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Arthritis and Infections of Bones and Joints in Children
Symposium on Common Orthopedic Problems
Arthritis and Infections of Bones and Joints in Children Jane G. Schaller, M.D.*
The term arthritis ("arthron" :joint, "itis" : inflammation of) implies the presence of synovial inflammation. Symptoms and signs of arthritis include swelling, loss of motion, pain, stiffness, and heat of the involved joint. Joint swelling is the most reliable physical sign of arthritis. In the absence of detectable joint swelling, two or more findings of pain, loss of motion, or warmth may be sufficient for diagnosis. Pain of joints alone with no other symptoms or signs is properly called arthralgia rather than arthritis. An inflamed joint is swollen because of increased amounts of synovial fluid and thickening of synovial tissues; swelling of periarticular tissues may also contribute to the appearance of joint swelling. Loss of motion of arthritic joints is related to increased amounts of fluid and synovial tissue within the joint, spasm or shortening of muscles and other structures about the joint, avoidance of pain that may occur during joint motion ("guarding"), or actual destruction of articular structures. Arthritis can subside with no permanent residua if synovial inflammation resolves without causing damage to articular cartilage and other joint structures (Fig. 1); however, if joint structures are damaged by inflammation, as happens often in septic arthritis (Fig. 2) and occasionally in juvenile rheumatoid arthritis (Fig. 3), affected joints will never regain normal status. Pain and loss of motion occur also at musculoskeletal sites other than joints. In evaluating any child with musculoskeletal dysfunction it is important to identify the exact site of trouble accurately. Bone pain, as in osteomyelitis, fractures, or malignancies; muscle pain as in myositis; nerve pain as in the Guillain-Barre syndrome; and the vague limb pains of childhood must not be confused with arthritis. Conditions that may cause or simulate childhood arthritis can be conveniently grouped into several categories; most commonly encountered are rheumatic diseases, infectious diseases, malignancies, and noninflammatory conditions of bones and joints. There is also a long list of other miscellaneous conditions which can simulate arthritis; of "'Professor of Pediatrics, University of Washington School of Medicine, Seattle, Washington
Pediatric Clinics of North America- VoL 24, No.4, November 1977
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Figure 1. Knee in pauciarticular juvenile rheumatoid arthritis. There is a notable lack of destruction of cartilage or joint despite 18 months of continuing synovitis.
these the "growing" or limb pains of childhood (see p. 731) and psychogenic musculoskeletal pain are perhaps most commonly encountered. Various noninflammatory conditions of bones and joints which can simulate arthritis in children are frequently confused with childhood arthritis; these are dealt with in other articles and are not further discussed here.
ARTHRITIS RELATED TO RHEUMATIC DISEASES OF CHILDHOOD Juvenile Rheumatoid Arthritis (IRA) The term juvenile rheumatoid arthritis ORA) describes the condition of chronic synovitis of childhood; several distinct subgroups of disease are included (Table 1). Arthritis affecting multiple joints (polyarthritis or polyarticular disease) occurs in three of the subgroups: systemic onset disease, polyarticular seronegative disease, and polyarticular seropositive disease. Polyarticular disease is distinguished by involvement of multiple joints, both large and small, characteristically including the small hand joints. Joint involvement is often symmetrical. Severe hip disease is the major cause of severe disability in patients with polyarthritis. Patients in the three subgroups are distinguishable on the basis of extraarticular manifestations, laboratory tests, and severity of arthritis. Systemic onset ]RA is characterized by the presence of high intermittent fevers, rheumatoid rash, and other extraarticular manifestations such as polyserositis organomegaly, and leukocytosis. These sys-
Figure 2. Joint destruction following synovial infection with Staphylococcus aureus in an ankle. This septic joint was unrecognized and untreated for two weeks with resulting severe joint destruction and secondary chronic osteomyelitis.
Figure 3. Symmetrical loss of cartilage spaces and destruction of finger and wrist joints in a 15 year old girl with rheumatoid factor-positive juvenile rheumatoid arthritis. Although the disease has been of only one year's duration, there are already advanced destructive changes.
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Table 1. Juvenile Rheumatoid Arthritis SUBTYPE Systemic onset Polyarticular RF-negative Polyarticular RF-positive Pauciarticular with chronic iridocyclitis
Pauciarticular with sacroilii tis
LABORATORY RF ANA RF ANA RF ANA RF ANA
neg neg neg 25% pOS pos neg >50%
RF neg ANA neg HLA B27 >50%
JOINTS AFFECTED Any Any Any Knees, ankles, elbows Knees, ankles, hips, sacroiliacs
PROGNOSIS 25% severe arthritis 10 to 15% severe arthritis 50% severe arthritis 50% severe iridocyclitis; severe arthritis rare Ankylosing spondylitis will emerge in a significant number of patients
RF = rheumatoid factors; ANA = antinuclear antibodies.
temic manifestations are nearly always present at onset of disease and are generally self-limited, although many patients have recurrent attacks. Systemic manifestations are dramatic but rarely life-threatening; occasionally pericarditis, myocarditis, or severe anemia demand heroic treatment. As many boys as girls are affected with systemic onset JRA; patients are seronegative for both rheumatoid factors and antinuclear antibodies. The disease may begin at any time during childhood. The ultimate morbidity for systemic onset JRA lies in the joints; about 25 per cent of patients are left with destructive chronic seronegative arthritis. Rheumatoid factor-negative polyarticular JRA without prominent systemic manifestations is a disease which affects predominantly girls. It may begin at any age during childhood. Twenty-five per cent of patients have positive tests for antinuclear antibodies. Although the arthritis may become chronic, the general prognosis is quite good; only 10 to 15 per cent of patients incur severe destructive arthritis. On the other hand, rheumatoid factor-positive polyarticular JRA is characterized by severe destructive arthritis and a bad prognosis (Fig. 3). Affected patients have positive tests for rheumatoid factors, and often have positive tests for antinuclear antibodies as well. Disease generally begins after the age of 8 years. Rheumatoid nodules are frequently associated. Although the prominent systemic manifestations of systemic onset JRA are not associated, patients with polyarticular rheumatoid factor-negative or rheumatoid factor-positive JRA may have low grade fevers, modest organomegaly, malaise, mild anemia, and growth retardation. Pauciarticular arthritis is characterized by involvement of only a few joints. Large joints such as knees, ankles, and elbows are generally affected, and the distribution of affected joints is often asymmetrical.
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Occasionally there may also be spotty involvement of small finger or toe joints, or of other joints. It is difficult to define pauciarticular arthritis solely on the basis of the number of joints affected; for official purposes a total joint count of four joints is generally accepted. Two subgroups exist within pauciarticular JRA. One consists of patients with onset of disease in early childhood, predominantly girls, who frequently have positive tests for antinuclear antibodies and frequently develop chronic iridocyclitis. In these patients, joint involvement is predominantly in knees, ankles, and elbows. Although joint inflammation may be chronic, the ultimate prognosis for joint function is good and severe joint destruction is unusual (Fig. 1). Affected patients generally have few extraarticular manifestations save chronic iridocyclitis; this ocular inflammation can begin up to 10 years after the onset of arthritis. The major ultimate morbidity for this group of patients lies in the eyes, not in the joints. A second group of children with pauciarticular arthritis have negative tests for antinuclear antibodies and do not develop chronic iridocyclitis. In addition to having frequent involvement of knees and ankles, the hips and hip girdles are also frequently affected. Such patients may have sacroiijitis detected by radiographs early in disease or during the time of follow-up. Tests for rheumatoid factors and antinuclear antibodies are both negative, but more than half of patients can be found to have histocompatibility antigen HLA B27. This type of disease affects boys predominantly and generally begins after the age of 8 years. Family histories may be positive for ankylosing spondylitis or acute iridocyclitis. With increasing lengths of follow-up, an increasing number of these patients will be found to have ankylosing spondylitis rather than JRA. Diagnosis of JRA rests on recognition of the clinical pictures described above and upon exclusion of the other conditions listed in Table 1. Laboratory tests such as rheumatoid factors and antinuclear antibodies are useful in classification of patients, but are not diagnostic. Radiographs of joints may be useful early in disease to exclude other conditions, but are not diagnostic; in late disease radiographs of severe rheumatoid arthritis are diagnostic, but are rarely needed for diagnosis at that point. Management of affected patients should be guided by the type of disease and the particular types of problems present in the individual patient. In general, anti-inflammatory agents are used to suppress joint inflammation. Of the anti-inflammatory drugs, salicylates remain the safest and the most effective for the majority of patients. In patients with seronegative polyarthritis and pauciarticular JRA, ancillary drugs are rarely needed. In patients with severe progressive arthritis of systemic onset disease or polyarticular rheumatoid factor-positive disease, other drugs such as gold or hydroxychloroquine may be added in patients who fail to respond to salicylates. Corticosteroids are rarely warranted for joint disease alone. In patients with pauciarticular arthritis of the ankylosing spondylitis type, drugs such as indomethacin may be useful if patients fail to respond to salicylates. The systemic manifestations of systemic onset JRA may
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demand therapy with systemic corticosteroids should salicylates fail to control disease, but the duration of total corticosteroid therapy should be limited to six months. Chronic iridocyclitis is generally managed with topical steroids and dilating agents; occasionally systemic corticosteroids may also be warranted for this complication. Regular monitoring of eyes by an ophthalmologist is important for early detection of iridocyclitis. Physical therapy is essential to optimum therapy for nearly all children with JRA. Exercises are prescribed to maintain joint motion, regain lost joint motion, and strengthen muscles about affected joints. Physical activity should be encouraged; bed rest should be avoided. Night splints may be helpful in maintaining good joint positions, but prolor.!,ged immobilization of joints without physical therapy is contraindicated. The role of synovectomy in JRA appears to be limited. Reconstructive surgical procedures such as joint replacements and soft tissue releases can play an important role in the rehabilitation of disabled patients, particularly after they have achieved full growth. Patients should be helped to attend regular schools, and to lead as "normal" lives as possible. Despite the chronic nature of synovitis in JRA, a surprising number of children emerge with no permanent joint damage and are able to lead unimpaired lives as adults.
