Immune System

 

Immune response
	Antigens
	Humoral immunity
	Cell-mediated immunity
	Complement system
	Polymorphonuclear leukocytes
Pathophysiologic manifestations
	Immune response malfunction
Disorders
	Acquired immunodeficiency syndrome
	Anaphylaxis
	Latex allergy
	Lupus erythematosus
	Rheumatoid arthritis

 

T he immune system is responsible for safeguarding the body from disease-causing microorganisms. It is part of a complex system of host defenses.

Host defenses may be innate or acquired. Innate defenses include physical and chemical barriers, the complement complex, and cells such as phagocytes (cells programmed to destroy foreign cells, such as bacteria) and natural killer lymphocytes.

Physical barriers, such as the skin and mucous membranes, prevent invasion by most organisms. Chemical barriers include lysozymes (found in such body secretions as tears, mucus, and saliva) and hydrochloric acid in the stomach. Lysozymes destroy bacteria by removing cell walls. Hydrochloric acid breaks down foods and destroys pathogens carried by food or swallowed mucus.

Organisms that penetrate this first line of defense simultaneously trigger the inflammatory and immune responses, some innate and others acquired.

Acquired immunity comes into play when the body encounters a cell or cell product that it recognizes as foreign, such as a bacterium or a virus. The two types of cell-mediated immunity are humoral (provided by B lymphocytes) and cell-mediated (provided by T lymphocytes). All cells involved in the inflammatory and immune responses arrive from a single type of stem cell in the bone marrow. B cells mature in the marrow, and T cells migrate to the thymus, where they mature.

The inflammatory response is the immediate local response to tissue injury, whether from trauma or infection. It involves the action of polymorphonuclear leukocytes, basophils and mast cells, platelets, and, to some extent, monocytes and macrophages. Each of these cells is described in a later section.

IMMUNE RESPONSE

The immune response primarily involves the interaction of antigens (foreign proteins), B lymphocytes, T lymphocytes, macrophages, cytokines, complement, and polymorphonuclear leukocytes. Some immunoactive cells circulate constantly; others remain in the tissues and organs of the immune system, such as the thymus, lymph nodes, bone marrow, spleen, and tonsils. In the thymus, the T lymphocytes, which are involved in cell-mediated immunity, become able to differentiate self (host) from nonself (foreign) substances (antigens). In contrast, B lymphocytes, which are involved in humoral immunity, mature in the bone marrow. The key mechanism in humoral immunity is the production of immunoglobulin by B cells and the subsequent activation of the complement cascade. The lymph nodes, spleen, liver, and intestinal lymphoid tissue help remove and destroy circulating antigens in the blood and lymph.

Antigens

An antigen is a substance that can induce an immune response. T and B lymphocytes have specific receptors that respond to specific antigen molecular shapes, called epitopes. In B cells, this receptor is an immunoglobulin, also called an antibody.

Major histocompatibility complex

The T-cell antigen receptor recognizes antigens only in association with specific cell-surface molecules known as the major histocompatibility complex (MHC).

The MHC, also known as the human leukocyte antigen (HLA) locus, is a cluster of genes on human chromosome 6 that has a pivotal role in the immune response. Every person receives one set of MHC genes from each parent, and both sets of genes are expressed on the individual's cells. These genes produce MHC molecules, which participate in:

• the recognition of self versus nonself
• the interaction of immunologically active cells by coding for cell-surface proteins.

MHC molecules differ among individuals. Slightly different antigen receptors can recognize a large number of distinct antigens, coded by distinct, variable region genes.

Groups or clones of lymphocytes exist that have identical receptors for a specific antigen. The clone of a lymphocyte rapidly proliferates when exposed to the specific antigen. Some lymphocytes further differentiate, while others become memory cells, which allow a more rapid response ― the memory or anamnestic response ― to subsequent challenge by the antigen.

Haptens

Most antigens are large molecules, such as proteins or polysaccharides. Smaller molecules, such as drugs, that aren't antigenic by themselves are known as haptens. They can bind with larger molecules, or carriers, and become antigenic or immunogenic.

Antigenicity

Many factors influence the intensity of a foreign substance's interaction with the host's immune system (antigenicity):

• physical and chemical characteristics of the antigen
• its relative foreignness; for example, little or no immune response may follow the transfusion of serum proteins between humans, but a vigorous immune response (serum sickness) commonly follows transfusion of horse serum proteins to a human
• the host's genetic makeup, especially the MHC molecules.

Humoral immunity

The humoral immune response is one of two types of immune responses that can occur when foreign substances invade the body. The other is the cell-mediated response. The humoral response is also called an antibody-mediated response.

B lymphocytes

B lymphocytes and their products, immunoglobulins, are the basis of humoral immunity. A soluble antigen binds with the B-cell antigen receptor, initiating the humoral immune response. The activated B cells differentiate into plasma cells, which secrete immunoglobulins, also called antibodies. This response is regulated by T lymphocytes and their products ― lymphokines, such as interleukin-2 (IL-2), IL-4, and IL-5, and interferon-8 ― which determine which class of immunoglobulins a B cell will manufacture.

Immunoglobulins

The immunoglobulins secreted by plasma cells are four-chain molecules with two heavy and two light chains. Each chain has a variable (V) region and one or more constant (C) regions, which are coded by separate genes. The V regions of both light and heavy chains participate in antigen binding. The C regions of the heavy chain provide a binding site for Fc receptors on cells and govern other mechanisms. (See Structure of the immunoglobulin molecule .)

 

STRUCTURE OF THE IMMUNOGLOBULIN MOLECULE The immunoglobulin molecule consists of four polypeptide chains: two heavy (H) and two light (L) chains held together by disulfide bonds. The H chain has one variable (V) and at least three constant (C) regions. The L chain has one V and one C region. Together, the V regions form a pocket known as the antigen-binding site. This site is located within the antigen-binding fragment (Fab) region of the molecule. Part of the C region of the H chains forms the crystallizable fragment (Fc) region of the molecule. This region mediates effector mechanisms, such as complement activation, and is the portion of the immunoglobulin molecule bound by Fc receptors on phagocytic cells, mast cells, and basophils. Each immunoglobulin molecule also has two antibody-combining sites (except for the immunoglobulin M [IgM] molecule, which has ten, and IgA, which may have two or more). <center> <a name="ch0012structureoftheimmunoglobulinmolecule"></a> <a name="ch0012structureoftheimmunoglobulinmolecule"></a> </center>

There are five known classes of immunoglobulins: IgG, IgM, IgA, IgE, and IgD. These are distinguished by the constant portions of their heavy chains. However, each class has a kappa or lambda light chain, which gives rise to many subtypes and provides almost limitless combinations of light and heavy chains that give immunoglobulins their specificity. (See Classification of immunoglobulins .)

A clone of B cells is specific for only one antigen, and the V regions of its Ig light chains determines that specificity. However, the class of immunoglobulin can change if the association between the cell's V region genes and heavy chain C region genes changes through a process known as isotype switching. For example, a clone of B cells genetically programmed to recognize tetanus toxoid will first make an IgM antibody against tetanus toxoid and later an IgG or other antibody against it.

Cell-mediated immunity

The cell-mediated immune response protects the body against bacterial, viral, and fungal infections and defends against transplanted cells and tumor cells. T lymphocytes and macrophages are the chief participants in the cell-mediated immune response. A macrophage processes the antigen and then presents it to T lymphocytes.

