Collagen Vascular Diseases in Children Nanette B. Silverberg, MD, and Amy S. Pallet, MD
Collagen vascular diseases (CVD) are a group of multisystem inflammatory illnesses with a complex immune basis. Although many organ systems may be affected, the most common are the joints and skin. It is currently estimated that 150 to 200 children per million will develop a CVD requiring tertiary care referral. Advances in immunology and diagnostic testing in the past 30 years have created a specific set of criteria by which diagnosis can be made. Children with CVD may have extensive morbidity and mortality related to these conditions. Management of CVD in children has become complex and involves early multispecialty intervention. The mainstay of treatment has been highdose oral steroids. In the past 20 years, there has been an integration of other treatments into the therapeutic approach, including immunosuppressives (such as methotrexate), immunomodulators (such as intravenous gamma globulin), and anti-inflammatory drugs (such as the nonsteroidals). Mortality has dramatically decreased because of these modifications in care. In addition, better early detection of illness has allowed for more rapid intervention and prevention of longterm sequelae. Photoprotection has become a crucial part of therapy of CVD. Recently, recognition of associated disease states and the need for aggressive nutritional intervention have improved the overall long-term health of children with CVD. Advances in physical therapy and psychosocial evaluation have improved the long-term function of the chronically ill child with CVD. In the future, better understanding of the molecular pathogenesis of autoimmunity will allow us to fine-tune the immune system, providing better long-term control of CVD. CVD is a diverse group of multisystem inflammatory disorders, affecting primarily the skin and joints. Autoantibody formation, inflammation, and vasculitis are common to these disorders. Improvements in immunodiagnosis and immunosuppressive therapy have prolonged survival, unmasking new issues of longterm sequelae. Disease registries are making access to and analysis of large-scale information available for study. Functional limitation, osteopenia, nutritional deficiencies, chronic pain, and psychological distress Curt Probl Dermatol, July/August 2000
may be chronic sequelae of these illnesses, especially in adolescents. The standard of care of CVD has become an integrated approach, addressing all these important issues. Theory has held that autoimmunity is the origin of these illnesses; this has been supported by the autoantibodies observed in a large proportion of patients with these illnesses. 1 Recently, it has been demonstrated that autoimmunity associated with CVD can be generated in susceptible individuals by T-cell recognition of infectious agents that have genetic sequence homology to human proteins. This homology has been called "molecular mimicry.''2 Furthermore, the immune system may modify the disease course through genetic polymorphisms and MHC-class II linkage. This article will focus primarily on recent advances in connective tissue diseases, highlighting the most common entities seen by pediatric dermatologists. CVD can be divided into connective tissue disease, vasculitis, arthritides, and infectious diseases. Extensive workup is required to make these diagnoses and to exclude other systemic disorders, such as malignancies, which may present with complaints that mimic the CVDs. 3 Antinuclear antibody (ANA) positivity should not be equated with CVD because the majority of these children will not progress to CVD when followed over a period of 5 years. 4 Systemic lupus erythematosus (SLE) occurs in 0.36 to 0.4 children per 100,000. 5,6 The ratio in children of girls to boys is estimated at 4:2 to 7:1. The diagnosis is rarely made before 5 years, with the incidence rising in puberty and peaking in young adulthood.7,8 The 1982 criteria of the American College of Rheumatology established a set of 11 criteria SLE (Table 1), diagnosis being made with fulfillment of 4 criteria. 9 These criteria have been demonstrated to be both sensitive and specific for the diagnosis of childhood SLE and include 4 cutaneous criteria: malar rash (74%), oral ulcers (46%), photosensitivity (40%), and discoid lupus (19%). 7-1° More than 80% of children with SLE initially demonstrate a cutaneous finding in combination with malaise, arthralgias, and immune markers. Cutaneous findings outside of the diagnostic criteria 177
TABLE 1. The American College of Rheumatology Criteria for SLE Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis (non-erosive, 2 or more joints) Serositis--pleuritis or pericarditis Renal disorder--proteinuria (0.5 gin/day) or cellular casts Neurologic disorder--seizures or psychosis Hematologic disorder (1 or more of the following) Hemolytic anemia Leukopenia (<4000/mm 3 on 2 occasions) Lymphopenia (<1500/mm 3 on 2 occasions) Thrombocytopenia (
