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The prevalence of Behçet's disease is highest in countries of the eastern Mediterranean, the Middle East, and East Asia.Aphthous oral ulcers are usually the first and most persistent clinical feature of Behçet's disease. Aphthous ulcers also occur frequently on the genitals (e.g., the scrotum or vulva).Uveitis-either anterior or posterior-is common in Behçet's disease and a source of major morbidity.Many forms of central nervous system disease may occur in Behçet's disease. These include aseptic meningitis and white matter lesions in the brainstem.Human leukocyte antigen (HLA)-B51 is a strong risk factor for Behçet's disease.The diagnosis of primary angiitis of the central nervous system is predicated upon either biopsy evidence of vasculitis or angiographic findings suggestive of vasculitis in the setting of other compelling features, for example, strokes demonstrated by magnetic resonance imaging or the findings of a cerebrospinal fluid pleocytosis.The diagnosis of primary angiitis of the central nervous system should never be made on the basis of an angiogram alone.Patients with benign angiopathy of the central nervous system are predominantly female, tend to present acutely with headache (with or without focal symptoms), and have normal or near normal cerebrospinal fluid.Cogan's syndrome refers to the association of inflammation in both the eyes and ears: specifically, the occurrence of nonsyphilitic interstitial keratitis and immune-mediated inner ear disease, resulting in audiovestibular dysfunction.Any type of ocular inflammation may occur in Cogan's syndrome (e.g., scleritis, uveitis, orbital pseudotumor). The inner ear disease associated with this condition often leads to deafness.■ In erythema elevatum diutinum, skin lesions consist of purple, red, or brown plaques and often have an annular or nodular appearance. The skin lesions have a predilection for the extensor surfaces of the distal extremities and often overlie joints, but may be generalized. [ABSTRACT FROM AUTHOR]

Relapsing polychondritis (RP) is a rare disease that occurs worldwide in all age groups and affects men and women equally.An associated rheumatologic or hematologic disorder is seen in over 30% of patients with RP. Inflammation of cartilaginous structures with lymphocytic infiltration and association with anticollagen antibodies are consistent with an autoimmune pathogenesis.The characteristic clinical findings are acute painful swelling and redness of the external ear, nasal cartilage, and laryngotracheal cartilage. Nonerosive arthritis, ocular inflammation, vestibular symptoms, and involvement of the heart and kidney also occur.Diagnosis is made on clinical grounds, though cartilage biopsy may be useful.Treatment with nonsteriodal anti-inflammatory drugs (NSAIDs) or corticosteroids may control inflammation, but immunosuppressive and biologic treatments may be required for severe disease.■ Laryngotracheal involvement is a serious complication that may require tracheostomy. [ABSTRACT FROM AUTHOR]

Kawasaki's disease (KD), once known as mucocutaneous lymph node syndrome, is a systemic inflammatory disorder occurring in children that is accompanied by vasculitis and a risk of coronary artery aneurysms.Other typical features of KD include spiking fevers, cervical lymphadenopathy, conjunctivitis, erythematous changes on the lips and in the oral cavity, dryness and cracking of the lips, a strawberry appearance to the tongue, and a polymorphous rash.Eighty percent of KD cases occur in children less than 5 years of age.Attempts to link KD definitively to some types of infection, particularly ones associated with superantigens, have thus far been unsuccessful.High dose aspirin and intravenous immune globulin (IVIG) are the cornerstones of therapy in KD. IVIG is essential to the prevention of coronary aneurysms.■ Years after KD has occurred during childhood years, some cases of myocardial infarction caused by thrombosis of coronary aneurysms have been reported. [ABSTRACT FROM AUTHOR]

Complementary and alternative therapies are popular and widely used among patients with rheumatic and musculoskeletal diseases.Marketing and word of mouth, ready availability, and interest in "natural" treatments contribute to their popularity.■ Scientific basis and clinical trails of most therapies is limited or lacking. [ABSTRACT FROM AUTHOR]

Surgical treatments of arthritis and musculoskeletal diseases may be used to prevent progression, relieve pain, and/or improve joint function.The success of surgical interventions is dependent on careful considerations of pre-, intra-, and postoperative aspects of the surgery.■ Total joint replacements are now possible for most of the major joints affected and damaged by arthritis. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) have powerful anti-inflammatory and immunomodulatory effects and are useful for treating many rheumatic diseases.Glucocorticoids work by inhibiting leukocyte access to infl amed tissues, interfering with the function of cells involved in the infl ammatory process, and suppressing the production of humoral factors such as cytokines and prostaglandins involved in immune infl ammatory processes.Glucocorticoids accomplish their effects by several mechanisms, including altering synthesis of proteins, releasing proteins from intracellular protein complexes that include GC receptors, and changing the properties of biological membranes.Initial GC dosage should be determined by the type and severity of the disease manifestation under treatment.■ Because of signifi cant toxicity associated with long-term GC use, doses of <7.5 mg daily are recommended only if required to control symptoms. [ABSTRACT FROM AUTHOR]

■Nonsteriodal anti-inflammatory drugs (NSAIDs) relieve inflammation and pain by inhibiting the production of prostaglandins.■Prostaglandin (PG) biosynthesis occurs via a three-enzyme cascade. Current NSAIDs inhibit the enzyme cyclooxygenase (COX), accounting for their efficacy and toxicity.■Pharmacologic properties of the different NSAIDs, including specificity for COX-1 or -2 and drug half-life, influence the toxicity profile.■The most important NSAID toxicities include gastrointestinal ulceration, asthma and allergic reactions, and effects on the kidneys, liver, and cardiovascular system.■Safe use of NSAIDs requires consideration of indi vidual comorbidities to choose the best agent, appropriate monitoring for toxicity, and use of appropriate gastroprotective agents. [ABSTRACT FROM AUTHOR]