 

CLASSIFICATION OF IMMUNOGLOBULINS The following chart shows the five classifications of immunoglobulins. CLASSIFICATION DESCRIPTION   IgA Secretory immunoglobulin (monomer in serum, dimer in secretory form) Found in colostrum, saliva, tears, nasal fluids, and respiratory, GI, and genitourinary secretions Accounts for 20% of total serum immunoglobulins Important role in preventing antigenic agents from attaching to epithelial surfaces IgD Minute amounts found in serum (monomer) Predominant on surface of B lymphocytes Primarily an antigen receptor Possible function in controlling lymphocyte activation or suppression IgE Found only in trace amounts Involved in release of vasoactive amines stored in basophils and tissue mast cell granules that cause the allergic effects IgG Smallest immunoglobulin (monomer) Found in all body fluids Can cross membranes as a single structural unit Accounts for 75% of total serum immunoglobulins Produced mainly in secondary immune response Classic antibody reactions, including precipitation, agglutination, neutralization, and complement fixation Major antibacterial and antiviral antibody IgM Largest immunoglobulin (pentamer) Usually found only in the vascular system Cannot readily cross membrane barriers because of its size Accounts for 5% of total serum immunoglobulins Dominant activity in primary or initial immune response Classic antibody reactions, including precipitation, agglutination, neutralization, and complement fixation

Macrophages

Macrophages influence both immune and inflammatory responses. Macrophage precursors circulate in the blood. When they collect in various tissues and organs, they differentiate into different types of macrophages. Unlike B and T lymphocytes, macrophages lack surface receptors for specific antigens. Instead, they have receptors for the C region of the heavy chain (Fc region) of immunoglobulin, for fragments of the third component of complement (C3), and for nonimmunologic substances such as carbohydrate molecules.

One of the most important functions of macrophages is presentation of antigen to T lymphocytes. Macrophages ingest and process the antigen, then deposit it on their own surfaces in association with HLA antigen. T lymphocytes become activated when they recognize the antigen-HLA complex. Macrophages also function in the inflammatory response by producing IL-1, which generates fever, and by synthesizing complement proteins and other mediators that have phagocytic, microbicidal, and tumoricidal effects.

T lymphocytes

Immature T lymphocytes are derived from the bone marrow and migrate to the thymus, where they mature. In maturation, the products of the MCH genes “teach” T cells to distinguish between self and nonself.

Five types of T cells exist with specific functions:

• memory cells, sensitized cells that remain dormant until second exposure to antigen, also known as secondary immune response
• lymphokine-producing cells, delayed hypersensitivity reactions
• cytotoxic T cells, direct destruction of antigen or the cells carrying the antigen
• helper T cells, also known as T4 cells, facilitate the humoral and cell-mediated responses
• suppressor T cells, also known as T8 cells, inhibit humoral and cell-mediated responses.

T cells acquire specific surface molecules (markers) that identify their potential role when needed in the immune response. These markers and the T cell antigen receptor together promote the particular activation of each type of T cell. T-cell activation requires presentation of antigens in the context of a specific HLA antigen: class II HLA for helper T cells; class I for cytotoxic T cells. T cell activation also requires IL-1, produced by macrophages, and IL-2, produced by T cells.

Natural killer cells. This is a discrete population of large lymphocytes, some of which resemble T cells. Natural killer cells recognize surface changes on body cells infected with a virus. They bind to and, in many cases, kill the infected cells.

Cytokines

Cytokines are low-molecular-weight proteins involved in the communication among macrophages and the lymphocytes. They induce or regulate a variety of immune or inflammatory responses. Cytokines include colony-stimulating factors, interferons, interleukins, tumor necrosis factors, and transforming growth factor.

Complement system

The chief humoral effector of the inflammatory response, the complement system includes more than 20 serum proteins. When activated, these proteins interact in a cascade-like process that has profound biological effects. Complement activation takes place through one of two pathways.

Classic pathway

In the classic pathway, IgM or IgG binds with the antigen to form antigen-antibody complexes that activate the first complement component, C1. This in turn activates C4, C2, and C3.

Alternate pathway

In the alternate pathway, activating surfaces such as bacterial cell membranes directly amplify spontaneous cleavage of C3. Once C3 is activated in either pathway, activation of the terminal components, C5 to C9, follows.

The major biological effects of complement activation include chemotaxis (phagocyte attraction), phagocyte activation, histamine release, viral neutralization, promotion of phagocytosis by opsonization (making the bacteria susceptible to phagocytosis), and lysis of cells and bacteria. Kinins (peptides that cause vasodilation and enhance vascular permeability and smooth muscle contraction) and other mediators of inflammation derived from the kinin and coagulation pathways interact with the complement system.

Polymorphonuclear leukocytes

Other key factors in the inflammatory response are the polymorphonuclear leukocytes: neutrophils, eosinophils, basophils, and mast cells.

Neutrophils

Neutrophils, the most numerous of these leukocytes, derive from bone marrow and increase dramatically in number in response to infection and inflammation. They're the first to respond in acute infection. Neutrophils are highly mobile cells attracted to areas of inflammation and are the main constituent of pus.

Neutrophils have surface receptors for immunoglobulins and complement fragments, and they avidly ingest bacteria or other particles that are coated with target-identifying antibodies (opsons). Toxic oxygen metabolites and enzymes such as lyzozyme promptly kill the ingested organisms. Unfortunately, in addition to killing invading organisms, neutrophils also damage host tissues.

Eosinophils

Eosinophils, also derived from bone marrow, multiply in allergic and parasitic disorders. Although their phagocytic function isn't clearly understood, evidence suggests that they participate in host defense against parasites. Their products may also diminish inflammatory response in allergic disorders.

Basophils and mast cells

Basophils and mast cells also function in immune disorders. Mast cells, unlike basophils, aren't blood cells. Basophils circulate in peripheral blood, whereas mast cells accumulate in connective tissue, particularly in the lungs, intestines, and skin. Both types of cells have surface receptors for IgE. When their receptors are cross-linked by an IgE antigen complex, they release mediators characteristic of the allergic response.

PATHOPHYSIOLOGIC MANIFESTATIONS

The host defense system and the immune response are highly complex processes, subject to malfunction at any point along the sequence of events. This malfunction may involve exaggeration, misdirection, or an absence or depression of activity leading to an immune disorder.

Immune response malfunction

When the immune system responds inappropriately, three basic categories of reactions may occur: hypersensitivity, autoimmune response, and alloimmune response. The type of reaction is determined by the source of the antigen, such as environmental, self, or other person, to which the immune system is responding.

Hypersensitivity

Hypersensitivity is an exaggerated or inappropriate response that occurs on second exposure to an antigen. The result is inflammation and the destruction of healthy tissue. Allergy refers to the harmful effects resulting from a hypersensitivity to antigens, also called allergens .

Hypersensitivity reactions may be immediate , occurring within minutes to hours of re-exposure, or delayed , occurring several hours after re-exposure. A delayed hypersensitivity reaction typically is most severe days after the re-exposure.

Generally, hypersensitivity reactions are classified as one of four types: type I (mediated by IgE), type II (tissue-specific), type III (immune-complex-mediated), type IV (cell-mediated). (See Classification of hypersensitivity reactions .)