are common, including alopecia (32%) and vasculitis (42%). The incidence of vasculitis is similar to that seen in adults and may occur in the presence or absence of the antiphospholipid antibody syndrome. Over 90% of children are ANA positive. More specific markers of SLE are more infrequent, including the anti-Smith (30%) and anti-double-stranded-DNA (dsDNA-25%) antibody. Anti-Ro and anti-La antibodies may be seen. Rising anti-ds-DNA antibody and falling serum C4 have been shown to be sensitive markers of early disease activity and may be used for long-term follow-up.4 Neurologic alterations may present as subtle problem-solving deficits or may mimic psychological disorders, such as depression, n Renal (64%-80%) and hematologic (76%-90%) manifestations are seen in a majority of patients and warrant therapy. Progression to chronic renal failure is not infrequent and is heralded by persistent hypertension, anemia, urinalysis abnormalities, and elevated serum creatinines. Aggressive therapy is warranted in the setting of chronic renal failure and vasculitis. 7,8,11 The antiphospholipid antibody syndrome can be seen in the presence or absence of other autoimmune conditions, SLE being most common. IgG anticardiolipin, lupus anticoagulant, and anti ~32 glycoprotein can be used to identify this condition. When this occurs, immunosuppressive therapy can be required to prevent pathologic infarcts. 12 Recent progress has demonstrated a complex network of etiologic factors. Major histocompatibility complex class II linkage to HLA-DR3, HLA-DR2, and 178
the A1, B8, DRBI*0301, DQBI*0201 or DRBI*0501, DQBI*0201, DRBI*1501, DQAI*0102, and DQBI* 0602 have been demonstrated to have a strong association with SLE. Furthermore, disease may be associated with genetic allelic polymorphisms, including relative deficiencies of early components of complement (C2 and C4) and female carriers of chronic granulomatous disease. Ultraviolet light induces cytokine release, which has been implicated in triggering disease expression. UV-B is also thought to induce antigen translocation to the cell membrane, where presentation to the immune system can occur. Tumor necrosis factor a-308 polymorphisms are associated with enhanced production of this proinflammatory cytokine and are more commonly seen in patients with SLE who are of African-American and Asian descent. 13 Therapy of SLE in children is akin to that of adults and is based on organ involvement. Oral prednisone is generally first-line therapy. Children on long-term high-dose steroids should be watched carefully for signs of infections, cataracts, aseptic necrosis of the femoral head, and osteoporosis leading to fractures. Other agents have been introduced because of the need for steroid dose reduction and for steroid-resistant cases. These include hydroxychloroquine, methotrexate, pulsed steroids, and intravenous gamma globulin. In addition, the cytotoxic agent cyclophosphamide has been used to treat severe renal disease, which may require hemodialysis. One of the most crucial therapies for SLE is photoprotection and sun avoidance. Patients require extensive education to prevent photoexacerbation of their cutaneous and systemic illness. 7,8,11 Cutaneous lupus has been divided into chronic and subacute cutaneous variants. The chronic discoid variant (DLE) is a scarring process of the central face and sun-exposed areas with erythematous hyperkeratotic plaques progressing to atrophy. DLE is uncommon in childhood. Children with discoid lupus generally benefit from mid-potency topical steroids and antimalarial therapy similar to adult patients. Although subacute cutaneous lupus (SCLE) is rare in children, more than 60% are ANA-positive, and these patients often progress to SLE. SCLE may be associated with anti-Ro antibody and C2 or C4 deficiency. Treatment combines topical steroid therapy, intralesional steroids, and in severe cases, may be similar to the therapy of SLE. Bullous lupus, an autoimmune disorder associated with SLE, which is caused by antibody production to collagen type VII, is also rare in childhood. Neonatal lupus erythematosus (NLE) is an MHCCurr Probl Dermatol, July/August 2000