Successful needle placement for joint and soft tissue aspiration and injection requires clear understanding of anatomy.Aspiration of joint and soft tissue fluids may be important for diagnosis and treatment.■ Joint or soft tissue injections with corticosteroids may be beneficial for short- and long-term treatment. [ABSTRACT FROM AUTHOR]

Patients suffering with chronic diffuse pain who lack objective clinical and laboratory findings (e.g., fibromyalgia) frequently are dismissed as not having real pain, which only perpetuates their illness.There are four principal categories of pain: nociceptive pain, neuropathic pain, chronic pain of complex etiology, and psychogenic pain.Pain assessment should include attention to possible psychological and sociocultural factors that could be contributing to the pain experience.Diagnostic waffling, the ordering of frightening tests, excessive use of physical therapy modalities, activity limitation after minor trauma, and overly liberal work release are among the important factors that can convert what should be a selflimited acute pain condition into a chronic pain syndrome.If the clinician suspects fibromyalgia, validation of the patient's pain is important.Pharmacologic agents that may be useful in the management of individual pain syndromes include nonsteroidal anti-inflammatory drugs, opioids, muscle relaxants, antidepressants, antiepileptic medications, and topical agents.■ Physical therapy, cognitive-behavioral therapy, aerobic exercise, and complementary and alternative medicine approaches may all be useful in the management of pain in selected patients. [ABSTRACT FROM AUTHOR]

Self-management activities, such as participation in education programs and physical activity, are central to the nonpharmacological management of arthritisSelf-management education, physical activity, and weight loss have all demonstrated health benefi ts for people with arthritis.■ Evidence suggests that very few people with arthritis participate in self-management education. [ABSTRACT FROM AUTHOR]

Psychosocial factors are essential to a patient's vulnerability to the most important symptoms of rheumatic diseases, including pain and fatigue.Positive and negative emotions influence adaptation to rheumatic diseases with depression predictive of adverse outcomes.Cognitive factors, including a sense of control over illness, are of great importance to daily well-being. Interventions that improve self-efficacy improve pain and psychological functioning.■ Social factors also affect impact of diseases, with social resources and the ability to utilize them being a strong determinant of well-being among rheumatic disease patients. [ABSTRACT FROM AUTHOR]

In the care of disabled individuals, the current system of health care delivery and education largely focuses on a disease-centered medical model that fails to consider the role of society and the interaction of the disabled individual in that society over a lifespan.A more holistic approach to the care of disabled individuals considers the impact of environmental factors on the patient and provides a biopsychosocial orientation rather than a purely medical one.Holistic health approaches promote optimal function of the disabled person by considering not only the underlying rheumatic disease but the individual as a whole functioning person. Central to this health promotion is involvement of patient responsibility for his or her health and well being, including physical, psychological, social, and societal aspects.■ Multidisciplinary efforts are important to effective rehabilitation of patients disabled by rheumatic disease. Critical members of the multidisciplinary team are the rheumatologist, orthopedist, physical and occupational therapists, rehabilitation nurse, psychologist, social worker, and vocational rehabilitation specialist. [ABSTRACT FROM AUTHOR]

The main goal of osteoporosis treatment is the prevention of fractures.Increases in bone density through the use of medications explain only a small proportion of the observed reduction in fracture risk. This suggests that agents that have some additional effects on bone quality to account for the reduction in fracture risk.Important considerations in bone health include adequate intake of calcium and vitamin D, regular weight-bearing exercise, and avoidance of cigarette smoking and other negative factors.Pharmacologic intervention is indicated for women who have T scores of -2.5 and below and for women with risk factors whose T scores are -1.5 or below.Medications employed to treat osteoporosis include the bisphosphonates, calcitonin, selective estrogenreceptor modulators (SERMs), and parathyroid hormone.Pharmacologic medications for the treatment of osteoporosis are classifi ed as either antiresorptive or anabolic agents. The only anabolic drug available currently is teriparatide (parathyroid hormone).Bisphosphonates work through two broad mechanisms: They reduce the ability of individual osteoclasts to resorb bone and they accelerate osteoclast apoptosis (programmed cell death).Calcitonin reduces bone resorption by binding to specifi c osteoclast receptors.Selective estrogen-receptor modulators produce different expression of estrogen-regulated genes in different tissues, activating some and inhibiting others. The net effect of this is a reduction in bone resorption and possibly a reduction in the risk of breast cancer.Teraparatide stimulates bone formation, producing gains in spine bone mineral density two to three times greater than those observed with antiresorptive drugs.■ Bisphosphonates remain the first-line therapy for most patients, but teraparatide may be preferred for higher risk patients and for those failing to achieve a desired response to treatment with antiresorptive drugs. [ABSTRACT FROM AUTHOR]