Type I hypersensitivity. Allergens activate T cells, which induce B-cell production of IgE, which binds to the Fc receptors on the surface of mast cells. Repeated exposure to relatively large doses of the allergen is usually necessary to cause this response. When enough IgE has been produced, the person is sensitized to the allergen. At the next exposure to the same antigen, the antigen binds with the surface IgE, cross-links the Fc receptors, and causes mast cells to degranulate and release various mediators. Degranulation also may be triggered by complement-driven anaphylatoxins ― C3a and C5a ― or by certain drugs such as morphine.

CLASSIFICATION OF HYPERSENSITIVITY REACTIONS Reactions Anaphylactic (immediate, atopic, mediated by immunoglobulin E Pathophysiology Binding of antigens to IgE antibodies on mast cell surfaces releases allergic mediators, causing vasodilation, increased capillary permeability, smooth muscle contraction, and eosinophilia Clinical examples Extrinsic asthma, seasonal allergic rhinitis, systemic anaphylaxis, reactions to insect stings, some food and drug reactions, some cases of urticaria, infantile eczema Reactions Cytotoxic (cytolytic, complement-dependent) Pathophysiology Binding of IgG or IgM antibodies to cellular or exogenous antigens activates the complement cascade, resulting in phagocytosis or cytolysis Clinical examples Goodpasture's syndrome, pernicious anemia, autoimmune hemolytic anemia, thrombocytopenia, some drug reactions, hyperacute renal allograft rejection, and hemolytic disease of the newborn Reactions Immune complex disease Pathophysiology Activation of complement by immune complexes causes infiltration of polymorphonuclear leukocytes and release of lysosomal enzymes and permeability factors, producing an inflammatory response Clinical examples Serum sickness, systemic lupus erythematosus, rheumatoid arthritis, polyarteritis Reactions Delayed (cell mediated) Pathophysiology Antigen-presenting cells present antigen to T cells in association with major histocompatibility complex (MCH). The sensitized T cells release lymphokines that stimulate macrophages. Lysozymes are released and surrounding tissue is damaged Clinical examples Contact dermatitis, graft-versus-host disease, allograft rejection, some drug sensitivities, Hashimoto's thyroiditis, sarcoidosis

Some of the mediators released are preformed, whereas others are newly synthesized on activation of the mast cells. Preformed mediators include heparin, histamine, proteolytic (protein-splitting) and other enzymes, and chemotactic factors for eosinophils and neutrophils. Newly synthesized mediators include prostaglandins and leukotrienes. Mast cells also produce a variety of cytokines, which initiate smooth muscle contraction, vasodilation, bronchospasm, edema, increased vascular permeability, mucus secretion, and cellular infiltration by eosinophils and neutrophils. These effects result in the some of the classic associated signs and symptoms, such as hypotension, wheezing, swelling, urticaria, and rhinorrhea.

Type II hypersensitivity. Type II hypersensitivity, a tissue-specific reaction, generally involves the destruction of a target cell by an antibody directed against cell-surface antigens. Alternatively, the antibody may be directed against small molecules adsorbed to cells or against cell-surface receptors, rather than against the cell constituents themselves. Tissue damage occurs through several mechanisms:

• binding of antigen and antibody activates complement, which ultimately disrupts cellular membranes ― complement-mediated lysis
• various phagocytic cells with receptors for immunoglobulin (Fc region) and complement fragments envelop and destroy opsonized targets, such as red blood cells, leukocytes, and platelets
• cytotoxic T cells and natural killer cells, although not antigen specific, also contribute to tissue damage by releasing toxic substances that destroy the cells
• antibody binding causes the target cell to malfunction rather than causing its destruction.

Type III hypersensitivity. Circulating antigen-antibody complexes (immune complexes) accumulate and are deposited in the tissues. The most common tissues involved are the kidneys, joints, skin, and blood vessels. Normally, they clear excess immune complexes from the circulation. However, immune complexes deposited in the tissues activate the complement cascade, causing local inflammation, and trigger platelet release of vasoactive amines that increase vascular permeability, so that more immune complexes accumulate in the vessel walls.

Probably the most harmful effects result from the generation of complement fragments that attract neutrophils. The neutrophils attempt to ingest the immune complexes. They are generally unsuccessful, but in the attempt, the neutrophils release lysosomal enzymes, which exacerbate the tissue damage.

The formation of immune complexes is dynamic and ever-changing. The complexes that form in children may be totally different from those formed in later years. Also, more than one type of immune complex may be present at one time.

Type IV hypersensitivity. These cell-mediated reactions involve the processing of the antigen by the macrophages. Once processed, the antigen is presented to the T cells. Cytotoxic T cells, if activated, attack and destroy the target cells directly. When lymphokine T cells are activated, they release lymphokines, which recruit and activate other lymphocytes, monocytes, macrophages, and polymorphonuclear leukocytes. The coagulation, kinin, and complement cascades also contribute to tissue damage in this type of reaction.

Autoimmune reactions

In autoimmune reactions, the body's normal defenses become self-destructive, recognizing self-antigens as foreign. What causes this misdirected response is not clearly understood. For example, drugs or viruses have been implicated as causing some autoimmune reactions, but in diseases such as rheumatoid arthritis and systemic lupus erythematosus, the mechanism for misdirection is unclear.

Autoimmune reactions are believed to result from a combination of factors, including genetic, hormonal, and environmental influences. Many are characterized by B-cell hyperactivity and by hypergammaglobulinemia. B-cell hyperactivity may be related to T-cell abnormalities. Hormonal and genetic factors strongly influence the onset of some autoimmune disorders.

 

AGE ALERT Immune function starts declining at sexual maturity and continues declining with age. During this decline, the immune system begins losing its ability to differentiate between self and nonself, leading to an increase in the incidence of autoimmune disorders.

Alloimmune reactions

Alloimmune reactions are directed at antigens from the tissues of others of the same species. Alloimmune reactions commonly occur in transplant and transfusion reactions, in which the recipient reacts to antigens, primarily HLA, on the donor cells. This immune response is also seen in infants with erythroblastosis fetalis (see Chapter 11 ). This type of response is commonly associated with a type II hypersensitivity reaction.

Immunodeficiency

An absent or depressed immune response increases susceptibility to infection. Immunodeficiency may be primary, reflecting a defect involving T cells, B cells, or lymphoid tissues, or secondary, resulting from an underlying disease or factor that depresses or blocks the immune response. The most common forms of immunodeficiency are caused by viral infection or are iatrogenic reactions to therapeutic drugs.

DISORDERS

The environment contains thousands of pathogenic microorganisms. Normally, our host defense system protects us from these harmful invaders. When this network of safeguards breaks down, the result is an altered immune response or immune system failure.

Acquired immunodeficiency syndrome

Human immunodeficiency virus (HIV) infection may cause acquired immunodeficiency syndrome (AIDS). Although it's characterized by gradual destruction of cell-mediated (T cell) immunity, it also affects humoral immunity and even autoimmunity because of the central role of the CD4 ⁺ (helper) T lymphocyte in immune reactions. The resulting immunodeficiency makes the patient susceptible to opportunistic infections, cancers, and other abnormalities that define AIDS.

This syndrome was first described by the Centers for Disease Control and Prevention (CDC) in 1981. Because transmission is similar, AIDS shares epidemiologic patterns with hepatitis B and sexually transmitted diseases.

As of June 1997, there were 612,078 reported cases of AIDS and 379,258 deaths from AIDS in adults, adolescents, and children in the United States.

