Polyarteritis nodosa

Overview

Definition

Polyarteritis nodosa Polyarteritis nodosa A form of necrotizing non-granulomatous inflammation occurring primarily in medium-sized arteries, often with microaneurysms. It is characterized by muscle, joint, and abdominal pain resulting from arterial infarction and scarring in affected organs. Polyarteritis nodosa with lung involvement is called churg-strauss syndrome. Vasculitides (PAN) is a systemic, primarily medium-vessel vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus characterized by necrotizing inflammatory lesions. This condition eventually results in microaneurysms, which lead to bleeding, thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus, organ ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage, and infarction.

Epidemiology

• Annual incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency:
  • Difficult to define
  • Becoming rare with:
    • Widespread vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination for hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology ( HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus)
    • Recent treatment options for HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus and hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology ( HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus)
• Affects individuals of any sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria or ethnic background (slightly more predominant in men) 
• Peak incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 45–65 years 

Etiology

• Idiopathic Idiopathic Dermatomyositis (most cases)
• Some cases are associated with:
  • HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus infection (< 5% of cases)
  • HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus infection
  • Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have “hair-like projections” visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
  • Recessive loss-of-function mutations in the CECR1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
    • Encodes adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs deaminase 2 (ADA2) 
    • Onset usually in childhood
    • Association with cutaneous PAN (limited to skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, not systemic)

Pathophysiology

• A “medium-vessel vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus”

• Exact pathophysiology is unknown.
• Most widely implicated mechanism: immune complex formation (particularly with HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus infection) → segmental arterial inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
  • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation begins at the intima → thickening and proliferation of the vessel wall → arterial narrowing → ↓ blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure and predisposition to thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Weakening in the vessel wall → aneurysm Aneurysm An aneurysm is a bulging, weakened area of a blood vessel that causes an abnormal widening of its diameter > 1.5 times the size of the native vessel. Aneurysms occur more often in arteries than in veins and are at risk of dissection and rupture, which can be life-threatening. Thoracic Aortic Aneurysms formation → risk of rupture and bleeding
  • Predisposition to ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage and infarction → clinical manifestations based on organ system involved
• Usually multisystem involvement, most commonly:
  • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology
  • Muscles and joints
  • GI tract

Clinical Presentation

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with PAN typically present with multisystem involvement and systemic signs and symptoms. However, there is also a skin-limited form called cutaneous PAN.

General symptoms and signs

• Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia 
• Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery and loss of appetite
• Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever 
• Generalized weakness 
• Arthralgia Arthralgia Pain in the joint. Rheumatic Fever

Diagnosis

The diagnosis of PAN is made based on history, physical examination, and laboratory test results and should be confirmed by biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma whenever possible.

History and physical examination

• Detailed history revealing multisystem involvement raises suspicion for PAN. 
• Other systemic inflammatory conditions need to be ruled out:
  • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus)
  • Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
  • Systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor 
• Physical examination aims to determine:
  • Extent of the vascular lesions 
  • Affected organs 
  • Severity of disease

Laboratory testing

Laboratory findings are generally nonspecific, and studies may be used to assess organ system involvement and rule out other likely diagnoses. 