Ankylosing Spondylitis Ankylosing spondylitis is a type of chronic arthritis which characteristically affects the sacroiliac joints and joints of the lumbothoracic and cervical spines. Peripheral joints may also be affected; indeed, as pointed out in the section on JRA, ankylosing spondylitis may begin with peripheral arthritis which simulates rheumatoid arthritis. Peripheral arthritis, particularly of large lower limb joints, may antedate the onset of characteristic back symptoms by many years. Sacroiliitis may be manifest by pain over the sacroiliac joints or pain and stiffness in the hip girdle; however, some patients have no associated clinical manifestations. Arthritis generally affects the spine in an ascending fashion, first affecting the lumbar spine. Back pain is often severe, episodic, and associated with loss of motion and paravertebral muscle spasm. Diagnosis of ankylosing spondylitis demands radiographic sacroiliitis and either measurable loss of motion or radiographic changes in the lumbar spine. There are no diagnostic laboratory tests; tests for rheumatoid factors and antinuclear antibodies are generally negative. Histocompatibility antigen HLA B27 is present in 95 per cent of affected patients; however, this antigen is also found in about 6 per cent of the normal population. Ankylosing spondylitis is generally considered a progressive disease with further involvement of the spine occurring over a period of many years. However, in some patients the disease becomes arrested, and it seems possible that some patients with peripheral arthritis related to this disease never manifest clinical back disease at all. Management of ankylosing spondylitis includes anti-inflammatory drugs and physical therapy. Salicylates are effective in the manage-
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ment of some patients; many patients require additional drugs such as indomethacin. Gold therapy is not thought to be helpful in ankylosing spondylitis; corticosteroid therapy is generally contraindicated. Maintenance of good posture is essential. Some patients are troubled with attacks of acute iridocyclitis, and a very few patients will develop aortitis in adult years.
Systemic Lupus Erythematosus Systemic lupus erythematosus is a multisystem disease invariably associated with the presence of antinuclear antibodies, and often associated with antibodies reactive with DNA and with lowered levels of serum hemolytic complement. Fever and arthritis are common presenting manifestations of lupus; however, involvement of other systems is also usually apparent at time of onset. Nephritis, polyserositis, anemia, thrombocytopenia, myositis, organomegaly, and central nervous system involvement are all common. The arthritis of systemic lupus may mimic that of juvenile rheumatoid arthritis; however, the arthritis of lupus is often transient and is not associated with destructive joint changes. Some affected patients have only anthralgia without objective signs of arthritis. A vascular necrosis, most often of the femoral heads, is also associated with systemic lupus; areas of bone about multiple joints may be affected. The diagnosis of systemic lupus is made on the basis of the clinical picture of multisystem disease along with the presence of antinuclear antibodies and other abnormal laboratory tests. The diagnosis is generally not hard to make if the possibility is considered. The course of arthritis in systemic lupus is generally benign. Management of lupus depends on the extent of systemic involvement. With severe systemic involvement, such as nephritis, drugs such as corticosteroids are warranted. For mild systemic lupus without severe organ involvement, arthritis can be managed with salicylates, as in JRA. Hydroxychloroquine may also be a useful adjunctive drug. A vascular necrosis of bone must be distinguished from synovitis. Rheumatic Fever Rheumatic fever is a poststreptococcal disease associated with arthritis and carditis; other findings such as rash (erythema multiforme), subcutaneous nodules, and chorea may also be present. The arthritis of rheumatic fever is generally acute and migratory. Several joints, generally large joints such as knees, ankles, and wrists, may be involved. Arthritis rarely persists longer than one week in an affected joint. Joint destruction is not associated. Symmetrical polyarthritis as in JRA occurs rarely, if ever. The diagnosis of rheumatic fever is made on clinical grounds and requires documentation of a prior streptococcal infection. Carditis is the most characteristic manifestation of rheumatic fever. Only symptomatic therapy is needed for the arthritis of rheumatic fever, since it is generally self-limited; joint manifestations often respond dramatically to salicylates. Therapy of carditis may be with either salicylates or corticosteroids. The most important aspect of treatment of rheumatic
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fever is the maintenance of antibiotic prophylaxis to prevent recurrent streptococcal infections, since the ultimate morbidity of rheumatic fever results from the additive heart damage of recurrent rheumatic attacks. Dermatomyositis Dermatomyositis is characterized by a distinctive rash of the face and extensor surfaces of the limbs, and myositis. Myositis affects primarily the proximal limb and paraspinal muscles. A few patients also have associated arthritis which can resemble JRA. Diagnosis is made by recognition of the distinctive rash and myositis. The course of arthritis is variable. There are no diagnostic laboratory tests; serum levels of enzymes found in muscle cells are generally elevated, and electromyograms show changes consistent with myositis. Management is geared to suppression of myositis as witnessed by return of muscle strength and return of serum muscle enzyme values to normal, and to physical therapy to preserve joint motion and restore normal muscle strength. Vasculitis Syndromes Henoch-Sch6nlein vasculitis or anaphylactoid purpura is the commonest vasculitis syndrome of children. Arthritis is frequently present in Henoch-Sch6nlein vasculitis. One or many joints may be affected in a transient fashion. Periarticular edema is often associated. The arthritis is never chronic or destructive, and generally resolves spontaneously within one or a few days. Other characteristic manifestations of the syndrome include rash, abdominal pain, angioneurotic edema, and nephritis. Diagnosis is based on clinical findings, particularly on the
Figure 4. The characteristic rash of Henoch-Schonlein vasculitis. Small red maculopapular lesions, some progressing to purpuric lesions, are distributed over the lower extremities. Sometimes lesions also occur over the gluteal areas as shown here; less frequently lesions occur over the arms, trunk, and face.
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characteristic appearance of the rash (Fig. 4). Occasionally other vasculitis syndromes such as polyarteritis nodosa and the mucocutaneous lymph node syndrome occur in children; these also may be associated with arthritis.
Scleroderma Scleroderma is characterized by hardening of skin either locally or generally; increased amounts of collagen are found in dermal and subdermal tissues. Raynaud's phenomenon is frequently present. Arthritis may be associated. Small joints of the hands may be affected symmetrically as in JRA; larger joints may also occasionally be affected. Diagnosis is based on clinical findings. The outcome for this type of joint disease is uncertain. Management of the patient is geared to therapy for the scleroderma; physical therapy should be included. Arthritis of Inflammatory Bowel Disease Both regional enteritis and ulcerative colitis may be associated with arthritis. Two general types of arthritis occur: peripheral arthritis and ankylosing spondylitis. In peripheral arthritis, generally only a few joints are affected and the outcome is good. Bouts of arthritis are often transient and related to flares of underlying bowel disease. Therapy is generally geared to control of underlying bowel manifestations. The spondylitis associated with inflammatory bowel disease, on the other hand, is chronic and pursues the course of ankylosing spondylitis without bowel disease. Therapy should be geared to both the spondylitis and the bowel disease. The possibility of inflammatory bowel disease should be entertained in all children with arthritis. Tip-offs to bowel disease include weight loss, poor growth, unexplained fevers, anemia, erythema nodosum, and mucosal ulcers. Arthritis may sometimes precede the onset of recognizable bowel symptoms by months or years. Reiter's Syndrome and Psoriatic Arthritis Both are uncommon in children. Reiter's syndrome is characterized by the triad of urethritis, conjunctivitis, and arthritis; it may follow acute infections, notably with shigella, or may be sexually transmitted. Psoriatic arthritis is characterized by the coexistence of psoriasis and arthritis. In Reiter's syndrome, arthritis is often acute and self-limited, and may demand only symptomatic therapy; a few patients have associated ankylosing spondylitis. Psoriatic arthritis is often chronic and demands therapy with anti-inflammatory drugs as in JRA; a few patients also have associated spondylitis.