AIDS is more prevalent in large urban areas with a high incidence of I.V. drug use and high-risk sexual practices. HIV is predominantly an infection of young people, with most cases involving persons between the ages of 17 and 55 years. However, it has also been reported in elderly men and women. In the United States, AIDS is the leading cause of death among women aged 25 to 44 years. The incidence is increasing faster among women than men, and heterosexual transmission of HIV is the major mode of transmission. The majority of women with heterosexually transmitted HIV infection report having had sexual contact with an I.V. drug user, often during adolescence. An increase of AIDS in this childbearing age group is expected to cause an increase in the number of children with HIV infection.

Depending on individual variations and the presence of cofactors that influence disease progression, the time from acute HIV infection to the appearance of symptoms (mild to severe) to the diagnosis of AIDS and, eventually, to death varies greatly. The average duration between HIV exposure and diagnosis is 8 to 10 years, but shorter and longer incubation periods have been reported. Current combination drug therapy in conjunction with treatment and prophylaxis of common opportunistic infections can delay the natural progression and prolong survival.

Causes

The HIV-I retrovirus is the primary etiologic agent. Transmission occurs by contact with infected blood or body fluids and is associated with identifiable high-risk behaviors. It's disproportionately represented in:

• homosexual and bisexual men
• I.V. drug users
• neonates of infected women
• recipients of contaminated blood or blood products (dramatically decreased since mid-1985)
• heterosexual partners of persons in the former groups.

Pathophysiology

The natural history of AIDS begins with infection by the HIV retrovirus, which is detectable only by laboratory tests, and ends with death. Twenty years of data strongly suggests that HIV isn't transmitted by casual household or social contact. The HIV virus may enter the body by any of several routes involving the transmission of blood or body fluids, for example:

• direct inoculation during intimate sexual contact, especially associated with the mucosal trauma of receptive rectal intercourse
• transfusion of contaminated blood or blood products (a risk diminished by routine testing of all blood products)
• sharing contaminated needles
• transplacental or postpartum transmission from infected mother to fetus (by cervical or blood contact at delivery and in breast milk).

HIV strikes helper T cells bearing the CD4 ⁺ antigen. Normally a receptor for MHC molecules, the antigen serves as a receptor for the retrovirus and allows it to enter the cell. Viral binding also requires the presence of a coreceptor (believed to be the chemokine receptor CCR5) on the cell surface. The virus also may infect CD4 ⁺ antigen-bearing cells of the GI tract, uterine cervix, and neuroglia.

Like other retroviruses, HIV copies its genetic material in a reverse manner compared with other viruses and cells. Through the action of reverse transcriptase, HIV produces DNA from its viral RNA. Transcription is often poor, leading to mutations, and some such mutations make HIV resistant to antiviral drugs. The viral DNA enters the nucleus of the cell and is incorporated into the host cell's DNA, where it is transcribed into more viral RNA. If the host cell reproduces, it duplicates the HIV DNA along with its own and passes it on to the daughter cells. Thus, if activated, the host cell carries this information and, if activated, replicates the virus. Viral enzymes, proteases, arrange the structural components and RNA into viral particles that move out to the periphery of the host cell, where the virus buds and emerges from the host cell. Thus, the virus is now free to travel and infect other cells.

HIV replication may lead to cell death or it may become latent. HIV infection leads to profound pathology, either directly through destruction of CD4 ⁺ cells, other immune cells, and neuroglial cells, or indirectly through the secondary effects of CD4 ⁺ T-cell dysfunction and resulting immunosuppression.

The HIV infectious process takes three forms:

• immunodeficiency (opportunistic infections and unusual cancers)
• autoimmunity (lymphoid interstitial pneumonitis, arthritis, hypergammaglobulinemia, and production of autoimmune antibodies)
• neurologic dysfunction (AIDS dementia complex, HIV encephalopathy, and peripheral neuropathies).

Signs and symptoms

HIV infection manifests in many ways. After a high-risk exposure and inoculation, the infected person usually experiences a mononucleosis-like syndrome, which may be attributed to flu or another virus and then may remain asymptomatic for years. In this latent stage, the only sign of HIV infection is laboratory evidence of seroconversion.

When symptoms appear, they may take many forms, including:

• persistent generalized lymphadenopathy secondary to impaired function of CD4+ cells
• nonspecific symptoms, including weight loss, fatigue, night sweats, fevers related to altered function of CD4+ cells, immunodeficiency, and infection of other CD4+ antigen-bearing cells
• neurologic symptoms resulting from HIV encephalopathy and infection of neuroglial cells
• opportunistic infection or cancer related to immunodeficiency.

 

AGE ALERT In children, HIV infection has a mean incubation time of 17 months. Signs and symptoms resemble those in adults, except for findings related to sexually transmitted diseases. Children have a high incidence of opportunistic bacterial infections: otitis media, sepsis, chronic salivary gland enlargement, lymphoid interstitial pneumonia, Mycobacterium avium complex function, and pneumonias, including Pneumocystis carinii .

Complications

Complications of AIDS are:

• repeated opportunistic infections. (See Opportunistic infections in AIDS .)

Diagnosis

The CDC has developed an HIV/AIDS classification matrix defining AIDS as an illness characterized by one or more indicator diseases, coexisting with laboratory evidence of HIV infection and other possible causes of immunosuppression. Diagnosis of AIDS includes one or more of the following:

• confirmed presence of HIV infection
• CD4+ T-cell count of less than 200 cells/μl
• the presence of one or more conditions specified by the CDC as Categories A, B, or C. (See Conditions associated with AIDS .)

Treatment

No cure has yet been found for AIDS. Primary therapy includes the use of various combinations of three different types of antiretroviral agents to try to gain the maximum benefit of inhibiting HIV viral replication with the fewest adverse reactions. Current recommendations include the use of two nucleosides plus one protease inhibitor, or two nucleosides and one nonnucleoside to help inhibit the production of resistant, mutant strains. The drugs include:

• protease inhibitors to block replication of virus particle formed through the action of viral protease (reducing the number of new virus particles produced)
• nucleoside reverse-transcriptase inhibitors to interfere with the copying of viral RNA into DNA by the enzyme reverse transcriptase
• nonnucleoside reverse-transcriptase inhibitors to interfere with the action of reverse transcriptase.

Additional treatment may include:

• immunomodulatory agents to boost the immune system weakened by AIDS and retroviral therapy
• human granulocyte colony-stimulating growth factor to stimulate neutrophil production (retroviral therapy causes anemia, so patients may receive epoetin alfa)
• anti-infective and antineoplastic agents to combat opportunistic infections and associated cancers (some prophylactically to help resist opportunistic infections)
• supportive therapy, including nutritional support, fluid and electrolyte replacement therapy, pain relief, and psychological support.

 

OPPORTUNISTIC INFECTIONS IN AIDS The following chart shows the complicating infections that may occur in acquired immunodeficiency syndrome (AIDS). MICROBIOLOGICAL AGENT ORGANISM CONDITION   Protozoa Pneumocystis carinii Cryptosporidium Toxoplasmosis gondii Histoplasma Pneumocystis carinii pneumonia Cryptosporidiosis Toxoplasmosis Histoplasmosis Fungi Candida albicans Cryptococcus neoformans Candidiasis Cryptococcosis Viruses Herpes Cytomegalovirus Herpes simplex 1 and 2 Cytomegalovirus retinitis Bacteria Mycobacteria tuberculosis Mycobacteria avium Tuberculosis Mycobacteria avium complex Other opportunistic conditions include: Kaposi's sarcoma Wasting syndrome AIDS dementia complex.

