Management of the Connective Tissue Diseases of Childhood

Rheumatic diseases in childhood, although biologically similar to those in adults, represent a unique class of disorders that often possess distinctive differences in clinical manifestations, therapeutic goals, and overall prognostic implications. The relative rarity of many of these diseases, accompanied with the ethical challenges of studying children, often limits adequate scientific research and clinical trials. Thus, management in children is often based largely on adult-based literature, retrospective reviews, case series, and anecdotal evidence, although some randomized studies have been performed. The purpose of this chapter is to describe, in detail, therapies for connective tissue diseases that are very unique in childhood (juvenile dermatomyositis [JDM], Kawasaki’s disease [KD], Henoch-Schönlein purpura [HSP], neonatal lupus, and linear scleroderma), while emphasizing variations in management of children with inflammatory diseases generally more prevalent in adults (systemic lupus erythematosus [SLE], antiphospholipid syndrome, Wegener’s granulomatosus [WG], and polyarteritis nodosa [PAN]).


JDM, the most common inflammatory myopathy of childhood, is a rare multisystemic autoimmune vasculopathy, primarily characterized by proximal muscle weakness and pathognomonic skin rashes ( Fig. 19-1 ). It affects approximately 3.2 million children in the United States per year, with the average onset at 7 years old. Other organ systems, particularly gastrointestinal, pulmonary, and cardiac may also be involved. Calcinosis of the cutaneous and subcutaneous tissues, muscles, tendons and ligaments, a rare complication in adult dermatomyositis, occurs in approximately 20% to 40% of children, particularly those in whom there is a delay to diagnosis or inadequate control of active disease inflammation. Children with extensive calcinosis may suffer from significant long-term disability; therefore, aggressive treatment regimens are often aimed at prevention of this outcome.

A 4-year-old girl with no significant past medical history presents with erythematous, scaly papules on her hands, elbows, knees and ankles bilaterally. According to her mother, the rash had been present for 3 months, with minimal improvement after using various topical treatments prescribed by her primary doctor. Recently, the patient has had decreased activity, refusing to rise up from a seated position on the floor or to climb up onto the couch. Her mother states that her symptoms have progressed, and the child prefers to “lie down in bed all day long.” She denies any dysphonia, dysphagia, or choking episodes. The patient has been afebrile and tolerating feeds without issue. Physical examination reveals an uncomfortable child, lying still in bed. Skin examination reveals a heliotrope discoloration of bilateral eyelids with mild periorbital edema and Gottron’s papules over her elbows, knees, dorsal proximal interphalangeal (PIP) joints, and metacarpophalangeal (MCP) joints bilaterally. Nailbed capillaroscopy reveals mild dilation and tortuosity of the vessels. The patient has significant proximal muscle weakness bilaterally, including a mild head lag and Trendelenberg gait. Initial laboratory evaluation reveals a creatine phophokinase (CPK) of 11,782, aldolase of 168, lactate dehydrogenase (LDH) of 1402, and aspartate aminotransferase (AST) of 1064.


Figure 19-1

Alopecia and heliotrope discoloration, with vasculitic infarcts and ulceration, in an 8-year-old girl with juvenile dermatomyositis.