The pathophysiology of osteoporosis includes many genetic, hormonal, nutritional, and environmental influences. Some risk factors for this condition are well defined.Although genetic factors contribute strongly to determining peak bone mass, hormonal, nutritional, and environmental influences during intrauterine life, childhood, and adolescence modulate the genetically determined pattern of skeletal growth.The bone mass of an individual in later life is a consequence of the peak bone mass accrued in utero and during childhood and puberty, as well as the subsequent rate of bone loss.The high rate of hip fracture in older people is not only due to their lower bone strength but also their increased risk of falling. Established risk factors for falls and, hence, hip fracture include impaired balance, muscle weakness, cognitive impairment, and psychotropic medication.Bone is continually undergoing a process of renewal called remodeling. In the normal adult skeleton, new bone laid down by osteoblasts exactly matches osteoclastic bone resorption; that is, bone formation and bone resorption are closely coupled.The principal cell types within bone are the osteoclasts, osteoblasts, and osteocytes. Osteoclasts are responsible for resorption of bone; osteoblasts are responsible directly for bone formation; osteocytes, derived from osteoblasts, appear to play a role in response to mechanical loading.■ Key regulators of osteoclastic bone resorption include RANK ligand and its two known receptors, RANK and osteoprotegerin (OPG). RANK and OPG have opposing effects on bone resorption. [ABSTRACT FROM AUTHOR]

More than 1.5 million osteoporosis-related fractures occur each year in the United States.Osteoporotic fractures most often involve the femoral neck, the vertebral bodies, or the wrist. Ninety percent (90%) of all hip and spinal fractures are related to osteoporosis.Among individuals now 50 years old, the lifetime risk of the any fracture in the hip, spine, or distal forearm is about 40% in Caucasion women and 13 % in Caucasian men.Two types of scores are used to quantify bone mineral density (BMD): The T score is the number of standard deviations the patient's BMD measurement is above or below the young-normal mean BMD. The Z score is the number of standard deviations the measurement is above or below the age-matched mean BMD.■ The World Health Organization (WHO) defines osteoporosis as a T score ≤ −2.5. [ABSTRACT FROM AUTHOR]

Osteonecrosis or vascular necrosis refers to the final result of a number of different pathways leading to bone death and ultimately to joint destruction. The femoral head is the most common site of osteonecrosis.Osteonecrosis develops bilaterally in more than 80% of cases. Besides the hip, the most common sites for necrosis are knees, shoulders, ankles, and elbows. ■ The most common risk factors for osteonecrosis are glucocorticoid use, excessive alcohol consumption, and cigarette smoking.The fi rst symptom associated with the disease is typically a deep, throbbing groin pain. This pain, usually intermittent and of gradual onset, occasionally appears abruptly.A variety of non-operative treatment interventions are available at some centers, including vasodilators, lipid-lowering agents, prostacyclin analogues, various types of anticoagulants, bisphosphonates, hyperbaric oxygen therapy, and extracorpeal shock wave therapy. Rigorous data on the effi cacy of these approaches are currently not available.There are currently four general categories of operative treatment options aimed toward preserving the femoral head and delaying (or preventing) total arthroplasty: (1) core decompression; (2) osteotomy; (3) nonvascularized bone grafting; and (4) vascularized bone grafting.■ Many patients eventually undergo total joint arthroplasty or resurfacing arthroplasty. [ABSTRACT FROM AUTHOR]

■Chondrodysplasias are inherited disorders of cartilage that affect its function as a template for bone growth.■Problems common to many chondrodysplasias are respiratory distress, osteoarthritis of the weightbearing joints, dental crowding, obesity, obstetrical difficulties, and psychological issues due to short stature.■The osteochondroses are a heterogeneous group of disorders in which localized non-inflammatory arthropathies result from regional disturbances of skeletal growth. [ABSTRACT FROM AUTHOR]

The genes that specify the hundreds of proteins involved in connective tissue have been mapped.The heritable disorders of connective tissue (HDCT) show both considerable variability within and among families and genetic heterogeneity.■ Phenotypes used: (1) disorders of fibrous elements, such as osteogenesis imperfecta and Marfan′s syndrome, (2) disorders of proteogylcan metabolism, such as mucopolysaccharidoses, (3) dysostoses and osteochondrodysplasias, such as achondroplasia, and (4) inborn errors of metabolism, such as homocystinuria. [ABSTRACT FROM AUTHOR]

The most common primary neoplasms of the joint are pigmented villonodular synovitis and synovial chondromatosis and a diagnosis is best made using magnetic resonance imaging (MRI).Other primary lesions are rare and include lipoma arborescens, synovial hemangiomas, intracapsular chondromas, and synovial chondrosarcomas.■Secondary neoplasms of the joint are synovial sarcoma and giant cell tumors.■ The malignancies that metastasize to bone also may invade the articular space. [ABSTRACT FROM AUTHOR]

The prevalence of amyloid diseases varies in different geographic areas. Alzheimer's disease is the most common form of localized amyloidosis, while AL amyloidosis is the most common systemic form of amyloidosis in the United States, while AA amyloidosis is the most common form worldwide.Amyloid fibrils resemble a woven cable and are deposited in tissues depending of the specific causative protein. Amyloid deposits do not cause an inflammatory reaction, but interfere with the function of surrounding tissues.Clinical manifestations vary according to the type of amyloid disease.Diagnosis is made by recognition of deposits with a characteristic "apple green" birefringence under polarizing microscopy and the specific subunit protein by immunohistochemistry.■ Treatment is directed toward reducing production of aberrant proteins or surgical removal of amyloid deposits or affected organs. [ABSTRACT FROM AUTHOR]