Anaphylaxis

Anaphylaxis is an acute, potentially life-threatening type I (immediate) hypersensitivity reaction marked by the sudden onset of rapidly progressive urticaria (vascular swelling in skin accompanied by itching) and respiratory distress. With prompt recognition and treatment, the prognosis is good. However, a severe reaction may precipitate vascular collapse, leading to systemic shock and, sometimes, death. The reaction typically occurs within minutes, but can occur up to 1 hour after re-exposure to the antigen.

Causes

The cause of anaphylaxis is usually the ingestion of or other systemic exposure to sensitizing drugs or other substances. Such substances may include:

• serums (usually horse serum)
• vaccines
• allergen extracts
• enzymes such L -asparginase
• hormones
• penicillin or other antibiotics (induce anaphylaxis in 1 to 4 of every 10,000 patients treated; most likely after parenteral administration or prolonged therapy and in patients with an inherited tendency to food or drug allergy, or atopy)
• sulfonamides
• local anesthetics
• salicylates
• polysaccharides
• diagnostic chemicals, such as sulfobromophthalein, sodium dehydrocholate, and radiographic contrast media
• food proteins, such as those in legumes, nuts, berries, seafood, and egg albumin
• food additives containing sulfite
• insect venom.

 

CONDITIONS ASSOCIATED WITH AIDS The Centers for Disease Control and Prevention (CDC) lists associated diseases under three categories. From time to time the CDC, adds to these lists. CATEGORY A persistent generalized lymph node enlargement acute primary HIV infection with accompanying illness history of acute HIV infection CATEGORY B bacillary angiomatosis oropharyngeal or persistent vulvovaginal candidiasis, fever or diarrhea lasting longer than 1 month idiopathic thrombocytopenic purpura pelvic inflammatory disease, especially with a tubulo-ovarian abscess peripheral neuropathy CATEGORY C candidiasis of the bronchi, trachea, lungs, or esophagus invasive cervical cancer disseminated or extrapulmonary coccoidiomycosis extrapulmonary cryptococcosis chronic interstitial cryptosporidiosis cytomegalovirus (CMV) disease affecting organs other than the liver, spleen, or lymph nodes CMV retinitis with vision loss encephalopathy related to HIV herpes simplex infection with chronic ulcers or herpetic bronchitis, pneumonitis, or exophagitis disseminated or extrapulmonary histoplasmosis chronic intestinal isopsoriasis Kaposi's sarcoma Burkitt's lymphoma or its equivalent immunoblastic lymphoma or its equivalent primary brain lymphoma disseminated or extrapulmonary Mycobacterium avium complex or M. kansasii pulmonary or extrapulmonary M. tuberculosis disseminated or extrapulmonary infection with any other species of Mycobacterium Pneumocystis carinii pneumonia recurrent pneumonia progressive multifocal leukoencephalopathy recurrent Salmonella septicemia toxoplasmosis of the brain wasting syndrome caused by HIV

Pathophysiology

Anaphylaxis requires previous sensitization or exposure to the specific antigen, resulting in IgE production by plasma cells in the lymph nodes and enhancement by helper T cells. IgE antibodies then bind to membrane receptors on mast cells in connective tissue, and basophils.

On re-exposure, the antigen binds to adjacent IgE antibodies or cross-linked IgE receptors, activating a series of cellular reactions that trigger mast cell degranulation. With degranulation, powerful chemical mediators, such as histamine, eosinophil chemotactic factor of anaphylaxis, and platelet-activating factor, are released from the mast cells. IgG or IgM enters into the reaction and activates the complement cascade, leading to the release of the complement fractions.

At the same time, two other chemical mediators, bradykinin and leukotrienes, induce vascular collapse by stimulating contraction of certain groups of smooth muscles and increasing vascular permeability. These substances, together with the other chemical mediators, cause vasodilation, smooth muscle contraction, enhanced vascular permeability, and increased mucus production. Continued release, along with the spread of these mediators through the body by way of the basophils in the circulation, triggers the systemic responses. Also, increased vascular permeability leads to decreased peripheral resistance and plasma leakage from the circulation to the extravascular tissues. Consequent reduction of blood volume causes hypotension, hypovolemic shock, and cardiac dysfunction. (See Understanding anaphylaxis .)

Signs and symptoms

An anaphylactic reaction produces sudden physical distress within seconds or minutes after exposure to an allergen. A delayed or persistent reaction may occur up to 24 hours later. The severity of the reaction is inversely related to the interval between exposure to the allergen and the onset of symptoms. Usually, the first symptoms include:

• feeling of impending doom or fright due to activation of IgE and subsequent release of chemical mediators
• sweating due to release of histamine and vasodilation
• sneezing, shortness of breath, nasal pruritus, urticaria, and angioedema (swelling of nerves and blood vessels) secondary to histamine release and increased capillary permeability.

Systemic manifestations may include:

• hypotension, shock, and sometimes cardiac arrhythmias due to increased vascular permeability and subsequent decrease in peripheral resistance and leakage of plasma fluids
• nasal mucosal edema, profuse watery rhinorrhea, itching, nasal congestion, and sudden sneezing attacks due to histamine release, vasodilation, and increased capillary permeability
• edema of the upper respiratory tract, resulting in hypopharyngeal and laryngeal obstruction, due to increased capillary permeability and mast cell degranulation
• hoarseness, stridor, wheezing, and accessory muscle use secondary to bronchiole smooth muscle contraction and increased mucus production
• severe stomach cramps, nausea, diarrhea, and urinary urgency and incontinence resulting from smooth muscle contraction of the intestines and bladder.

Complications

Complications of anaphylaxis include:

• respiratory obstruction
• systemic vascular collapse
• death.

Diagnosis

No single diagnostic test can identify anaphylaxis. Anaphylaxis can be diagnosed by the rapid onset of severe respiratory or cardiovascular symptoms after ingestion or injection of a drug, vaccine, diagnostic agent, food, or food additive, or after an insect sting. If these symptoms occur without a known allergic stimulus, other possible causes of shock (such as acute myocardial infarction, status asthmaticus, or heart failure) must be ruled out.

The following test results may provide some clues to the patient's risk for anaphylaxis:

• skin tests showing hypersensitivity to a specific allergen
• elevated serum IgE levels.

Treatment

Treatment includes:

• immediate administration of epinephrine 1:1000 aqueous solution to reverse bronchoconstriction and cause vasoconstriction, IM or subcutaneously if the patient has not lost consciousness and is normotensive, or I.V. if the reaction is severe (repeating dosage every 5 to 20 minutes as needed)
• tracheostomy or endotracheal intubation and mechanical ventilation to maintain a patent airway
• oxygen therapy to increase tissue perfusion
• longer-acting epinephrine, corticosteroids, and diphenhydramine (Benadryl) to reduce the allergic response (long-term management)
• albuterol mini-nebulizer treatment
• tagamet or another histamine-2 blocker
• aminophylline to reverse bronchospasm
• volume expanders to maintain and restore circulating plasma volume
• I.V. vasopressors such as norepinephrine (Levophed) and dopamine (Intropin) to stabilize blood pressure
• cardiopulmonary resuscitation to treat cardiac arrest.