ARTHRITIS RELATED TO INFECTIONS Infectious diseases may cause arthritis by direct infection of the synovium or by causing synovial reactions without direct presence of organisms. Several categories of infection-related arthritis can be considered.
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Septic Arthritis In septic arthritis, the synovium becomes directly infected by pyogenic bacteria or by other organisms such as mycobacteria. Organisms generally arrive at affected joints via the blood stream, although penetrating wounds to a joint can also result in joint infection. Infection in synovial tissues rapidly results in an inflammatory response. Resulting joint effusions contain many white blood cells (in excess of 50,000 per cu mm), predominantly polymorphonuclear leukocytes; synovial fluid sugar levels are generally low. Often the infecting organisms may be seen in gram smears of synovial fluid. The inflamed synovial tissue swells, hypertrophies, and extends over the articular cartilage. Products of bacterial inflammation are extremely damaging to articular cartilage and generally cause permanent joint damage if infection is allowed to proceed untreated for periods of several days or more. Once articular cartilage is thus damaged, the joint has been permanently harmed (Fig. 2). Patients with septic joints generally have bacteremia or sepsis and are thus usually systemically ill with high fevers and malaise. Septic joints are generally very painful, hot, and swollen; overlying skin is often red. Although most often a single joint becomes the site of infection, it is possible that with a hematogenous route of spread more than one joint may be infected in a single patient. In gonococcal arthritis, signs and symptoms of systemic illness may be less severe, and multiple joints are often affected. In tuberculous arthritis, or arthritis with atypical mycobacteria, symptoms and signs of systemic illness may be lacking. Diagnosis of septic joint is generally made by joint aspiration. Demonstration of organisms in synovial fluid smears is diagnostic. Sometimes when organisms are not found in synovial fluid they may be found in synovial tissues; this is particularly true for tuberculous arthritis. As noted above, septic synovial fluid contains large numbers of granulocytes and reduced levels of sugar; however, some sterile fluids from patients with rheumatoid arthritis demonstrate similar findings. Synovial fluids should be cultured for bacteria; such cultures will be positive in septic arthritis in 60 to 70 per cent of cases. Blood cultures should also be obtained; about 15 per cent of patients with septic arthritis will have positive blood cultures in the absence of positive synovial fluid cultures. If gonococcal arthritis is suspected, appropriate genital cultures should also be obtained. If tuberculous or mycobacterial joint infection is suspected, chest films and appropriate skin tests should be made. Untreated septic arthritis has a dismal prognosis. Joint structures are destroyed and surrounding bones are also ultimately infected. Tuberculosis of the joint may pursue a more long-term course. Gonococcal arthritis is sometimes associated with no or minimal joint destruction even without appropriate therapy. Prompt recognition and therapy of septic arthritis is extremely important for good outcome. Once the diagnosis is reasonably suspected and joint aspiration and appropriate cultures have been obtained, therapy with appropriate antibiotics should be started promptly.
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Staphylococcus aureus is the commonest organism associated with septic arthritis in children over 4 years of age; in children under 4 years of age Hemophilus influenzae is an equally common etiologic agent. In small infants, other organisms, including gram-negative bacteria, may be responsible. Gonococci are the second most common organisms causing septic arthritis in older children. Other possible organisms include streptococci, pneumococci, meningococci, various gram-negative organisms, Mycobacterium tuberculosis, and atypical mycobacteria. In the absence of an identified organism in aspirated joint fluid, antibiotic therapy should be geared to the likelihood of the organism present in the particular environment and age group. High-dose antibiotic therapy given by a reliable route, notably intravenously, is important for good results. Therapy should be continued for a minimum of 2 to 3 weeks. Patients are often most comfortable if affected joints are splinted until acute inflammation settles; however, the role of rigid immobilization in hastening healing has never been proved. Removal of purulent material from the joint cavity and avoidance of increased intraarticular pressure are important. These can usually be achieved through repeated joint aspirations, except for septic arthritis of the hip, where open drainage is essential. With appropriate early recognition and management of septic arthritis, most patients have a good prognosis for subsequent normal joint function.
Viral Related Arthritis An increasing number of viral infections are being shown to be associated with arthritis. Several pathogenic mechanisms may be operative. Direct viral synovial infection has been demonstrated in the case of rubella. Immune complex disease with virus particles as antigen has been demonstrated in the case of Australia antigen disease. Viruses known to be associated with arthritis include rubella, mumps, chickenpox, adenovirus, hepatitis, and Epstein-Barr virus; it is likely that a number of other viral diseases may also sometimes have a component of synovitis. Viral related arthritis generally occurs after the onset of the associated virus infection; an exception to this is the arthritis of Australia antigen disease which precedes the recognition of hepatitis. Viral synovitis may affect one or multiple joints and is self-limited. Joint destruction is not associated. Only symptomatic treatment is indicated. Appreciation of the possibility of viral arthritis is important; children with short-lived synovitis should not be labeled as having chronic diseases such as JRA. Reactive Arthritis Reactive arthritis is the term given to sterile arthritis associated with bacterial infections elsewhere in the body. Three organisms, all causing gastroenteritis, have been associated with this type of reaction: Salmonella, Shigella, and Yersinia enterocolitica. Reactive arthritis is rarely recognized in the United States. Coexistence of gastroenteritis with arthritis should, however, be sought in evaluation of new patients.
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Sympathetic Effusions of Osteomyelitis Osteomyelitis affecting the metaphyseal areas of long bone may be associated with sterile effusions in adjacent joints. The exact mechanisms for production of such effusions are unknown. The resulting swollen joints may be a source of confusion in evaluating patients. The possibility of osteomyelitis should be considered in .any child with acute joint swelling. The joint fluid in sympathetic effusions is sterile and generally has low cell counts.
MALIGNANCIES OF CHILDHOOD Most childhood malignancies may be associated with musculoskeletal complaints which may closely mimic arthritis. This "arthritis" is generally caused by infiltrations of malignant cells in structures about the joint and in the periosteum of adjacent bones; direct infiltration of synovium with malignant cells is unusual, although it has been reported in leukemia. "Arthritis" has been noted most frequently in childhood leukemia and neuroblastoma; it also occurs in lymphoma, Hodgkin's disease, malignant histocytosis, and rhabdomyosarcoma. Affected joints are generally very painful, probably because the infiltrated periarticular tissues are richly supplied with nerve endings. Extreme joint pain or tenderness, or refusal to walk because of joint pain, should always raise the suspicion of malignancy. Affected joints are often warm and swollen and may closely resemble arthritic joints. One or many joints may be
Figure 5. The bone changes of leukemia. Rarefaction is seen in the metaphyseal areas in the distal femur and proximal tibia. This 10 year old boy was referred to Arthritis Clinic because of pain and swelling in several joints.
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affected. Joint complaints may be transient and recurrent, or persistent. When musculoskeletal complaints are a predominant early finding in childhood malignancy, patients may be initially suspected of having rheumatic diseases. Diagnosis of the underlying malignancy rests first of all on consideration of malignancy as a possibility. As noted above, severe bone and joint pain should always suggest malignancy. Abnormal blood findings such as leukopenia or bizarre leukocyte forms in the peripheral blood, severe anemia, or thrombocytopenia should also suggest malignancy. Hepatosplenomegaly or lymphadenopathy also raise the question of malignancy, although as noted above they may occur in patients with JRA as well. Radiographic changes of metaphyseal rarefaction, osteolytic lesions, or periostitis about affected joints may be helpful (Fig. 5); however, a significant number of children with malignancy and joint complaints have normal radiographs. If there is a reasonable suspicion of malignancy in any child with arthritis, appropriate tests such as bone marrow examinations should be promptly made. The musculoskeletal complaints of malignancy respond to therapy of the malignancy; they do not respond well to ordinary antirheumatic therapy with salicylates.