Differential Diagnosis

The differential diagnosis of JDM differs greatly from inflammatory myositis seen in adults. Children very rarely have polymyositis, focal myositis, inclusion body myositis, eosinophilic myositis, or dermatomyositis associated with malignancy. More commonly, etiologies to consider are postinfectious myositis, primary neuromuscular myopathies, and inflammatory myopathies associated with other connective tissue diseases including scleroderma and mixed connective tissue disease. Acute, transient, postinfectious myositis may follow various infections including viruses, particularly influenza A/B, coxsackievirus B and varicella; or bacterial infections such as staphylococcal or streptococcal bacteremia. These illnesses are typically preceded by fever, symptoms of upper respiratory infection (URI), nausea, vomiting and headache. Myalgias in viral myositis are more commonly found in the proximal calf and may result in transient elevations of muscle specific enzymes. Similarly, myositis secondary to bacterial infections, are typically transient; however, complications with localized abscess formation may occur. In contrast, primary neuromuscular myopathies, such as Duchenne’s muscular dystrophy, often lack constitutional symptoms and muscle tenderness. Instead, they are often characterized by marked elevation of serum CPK levels, slowly progressive proximal muscle weakness, and hypertrophy of distal muscles, particularly the calves. Suspicion for these disorders should be elevated in cases of younger children with an absence of characteristic skin changes, loss of developmental milestones, and a positive family history. Electromyographic findings or muscle biopsy pathology are often necessary for diagnostic purposes. Finally, children with connective tissue diseases such as SLE, scleroderma, and mixed connective tissue disease may have skin and muscle involvement that may initially appear similar to those seen in JDM, however, additional organ manifestations and serologic laboratory evaluations should provide further definitive diagnostic information. Overall, the presence of the characteristic rash, proximal muscle weakness, and elevated muscle enzymes is often sufficient to make the diagnosis; however, in certain cases muscle histopathology not only aids in diagnosis but also may provide evidence of prognostic features, including perifascicular myopathy, obvious capillary loss, central nucleation of myofibers, necrosis, and fibrosis ( Fig. 19-2 ). Reports suggest that the pathogenesis of vasculopathy seen in JDM may be secondary to an imbalance between angiostatic and angiogenic chemokines within muscle, resulting in significantly higher levels of interferon-induced angiostatic chemokines, which often parallels the degree of vasculopathy.

Figure 19-2

Muscle biopsy in a patient with juvenile dermatomyositis revealing capillary loss, variable myofiber atrophy, infarct and central nuclei.

(From Miles L, Bove KE, Lovell D, Wargula JC, Bukulmez H, Shao M, et al. Predictability of the clinical course of juvenile dermatomyositis based on initial muscle biopsy: a retrospective study of 72 patients. Arthritis Care Res 2007;57:1183–91.)


Historically, outcomes in JDM varied dramatically; with one third of patients spontaneously recovering, one third developing moderate to severe disability, and the final third eventually succumbing to the illness. In the 1970s, with the introduction of corticosteroids as the mainstay of treatment in JDM, functional outcomes and mortality have significantly improved. Owing to the lack of randomized, controlled clinical trials, management depends primarily on information from retrospective reviews, observational data, and clinical experience. In an emergent setting, adequacy of ventilatory effort, swallowing ability, and risk of aspiration must be rapidly assessed and aggressively treated. Over time, goals of therapy should be aimed at suppression of both clinical and laboratory signs of immunoinflammatory response, preservation of muscle strength and function, and prevention of long-term complications, including calcinosis, lipodystrophy and functional disability.

Assessment of treatment efficacy is often measured in terms of frequent assessments of muscle strength and function, as well as improvement in serum concentrations of muscle enzymes. Collaborative study groups have standardized and validated clinical disease activity scales including the Childhood Myositis Assessment Scale (CMAS) as a tool to assess adequate clinical response to treatment. In addition, muscle enzymes are frequently monitored; however, individual enzyme levels do not always correlate with disease activity. In particular, creatine kinase may be the poorest predictor of disease exacerbation, whereas LDH and AST, although less specific, more often mirror disease activity. The measurement of immunologic and endothelial activation markers, including von Willebrand’s factor antigen, neopterin, mononuclear cell subsets, cytokines, and adhesion molecules may also have a role in the assessment of disease activity; however there is not yet general acceptance of these latter biomarkers. Changes seen in magnetic resonance imaging (MRI) scans, particularly short tau inversion recovery or fat-suppressed T2-weighted images, may be a more sensitive, quantitative assessment of initial muscle inflammation and subsequent recovery following treatment ( Fig. 19-3 ). Changes in dermatologic manifestations seem to correlate moderately with changes in measures of muscle inflammation; however, skin improvement is unpredictable and therefore should not guide therapeutic decisions.