 

UNDERSTANDING ANAPHYLAXIS An anaphylactic reaction requires previous sensitization or exposure to the specific antigen. What happens in anaphylaxis is described next. <center> <a name="ch0012understandinganaphylaxis"></a> </center> 1. RESPONSE TO THE ANTIGEN Immunoglobulin M (IgM) and IgG recognize the antigen as a foreign substance and attach to it. Destruction of the antigen by the complement cascade begins but remains unfinished, either because of insufficient amounts of the protein catalyst or because the antigen inhibits certain complement enzymes. The patient has no signs and symptoms at this stage. <center> <a name="ch0012understandinganaphylaxis"></a> </center> 2. RELEASED CHEMICAL MEDIATORS The antigen's continued presence activates IgE on basophils. The activated IgE promotes the release of mediators, including histamine, serotonin, and slow-reacting substance of anaphylaxis (SRS-A). The sudden release of histamine causes vasodilation and increases capillary permeability. The patient begins to have signs and symptoms, including sudden nasal congestion, itchy and watery eyes, flushing, sweating, weakness, and anxiety. <center> <a name="ch0012understandinganaphylaxis"></a> </center> 3. INTENSIFIED RESPONSE The activated IgE also stimulates mast cells in connective tissue along the venule walls to release more histamine and eosinophil chemotactic factor of anaphylaxis (ECF-A). These substances produce disruptive lesions that weaken the venules. Now, red and itchy skin, wheals, and swelling appear, and signs and symptoms worsen. <center> <a name="ch0012understandinganaphylaxis"></a> </center> 4. DISTRESS In the lungs, histamine causes endothelial cells to burst and endothelial tissue to tear away from surrounding tissue. Fluids leak into the alveoli, and SRS-A prevents the alveoli from expanding, thus reducing pulmonary compliance. Tachypnea, crowing, use of accessory muscles, and cyanosis signal respiratory distress. Resulting neurologic signs and symptoms include changes in level of consciousness, severe anxiety, and possibly seizures. <center> <a name="ch0012understandinganaphylaxis"></a> </center> 5. DETERIORATION Meanwhile, basophils and mast cells begin to release prostaglandins and bradykinin along with histamine and serotonin. These substances increase vascular permeability, causing fluids to leak from the vessels. Shock, confusion, cool and pale skin, generalized edema, tachycardia, and hypotension signal rapid vascular collapse. <center> <a name="ch0012understandinganaphylaxis"></a> </center> 6. FAILED COMPENSATORY MECHANISMS Damage to the endothelial cells causes basophils and mast cells to release heparin. Additional substances are also released to neutralize the other mediators. Eosinophils release arylsulfatase B to neutralize SRS-A, phospholipase D to neutralize heparin, and cyclic adenosine monophosphate and the prostaglandins E 1 and E 2 to increase the metabolic rate. But these events can't reverse anaphylaxis. Hemorrhage, disseminated intravascular coagulation, and cardiopulmonary arrest result.

Latex allergy

Latex allergy is a hypersensitivity reaction to products that contain natural latex, a substance found in an increasing number of products at home and at work, that is derived from the sap of a rubber tree, not synthetic latex. The hypersensitivity reactions can range from local dermatitis to life-threatening anaphylactic reaction.

Until 1980, there were few reports of latex allergy. However, since the 1987 recommendation of the Centers for Disease Control and Prevention for universal precautions and the Occupational Safety and Health Administration requirement that employers provide gloves and other protective measures for their employees, the number of hypersensitivity reactions to latex has increased. Currently more than 40,000 products on the market are made with natural rubber latex.

The exact incidence of latex allergy isn't known. As of 1997, the Food and Drug Administration had received slightly more than 1,000 reports of reactions to latex products, including 16 deaths (attributed to the use of latex catheters for barium enemas).

The term “allergy” has been used loosely to describe any reaction that occurred after exposure to latex. The National Institute for Occupational Safety and Health developed a classification system to distinguish a true latex allergy from other types of reactions, as follows:

• irritant contact dermatitis, the most common response to latex exposure and largely associated with glove use, is the result of a direct skin injury, not an allergic reaction, possibly from the glove itself, the glove powder, or perspiration during glove use
• chemical sensitivity dermatitis (delayed hypersensitivity) results from a hypersensitivity to the chemicals added to latex during harvesting, processing, or manufacturing; the rash appears 24 to 48 hours after latex exposure
• latex allergy (immediate hypersensitivity) is the result of a response to latex proteins. A number of exposures are necessary before allergy occurs, and the symptoms appear within minutes of exposure, often mild at first, possibly progressing to anaphylaxis.

Causes

Exposure to latex proteins found in natural rubber products produces a true latex allergy. Those in frequent contact with latex-containing products are at risk for developing a latex allergy. More frequent exposure leads to a higher risk.

The populations at highest risk are:

• medical and dental professionals
• workers in latex companies
• patients with spina bifida, or other conditions that require multiple surgeries involving latex material.

Other individuals at risk include patients with a history of the following conditions:

• asthma or other allergies, especially to bananas, avocados, tropical fruits, or chestnuts
• multiple intra-abdominal or genitourinary surgeries
• frequent intermittent urinary catheterization.

Pathophysiology

A true latex allergy is an IgE-mediated immediate hypersensitivity reaction. Mast cells release histamine and other secretory products. Vascular permeability increases and vasodilation and bronchoconstriction occur.

Chemical sensitivity dermatitis is a type IV delayed hypersensitivity reaction to the chemicals used in processing rather than the latex itself. In a cell-mediated allergic reaction, sensitized T lymphocytes are triggered, stimulating the proliferation of other lymphocytes and mononuclear cells. This results in tissue inflammation and contact dermatitis.

Signs and symptoms

With a true latex allergy, the patient shows signs and symptoms of anaphylaxis, including:

• hypotension due to vasodilation and increased vascular permeability
• tachycardia secondary to hypotension
• urticaria and pruritus due to histamine release
• difficulty breathing, bronchospasm, wheezing, and stridor secondary to bronchoconstriction
• angioedema from increased vascular permeability and loss of water to tissues.

Complications

Like anaphylaxis, a true latex allergy may lead to:

• respiratory obstruction
• systemic vascular collapse
• death.

Diagnosis

Diagnosis of latex allergy may include:

• radioallergosorbent test showing specific IgE antibodies to latex (safest for use in patients with history of type I hypersensitivity)
• skin prick test showing positive response as an indicator of IgE sensitivity
• patch test resulting in hives with itching or redness as a positive response.

Treatment

Treatment includes:

• prevention of exposure, including use of latex-free products to decrease possible exacerbation of hypersensitivity
• drug therapy, such as corticosteroids, antihistamines, and histamine ₂ receptor blockers before and after possible exposure to latex to depress immune response and block histamine release.

If the patient is experiencing an acute emergency, treatment includes:

• immediate administration of epinephrine 1:1000 aqueous solution to reverse bronchoconstriction and cause vasoconstriction, IM or subcutaneously if the patient has not lost consciousness and is normotensive, or I.V. if the reaction is severe (repeating dosage every 5 to 20 minutes as needed)
• tracheostomy or endotracheal intubation and mechanical ventilation to maintain a patent airway
• oxygen therapy to increase tissue perfusion
• volume expanders to maintain and restore circulating plasma volume
• I.V. vasopressors such as norepinephrine (Levophed) and dopamine (Intropin) to stabilize blood pressure
• cardiopulmonary resuscitation to treat cardiac arrest
• longer acting epinephrine, corticosteroids, and diphenhydramine (Benedryl) to reduce the allergic response (long-term management)
• drugs to reverse bronchospasm, including aminophylline, histamine-2 blockers, albuterol.