class II linked condition affecting roughly 1 in 2500 to 25,000 births. Mothers of children with NLE tend to be HLA-DR3 positive, have autoantibodies such as ANA, anti-Ro, anti-La, or anti-U1RNP positive, and are generally asymptomatic, although a large proportion will go on to have SLE or Sj6gren's syndrome. NLE mothers and children tend to have uncommon immunogenetic alterations, including C4 allotype anomalies, with the null phenotype being seen in the infant and C4 duplication in the mother. The most devastating complication is congenital heart block, which is associated with a mortality of 15% to 35%. Cardiac involvement is seen in patients who show anti-Ro antibodies and is not a feature of neonatal lupus related to anti-U 1 ribonucleoprotein antibodies. Nearly all patients with third-degree heart block will require a pacemaker before their eighteenth birthday. Cardiac damage begins in utero when the atrioventricular node is damaged by inflammation and consequent fibrosis caused by the anti-Ro antibody beginning during the tenth week of gestation. 1% to 10% of women with SLE will have a child with NLE, and 10% to 40% of these women will have a second affected child. Prenatal ultrasounds can determine cardiac problems by the 24th week of gestation, indicating the need for maternal steroid therapy. Hepatic and hematologic involvement may occur in 10% to 15% of patients. Cutaneous lesions, seen in more than 50% of patients, resemble annular SCLE, discoid lesions, or raccoon eyes. Atrophy and telangiectasias can be persistent, despite resolution of the active skin disease by 6 months. Children with NLE may grow up to have SLE, but this is believed to be related to their enhanced genetic predisposition. 1°,14 Drug-induced lupus erythematosus may be seen at any age. Though originally described in association with hydralazine usage, drug-induced lupus can be seen in association with many medications, most notably minocycline. Drug-induced lupus tends to present with cutaneous, joint, hematologic, and hepatic complaints, and rarely involves the kidneys. Anti-histone antibodies and antibodies to myeloperoxidase have been described in minocycline-induced lupus. After stopping the medication, the rate of clearance can be slow. 15 Juvenile dermatomyositis (JDM) is an inflammatory vasculopathy, primarily affecting the skin and muscle, with rare cardiac and pulmonary involvement. Bohan and Peter ~6published criteria in 1975, which created a uniform system of diagnosis. The characteristic rash in Curt Probl Dermatol, July/August 2000
conjunction with 3 of the following 4 criteria is required for diagnosis: symmetrical proximal muscle weakness, elevated muscle-derived enzymes, muscle histopathology demonstrating vasculopathy and chronic inflammation, and electromyogram changes consistent with inflammatory myopathy. Recently, electronystagmograms have fallen out of vogue and have been replaced by the more sensitive magnetic resonance imaging (MRI). Full-body MRI with T2-weighted imaging and fat suppression localizes muscle inflammation and can be used as a noninvasive method to improve the yield of muscle biopsy. JDM is an inflammatory myopathy presenting with fatigue and proximal muscle weakness. As the disease progresses, phonation and swallowing may be affected. All children with the classic rash will eventually progress to JDM. JDM presents with cutaneous findings in over 75% of patients. The heliotrope rash, a periorbital violaceous induration, lichenoid erythematous papules of the extensor joints, periungual telangiectasias, and poikiloderma of the sun-exposed skin (shawl sign on the trunk) are the most common cutaneous findings in children. In addition, alopecia, periorbital edema, hypertrichosis, vasculitis, Raynaud's phenomenon, lipoatrophy, and a rare pityriasis rubra pilaris-like eruption with palmoplantar keratoderma have been recognized as manifestations of JDM. Calcinosis of the skin is seen more commonly in children with JDM, rather than in adults. Calcinosis is seen in nearly all children who are untreated or uncontrolled and usually appears 1 to 3 years after onset of the disease. Dystrophic calcium deposits may cause pain or may become superinfected, warranting surgical excision. Nail fold capillary loop alterations on microscopy, including tortuosity and dropout of vessels, have been shown to be sensitive indicators of disease activity. The incidence of malignancy is not increased in children with JDM, although there have been scattered case reports of malignancy occurring in a patient with JDM. Muscle enzymes help make the diagnosis, but are difficult to use for long-term follow-up as they fall slowly, despite disease improvement. The immune workup of JDM will often demonstrate a positive ANA (>60%), less commonly anti-Mi-2 muscle antibody (10%), and rarely anti-Jo-1 antibody (0.5%), associated with pulmonary fibrosis. More helpful disease markers in children include elevations of the von Willebrand factor antigen (50%), neopterin, a marker of macrophage activation (60%), and increases in the 179
TABLE 2. Childhood CVD registries and support groups27 Lupus Foundation of America, Inc Contact: Deb Blom, Field Service Manager Address: 1300 Piccard Dr Suite 200 Rockvilie, MD 20850 Phone: 301-670-9292 or 800-558-0121 Fax: 301-670-9486 Web page: www.lupus.org New-Onset Juvenile Dermatomyositis Registry Principal Investigator: Dr Lauren Pachman Coordinator: Eduardo Mendez, Research Nurse Address: Juvenile Dermatomyositis Incidence Registry Children's Memorial Hospital 2300 Children's Plaza Chicago, IL 60614 Phone: 773-880-3333 Fax: 773-880-4179 Registry for Juvenile Rheumatoid Arthritis-Affected Sib-Pairs Principal Investigator: Dr Edward H. Giannini Coordinator: B, Link Tague, CRA Address: The Juvenile Rheumatoid Arthritis Registry Children's Hospital Medical Center 3333 Burner Ave, Pavilion 2-129 Cincinnati, OH 45229 Phone: 800-559-7011 Fax: 513-636-5990 United Scleroderma Foundation, Inc (USF) Address: 89 Newbury St, Suite 201 Danvers, MA 01923 Phone: 408-728-2202 or 800-722-HOPE Fax: 408-728-3328 Web page: www.scleroderma.com