Some unusual arthropathies are caused by deposition of normal material, such as metal ions, or storage of abnormal material, such as lipids.Hemochromatosis, ochronosis, and Wilson's disease are characterized by cellular deposition of the normal metal ions: iron, calcium, and copper, respectively.■ In Gaucher's disease, Fabry's disease, Farber's disease, and multicentric reticulohistiocytosis, rheumatic manifestations result from cellular storage of abnormal lipids. [ABSTRACT FROM AUTHOR]

Systemic inflammatory disorder with noncaseating granulomatous inflammation in affected organs, commonly involving the lungs, eyes, skin, joints, lymph nodes, and upper respiratory tract.Diagnosis attained via consensus between the clinical presentation and natural history, pattern of major organ involvement, confirmatory biopsy, and response to therapy.■ When treatment is indicated, glucocorticoids remain the only recognized effective therapy for active sarcoidosis. [ABSTRACT FROM AUTHOR]

Complex regional pain syndrome is an uncommon but long recognized and high-impact regional musculoskeletal pain disorder.■ Current emphasis on pain sensitization mechanisms and earlier clinical recognition is facilitating management and improving outcomes. [ABSTRACT FROM AUTHOR]

Hypertrophic osteoarthropathy is characterized by abnormal proliferation of skin and bone at the distal parts of the extremities.Clinical features include bulbous deformity of the tips of the digits (conventionally known as clubbing) and periostosis of the tubular bones.The development of hypertrophic osteoarthropathy may indicate the presence of a significant internal illness, often a pulmonary malignancy or inflammatory disease of the lung.■ Abnormal vascular endothelial growth factor expression may play a central role in the pathogenesis of this condition. [ABSTRACT FROM AUTHOR]

Many rheumatologic diseases have prominent cutaneous findings.Careful examination of the skin may lead to prompt diagnoses, relatively noninvasive means of defining systemic disorders, and possibly better outcomes.■ Entities discussed in this chapter include the neutrophilic dermatoses (Sweet's syndrome, pyoderma gangrenosum), panniculitis (e.g., erythema nodosum), the sclerosing/fibrosing diseases (e.g., morphea and scleromyxedema), pustular conditions, and a variety of cutaneous conditions with possible implications for rheumatic disease. [ABSTRACT FROM AUTHOR]

Neuropathic arthropathy, also known as a Charcot joint, is a destructive arthritis characterized by fracture, subluxation, and dislocation of the articular structures in the setting of neurologic damage to the involved joint or limb.Both central (upper motor neuron) and peripheral (lower motor neuron) lesions may lead to the development of neuropathic arthropathy.Diabetic neuropathy is now the most common cause of neuropathic arthropathy. Neuropathic arthropathy occurs in 7.5% of diabetic patients.The pathologic features of Charcot arthropathy include cartilage destruction, bone eburnation, osteophytosis, and loose body formation.Two major theories have been proposed to explain the development of neuropathic arthropathy: the neurovascular theory and the neurotraumatic theory.Neuropathic arthropathy typically presents as an acute or subacute monoarthritis with swelling, erythema, and variable amounts of pain in the affected joint.Two consistent clinical features of neuropathic arthropathy are the presence of a significant sensory deficit and a degree of pain that is less than would be expected considering the amount of joint destruction evident on radiographs.The differential diagnosis of neuropathic arthropathy includes osteomyelitis and other deep tissue infections, fracture, gout, calcium pyrophosphate dihydrate deposition disease, Milwaukee shoulder/knee syndrome, osteonecrosis, and osteoarthritis.■ Plain radiographs are extremely helpful in making the diagnosis of neuropathic arthropathy. ■ Categorizing the disease into three clinical stages— acute, subacute, and remodeling—is a useful way to organize approaches to therapy. [ABSTRACT FROM AUTHOR]

Several recognized heritable disorders of lipid metabolism result in a variety of clinical phenotypes, each of which may be associated with distinct musculoskeletal manifestations.Tendinous xanthomas are associated most often with the type II and type III hyperlipoproteinemias, known respectively as familial hypercholesterolemia and familial dysbetalipoproteinemia.Tendinous xanthomas characteristically occur on the dorsum of the hands over the digit extensor tendons, or on the heels at the Achilles tendon insertions.Osseous xanthomas, observed occasionally in type III hyperlipoproteinemia, can predispose patients to pathologic fractures, particularly in long bones.An episodic, acute, migratory inflammatory arthritis occurs in up to 50% of homozygotes with type II hyperlipoproteinemia. The joints are erythematous, warm, and swollen, and acute-phase reactants are elevated.■ Gout can be associated with hypertriglyceridemia in types I, IV, and V hyperlipoproteinemia. [ABSTRACT FROM AUTHOR]

Musculoskeletal signs and symptoms frequently occur in endocrinopathies.A number of syndromes of limited joint mobility occur in people with diabetes mellitus, including diabetic hand syndrome (diabetic cheiroarthropathy), adhesive capsulitis (frozen shoulder, periarthritis), Dupuytren's contractures, trigger finger (flexor tenosynovitis), diffuse idiopathic skeletal hyperostosis (DISH syndrome), neuropathic arthritis (Charcot joints, diabetic osteoarthropathy), and diabetic muscle infarction.Hyperthyroidism may be associated with proximal myopathy, usually without serum creatine kinase (CK) elevation; thyroid acropachy; and drug-induced vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA), usually caused by propylthiouracil.Hypothyroidism may be associated with polyarthralgias, carpal tunnel syndrome, and proximal myopathy, with serum CK elevation.Hyperparathyroidism may cause osteoporosis, osteitis fibrosa cystica, chondrocalcinosis, and pseudogout.■ Other endocrinopathies that may lead to musculoskeletal complaints are hypoparathyroidism, acromegaly, and glucocorticoid-induced Cushing's syndrome. [ABSTRACT FROM AUTHOR]