Lupus erythematosus

Lupus erythematosus is a chronic inflammatory disorder of the connective tissues that appears in two forms: discoid lupus erythematosus, which affects only the skin, and systemic 1upus erythematosus (SLE), which affects multiple organ systems as well as the skin and can be fatal. SLE is characterized by recurring remissions and exacerbations, which are especially common during the spring and summer.

The annual incidence of SLE averages 27.5 cases per 1 million whites and 75.4 cases per 1 million blacks.

 

CULTURAL DIVERSITY SLE strikes women 8 times as often as men, increasing to 15 times as often during childbearing years. It occurs worldwide but is most prevalent among people of Asian, Hispanic, or African origin.

The prognosis improves with early detection and treatment but remains poor for patients who develop cardiovascular, renal, or neurologic complications, or severe bacterial infections.

Causes

The exact cause of SLE remains a mystery, but available evidence points to interrelated immunologic, environmental, hormonal, and genetic factors. These may include:

• physical or mental stress
• streptococcal or viral infections
• exposure to sunlight or ultraviolet light
• immunization
• pregnancy
• abnormal estrogen metabolism
• treatment with certain drugs, such as procainamide (Pronestyl), hydralazine (Apresoline), anticonvulsants, and, less frequently, penicillins, sulfa drugs, and oral contraceptives.

Pathophysiology

Autoimmunity is believed to be the prime mechanism involved with SLE. The body produces antibodies against components of its own cells, such as the antinuclear antibody (ANA), and immune complex disease follows. Patients with SLE may produce antibodies against many different tissue components, such as red blood cells, neutrophils, platelets, lymphocytes, or almost any organ or tissue in the body.

Signs and symptoms

The onset of SLE may be acute or insidious and produces no characteristic clinical pattern. (See Signs of systemic lupus erythematosis .)

Although SLE may involve any organ system, symptoms all relate to tissue injury and subsequent inflammation and necrosis resulting from the invasion by immune complexes. They commonly include:

• fever
• weight loss
• malaise
• fatigue
• rashes
• polyarthralgia.

Additional signs and symptoms may include:

• joint involvement, similar to rheumatoid arthritis (although the arthritis of lupus is usually nonerosive)
• skin lesions, most commonly an erythematous rash in areas exposed to light (the classic butterfly rash over the nose and cheeks occurs in less than 50% of the patients) or a scaly, papular rash (mimics psoriasis), especially in sun-exposed areas
• vasculitis (especially in the digits), possibly leading to infarctive lesions, necrotic leg ulcers, or digital gangrene
• Raynaud's phenomenon (about 20% of patients)
• patchy alopecia and painless ulcers of the mucous membranes
• pulmonary abnormalities, such as pleurisy, pleural effusions, pneumonitis, pulmonary hypertension, and, rarely, pulmonary hemorrhage
• cardiac involvement, such as pericarditis, myocarditis, endocarditis, and early coronary atherosclerosis
• microscopic hematuria, pyuria, and urine sediment with cellular casts due to glomerulonephritis, possibly progressing to kidney failure (particularly when untreated)
• urinary tract infections, possibly due to heightened susceptibility to infection
• seizure disorders and mental dysfunction
• central nervous system (CNS) involvement, such as emotional instability, psychosis, and organic brain syndrome
• headaches, irritability, and depression (common).

Constitutional symptoms of SLE include:

• aching, malaise, fatigue
• low-grade or spiking fever and chills
• anorexia and weight loss
• lymph node enlargement (diffuse or local, and nontender)
• abdominal pain
• nausea, vomiting, diarrhea, constipation
• irregular menstrual periods or amenorrhea during the active phase of SLE.

Complications

Possible complications of SLE include:

• concomitant infections
• urinary tract infections
• renal failure
• osteonecrosis of hip from long-term steroid use.

Diagnosis

Test results that may indicate SLE include:

• complete blood count with differential possibly showing anemia and a decreased white blood cell count
• platelet count, which may be decreased
• erythrocyte sedimentation rate, which is often elevated
• serum electrophoresis, which may show hypergammaglobulinemia.

Other diagnostic tests include:

• Antinuclear antibodies (ANA), and lupus erythematosus cell tests showing positive results in active SLE
• anti�double-stranded deoxyribonucleic acid antibody (anti-dsDNA); most specific test for SLE, correlates with disease activity, especially renal involvement, and helps monitor response to therapy; may be low or absent in remission
• additional autoantibody testing ― such as Smith antigen (anti-SM, highly specific for SLE), Sj?gren's syndrome (anti-SSA and anti-SSB [Sj?gren's syndrome antigen B]), and anti-ribonucleoprotein (RNP, antibodies to nuclear antigens) ― to differentiate autoimmune disorders from those with similar signs and symptoms
• urine studies possibly showing red blood cells and white blood cells, urine casts and sediment, and significant protein loss (more than 0.5 g/24 hours)
• serum complement blood studies showing decreased serum complement (C3 and C4) levels indicating active disease
• chest X-ray possibly showing pleurisy or lupus pneumonitis
• electrocardiography possibly showing a conduction defect with cardiac involvement or pericarditis
• kidney biopsy to determine disease stage and extent of renal involvement
• lupus anticoagulant and anticardiolipin tests possibly positive in some patients (usually in patients prone to antiphospholipid syndrome of thrombosis, abortion, and thrombocytopenia).

 

SIGNS OF SYSTEMIC LUPUS ERYTHEMATOSUS Diagnosing systemic lupus erythematosus (SLE) is difficult because it often mimics other diseases; symptoms may be vague and vary greatly among patients. For these reasons, the American Rheumatism Association issued a list of criteria for classifying SLE to be used primarily for consistency in epidemiologic surveys. Usually, four or more of these signs are present at some time during the course of the disease: malar or discoid rash photosensitivity oral or nasopharyngeal ulcerations nonerosive arthritis (of two or more peripheral joints) pleuritis or pericarditis profuse proteinuria (more than 0.5 g/day) or excessive cellular casts in the urine seizures or psychoses hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia anti�double-stranded deoxyribonucleic acid or anti-Smith antibody test or positive findings of antiphospholipid antibodies (elevated immunoglobulin G [IgG] or IgM anticardiolipin antibodies, positive test result for lupus anticoagulant, or false-positive serologic test results for syphilis) abnormal antinuclear antibody titer.

Treatment

Treatment for SLE may include:

• nonsteroidal anti-inflammatory compounds, including aspirin, to control arthritis symptoms
• topical corticosteroid creams such as hydrocortisone (Acticort) or triamcinolone (Aristocort) for acute skin lesions
• intralesional corticosteroids or antimalarials such as hydroxychloroquine (Plaquenil Sulfate) to treat refractory skin lesions
• systemic corticosteroids to reduce systemic symptoms of SLE, for acute generalized exacerbations, or for serious disease related to vital organ systems, such as pleuritis, pericarditis, lupus nephritis, vasculitis, and CNS involvement
• high-dose steroids and cytotoxic therapy (such as cyclophosphamide [Cytoxin]) to treat diffuse proliferative glomerulonephritis
• dialysis or kidney transplant for renal failure
• antihypertensive drugs and dietary changes to minimize effects of renal involvement.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that primarily attacks peripheral joints and the surrounding muscles, tendons, ligaments, and blood vessels. Partial remissions and unpredictable exacerbations mark the course of this potentially crippling disease. Rheumatoid arthritis strikes women three times more often than men.