• Complete blood count → findings may be consistent with an inflammatory process:
  • Leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus 
  • Normochromic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types 
  • Thrombocytosis 
• Inflammatory markers (nonspecific):
  • ↑ Erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Soft Tissue Abscess ( ESR ESR Soft Tissue Abscess)
  • ↑ C-reactive protein (CRP)
• Assess renal involvement:
  • ↑ Creatinine
  • Urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children:
    • Normal or minimal proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
    • Possible microscopic hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma without red blood cell casts Red Blood Cell Casts Nephritic Syndrome in Children
• Additional assessments of organ involvement:
  • Hepatic function panel
  • Creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury kinase (CK)
• Infection workup:
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus → evaluate for HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus or HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus infection
  • HIV HIV Anti-HIV Drugs serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus → potential for HIV HIV Anti-HIV Drugs coinfection in individuals with hepatitis
  • Lyme titers → rule out Lyme disease Lyme disease Lyme disease is a tick-borne infection caused by the gram-negative spirochete Borrelia burgdorferi. Lyme disease is transmitted by the black-legged Ixodes tick (known as a deer tick), which is only found in specific geographic regions. Patient presentation can vary depending on the stage of the disease and may include a characteristic erythema migrans rash. Lyme Disease in endemic regions
  • Blood culture → rule out bacterial infection
• Additional workup:
  • Antineutrophil cytoplasmic antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (ANCAs) → rule out ANCA-associated vasculitides Vasculitides Vasculitides are a group of conditions characterized by vasculitis, ischemia, and damage to the organs supplied by the affected vessels. The affected arteries are of different sizes and locations and vary by the type of vasculitis. Vasculitides
  • Antinuclear antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (ANAs) → ↑ titers suggest an autoimmune disease (e.g., SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus, systemic sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor, or an overlap syndrome) 
  • Rheumatoid factor Rheumatoid factor Antibodies found in adult rheumatoid arthritis patients that are directed against gamma-chain immunoglobulins. Autoimmune Hepatitis ( RF RF Rheumatoid Arthritis) and anti-cyclic citrullinated peptide (anti-CCP) → rule out rheumatoid vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
  • Complement components (C3 and C4) → ↓ levels suggest mixed cryoglobulinemia Cryoglobulinemia A condition characterized by the presence of abnormal quantities of cryoglobulins in the blood. Upon cold exposure, these abnormal proteins precipitate into the microvasculature leading to restricted blood flow in the exposed areas. Rapidly Progressive Glomerulonephritis
  • Protein electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques (serum and urine) → evaluate for monoclonal gammopathy Monoclonal gammopathy Conditions characterized by the presence of m protein (monoclonal protein) in serum or urine without clinical manifestations of plasma cell dyscrasia. MALT Lymphoma

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

• Helps confirm the diagnosis
• Assesses a clinically affected organ, such as:
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions 
  • Kidney
  • Testes Testes Gonadal Hormones 
  • Skeletal muscle 
• Characteristic histologic findings in blood vessels:
  • Segmental transmural inflammation Transmural inflammation Crohn’s Disease
  • Cellular infiltrate with polymorphonuclear leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology or mononuclear cells 
  • White blood cell fragments (leukocytoclasia)
  • Disruption of internal and elastic Elastic Connective Tissue: Histology lamina
  • Fibrinoid necrosis Fibrinoid Necrosis Cell Injury and Death (results in a homogeneous Homogeneous Imaging of the Spleen, eosinophilic appearance of the vessel wall)
  • Lesions within the same sample are often of different ages.

Other tests

• Mesenteric or renal angiography Angiography Radiography of blood vessels after injection of a contrast medium. Cardiac Surgery may demonstrate:
  • Multiple aneurysms
  • Stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS) of larger vessels 
  • Occlusion of small arteries Small arteries Arteries: Histology 
• CT and MRI detect nonspecific findings, such as:
  • Wedge-shaped ischemic areas in the kidney 
  • Bowel wall thickening 
  • Engorgement Engorgement Mastitis of mesenteric vasculature
  • Diffuse thickening of GI mucosal folds
• Electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy and nerve conduction studies:
  • May assist with selecting site for nerve or muscle biopsy Muscle Biopsy Trichinella/Trichinellosis 
  • Can be used to assess peripheral neuropathy Neuropathy Leprosy

Assessment of disease severity

Assessing disease severity is helpful for determining the best management option.

• Mild:
  • Signs and symptoms:
    • Constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
    • Arthralgias
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions 
  • Normal renal function 
  • Absence of significant multiorgan or life-threatening manifestations 
• Moderate to severe:
  • Renal dysfunction
  • New or worsened hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension 
  • Multisystem involvement (e.g., GI, cardiac, neurologic) or life-threatening manifestations

Management and Prognosis

Management depends on the severity and extent of the disease and should be guided by a specialist (rheumatologist). The primary treatment method is with oral glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids. Immunosuppressive agents may also be needed for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with moderate-to-severe disease.