B-cell count seen in more than 80% of children with JDM. In addition, markers of other autoimmune conditions can be positive and may indicate disease overlap with systemic sclerosis, juvenile rheumatoid arthritis, or SLE. Pathogenesis has been extensively explored in JDM. It is currently believed that molecular mimicry of muscle antigens occurs with infectious agents, such as streptococcus and coxsackie viruses, explaining seasonal peaks in spring and summer. In addition, patients are likely to be HLA-DR3, B8, or DQA*0501 positive. Furthermore, the -308 tumor necrosis factor-(z (TNF-o0 allelic polymorphism has been linked to extended muscle disease and calcinosis cutis. Sun exposure has been implicated in skin disease development in more than 50% of patients. Data are being analyzed from a nationwide disease registry that are 180
redefining the nature of immunogenetic abnormalities in JDM (Table 2). The standard of care for JDM is aggressive and includes the combination of steroids and physical therapy. Initial control can be gained through early alternate-day pulsed intravenous steroids. Oral therapy initially is limited by the malabsorption associated with low-grade vasculitis. Intravenous gammaglobulin, hydroxychloroquine, methotrexate, and cyclosporine have been used in refractory cases. Photoprotection is required to prevent disease flares. Despite aggressive management and apparently good muscular disease control, skin disease may persist for an extended period of time.7-9,16-18 Scleroderma can be systemic and localized, with the ratio of systemic to localized cases being in the range of 1:62 to 1:80. It is estimated that 7% of systemic sclerosis patients have onset in childhood. Systemic scleroderma in children is similar to that of adult disease, with proximal sclerosis, dysphagia, and renal involvement leading the list of symptoms. Nail fold capillary changes may also be seen on microscopy. Digital pits, sclerodactyly, Raynaud's phenomenon, calcinosis, and telangiectases may be seen, the latter 3 being associated with the limited variant, the CREST syndrome (calcinosis, Raynaud's, esophageal dysmotility, sclerosis, and telangiectases). Although limited cases occur, pulmonary disease is common in childhood scleroderma and should be aggressively sought with pulmonary scans. Treatment of pulmonary disease should be early and aggressive. A neonatal scleroderma syndrome presenting with pulmonary hypertension has been reported. Linear scleroderma, which follows a Blaschkoid pattern, is the most common localized variant, with plaque-type and generalized scleroderma comprising most of the residual cases. The Parry-Romberg syndrome is the association with hemifacial atrophy, and less commonly can be the association with uveitis, intracranial calcifications, aseptic meningitis, trigeminal nerve palsy, and seizures. Linear scleroderma crossing joints can result in flexion contractures. In addition, localized disease can be associated with underlying fasciitis (morphea profunda). Despite the presence of an ANA in a majority of children with localized scleroderma, progression to systemic illness is seen in less than 1% of patients. Pathogenesis has been attributed in part to extensive production of TGF-~, causing cutaneous sclerosis. European reports of an association with Borrelia have not been confirmed in the United States. Therapy of Curr Probl Dermatol, July/August 2000
systemic illness involves steroids, calcium channel blockers, and vasodilating agents to improve blood flow to the extremities. Prednisone and methotrexate, as well as penicillamine, have been used for the ParryRomberg syndrome. Recently, calcipotriene has been shown to be effective topically in localized scleroderma and systemically in linear scleroderma. 7-9,19-21 Childhood arthritis that is not rheumatoid can include psoriatic arthritis and HLA-B27 positive spondyloarthropathies. Psoriatic arthritis can be defined as psoriasis and arthritis or arthritis with 3 of the following 4 criteria: dactylitis, nail pitting, psoriasis-like rash, and family history. Antinuclear (2/3) and anticollagen (1/3) antibodies can be seen with juvenile psoriatic arthritis. Nonsteroidal anti-inflammatory agents and physical therapy remain the mainstay of therapy with steroid avoidance because of the psoriatic component. 6-s Numerous congenital syndromes can also be associated with altered mobility of the joints. 