Rheumatoid arthritis occurs worldwide, affecting more than 6.5 million people in the United States alone.

 

AGE ALERT RA can occur at any age, but 80% of the patients develop rheumatoid arthritis between the ages of 35 and 50 years.

This disease usually requires lifelong treatment and, sometimes, surgery. (See Drug therapy for rheumatoid arthritis .) In most patients, it follows an intermittent course and allows normal activity between flares, although 10% of affected people have total disability from severe joint deformity, associated extra-articular symptoms, such as vasculitis, or both. The prognosis worsens with the development of nodules, vasculitis, and high titers of rheumatoid factor (RF).

Causes

The cause of the chronic inflammation characteristic of rheumatoid arthritis isn't known. Possible theories include:

• abnormal immune activation (occurring in a genetically susceptible individual) leading to inflammation, complement activation, and cell proliferation within joints and tendon sheaths
• possible infection (viral or bacterial), hormone action, or lifestyle factors influencing onset
• development of an IgM antibody against the body's own IgG (also called rheumatoid factor, RF ); RF aggregates into complexes, generates inflammation, causing eventual cartilage damage and triggering other immune responses.

Pathophysiology

If not arrested, the inflammatory process in the joints occurs in four stages:

• synovitis develops from congestion and edema of the synovial membrane and joint capsule. Infiltration by lymphocytes, macrophages, and neutrophils continues the local inflammatory response. These cells, as well as fibroblast-like synovial cells, produce enzymes that help to degrade bone and cartilage
• pannus ― thickened layers of granulation tissue ― covers and invades cartilage and eventually destroys the joint capsule and bone
• fibrous ankylosis ― fibrous invasion of the pannus and scar formation ― occludes the joint space. Bone atrophy and misalignment cause visible deformities and disrupt the articulation of opposing bones, causing muscle atrophy and imbalance and, possibly, partial dislocations (subluxations).
• fibrous tissue calcifies, resulting in bony ankylosis and total immobility.

Signs and symptoms

Rheumatoid arthritis usually develops insidiously and initially causes nonspecific symptoms, most likely related to the initial inflammatory reactions before the inflammation of the synovium, including:

• fatigue
• malaise
• anorexia and weight loss
• persistent low-grade fever
• lymphadenopathy
• vague articular symptoms.

As the disease progresses, signs and symptoms include:

• specific localized, bilateral, and symmetric articular symptoms, frequently in the fingers at the proximal interphalangeal, metacarpophalangeal, and metatarsophalangeal joints, possibly extending to the wrists, knees, elbows, and ankles from inflammation of the synovium
• stiffening of affected joints after inactivity, especially on arising in the morning, due to progressive synovial inflammation and destruction
• spindle-shaped fingers from marked edema and congestion in the joints
• joint pain and tenderness, at first only with movement but eventually even at rest, due to prostaglandin release, edema, and synovial inflammation and destruction
• feeling of warmth at joint from inflammation
• diminished joint function and deformities as synovial destruction continues
• flexion deformities or hyperextension of metacarpophalangeal joints, subluxation of the wrist, and stretching of tendons pulling the fingers to the ulnar side (ulnar drift), or characteristic “swan's neck” appearance or “boutonnière” deformity from joint swelling and loss of joint space
• carpal tunnel syndrome from synovial pressure on the median nerve causing paresthesia in the fingers.

Extra-articular findings may include:

• gradual appearance of rheumatoid nodules ― subcutaneous, round or oval, nontender masses (20% of RF-positive patients), usually on elbows, hands, or Achilles tendon from destruction of the synovium
• vasculitis possibly leading to skin lesions, leg ulcers, and multiple systemic complications from infiltration of immune complexes and subsequent tissue damage and necrosis in the vasculature
• pericarditis, pulmonary nodules or fibrosis, pleuritis, or inflammation of the sclera and overlying tissues of the eye from immune complex invasion and subsequent tissue damage and necrosis
• peripheral neuropathy with numbness or tingling in the feet or weakness and loss of sensation in the fingers from infiltration of the nerve fibers
• stiff, weak, or painful muscles secondary to limited mobility and decreased use.

Complications

Complications of rheumatoid arthritis include:

• fibrosis and ankylosis
• soft tissue contractures
• pain
• joint deformities
• Sj?gren's syndrome
• destruction of second cervical vertebra
• spinal cord compression
• temporomandibular joint disease
• infection
• osteoporosis
• myositis (inflammation of voluntary muscles)
• cardiopulmonary lesions
• lymphadenopathy
• peripheral neuritis.

 

DRUG THERAPY FOR RHEUMATOID ARTHRITIS The following flow chart identifies the major pathophysiologic events in rheumatoid arthritis and shows where in this chain of events the major drug therapies act to control the disease. <center> <a name="ch0012drugtherapyforrheumatoidarthritis"></a> <a name="ch0012drugtherapyforrheumatoidarthritis"></a> </center>

Diagnosis

Test results indicating rheumatoid arthritis include:

• X-rays showing bone demineralization and soft-tissue swelling (early stages), cartilage loss and narrowed joint spaces, and, finally, cartilage and bone destruction and erosion, subluxations, and deformities (later stages)
• RF titer positive in 75% to 80% of patients (titer of 1:160 or higher)
• synovial fluid analysis showing increased volume and turbidity but decreased viscosity and elevated white blood cell counts (often greater than 10,000/μl)
• serum protein electrophoresis possibly showing elevated serum globulin levels
• erythrocyte sedimentation rate and C-reactive protein levels showing elevations in 85% to 90% of patients (may be useful to monitor response to therapy because elevation frequently parallels disease activity)
• complete blood count usually showing moderate anemia (hemoglobin less than 12 g/dl, hematocrit less than 38%), slight leukocytosis (11,000 to 20,000/μl), and thrombocytosis (alkaline phosphatase greater than 2.0 U/dl).

Treatment

Treatment for rheumatoid arthritis involves pharmacologic therapy and supportive measures, including:

• salicylates, particularly aspirin (mainstay of therapy) to decrease inflammation and relieve joint pain
• nonsteroidal anti-inflammatory agents such as indomethacin (Indocin), fenoprofen (Nalfon), and ibuprofen (Motrin) to relieve inflammation and pain
• antimalarials such as hydroxychloroquine (Plaquenil Sulfate), sulfasalazine (Azulfidine), gold salts, and penicillamine (Cupramine) to reduce acute and chronic inflammation
• corticosteroids (prednisone) in low doses for anti-inflammatory effects, in higher doses for immunosuppressive effect on T cells
• methotrexate (Folex), cyclosporine (Neoral), and azathioprine (Imuran) in early disease for immunosuppression by suppressing T and B lymphocyte proliferation causing destruction of the synovium
• supportive measures, including rest, splinting to rest inflamed joints, range-of-motion exercises, physical therapy, heat applications for chronic disease and ice application for acute episodes
• synovectomy (removal of destructive, proliferating synovium, usually in the wrists, knees, and fingers) to possibly halt or delay the course of the disease
• osteotomy (cutting of bone or excision of a wedge of bone) to realign joint surfaces and redistribute stress
• tendon transfers to prevent deformities or relieve contractures
• joint reconstruction or total joint arthroplasty, including metatarsal head and distal ulnar resectional arthroplasty, insertion of a Silastic prosthesis between metacarpophalangeal and proximal interphalangeal joints (severe disease)
• arthrodesis (joint fusion) for stability and relief of pain (sacrifices joint mobility).