Recurrent hemarthrosis is the primary clinical manifestation of hemophilia.Hemophilia A (classic hemophilia) is a heritable, X-linked recessive disorder of blood coagulation, occurring almost exclusively in males. The disorder is associated with a deficiency of factor VIII.Hemophilia B (Christmas disease), somewhat rarer but essentially indistinguishable clinically from hemophilia A, is caused by factor IX deficiency.Sickle-cell hemoglobinopathies associated with chronic hemolytic anemia and rheumatic manifestations include both homozygous sickle-cell anemia (Hb SS) and the heterozygous states: sickle-beta thalassemia, sickle-C (S-C) disease, and sickle-D (S-D) disease.Sickle-cell disease results from a single nucleotide substitution of valine for glutamic acid in the beta globin gene.In SS disease, the painful crises, osteonecrosis, and dactylitis are the result of small blood vessel occlusion in the bone marrow by sickled red cells.Osteomyelitis in patients with Hb SS disease is due to a combination of ischemic bone infarction and impaired host immunity. Salmonella is the most common organism.Thalassemia is a group of inherited hemoglobin disorders characterized by defects in the synthesis of one or more of the alpha or beta subunits of Hb.In beta-thalassemia, the reduced or absent production of beta chains leads to the production of an imbalance between the numbers of alpha and beta chains. This leads, in turn, to unstable Hb molecules, precipitation of the unaffected chains during erythropoiesis, and hemolysis.■ Mechanisms by which cancer can cause musculoskeletal symptoms include direct tumor invasion of bones and joints, hemorrhage into the joint, secondary gout, and paraneoplastic syndromes. [ABSTRACT FROM AUTHOR]

Hereditary periodic fever syndromes are autoinflammatory diseases characterized by episodes of fever with serosal, synovial, and/or skin inflammation.Familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) are inherited in an autosomal recessive manner and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) are dominantly inherited.■ Colchicine and biologic therapies such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) receptor agonists are successful in the treatment of some of these inherited diseases. [ABSTRACT FROM AUTHOR]

Diagnosis is one of exclusion and is suggested by the characteristic febrile pattern, evanescent rash, organomegaly, elevated white blood cell count, and a markedly elevated serum ferritin, serum IL-18 when available, and a reduced glycosylated fraction of ferritin.A predominance of T-helper cell (Th1) cytokines such as interleukin (IL)-2, IL-6, IL-18, interferon gamma, tumor necrosis factor (TNF) alpha have been reported in persons with active adult Still's disease and therapy against these cytokines is an active area of investigation.■ Most have a chronic course with morbidity arising from a polyarthritis. [ABSTRACT FROM AUTHOR]

Pathogenic immune complexes formed between antigen and antibodies tend to occur during periods of antigen excess. When the immune complexes precipitate into the tissues, they fix complement, leading to an intense immune reaction.In immune complex vasculitis, immune complexes deposit in the vascular endothelium or in capillary beds, such as those found in the skin, kidneys, or lungs.The most common skin manifestation of small vessel vasculitis is palpable purpura.Hypersensitivity vasculitis is characterized by immune complex deposition in capillaries, postcapillary venules, and arterioles. The usual causes are either medications (e.g., penicillins, sulfonamides, or cephalosporins) or infections.Cryoglobulinemic vasculitis is usually caused by hepatitis C infections. The antigens involved in cryoglobulinemic vasculitis are portions of the hepatitis C virus (HCV) virion. The relevant antibodies are both IgG and IgM, leading to the designation"mixed" cryoglobulinemia.Henoch-Schönlein purpura is associated strongly with IgA deposition within blood vessel walls.■ Hypocomplementemic urticarial vasculitis has many features that overlap with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Many patients with Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), or the Churg-Strauss syndrome (CSS) have antineutrophil cytoplasmic antibodies (ANCA) within their serum.As a result, these three disorders are termed the ANCA-associated vasculitides (AAV), even though not all patients with these conditions have ANCA.Multiple antibodies may lead to positive immunofluorescence testing for ANCA in either perinuclear (PANCA) or cytoplasmic (C-ANCA) patterns. However, only antibodies to myeloperoxidase (MPO) and proteinase-3 (PR3) are associated with the AAV.Wegener's granulomatosis may be associated with destructive upper respiratory tract disease, including saddle-nose deformity, erosive sinusitis, and subglottic stenosis. The CSS is often associated with allergic rhinitis, nasal polyposis, or sinusitis, but is rarely associated with destructive lesions.A host of ocular lesions may occur in the AAV, including episcleritis, scleritis, peripheral ulcerative keratitis, and orbital pseudotumor.Lung disease is common in the AAV and ranges from asthma (in CSS) to nodular lesions with a tendency to cavitate (in WG) to interstitial lung disease (MPA) to alveolar hemorrhage (all forms of AAV).Segmental, necrotizing glomerulonephritis commonly accompanies the AAV, particularly WG and MPA.■ Eosinophilia is the sine qua non of CSS. [ABSTRACT FROM AUTHOR]