MISCELLANEOUS CAUSES OF MUSCULOSKELETAL PAIN IN CHILDREN A legion of conditions which may cause musculoskeletal problems in children are sometimes misinterpreted as arthritis. Only two will be considered here. The ubiquitous limb pains of childhood or "growing pains" are a problem common to all physicians dealing with children (see p. 731). In the absence of objective physical findings, physicians should avoid labeling such patients with diagnoses such as rheumatoid arthritis. Psychogenic musculoskeletal complaints may also be a cause of significant disability in some children. Again, the complaints and disability of joint or musculoskeletal pain are inconsistent with the absence of physical findings. Psychiatric intervention is usually required.
OSTEOMYELITIS Osteomyelitis, or bone infection, in children is generally spread by the hematogenous route and is a disease affecting the metaphyseal regions of bone. The predilection of osteomyelitis for the metaphyseal areas of bone is probably related to the plentiful and sluggish blood supply of the metaphysis. So long as the child is growing and the epiphyseal plates are intact, there is little or no communication between the blood supplies of the metaphyseal region and the epiphyseal and joint regions; therefore osteomyelitis rarely results in secondary septic arthritis, except in joints where the joint capsule inserts distal to the metaphysis (notably the hip and the shoulder). Since bone is a rigid tissue, the occurrence of an abscess in bone with resulting inflammation and swelling has several predictable effects. With increasing pres-
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sure, pus spreads through available channels in the bone, the haversian and Volkmann's canals, resulting in dissemination of infection longitudinally in the bone and in extrusion of pus outward under the periosteum. Necrosis of bone occurs when pressure and swelling from inflammation interfere with blood supply to local bone. Since the nerve supply to the periosteal regions and, to a lesser extent, to cortical and metaphyseal bone, is plentiful, osteomyelitis is generally an extremely painful condition. Patients with hematogenous osteomyelitis are usually systemically ill with high fevers and other signs of sepsis. Affected bone sites are usually extremely painful and patients frequently refuse to move the affected part. On physical examination, swelling and tenderness may be elicited in the affected area; it is therefore extremely important to search for local areas of swelling or bone tenderness. Any bone may be affected; the metaphyseal regions of long bones are the most frequent sites. Sterile effusions may occur in joints adjacent to areas of osteomyelitis ("sympathetic effusions"). The possibility of osteomyelitis should be entertained in any ill, febrile child, particularly if there are associated musculoskeletal complaints. Laboratory findings of leukocytosis and elevated sedimentation rates are not specific. Blood cultures will provide the offending organism in more than half of cases. Staphylococcus aureus is by far the most common organism responsible for hematogenous osteomyelitis in all age groups. Other possible agents include streptococci, pneumococci, Hemophilus influenzae, salmonellae (particularly in individuals with sickle cell hemoglobinopathy), and other gram-negative organisms (particularly in young infants or immunosuppressed patients). The question of whether or not to tap the suspected area of bone infection remains somewhat controversial; local taps can sometimes provide further help in identifying causative bacteria. The possibility of tuberculous bone infection should be kept in mind, although this is becoming increasingly rare in the United States; chest radiographs and appropriate skin tests are indicated. The earliest radiographic changes of osteomyelitis occur too late in the course of disease to be of any help with early diagnosis. The first radiographic finding is that of periosteal new bone formation in areas where the periosteum has been elevated by escaping pus; this change appears at 10 to 14 days after onset of infection. Later changes include radiolucent and radiodense areas in affected bone (Fig. 6). An earlier aid to the diagnosis of osteomyelitis is the bone scan utilizing boneseeking isotopes which will detect changes in affected regions as early as the first day of disease. The course of untreated osteomyelitis is dismal. Before the advent of antibiotics more than 25 per cent of affected patients died and remaining patients usually were disabled with chronic bone infections, draining sinuses, and loss of limbs. With early diagnosis and appropriate antibiotic therapy, the course of osteomyelitis is much more benign now, with most adequately treated patients recovering fully. Institution of specific therapy early in the course of osteomyelitis, before large amounts of bone necrosis and destruction occur, is essential to good outcome.
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Figure 6. Bone destruction of osteomyelitis which was recognized late and inadequately treated. Despite later medical and surgical therapy, this child has been plagued by chronic osteomyelitis with draining cutaneous sinuses.
Appropriate therapy consists of identification of infecting bacteria and therapy with large doses of antibiotics. Antibiotics should be given initially by an intravenous route for 1 to 2 or more weeks, followed by oral or intramuscular antibiotics until the patient is clinically well, there is radiographic evidence of healing, and the sedimentation rate is normal. Since Staphylococcus aureus is the most common cause of hematogenous osteomyelitis, initial appropriate therapy is usually directed against staphylococcus. Should there be reason to suspect another organism, therapy may be modified. If the patient does not improve in 24 to 36 hours of intensive antibiotic therapy, drainage of the area of osteomyelitis should be strongly considered. There is no good evidence that immobilization of the affected part aids healing, although patients may be more comfortable in immobilization during the first few days of treatment. For patients with extensive lesions, casting is important to protect weakened bone from pathologic fractures. The importance of recognizing bone and joint infections in children early and managing them appropriately cannot be overemphasized; it is tragic for such lesions to be missed.
EVALUATION OF A PATIENT WITH ARTHRITIS AND MUSCULOSKELETAL COMPLAINTS A complete history and physical examination are the most helpful tools in sorting out the various causes of arthritis and musculoskeletal complaints in children. History and review of systems should be made, with various conditions discussed earlier kept in mind. Physical examinations should be thorough and should include accurate assessment of bone, joint, muscle, and nervous status. There are no clear-cut diagnostic laboratory tests for most of the conditions that need to be considered. When first seeing a patient it is important to make a judgment about whether any potentially treatable diseases such as septic arthritis
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or osteomyelitis are present before coming to rest with a diagnosis of chronic rheumatic illness. It is also important to avoid making a diagnosis of arthritis unless the patient has in fact objective findings of arthritis, and to avoid mislabeling transient conditions such as viral arthritis as chronic diseases such as JRA. Laboratory studies should be based on findings in the history and physical examination. If there is any suspicion of septic arthritis or osteomyelitis, appropriate cultures and bone scans should be obtained at once. Blood smears may provide evidence for underlying malignancy; if so, further investigations such as bone marrow examination should be pursued. The so-called acute phase reactants, of which the sedimentation rate is most frequently done, are not diagnostic; furthermore, some patients with active inflammatory diseases will not have elevated sedimentation rates or other acute phase reactants. Immunologic tests such as antinuclear antibodies, rheumatoid factors, and immunoglobulin levels are not diagnostic of any disease, but are helpful in classification of patients with rheumatic diseases. Systemic lupus erythematosus cannot be diagnosed in the absence of antinuclear antibodies. It should be remembered that some patients with nonrheumatic diseases will have positive tests for either rheumatoid factors or antinuclear antibodies; this happens for example, after certain viral infections and in certain malignancies. Tests for complement levels and DNA antibodies are rarely indicated except in patients with systemic lupus. The presence of nephritis as witnessed by abnormal urinalysis suggests the possibility of a rheumatic disease which affects the kidneys such as systemic lupus, Henoch-Schonlein vasculitis, or polyarteritis; a few patients with immune complex disease related to bacterial infections may also have arthritis and nephritis. Genetic tests such as the test for histocompatibility antigen HLA B27 are not diagnostic of any rheumatic disease, although they are of great interest in clinical research. Radiographs of bones and joints may be extremely helpful in detecting certain musculoskeletal conditions, notably noninflammatory conditions such as fractures, avascular necrosis, and certain congenital musculoskeletal conditions; late in the course of osteomyelitis and severe JRA they will also be abnormal. REFERENCES 1. Nelson, J. D.: Follow-up: Septic arthritis. Pediatrics, 50:437-440,1972. 2. Proceedings of First American Rheumatism Association Conference on the Rheumatic Diseases of Childhood. (Schaller, J. G., and Hanson, V., Conference Chairmen), Supplement, March 1977. 3. Schaller, J., and Wedgwood, R. J.: Is juvenile rheumatoid arthritis a single disease? A review. Pediatrics, 50:940-953,1972. 4. Wadvogel, F. A., Medoff, G., and Schwartz, M. N.: Osteomyelitis: A review of clinical features, therapeutic considerations and unusual aspects. New Engl. J. Med., 282:198-206, 260-266,316-322,1970.
