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

Rheumatoid Arthritis

Rheumatoid Arthritis - B. Pharma 2nd Semester Pathophysiology notes pdf


At the end of the lecture students were able to

       Define Rheumatoid Arthritis

        Explain etiopathogenesis of Rheumatoid arthritis

        Treatment of Rheumatoid arthritis

Rheumatoid arthritis (RA

       Rheumatoid arthritis (RA) is the most common systemic inflammatory disease characterized by symmetrical joint involvement

       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


       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


       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:-

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

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

3rd 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


       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


       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


       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.


       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


       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 of Rheumatoid arthritis

       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.


       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

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

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