Treatment goals

• Achieve remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches (absence of active disease) 
• Resolve reversible symptoms 
• Prevent progression to severe disease

Management

Mild PAN: 

• Initial monotherapy with oral glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
• Additional immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants may be added, depending on response to treatment:
  • Azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
  • Mycophenolate Mycophenolate Immunosuppressants mofetil
• If associated with HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus or HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus infection, antiviral Antiviral Antivirals for Hepatitis B therapy warranted

Moderate-to-severe PAN:

• Initial therapy: combination of glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids and cyclophosphamide Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Immunosuppressants 
• Maintenance therapy with:
  • Azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants
  • Methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy
• Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension management:
  • ACE inhibitors ACE inhibitors Truncus Arteriosus or angiotensin receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers ( ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication) are preferred.
  • If renal function worsens, switch to another antihypertensive class (e.g., calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers)
• If associated with HBV HBV Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Hepatitis B virus is transmitted by exposure to infectious blood or body fluids. Examples of types of exposure include sexual intercourse, IV drug use, and childbirth. Hepatitis B Virus or HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus infection, treatment may also include:
  • Antiviral Antiviral Antivirals for Hepatitis B therapy
  • Plasma exchange Plasma exchange Removal of plasma and replacement with various fluids, e.g., fresh frozen plasma, plasma protein fractions (ppf), albumin preparations, dextran solutions, saline. Used in treatment of autoimmune diseases, immune complex diseases, diseases of excess plasma factors, and other conditions. Thrombotic Thrombocytopenic Purpura

Monitoring of PAN: 

• Regular Regular Insulin, long-term monitoring for progression and adverse effects of drugs
• Parameters monitored:
  • Routine physical examination 
  • Blood pressure 
  • Laboratory analysis 
  • Monitoring for drug toxicities 
  • Serum creatinine and urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children 
  • Assessment of new symptoms

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

The prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas depends on disease severity and response to treatment. 

• Untreated PAN: poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas with 5-year survival, approximately 10%
• With appropriate treatment: 5-year survival, approximately 80% 
• Worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas associated with:
  • Renal involvement 
  • GI involvement (e.g., ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage, perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis)
  • CNS involvement
  • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
• Disease relapse Relapse Relapsing Fever after successful remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches is approximately 20%.
• Survival rate is higher in non-HBV-associated PAN than in HBV-associated PAN.