Polyarteritis nodosa (PAN) primarily affects mediumsized arteries that supply the skin, gut, nerve, and kidney, but may involve multiple organs.Microaneurysms of arteries to or within the kidneys, liver, or gastrointestinal tract are highly characteristic of PAN.Polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies (ANCA) directed against either proteinase-3 or myeloperoxidase.Mononeuritis multiplex, an asymmetric sensory and motor neuropathy due to ischemia and infarction of peripheral nerves, occurs frequently in PAN.In mononeuritis multiplex, nerve conduction studies of peripheral nerves reveal a distal, asymmetric, axonal neuropathy involving both motor and sensory nerves.Polyarteritis nodosa is characterized pathologically by patchy, transmural inflammation in medium- and small-sized muscular arteries, sparing large arteries, capillaries, and the venous system. The inflammation leads to fibrinoid necrosis, but is not associated with granulomatous features.High-dose glucocorticoids are the mainstay of therapy in PAN. In cases that are rapidly progressive or life- or organ-threatening, however, cyclophosphamide is added to glucocorticoid treatment.Most cases of idiopathic PAN do not recur once a sound remission has been achieved with 6 to 12 months of therapy.■ A minority of PAN cases (now >10%) are associated with acute hepatitis B infection. Cases associated with hepatitis B are treated with regimens emphasizing antiviral therapy and only short courses of immunosuppression and plasmapheresis. [ABSTRACT FROM AUTHOR]

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are prototypes of large vessel vasculitis, tending to involve the aorta and its branches.Giant cell arteritis predominantly affects the secondto fifth-order aortic branches, often in the extracranial arteries of the head.Giant cell arteritis occurs exclusively among individuals who are 50 years of age or older. The mean age at diagnosis onset is approximately 72.In TA, the aorta and its major branches are the prime disease targets.Both GCA and TA are associated with granulomatous inflammation within the blood vessel wall.In both GCA and TA, clinical symptoms of vascular inflammation and vascular insufficiency are usually accompanied or preceded by a systemic inflammatory process.Visual loss is the most feared complication of GCA. Visual loss may occur through the syndrome of anterior ischemic optic neuropathy, caused by narrowing of the posterior ciliary artery and other vessels to the eye.The diagnosis of GCA is made usually by biopsy of the temporal artery.Polymyalgia rheumatica (PMR), a syndrome of muscle pain and stiffness in the neck, shoulders, and hips, often occurs with GCA but can occur independently.■ Glucocorticoids are the cornerstone of treatment for GCA, TA, and PMR. Isolated PMR requires a lower dose of prednisone for disease control. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with early and gradually progressive lacrimal and salivary dysfunction.Secondary SS occurs in association with other autoimmune disorders, the most common of which is rheumatoid arthritis.Minor salivary glands and lacrimal glands in SS exhibit a particular pattern of periductal lymphocytic infiltration known as focal lymphocytic sialadenitis.About 90% of patients with SS are women.Sjögren's syndrome is very common, with a community prevalence of pSS ranging from 0.1% to 0.6% of all individuals.The major eye problem in SS is keratoconjunctivitis sicca, leading to xerophthalmia. The principal oral manifestation of SS is decreased salivary gland production, leading to xerostomia and a predilection for dental caries.Extraglandular manifestations of SS include arthralgias, thyroiditis, renal involvement (leading to renal tubular acidosis), peripheral neuropathy, cutaneous vasculitis, and lymphoma.The risk of lymphoma in pSS is approximately 5%.Most patients with SS develop increased circulating polyclonal immunoglobulins and autoantibodies. These autoantibodies include two fairly specific antibodies directed against the Ro (SS-A) and La (SS-B) antigens.■ Anti-Ro and -La antibodies may be associated with fetal heart block during the pregnancies of women with SS. [ABSTRACT FROM AUTHOR]

The metabolic myopathies are a heterogeneous group of diseases characterized by impaired skeletal muscle energy production.Primary metabolic myopathies are associated with genetic defects in glycogen and lipid metabolism.Secondary types occur with abnormal production of parathyroid, thyroid, and cortisol production and vitamin D defi ciency.■ Symptoms occur mainly during or shortly after exercise and include pain, weakness, and cramping, and can result in myoglobinuria due to muscle necrosis. [ABSTRACT FROM AUTHOR]

Major pathology consists of focal inhomogeneous infl ammation with injury, death, and repair of muscle cells.Each subgroup of myositis has characteristic changes on microscopy and immunochemistry.■ Etiology is still unclear but selected environmental exposures in genetically predisposed hosts have been found. [ABSTRACT FROM AUTHOR]