Department of Pediatrics RD-20 University of Washington School of Medicine Seattle, Washington 98195
Arthritis and Infections of Bones and Joints in Children Jane G. Schaller, M.D.*
The term arthritis ("arthron" :joint, "itis" : inflammation of) implies the presence of synovial inflammation. Symptoms and signs of arthritis include swelling, loss of motion, pain, stiffness, and heat of the involved joint. Joint swelling is the most reliable physical sign of arthritis. In the absence of detectable joint swelling, two or more findings of pain, loss of motion, or warmth may be sufficient for diagnosis. Pain of joints alone with no other symptoms or signs is properly called arthralgia rather than arthritis. An inflamed joint is swollen because of increased amounts of synovial fluid and thickening of synovial tissues; swelling of periarticular tissues may also contribute to the appearance of joint swelling. Loss of motion of arthritic joints is related to increased amounts of fluid and synovial tissue within the joint, spasm or shortening of muscles and other structures about the joint, avoidance of pain that may occur during joint motion ("guarding"), or actual destruction of articular structures. Arthritis can subside with no permanent residua if synovial inflammation resolves without causing damage to articular cartilage and other joint structures (Fig. 1); however, if joint structures are damaged by inflammation, as happens often in septic arthritis (Fig. 2) and occasionally in juvenile rheumatoid arthritis (Fig. 3), affected joints will never regain normal status. Pain and loss of motion occur also at musculoskeletal sites other than joints. In evaluating any child with musculoskeletal dysfunction it is important to identify the exact site of trouble accurately. Bone pain, as in osteomyelitis, fractures, or malignancies; muscle pain as in myositis; nerve pain as in the Guillain-Barre syndrome; and the vague limb pains of childhood must not be confused with arthritis. Conditions that may cause or simulate childhood arthritis can be conveniently grouped into several categories; most commonly encountered are rheumatic diseases, infectious diseases, malignancies, and noninflammatory conditions of bones and joints. There is also a long list of other miscellaneous conditions which can simulate arthritis; of "'Professor of Pediatrics, University of Washington School of Medicine, Seattle, Washington
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Figure 1. Knee in pauciarticular juvenile rheumatoid arthritis. There is a notable lack of destruction of cartilage or joint despite 18 months of continuing synovitis.
these the "growing" or limb pains of childhood (see p. 731) and psychogenic musculoskeletal pain are perhaps most commonly encountered. Various noninflammatory conditions of bones and joints which can simulate arthritis in children are frequently confused with childhood arthritis; these are dealt with in other articles and are not further discussed here.
ARTHRITIS RELATED TO RHEUMATIC DISEASES OF CHILDHOOD Juvenile Rheumatoid Arthritis (IRA) The term juvenile rheumatoid arthritis ORA) describes the condition of chronic synovitis of childhood; several distinct subgroups of disease are included (Table 1). Arthritis affecting multiple joints (polyarthritis or polyarticular disease) occurs in three of the subgroups: systemic onset disease, polyarticular seronegative disease, and polyarticular seropositive disease. Polyarticular disease is distinguished by involvement of multiple joints, both large and small, characteristically including the small hand joints. Joint involvement is often symmetrical. Severe hip disease is the major cause of severe disability in patients with polyarthritis. Patients in the three subgroups are distinguishable on the basis of extraarticular manifestations, laboratory tests, and severity of arthritis. Systemic onset ]RA is characterized by the presence of high intermittent fevers, rheumatoid rash, and other extraarticular manifestations such as polyserositis organomegaly, and leukocytosis. These sys-
Figure 2. Joint destruction following synovial infection with Staphylococcus aureus in an ankle. This septic joint was unrecognized and untreated for two weeks with resulting severe joint destruction and secondary chronic osteomyelitis.
Figure 3. Symmetrical loss of cartilage spaces and destruction of finger and wrist joints in a 15 year old girl with rheumatoid factor-positive juvenile rheumatoid arthritis. Although the disease has been of only one year's duration, there are already advanced destructive changes.
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Table 1. Juvenile Rheumatoid Arthritis SUBTYPE Systemic onset Polyarticular RF-negative Polyarticular RF-positive Pauciarticular with chronic iridocyclitis
Pauciarticular with sacroilii tis
LABORATORY RF ANA RF ANA RF ANA RF ANA
neg neg neg 25% pOS pos neg >50%
RF neg ANA neg HLA B27 >50%
JOINTS AFFECTED Any Any Any Knees, ankles, elbows Knees, ankles, hips, sacroiliacs
PROGNOSIS 25% severe arthritis 10 to 15% severe arthritis 50% severe arthritis 50% severe iridocyclitis; severe arthritis rare Ankylosing spondylitis will emerge in a significant number of patients
RF = rheumatoid factors; ANA = antinuclear antibodies.
temic manifestations are nearly always present at onset of disease and are generally self-limited, although many patients have recurrent attacks. Systemic manifestations are dramatic but rarely life-threatening; occasionally pericarditis, myocarditis, or severe anemia demand heroic treatment. As many boys as girls are affected with systemic onset JRA; patients are seronegative for both rheumatoid factors and antinuclear antibodies. The disease may begin at any time during childhood. The ultimate morbidity for systemic onset JRA lies in the joints; about 25 per cent of patients are left with destructive chronic seronegative arthritis. Rheumatoid factor-negative polyarticular JRA without prominent systemic manifestations is a disease which affects predominantly girls. It may begin at any age during childhood. Twenty-five per cent of patients have positive tests for antinuclear antibodies. Although the arthritis may become chronic, the general prognosis is quite good; only 10 to 15 per cent of patients incur severe destructive arthritis. On the other hand, rheumatoid factor-positive polyarticular JRA is characterized by severe destructive arthritis and a bad prognosis (Fig. 3). Affected patients have positive tests for rheumatoid factors, and often have positive tests for antinuclear antibodies as well. Disease generally begins after the age of 8 years. Rheumatoid nodules are frequently associated. Although the prominent systemic manifestations of systemic onset JRA are not associated, patients with polyarticular rheumatoid factor-negative or rheumatoid factor-positive JRA may have low grade fevers, modest organomegaly, malaise, mild anemia, and growth retardation. Pauciarticular arthritis is characterized by involvement of only a few joints. Large joints such as knees, ankles, and elbows are generally affected, and the distribution of affected joints is often asymmetrical.
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Occasionally there may also be spotty involvement of small finger or toe joints, or of other joints. It is difficult to define pauciarticular arthritis solely on the basis of the number of joints affected; for official purposes a total joint count of four joints is generally accepted. Two subgroups exist within pauciarticular JRA. One consists of patients with onset of disease in early childhood, predominantly girls, who frequently have positive tests for antinuclear antibodies and frequently develop chronic iridocyclitis. In these patients, joint involvement is predominantly in knees, ankles, and elbows. Although joint inflammation may be chronic, the ultimate prognosis for joint function is good and severe joint destruction is unusual (Fig. 1). Affected patients generally have few extraarticular manifestations save chronic iridocyclitis; this ocular inflammation can begin up to 10 years after the onset of arthritis. The major ultimate morbidity for this group of patients lies in the eyes, not in the joints. A second group of children with pauciarticular arthritis have negative tests for antinuclear antibodies and do not develop chronic iridocyclitis. In addition to having frequent involvement of knees and ankles, the hips and hip girdles are also frequently affected. Such patients may have sacroiijitis detected by radiographs early in disease or during the time of follow-up. Tests for rheumatoid factors and antinuclear antibodies are both negative, but more than half of patients can be found to have histocompatibility antigen HLA B27. This type of disease affects boys predominantly and generally begins after the age of 8 years. Family histories may be positive for ankylosing spondylitis or acute iridocyclitis. With increasing lengths of follow-up, an increasing number of these patients will be found to have ankylosing spondylitis rather than JRA. Diagnosis of JRA rests on recognition of the clinical pictures described above and upon exclusion of the other conditions listed in Table 1. Laboratory tests such as rheumatoid factors and antinuclear antibodies are useful in classification of patients, but are not diagnostic. Radiographs of joints may be useful early in disease to exclude other conditions, but are not diagnostic; in late disease radiographs of severe rheumatoid arthritis are diagnostic, but are rarely needed for diagnosis at that point. Management of affected patients should be guided by the type of disease and the particular types of problems present in the individual patient. In general, anti-inflammatory agents are used to suppress joint inflammation. Of the anti-inflammatory drugs, salicylates remain the safest and the most effective for the majority of patients. In patients with seronegative polyarthritis and pauciarticular JRA, ancillary drugs are rarely needed. In patients with severe progressive arthritis of systemic onset disease or polyarticular rheumatoid factor-positive disease, other drugs such as gold or hydroxychloroquine may be added in patients who fail to respond to salicylates. Corticosteroids are rarely warranted for joint disease alone. In patients with pauciarticular arthritis of the ankylosing spondylitis type, drugs such as indomethacin may be useful if patients fail to respond to salicylates. The systemic manifestations of systemic onset JRA may
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demand therapy with systemic corticosteroids should salicylates fail to control disease, but the duration of total corticosteroid therapy should be limited to six months. Chronic iridocyclitis is generally managed with topical steroids and dilating agents; occasionally systemic corticosteroids may also be warranted for this complication. Regular monitoring of eyes by an ophthalmologist is important for early detection of iridocyclitis. Physical therapy is essential to optimum therapy for nearly all children with JRA. Exercises are prescribed to maintain joint motion, regain lost joint motion, and strengthen muscles about affected joints. Physical activity should be encouraged; bed rest should be avoided. Night splints may be helpful in maintaining good joint positions, but prolor.!,ged immobilization of joints without physical therapy is contraindicated. The role of synovectomy in JRA appears to be limited. Reconstructive surgical procedures such as joint replacements and soft tissue releases can play an important role in the rehabilitation of disabled patients, particularly after they have achieved full growth. Patients should be helped to attend regular schools, and to lead as "normal" lives as possible. Despite the chronic nature of synovitis in JRA, a surprising number of children emerge with no permanent joint damage and are able to lead unimpaired lives as adults.
