeral joint

• Shoulder
pain may result from involvement of the joint itself or from tendon inflammation
(tendinitis) or inflammation of the bursa (bursitis) near the deltoid muscle

• The
knee also can be involved, with loss of cartilage, instability, and joint pain

• Foot
and ankle involvement in rheumatoid arthritis is common

• The
metatarsophalangeal joints are involved commonly in rheumatoid arthritis,
making walking difficult

• Subluxation
of the metatarsal heads leads to “cock-up” or hammer-toe deformities

• Involvement
of the spine usually occurs in the cervical vertebrae; lumbar vertebral
involvement is rare

• The
temporomandibular joint (jaw) can be affected, resulting in difficulty in
chewing food

• Inflammation
of cartilage in the chest can lead to chest wall pain

• Hip
pain may occur as a result of destructive changes in the hip joint, soft-tissue
inflammation (e.g., bursitis), or referred pain from nerve entrapment at the
lumbar vertebrae

EXTRA-ARTICULAR
INVOLVEMENT

• RHEUMATOID
NODULES (on extensor surfaces of elbows, forearms, and hands)

• VASCULITIS
(Invasion of blood vessel walls by inflammatory cells)

• PULMONARY
COMPLICATIONS (pleural effusion,fibrosis)

• OCULAR
MANIFESTATIONS (keratoconjunctivitis, Sjogren’s syndrome)

• CARDIAC
INVOLVEMENT (pericarditis)

• FELTY’S
SYNDROME (splenomegaly and neutropenia)

• OTHER
COMPLICATIONS (Lymphadenopathy)

TREATMENT
GOALS

• The
ultimate goal is to achieve complete disease remission, although this goal is
hardly ever achieved.

• Additional
goals include

– controlling
disease activity and joint pain,

– maintaining
the ability to function in daily activities or work,

– improving
the quality of life,

– slowing
destructive joint changes.

Treatment of
Rheumatoid arthritis

• Includes
pharmacologic and nonpharmacologic therapies.

NONPHARMACOLOGIC
THERAPY

• Rest
(relieves stress on inflamed joints), occupational therapy (skills and
exercises), physical therapy, use of assistive devices, weight reduction, and
surgery are the most useful types of nonpharmacologic therapy.

Pharmacologic
Therapy

• A
disease-modifying antirheumatic drug (DMARD) should be started within the first
3 months of onset of symptoms of rheumatoid arthritis provides more favorable
outcome.

• NSAIDs
and/or corticosteroids may be used for symptomatic relief if needed.

• They
provide relatively rapid improvement in symptoms compared with DMARDs

• DMARDs
may take weeks to months for any benefit.

• NSAIDs
have no impact on disease progression, and corticosteroid use carries a
long-term risk of complications

• Commonly
used DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and
leflunomide

• The
biologic agents that have also been demonstrated to have disease-modifying
activity include

• The
anti-TNF drugs

• The
interleukin-1–receptor antagonist, anakinra

• Less
frequently used are azathioprine,
d-penicillamine, gold (including auranofin), minocycline, cyclosporine,
and cyclophosphamide

• This
is due to either less efficacy, high toxicity, or both

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Rheumatoid arthritis – B. Pharma 2nd Semester Pathophysiology notes pdf

Rheumatoid arthritis

Rheumatoid arthritis (RA