Precise diagnosis is essential and muscle biopsy may identify myositis not responsive to therapy.Autoantibodies define heterogeneous clinical subsets.Steroids are the main pillar of therapy with immuno-suppressive drugs, such as methotrexate and azathio-prine, utilized as steroid-sparing agents.■ A core set of measures has been developed for assessing disease activity. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc; scleroderma) targets several aspects of disease pathophysiology: vascular features that are currently highly treatable; inflammatory features that are currently partly amenable to therapy; fibrotic features for which therapies of modest efficacy (at best) exist; and atrophic, end organ damage for which only supportive therapy is available.The extent of skin involvement is neither a robust primary outcome measure for clinical trials nor a reliable guide to the therapy of individual patients.Regular pulmonary function testing is a cornerstone of assessment.Continuous intravenous epoprostenol, subcutaneous or intravenous treprostinil, and bosentan all have important roles in selected patients with pulmonary arterial hypertension.Early recognition of scleroderma renal crisis (SRC) and prompt treatment with angiotensin-converting enzyme (ACE) inhibitors has improved outcomes in SRC dramatically.Cyclophosphamide is a cornerstone of interstitial lung disease treatment in SSc, but the therapeutic gains from this agent are relatively small.■ Long-term proton-pump inhibition is highly effective in treating the gastroesophageal reflux. High doses, sometimes two to three times the normal therapeutic dose, are required to alleviate symptoms. [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory myopathies (IIM) is a heterogeneous group of disorders characterized by chronic inflammation of striated muscle and skin.Painless proximal muscle weakness with or without rash is the hallmark feature.■ Increased serum muscle enzymes, muscle biopsy, electromyography (EMG), and magnetic resonance imaging (MRI) can assist in the diagnosis. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a chronic, multisystem disease of unknown etiology characterized by autoimmunity and inflammation, functional and structural abnormalities in small blood vessels, and progressive fibrosis of the skin and visceral organs.Estimates of its incidence in the United States range from 9 to 19 cases per million per year. The only community-based survey of SSc yielded a prevalence of 286 cases per million population.SSc is more common in females, with women-to-men ratios of 3 to 5 : 1.African Americans have a higher incidence than whites, and disease onset occurs at an earlier age. Furthermore, African Americans are more likely to have the diffuse cutaneous form of the disease with interstitial lung involvement and worse prognosis.Some SSc patients (1.6%) have a first-degree relative with the disease [relative risk (RR) = 13], indicating an important genetic contribution to disease susceptibility.Among environmental factors, infectious agents (particularly viruses), exposure to environmental and occupational toxins, and drugs have been suspected of playing a role in the etiology of SSc.The distinguishing pathological hallmark of SSc is an obliterative vasculopathy of small arteries and arterioles, combined vascular and interstitial fibrosis in target organs. In patients with established SSc, these lesions occur in the absence of inflammation.In relatively early-stage disease, perivascular cellular infiltrates are detected in many organs prior to the appearance of fibrosis.The organs most prominently affected by obliterative vasculopathy are the heart, lungs, kidneys, and intestinal tract.Fibrosis is prominent in the skin, lungs, gastrointestinal tract, heart, tendon sheath, perifascicular tissue surrounding skeletal muscle, and in some endocrine organs, such as the thyroid gland.Multiple cell types and their products interact in the processes that underlie the diverse clinical manifestations of SSc.An integrated view of the pathogenesis of SSc must incorporate the development of vasculopathy, activation of the cellular and humoral immune responses, and progressive fi brosis of multiple organs.■ Autoimmunity, altered endothelial cell function, and vascular reactivity may be the earliest manifestations of SSc, leading to Raynaud's phenomenon years before other disease features are present. Complex interplay among these processes initiates, amplifies, and sustains aberrant tissue repair and fibrosis. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (scleroderma; SSc) is divided further into limited cutaneous disease and diffuse cutaneous disease on the basis of the extent of skin thickening.Limited disease is defi ned as skin thickening that only affects the extremities below the elbows and/or below the knees. Diffuse cutaneous disease is defi ned as skin thickening proximal to the elbows and/or knees in addition to distal extremity involvement. Truncal skin may also be involved in diffuse cutaneous systemic sclerosis (dcSSc).The face can be involved in both forms and has no bearing on subset designation.The clinical manifestations of SSc may be considered the result of three pathological processes: (1) a small vessel non-infl ammatory obliterative vasculopathy; (2) the pathological accumulation of collagen in skin and other organs (fibrosis); and (3) autoimmunity.The obliterative small vessel vasculopathy is responsible for Raynaud's phenomenon, scleroderma renal crisis, and pulmonary artery hypertension.The fibrosing process results in thickened skin, pulmonary parenchymal disease, and gastrointestinal dysmotility.Tendon friction rubs, caused by an inflammation in the tendon sheath, are usually palpable on examination and sometimes cause pain with motion.A variety of autoantibodies occur in SSc, including those anti-topoisomerase III antibodies and anticentromere antibodies.Raynaud's phenomenon, usually the first manifestation of SSc, may precede the development of other features by months to years.Pulmonary disease is now the leading cause of death in SSc. Pulmonary fibrosis occurs in many SSc patients, with 20% ultimately requiring supplemental oxygen.■ Scleroderma renal crisis, the most common cause of death in SSc prior to the introduction of angiotensin converting enzyme (ACE) inhibitors, remains an important source of patient morbidity in SSc. [ABSTRACT FROM AUTHOR]

An acquired cause of hypercoagulability; 50% of antiphospholipid syndrome (APS) patients have systemic lupus erythematosus (SLE).Antiphospholipid syndrome predisposes to both venous and arterial thrombosis. The most common venous thrombosis is deep venous thrombosis; the most common arterial thrombosis is stroke.Antiphospholipid syndrome predisposes to miscarriage and other pregnancy morbidity.Antiphospholipid syndrome may cause thrombocytopenia.■ Antiphospholipid syndrome is diagnosed by persistent antiphospholipid antibody: lupus anticoagulant; anticardiolipin; and anti-beta 2 glycoprotein I. [ABSTRACT FROM AUTHOR]