Ankylosing Spondylitis Ankylosing spondylitis is a type of chronic arthritis which characteristically affects the sacroiliac joints and joints of the lumbothoracic and cervical spines. Peripheral joints may also be affected; indeed, as pointed out in the section on JRA, ankylosing spondylitis may begin with peripheral arthritis which simulates rheumatoid arthritis. Peripheral arthritis, particularly of large lower limb joints, may antedate the onset of characteristic back symptoms by many years. Sacroiliitis may be manifest by pain over the sacroiliac joints or pain and stiffness in the hip girdle; however, some patients have no associated clinical manifestations. Arthritis generally affects the spine in an ascending fashion, first affecting the lumbar spine. Back pain is often severe, episodic, and associated with loss of motion and paravertebral muscle spasm. Diagnosis of ankylosing spondylitis demands radiographic sacroiliitis and either measurable loss of motion or radiographic changes in the lumbar spine. There are no diagnostic laboratory tests; tests for rheumatoid factors and antinuclear antibodies are generally negative. Histocompatibility antigen HLA B27 is present in 95 per cent of affected patients; however, this antigen is also found in about 6 per cent of the normal population. Ankylosing spondylitis is generally considered a progressive disease with further involvement of the spine occurring over a period of many years. However, in some patients the disease becomes arrested, and it seems possible that some patients with peripheral arthritis related to this disease never manifest clinical back disease at all. Management of ankylosing spondylitis includes anti-inflammatory drugs and physical therapy. Salicylates are effective in the manage-
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ment of some patients; many patients require additional drugs such as indomethacin. Gold therapy is not thought to be helpful in ankylosing spondylitis; corticosteroid therapy is generally contraindicated. Maintenance of good posture is essential. Some patients are troubled with attacks of acute iridocyclitis, and a very few patients will develop aortitis in adult years.
Systemic Lupus Erythematosus Systemic lupus erythematosus is a multisystem disease invariably associated with the presence of antinuclear antibodies, and often associated with antibodies reactive with DNA and with lowered levels of serum hemolytic complement. Fever and arthritis are common presenting manifestations of lupus; however, involvement of other systems is also usually apparent at time of onset. Nephritis, polyserositis, anemia, thrombocytopenia, myositis, organomegaly, and central nervous system involvement are all common. The arthritis of systemic lupus may mimic that of juvenile rheumatoid arthritis; however, the arthritis of lupus is often transient and is not associated with destructive joint changes. Some affected patients have only anthralgia without objective signs of arthritis. A vascular necrosis, most often of the femoral heads, is also associated with systemic lupus; areas of bone about multiple joints may be affected. The diagnosis of systemic lupus is made on the basis of the clinical picture of multisystem disease along with the presence of antinuclear antibodies and other abnormal laboratory tests. The diagnosis is generally not hard to make if the possibility is considered. The course of arthritis in systemic lupus is generally benign. Management of lupus depends on the extent of systemic involvement. With severe systemic involvement, such as nephritis, drugs such as corticosteroids are warranted. For mild systemic lupus without severe organ involvement, arthritis can be managed with salicylates, as in JRA. Hydroxychloroquine may also be a useful adjunctive drug. A vascular necrosis of bone must be distinguished from synovitis. Rheumatic Fever Rheumatic fever is a poststreptococcal disease associated with arthritis and carditis; other findings such as rash (erythema multiforme), subcutaneous nodules, and chorea may also be present. The arthritis of rheumatic fever is generally acute and migratory. Several joints, generally large joints such as knees, ankles, and wrists, may be involved. Arthritis rarely persists longer than one week in an affected joint. Joint destruction is not associated. Symmetrical polyarthritis as in JRA occurs rarely, if ever. The diagnosis of rheumatic fever is made on clinical grounds and requires documentation of a prior streptococcal infection. Carditis is the most characteristic manifestation of rheumatic fever. Only symptomatic therapy is needed for the arthritis of rheumatic fever, since it is generally self-limited; joint manifestations often respond dramatically to salicylates. Therapy of carditis may be with either salicylates or corticosteroids. The most important aspect of treatment of rheumatic
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fever is the maintenance of antibiotic prophylaxis to prevent recurrent streptococcal infections, since the ultimate morbidity of rheumatic fever results from the additive heart damage of recurrent rheumatic attacks. Dermatomyositis Dermatomyositis is characterized by a distinctive rash of the face and extensor surfaces of the limbs, and myositis. Myositis affects primarily the proximal limb and paraspinal muscles. A few patients also have associated arthritis which can resemble JRA. Diagnosis is made by recognition of the distinctive rash and myositis. The course of arthritis is variable. There are no diagnostic laboratory tests; serum levels of enzymes found in muscle cells are generally elevated, and electromyograms show changes consistent with myositis. Management is geared to suppression of myositis as witnessed by return of muscle strength and return of serum muscle enzyme values to normal, and to physical therapy to preserve joint motion and restore normal muscle strength. Vasculitis Syndromes Henoch-Sch6nlein vasculitis or anaphylactoid purpura is the commonest vasculitis syndrome of children. Arthritis is frequently present in Henoch-Sch6nlein vasculitis. One or many joints may be affected in a transient fashion. Periarticular edema is often associated. The arthritis is never chronic or destructive, and generally resolves spontaneously within one or a few days. Other characteristic manifestations of the syndrome include rash, abdominal pain, angioneurotic edema, and nephritis. Diagnosis is based on clinical findings, particularly on the
Figure 4. The characteristic rash of Henoch-Schonlein vasculitis. Small red maculopapular lesions, some progressing to purpuric lesions, are distributed over the lower extremities. Sometimes lesions also occur over the gluteal areas as shown here; less frequently lesions occur over the arms, trunk, and face.
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characteristic appearance of the rash (Fig. 4). Occasionally other vasculitis syndromes such as polyarteritis nodosa and the mucocutaneous lymph node syndrome occur in children; these also may be associated with arthritis.
Scleroderma Scleroderma is characterized by hardening of skin either locally or generally; increased amounts of collagen are found in dermal and subdermal tissues. Raynaud's phenomenon is frequently present. Arthritis may be associated. Small joints of the hands may be affected symmetrically as in JRA; larger joints may also occasionally be affected. Diagnosis is based on clinical findings. The outcome for this type of joint disease is uncertain. Management of the patient is geared to therapy for the scleroderma; physical therapy should be included. Arthritis of Inflammatory Bowel Disease Both regional enteritis and ulcerative colitis may be associated with arthritis. Two general types of arthritis occur: peripheral arthritis and ankylosing spondylitis. In peripheral arthritis, generally only a few joints are affected and the outcome is good. Bouts of arthritis are often transient and related to flares of underlying bowel disease. Therapy is generally geared to control of underlying bowel manifestations. The spondylitis associated with inflammatory bowel disease, on the other hand, is chronic and pursues the course of ankylosing spondylitis without bowel disease. Therapy should be geared to both the spondylitis and the bowel disease. The possibility of inflammatory bowel disease should be entertained in all children with arthritis. Tip-offs to bowel disease include weight loss, poor growth, unexplained fevers, anemia, erythema nodosum, and mucosal ulcers. Arthritis may sometimes precede the onset of recognizable bowel symptoms by months or years. Reiter's Syndrome and Psoriatic Arthritis Both are uncommon in children. Reiter's syndrome is characterized by the triad of urethritis, conjunctivitis, and arthritis; it may follow acute infections, notably with shigella, or may be sexually transmitted. Psoriatic arthritis is characterized by the coexistence of psoriasis and arthritis. In Reiter's syndrome, arthritis is often acute and self-limited, and may demand only symptomatic therapy; a few patients have associated ankylosing spondylitis. Psoriatic arthritis is often chronic and demands therapy with anti-inflammatory drugs as in JRA; a few patients also have associated spondylitis.