Differential Diagnosis

• Anti–glomerular basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN) (GBM) disease: an autoimmune disorder Autoimmune Disorder Septic Arthritis characterized by circulating antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions directed against glomerular and alveolar basement membranes. Clinical presentation may include fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, epistaxis Epistaxis Bleeding from the nose. Granulomatosis with Polyangiitis, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, cough, hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, oliguria Oliguria Decreased urine output that is below the normal range. Oliguria can be defined as urine output of less than or equal to 0. 5 or 1 ml/kg/hr depending on the age. Renal Potassium Regulation, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, and anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types. Detection of anti-GBM antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions and renal biopsy Renal Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis findings of crescentic glomerulonephritis with linear IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis deposition along the basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN) provide the diagnosis. Management is with plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome plus immunosuppressive agents. 
• Drug-induced vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus: Almost every class of medication, and many illicit drugs Illicit Drugs Drugs that are manufactured, obtained, or sold illegally. They include prescription drugs obtained or sold without prescription and non-prescription drugs. Illicit drugs are widely distributed, tend to be grossly impure and may cause unexpected toxicity. Delirium, have been associated with vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus owing to an inflammatory immune response. Clinical manifestations range from asymptomatic rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes to multisystem involvement. Rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes include petechiae Petechiae Primary Skin Lesions or palpable purpura and may be associated with edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers. Diagnosis is made by histopathologic examination or immunofluorescence. Treatment includes withdrawing the causative agent. Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions can be treated with topical glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
• Antiphospholipid syndrome Antiphospholipid syndrome Antiphospholipid syndrome (APLS) is an acquired autoimmune disorder characterized by the persistent presence of antiphospholipid antibodies, which create a hypercoagulable state. These antibodies are most commonly discovered during a workup for a thrombotic event or recurrent pregnancy loss, which are the 2 most common clinical manifestations. Antiphospholipid Syndrome: an acquired autoimmune disorder Autoimmune Disorder Septic Arthritis that clinically presents with recurrent venous or arterial thrombosis Arterial Thrombosis Hypercoagulable States or fetal loss. Clinical suspicion should occur with unexplained thrombotic events (especially in younger patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship) or adverse pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care outcomes. The diagnosis involves laboratory testing for antiphospholipid antibodies Antiphospholipid antibodies Autoantibodies directed against phospholipids. These antibodies are characteristically found in patients with systemic lupus erythematosus, antiphospholipid syndrome; related autoimmune diseases, some non-autoimmune diseases, and also in healthy individuals. Antiphospholipid Syndrome, such as anticardiolipin antibodies Anticardiolipin antibodies Antiphospholipid antibodies found in association with systemic lupus erythematosus, antiphospholipid syndrome; and in a variety of other diseases as well as in healthy individuals. The antibodies are detected by solid-phase immunoassay employing the purified phospholipid antigen cardiolipin. Antiphospholipid Syndrome, lupus anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants, and anti-beta-2 glycoprotein I antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions. Anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants are the mainstay treatment for symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with recurrent thromboses.  
• Eosinophilic granulomatosis with polyangiitis Granulomatosis with Polyangiitis A multisystemic disease of a complex genetic background. It is characterized by inflammation of the blood vessels (vasculitis) leading to damage in any number of organs. The common features include granulomatous inflammation of the respiratory tract and kidneys. Most patients have measurable autoantibodies (antineutrophil cytoplasmic antibodies) against myeloblastin. Granulomatosis with Polyangiitis (EGPA): a type of necrotizing vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus that affects small to medium-sized vessels and is associated with asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma and eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome in blood and tissues. Multisystem involvement results in various signs and symptoms. Laboratory studies may demonstrate eosinophilia Eosinophilia Abnormal increase of eosinophils in the blood, tissues or organs. Autosomal Dominant Hyperimmunoglobulin E Syndrome and myeloperoxidase-ANCA Myeloperoxidase-ANCA Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis ( p-ANCA p-ANCA Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis), and the diagnosis is confirmed with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Management depends on the severity of the disease, but glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids and immunosuppressive drugs Immunosuppressive drugs Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-cells or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. Organ Transplantation continue to be the mainstay of treatment. 
• Cryoglobulinemia Cryoglobulinemia A condition characterized by the presence of abnormal quantities of cryoglobulins in the blood. Upon cold exposure, these abnormal proteins precipitate into the microvasculature leading to restricted blood flow in the exposed areas. Rapidly Progressive Glomerulonephritis: a rare disorder caused by an abundance of cryoglobulins (a type of protein) in the serum, which leads to vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus. Etiologic factors include infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (e.g., HCV HCV Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus), malignancies, and autoimmune conditions. The abnormal proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis may clump together and cause skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions, arthralgias, and peripheral neuropathy Neuropathy Leprosy. Decreased complement levels and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma can assist in the diagnosis. Management includes immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants and treatment of the underlying cause.
• Henoch-Schönlein purpura Henoch-Schönlein Purpura Henoch-Schönlein purpura (HSP), also known as immunoglobulin A vasculitis, is an autoimmune small-vessel vasculitis that typically presents as a tetrad of abdominal pain, arthralgia, hematuria, and purpuric rash. Henoch-Schönlein Purpura ( HSP HSP Henoch-Schönlein purpura (HSP), also known as immunoglobulin A vasculitis, is an autoimmune small-vessel vasculitis that typically presents as a tetrad of abdominal pain, arthralgia, hematuria, and purpuric rash. Henoch-Schönlein Purpura): an IgA-mediated disorder characterized by inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of small blood vessels. Triggers include infection (especially group A streptococcal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease), vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination, and environmental exposures. HSP HSP Henoch-Schönlein purpura (HSP), also known as immunoglobulin A vasculitis, is an autoimmune small-vessel vasculitis that typically presents as a tetrad of abdominal pain, arthralgia, hematuria, and purpuric rash. Henoch-Schönlein Purpura presents with a prodrome Prodrome Symptoms that appear 24–48 hours prior to migraine onset. Migraine Headache of headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Other common symptoms are rash Rash Rocky Mountain Spotted Fever, abdominal pain Abdominal Pain Acute Abdomen, arthralgias, and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. Diagnosis is clinical, though laboratory studies can rule out other diagnoses. Management includes supportive therapy, NSAIDs NSAIDS Primary vs Secondary Headaches for joint pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids/ immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants for severe disease.