Global management of systemic lupus erythematosus (SLE) importantly includes education, photoprotection, maintaining good physical conditioning, appropriate immunization, and identifying and treating risk factors for cardiovascular disease.Many traditional treatments are available for the nonorgan manifestations of SLE, including nonsteriodal anti-infl ammatory drugs (NSAIDs), corticosteroids, and antimalarials.Treatment of severe organ involvement typically requires immunosuppressive agents.■ Targeted biologic therapies are under development that may change treatment algorithms in the future. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is primarily a disease of young women, though it can be seen in both pediatric and older patients where the sex ratio is more balanced.The pathologic findings of SLE occur throughout the body and are manifested by inflammation, blood vessel abnormalities that encompass bland vasculopathy and vasculitis, and immune-complex deposition.Autoantibodies can occur in the absence of clinical lupus, but pathogenic autoantibodies are important contributors to tissue damage in the kidney as well as in other involved organs.Autoantibodies in lupus may be driven by selfantigens implicating a more generalized immune cell dysfunction. which promotes B-cell hyperactivity.Genetic susceptibility to lupus is likely polygenic, as exemplified by multiple types of genes associated with lupuslike diseases in mice.■ Triggering events for disease initiation and flares may include may environmental exposures, such as hormones, infectious agents, diet, sunlight, toxins (including drugs), and others. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a common autoimmune disorder occurring predominantly in women during reproductive years and having strong minority representation.The hallmark of SLE is its diversity of presentation with accumulation of manifestations over time and undulating disease course.Essentially any organ system can be affected by SLE with constitutional symptoms, mucocutaneous, musculoskeletal, renal, and central nervous system (CNS) being most common.Presence of autoantibodies, the unifying manifestation of SLE, is useful for diagnosis and the pattern of autoantibodies may help to predict clinical manifestations. Anti-double-stranded DNA antibodies are useful, along with changes in complement levels, for predicting disease flares in some patients.Special attention during pregnancy may help to avoid disease flares and adverse fetal outcome.■ Many drugs can trigger a lupuslike illness associated with autoantibodies, but typically with fewer disease manifestations and temporal association with the offending agent. [ABSTRACT FROM AUTHOR]

Acute rheumatic fever (ARF) is most frequent among 5 to 15 year olds, with a declining incidence in adults.It is extremely rare in children under age 3, prompting some speculation that more than one group A streptococcal (GAS) respiratory tract infection is needed before a host develops the immune mechanisms required to develop ARF.■ With the exception of chorea, the latent period between the inciting GAS infection and symptoms of ARF is approximately 3 weeks. [ABSTRACT FROM AUTHOR]

Osteoarticular involvement occurs in about 5% of patients with tuberculosis (TB), with estimated percentage ranging from about 2% of all TB cases in the United States to more than 6% in developing countries.Pott's disease (spinal tuberculosis) is the most common form of osteoarticular infection with Mycobacterium tuberculosis.Articular TB is usually due to reactivation of a hematogenously seeded focus and need not be associated with active disease elsewhere; it can also spread from adjacent osteomyelitis.Lengthy delays in diagnosis-on the order of 3 to 4 years-are reported.Poncet's disease is a form of reactive arthritis occurring during active TB.Mycobacterium marinum infection is often associated with such aquatic exposures as fish tank water, fish hook lacerations, skin punctures by fish spines, and cuts from boat motor propellers.The syndrome of erythema nodosum leprosum, manifested as crops of subcutaneous nodules, fever, and arthralgia or arthritis, occurs in patients with lepromatous leprosy.Valley fever (or desert rheumatism) are terms used for an immune complex-mediated syndrome associated with cocciodiomycosis infection. This syndrome, which is self-limited, is characterized by joint complaints, fever, rash, erythema nodosum, erythema multiforme, eosinophilia, and hilar adenopathy.■ Sporotrichosis, which usually presents as a painful erythematous nodule at the site of a skin wound. Inoculation of the organism Sporothrix schenckii into the skin through gardening or landscape exposures to soil or plant material is the mode of pathogenesis (the classic exposure is to a rose thorn). [ABSTRACT FROM AUTHOR]

Lyme disease is a tick-borne zoonosis caused by spirochetes of the genus Borrelia burgdorferi sensu lato.The majority of Lyme disease cases are localized to endemic foci in the United States, Europe, and Asia.In the United States, more than 90% of cases occur in only nine states: New York, Connecticut, New Jersey, Pennsylvania, Massachusetts, Maryland, Rhode Island, Wisconsin, and Minnesota.B. burgdorferi species are transmitted by hard-shelled ticks of the Ixodes complex, for example, Ixodes scapularis in the northeastern and north central United States.Upon infecting humans, B. burgdorferi replicates in the skin and then disseminates via the bloodstream to other organs, leading to extracutaneous disease manifestations.Seventy to eighty percent of Lyme disease patients develop a characteristic skin rash, erythema migrans (EM), at the site of tick feeding. The rash usually appears within days to weeks of the tick bite (range, 3-30 days).The hallmark of disseminated Lyme disease is the appearance of multiple EM lesions. These arise in about 50% of untreated patients with early localized disease. Secondary lesions are similar to the primary lesion, although are generally smaller in size and can appear anywhere on the body.Fever, malaise, myalgias, and arthralgias generally accompany dissemination of the Borrelia infection.Cardiac involvement in Lyme disease occurs in 4% to 10% of untreated patients, usually as varying degrees of atrioventricular heart block.Acute peripheral nervous system disease may take several forms in Lyme disease: cranial nerve palsies (unilateral or bilateral seventh nerve palsy is the most common neurological manifestation), sensorimotor radiculopathies, and mononeuritis multiplex.■ Late manifestations of Lyme disease may occur in the joints, nervous system, and skin. At this stage, joint involvement usually presents as an intermittent, oligoarticular arthritis. The knee is most commonly affected. [ABSTRACT FROM AUTHOR]