ARTHRITIS RELATED TO INFECTIONS Infectious diseases may cause arthritis by direct infection of the synovium or by causing synovial reactions without direct presence of organisms. Several categories of infection-related arthritis can be considered.
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Septic Arthritis In septic arthritis, the synovium becomes directly infected by pyogenic bacteria or by other organisms such as mycobacteria. Organisms generally arrive at affected joints via the blood stream, although penetrating wounds to a joint can also result in joint infection. Infection in synovial tissues rapidly results in an inflammatory response. Resulting joint effusions contain many white blood cells (in excess of 50,000 per cu mm), predominantly polymorphonuclear leukocytes; synovial fluid sugar levels are generally low. Often the infecting organisms may be seen in gram smears of synovial fluid. The inflamed synovial tissue swells, hypertrophies, and extends over the articular cartilage. Products of bacterial inflammation are extremely damaging to articular cartilage and generally cause permanent joint damage if infection is allowed to proceed untreated for periods of several days or more. Once articular cartilage is thus damaged, the joint has been permanently harmed (Fig. 2). Patients with septic joints generally have bacteremia or sepsis and are thus usually systemically ill with high fevers and malaise. Septic joints are generally very painful, hot, and swollen; overlying skin is often red. Although most often a single joint becomes the site of infection, it is possible that with a hematogenous route of spread more than one joint may be infected in a single patient. In gonococcal arthritis, signs and symptoms of systemic illness may be less severe, and multiple joints are often affected. In tuberculous arthritis, or arthritis with atypical mycobacteria, symptoms and signs of systemic illness may be lacking. Diagnosis of septic joint is generally made by joint aspiration. Demonstration of organisms in synovial fluid smears is diagnostic. Sometimes when organisms are not found in synovial fluid they may be found in synovial tissues; this is particularly true for tuberculous arthritis. As noted above, septic synovial fluid contains large numbers of granulocytes and reduced levels of sugar; however, some sterile fluids from patients with rheumatoid arthritis demonstrate similar findings. Synovial fluids should be cultured for bacteria; such cultures will be positive in septic arthritis in 60 to 70 per cent of cases. Blood cultures should also be obtained; about 15 per cent of patients with septic arthritis will have positive blood cultures in the absence of positive synovial fluid cultures. If gonococcal arthritis is suspected, appropriate genital cultures should also be obtained. If tuberculous or mycobacterial joint infection is suspected, chest films and appropriate skin tests should be made. Untreated septic arthritis has a dismal prognosis. Joint structures are destroyed and surrounding bones are also ultimately infected. Tuberculosis of the joint may pursue a more long-term course. Gonococcal arthritis is sometimes associated with no or minimal joint destruction even without appropriate therapy. Prompt recognition and therapy of septic arthritis is extremely important for good outcome. Once the diagnosis is reasonably suspected and joint aspiration and appropriate cultures have been obtained, therapy with appropriate antibiotics should be started promptly.
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Staphylococcus aureus is the commonest organism associated with septic arthritis in children over 4 years of age; in children under 4 years of age Hemophilus influenzae is an equally common etiologic agent. In small infants, other organisms, including gram-negative bacteria, may be responsible. Gonococci are the second most common organisms causing septic arthritis in older children. Other possible organisms include streptococci, pneumococci, meningococci, various gram-negative organisms, Mycobacterium tuberculosis, and atypical mycobacteria. In the absence of an identified organism in aspirated joint fluid, antibiotic therapy should be geared to the likelihood of the organism present in the particular environment and age group. High-dose antibiotic therapy given by a reliable route, notably intravenously, is important for good results. Therapy should be continued for a minimum of 2 to 3 weeks. Patients are often most comfortable if affected joints are splinted until acute inflammation settles; however, the role of rigid immobilization in hastening healing has never been proved. Removal of purulent material from the joint cavity and avoidance of increased intraarticular pressure are important. These can usually be achieved through repeated joint aspirations, except for septic arthritis of the hip, where open drainage is essential. With appropriate early recognition and management of septic arthritis, most patients have a good prognosis for subsequent normal joint function.
Viral Related Arthritis An increasing number of viral infections are being shown to be associated with arthritis. Several pathogenic mechanisms may be operative. Direct viral synovial infection has been demonstrated in the case of rubella. Immune complex disease with virus particles as antigen has been demonstrated in the case of Australia antigen disease. Viruses known to be associated with arthritis include rubella, mumps, chickenpox, adenovirus, hepatitis, and Epstein-Barr virus; it is likely that a number of other viral diseases may also sometimes have a component of synovitis. Viral related arthritis generally occurs after the onset of the associated virus infection; an exception to this is the arthritis of Australia antigen disease which precedes the recognition of hepatitis. Viral synovitis may affect one or multiple joints and is self-limited. Joint destruction is not associated. Only symptomatic treatment is indicated. Appreciation of the possibility of viral arthritis is important; children with short-lived synovitis should not be labeled as having chronic diseases such as JRA. Reactive Arthritis Reactive arthritis is the term given to sterile arthritis associated with bacterial infections elsewhere in the body. Three organisms, all causing gastroenteritis, have been associated with this type of reaction: Salmonella, Shigella, and Yersinia enterocolitica. Reactive arthritis is rarely recognized in the United States. Coexistence of gastroenteritis with arthritis should, however, be sought in evaluation of new patients.
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Sympathetic Effusions of Osteomyelitis Osteomyelitis affecting the metaphyseal areas of long bone may be associated with sterile effusions in adjacent joints. The exact mechanisms for production of such effusions are unknown. The resulting swollen joints may be a source of confusion in evaluating patients. The possibility of osteomyelitis should be considered in .any child with acute joint swelling. The joint fluid in sympathetic effusions is sterile and generally has low cell counts.
MALIGNANCIES OF CHILDHOOD Most childhood malignancies may be associated with musculoskeletal complaints which may closely mimic arthritis. This "arthritis" is generally caused by infiltrations of malignant cells in structures about the joint and in the periosteum of adjacent bones; direct infiltration of synovium with malignant cells is unusual, although it has been reported in leukemia. "Arthritis" has been noted most frequently in childhood leukemia and neuroblastoma; it also occurs in lymphoma, Hodgkin's disease, malignant histocytosis, and rhabdomyosarcoma. Affected joints are generally very painful, probably because the infiltrated periarticular tissues are richly supplied with nerve endings. Extreme joint pain or tenderness, or refusal to walk because of joint pain, should always raise the suspicion of malignancy. Affected joints are often warm and swollen and may closely resemble arthritic joints. One or many joints may be
Figure 5. The bone changes of leukemia. Rarefaction is seen in the metaphyseal areas in the distal femur and proximal tibia. This 10 year old boy was referred to Arthritis Clinic because of pain and swelling in several joints.
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affected. Joint complaints may be transient and recurrent, or persistent. When musculoskeletal complaints are a predominant early finding in childhood malignancy, patients may be initially suspected of having rheumatic diseases. Diagnosis of the underlying malignancy rests first of all on consideration of malignancy as a possibility. As noted above, severe bone and joint pain should always suggest malignancy. Abnormal blood findings such as leukopenia or bizarre leukocyte forms in the peripheral blood, severe anemia, or thrombocytopenia should also suggest malignancy. Hepatosplenomegaly or lymphadenopathy also raise the question of malignancy, although as noted above they may occur in patients with JRA as well. Radiographic changes of metaphyseal rarefaction, osteolytic lesions, or periostitis about affected joints may be helpful (Fig. 5); however, a significant number of children with malignancy and joint complaints have normal radiographs. If there is a reasonable suspicion of malignancy in any child with arthritis, appropriate tests such as bone marrow examinations should be promptly made. The musculoskeletal complaints of malignancy respond to therapy of the malignancy; they do not respond well to ordinary antirheumatic therapy with salicylates.