22 Vasculitis is an inflammation of the blood vessels and their surrounding organs. In childhood, 3 diagnoses are most common: polyarteritis nodosa (PAN), Kawasaki disease, and Henoch Schonlein Purpura (HSP). Recently, new guidelines have been published for making the diagnosis of PAN in children, requiring the presence of 1 major criterion and 4 other criteria, major or minor. The major criteria include renal and musculoskeletal findings. Cutaneous findings, such as nodules, purpura, livedo, and cutaneous infarcts, are considered minor criteria, although skin disease is present in 81% of patients. Gastrointestinal, cardiac, hepatic, and pulmonary vasculitis may also occur. In addition, PAN has been linked to hepatitis B and C infection. Immunosuppression with steroids and cyclophosphamide constitute the mainstay of therapy. 23 Kawasaki disease was first described in Japan in 1967. Kawasaki disease is a vasculitis that is most common in children under 4 years of age. The illness is defined by diagnostic criteria including obligatory fever for at least 5 days, and 4 of 5 of the following criteria, which are seen in more than 90% of patients: (1) bilateral conjunctival injection without exudate, (2) polymorphous exanthem, (3) palmoplantar changes, including erythema, edema, or periungual desquamation, (4) changes of the lips and oral cavity, including erythema and cracking, strawberry tongue, and diffuse injection of oral and pharyngeal mucosae, and (5) acute nonpurulent cervical lymphadenopathy, the least common of the symptoms (50% to 75%). Atypical cases with fewer criteria represent a diagnostic dilemma. Curr Probl Dermatol, July/August 2000
Cardiac changes include electrocardiogram abnormalities, cardiomegaly on radiograph, and pericardial effusions. The dreaded complication of aortic artery aneurysms is more common in boys and children under 6 months of age and can lead to adult coronary artery disease and myocardial infarction. The immunopathogenesis of Kawasaki's disease has been linked to staphylococcal superantigens. Serum TNF-c~ and von Willebrand factor antigen levels are elevated in Kawasaki patients. P-antineutrophil cytoplasm antibodies have been linked to disease activity. Late thrombocytosis is seen. The incidence of coronary artery aneurysm has been drastically reduced by the institution of intravenous gammaglobulin therapy and high-dose aspirin, combining blockade of superantigen by IgG and reduction of platelet activity. 1°2425 HSP is a hypersensitivity vasculitis occurring in children between 3 and 10 years of age, peaking at age 4. HSP presents with abdominal pain, arthralgias, and palpable purpura. A less common finding is intussusception, and proteinuria with progressive renal disease can occur. Younger children tend to present with extensive scalp and eye edema. This disease may be in the same spectrum as acute hemorrhagic edema of infancy, which presents primarily with acral edema and annular purpuric lesions, and adult IgA vasculitis, which shares the histologic finding of IgA leukocytoclastic vasculitis with HSR The cause of the illness is unknown; however, an infectious trigger has been hypothesized because of a linkage to upper respiratory tract infection, reports of multiple infectious agents, and seasonal peaks in spring and fall. Treatment with steroids is warranted for patients who are symptomatic.7,8 Infectious agents can be the cause of a collagen vascular-like illness. These include infectious arthritides, such as gonococcemia, poststreptococcal arthritis, Lyme disease, and viral infection (eg, B 19 parvovirus, rubella, and Epstein Barr virus). Reiter's syndrome is characterized by an HLA-B27 positive arthritis and conjunctivitis linked to Salmonella and Shigella in early childhood and Chlamydia trachomatis infection in adolescence. Migratory polyarthralgias are one of the major criteria of rheumatic fever. In addition, serum sickness and erythema multiforme can present with arthralgias. 26
Summary CVDs are a complex group of multisystem disorders that present diagnostic and therapeutic dilemmas in children. The past 30 years have seen extensive advances 181
in defining CVD in children. Light has been shed on the cause and pathogenesis of immunologic disease. Common proinflammatory pathways that can contribute to disease expression include cytokine polymorphisms and MHC Class II linkage. Increasing awareness of pathogenesis has generated new markers of early disease that permit early intervention. Advances in immunosuppression and the ability to use a wide variety of steroid-sparing agents have made therapy of CVD less toxic and more efficacious. Sun avoidance and protection, physical therapy, psychosocial therapy, and nutritional evaluation are integral to the care of CVD. The future of childhood CVD lies in continuation of research into the immunologic basis of disease and integration of a multisystem therapeutic approach into standard practice.
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