MISCELLANEOUS CAUSES OF MUSCULOSKELETAL PAIN IN CHILDREN A legion of conditions which may cause musculoskeletal problems in children are sometimes misinterpreted as arthritis. Only two will be considered here. The ubiquitous limb pains of childhood or "growing pains" are a problem common to all physicians dealing with children (see p. 731). In the absence of objective physical findings, physicians should avoid labeling such patients with diagnoses such as rheumatoid arthritis. Psychogenic musculoskeletal complaints may also be a cause of significant disability in some children. Again, the complaints and disability of joint or musculoskeletal pain are inconsistent with the absence of physical findings. Psychiatric intervention is usually required.
OSTEOMYELITIS Osteomyelitis, or bone infection, in children is generally spread by the hematogenous route and is a disease affecting the metaphyseal regions of bone. The predilection of osteomyelitis for the metaphyseal areas of bone is probably related to the plentiful and sluggish blood supply of the metaphysis. So long as the child is growing and the epiphyseal plates are intact, there is little or no communication between the blood supplies of the metaphyseal region and the epiphyseal and joint regions; therefore osteomyelitis rarely results in secondary septic arthritis, except in joints where the joint capsule inserts distal to the metaphysis (notably the hip and the shoulder). Since bone is a rigid tissue, the occurrence of an abscess in bone with resulting inflammation and swelling has several predictable effects. With increasing pres-
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sure, pus spreads through available channels in the bone, the haversian and Volkmann's canals, resulting in dissemination of infection longitudinally in the bone and in extrusion of pus outward under the periosteum. Necrosis of bone occurs when pressure and swelling from inflammation interfere with blood supply to local bone. Since the nerve supply to the periosteal regions and, to a lesser extent, to cortical and metaphyseal bone, is plentiful, osteomyelitis is generally an extremely painful condition. Patients with hematogenous osteomyelitis are usually systemically ill with high fevers and other signs of sepsis. Affected bone sites are usually extremely painful and patients frequently refuse to move the affected part. On physical examination, swelling and tenderness may be elicited in the affected area; it is therefore extremely important to search for local areas of swelling or bone tenderness. Any bone may be affected; the metaphyseal regions of long bones are the most frequent sites. Sterile effusions may occur in joints adjacent to areas of osteomyelitis ("sympathetic effusions"). The possibility of osteomyelitis should be entertained in any ill, febrile child, particularly if there are associated musculoskeletal complaints. Laboratory findings of leukocytosis and elevated sedimentation rates are not specific. Blood cultures will provide the offending organism in more than half of cases. Staphylococcus aureus is by far the most common organism responsible for hematogenous osteomyelitis in all age groups. Other possible agents include streptococci, pneumococci, Hemophilus influenzae, salmonellae (particularly in individuals with sickle cell hemoglobinopathy), and other gram-negative organisms (particularly in young infants or immunosuppressed patients). The question of whether or not to tap the suspected area of bone infection remains somewhat controversial; local taps can sometimes provide further help in identifying causative bacteria. The possibility of tuberculous bone infection should be kept in mind, although this is becoming increasingly rare in the United States; chest radiographs and appropriate skin tests are indicated. The earliest radiographic changes of osteomyelitis occur too late in the course of disease to be of any help with early diagnosis. The first radiographic finding is that of periosteal new bone formation in areas where the periosteum has been elevated by escaping pus; this change appears at 10 to 14 days after onset of infection. Later changes include radiolucent and radiodense areas in affected bone (Fig. 6). An earlier aid to the diagnosis of osteomyelitis is the bone scan utilizing boneseeking isotopes which will detect changes in affected regions as early as the first day of disease. The course of untreated osteomyelitis is dismal. Before the advent of antibiotics more than 25 per cent of affected patients died and remaining patients usually were disabled with chronic bone infections, draining sinuses, and loss of limbs. With early diagnosis and appropriate antibiotic therapy, the course of osteomyelitis is much more benign now, with most adequately treated patients recovering fully. Institution of specific therapy early in the course of osteomyelitis, before large amounts of bone necrosis and destruction occur, is essential to good outcome.
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Figure 6. Bone destruction of osteomyelitis which was recognized late and inadequately treated. Despite later medical and surgical therapy, this child has been plagued by chronic osteomyelitis with draining cutaneous sinuses.
Appropriate therapy consists of identification of infecting bacteria and therapy with large doses of antibiotics. Antibiotics should be given initially by an intravenous route for 1 to 2 or more weeks, followed by oral or intramuscular antibiotics until the patient is clinically well, there is radiographic evidence of healing, and the sedimentation rate is normal. Since Staphylococcus aureus is the most common cause of hematogenous osteomyelitis, initial appropriate therapy is usually directed against staphylococcus. Should there be reason to suspect another organism, therapy may be modified. If the patient does not improve in 24 to 36 hours of intensive antibiotic therapy, drainage of the area of osteomyelitis should be strongly considered. There is no good evidence that immobilization of the affected part aids healing, although patients may be more comfortable in immobilization during the first few days of treatment. For patients with extensive lesions, casting is important to protect weakened bone from pathologic fractures. The importance of recognizing bone and joint infections in children early and managing them appropriately cannot be overemphasized; it is tragic for such lesions to be missed.
EVALUATION OF A PATIENT WITH ARTHRITIS AND MUSCULOSKELETAL COMPLAINTS A complete history and physical examination are the most helpful tools in sorting out the various causes of arthritis and musculoskeletal complaints in children. History and review of systems should be made, with various conditions discussed earlier kept in mind. Physical examinations should be thorough and should include accurate assessment of bone, joint, muscle, and nervous status. There are no clear-cut diagnostic laboratory tests for most of the conditions that need to be considered. When first seeing a patient it is important to make a judgment about whether any potentially treatable diseases such as septic arthritis
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or osteomyelitis are present before coming to rest with a diagnosis of chronic rheumatic illness. It is also important to avoid making a diagnosis of arthritis unless the patient has in fact objective findings of arthritis, and to avoid mislabeling transient conditions such as viral arthritis as chronic diseases such as JRA. Laboratory studies should be based on findings in the history and physical examination. If there is any suspicion of septic arthritis or osteomyelitis, appropriate cultures and bone scans should be obtained at once. Blood smears may provide evidence for underlying malignancy; if so, further investigations such as bone marrow examination should be pursued. The so-called acute phase reactants, of which the sedimentation rate is most frequently done, are not diagnostic; furthermore, some patients with active inflammatory diseases will not have elevated sedimentation rates or other acute phase reactants. Immunologic tests such as antinuclear antibodies, rheumatoid factors, and immunoglobulin levels are not diagnostic of any disease, but are helpful in classification of patients with rheumatic diseases. Systemic lupus erythematosus cannot be diagnosed in the absence of antinuclear antibodies. It should be remembered that some patients with nonrheumatic diseases will have positive tests for either rheumatoid factors or antinuclear antibodies; this happens for example, after certain viral infections and in certain malignancies. Tests for complement levels and DNA antibodies are rarely indicated except in patients with systemic lupus. The presence of nephritis as witnessed by abnormal urinalysis suggests the possibility of a rheumatic disease which affects the kidneys such as systemic lupus, Henoch-Schonlein vasculitis, or polyarteritis; a few patients with immune complex disease related to bacterial infections may also have arthritis and nephritis. Genetic tests such as the test for histocompatibility antigen HLA B27 are not diagnostic of any rheumatic disease, although they are of great interest in clinical research. Radiographs of bones and joints may be extremely helpful in detecting certain musculoskeletal conditions, notably noninflammatory conditions such as fractures, avascular necrosis, and certain congenital musculoskeletal conditions; late in the course of osteomyelitis and severe JRA they will also be abnormal. REFERENCES 1. Nelson, J. D.: Follow-up: Septic arthritis. Pediatrics, 50:437-440,1972. 2. Proceedings of First American Rheumatism Association Conference on the Rheumatic Diseases of Childhood. (Schaller, J. G., and Hanson, V., Conference Chairmen), Supplement, March 1977. 3. Schaller, J., and Wedgwood, R. J.: Is juvenile rheumatoid arthritis a single disease? A review. Pediatrics, 50:940-953,1972. 4. Wadvogel, F. A., Medoff, G., and Schwartz, M. N.: Osteomyelitis: A review of clinical features, therapeutic considerations and unusual aspects. New Engl. J. Med., 282:198-206, 260-266,316-322,1970.
Department of Pediatrics RD-20 University of Washington School of Medicine Seattle, Washington 98195