Figure 19-3

A, Fat-suppressed T2-weighted magnetic resonance imaging (MRI) scan before initiation of therapy in a 7-year-old patient with juvenile dermatomyositis. Hyperintense signal can be noted predominantly in the hamstrings bilaterally, as well as the quadriceps muscles. B, Follow up T2-weighted MRI in the same patient after treatment with corticosteroids and methotrexate showing attenuation of abnormal signal.


Early and adequate treatment with high-dose oral corticosteroids has been widely accepted as a critical component in the management of JDM. Typically, patients receive prednisone (up to 2 mg/kg/day divided into two to three doses) for 2 months, with close monitoring for resolution of both clinical and laboratory manifestations. With an adequate response evident, corticosteroids are then slowly tapered over a 2-year period. Several studies also suggest that aggressive initial management with intravenous (IV) pulse corticosteroids may result in a more favorable outcome. The proposed rationale is to gain rapid control of inflammation, preventing both acute and chronic complications, and in the long-term, minimizing chronic corticosteroid use and associated toxicity. In addition, early aggressive management may induce earlier disease remission and greatly decrease hospitalizations. Further justification suggests that a likely gastrointestinal vasculopathy in active JDM may impair oral corticosteroid absorption therefore impairing efficacy. In contrast, data reported in a retrospective, propensity score analysis did not support any significant difference in efficacy outcomes between standard therapy with oral prednisone and aggressive management with IV corticosteroids.

Despite significant improvements in prognosis of JDM, calcinosis remains a considerable source of long-term morbidity ( Figs. 19-4 and 19-5 ). It appears that calcinosis is significantly correlated with a longer time to diagnosis and overall longer active disease duration. Retrospective data and observational studies are somewhat inconsistent; however, the majority indicate that early treatment with IV methylprednisolone (30 mg/kg), followed by high-dose oral corticosteroids may be associated with a more rapid normalization of muscle enzymes, earlier clinical remission, and therefore, decreased incidence of calcinosis. Similarly, some studies propose that intermittent IV methylprednisolone pulses given on a weekly to monthly basis many induce remission more rapidly. Retrospective reviews, in which a reduction of calcinosis was not significantly associated with initial management with IV methylprednisolone, noted the likelihood of higher disease severity in these patients and, therefore, the increased risk of long-term complications.

Figure 19-4

A, Calcinosis circumscripta—superficial plaques of dystrophic calcium deposition in subcutaneous tissue in a patient with juvenile dermatomyositis. B, Tumoral calcinosis (i.e., calcinosis universalis)–nodular calcium deposits into deeper tissue layers.

(Courtesy of Dr. Lisa G. Rider, MD, NIH.)

Figure 19-5

A, Radiographic evidence of planar calcinosis in the arm of a patient with juvenile dermatomyositis. B, Further delineation of interfascial deposition of calcium in the same patient.

Despite the enormous benefits gained from corticosteroids, long-term use is often associated with undesirable steroid toxicity. Among others, side effects that may limit therapy include significant osteopenia, osteoporosis, avascular necrosis of bone, compression fractures, Cushing’s syndrome, growth retardation, and steroid myopathy. Subsequent management and the institution of additional immunosuppressant medications often aim to reduce corticosteroid dose while maintaining adequate disease control. The addition of calcium and vitamin D appears to be beneficial in the reduction of bone loss; however, they may be insufficient in the management of severe osteoporosis. In contrast, calcitonin and bisphosphonates have been shown to be effective in the treatment of adults with osteoporosis; however, use in children is limited due to unknown long-term effects on growing bone. At present, there is an increasing body of evidence that bisphosphonates are relatively safe in the treatment of osteoporosis in children with rheumatic and metabolic bone disease.


Based primarily on anecdotal evidence, hydroxychloroquine (6 mg/kg/day) has been recommended as a steroid-sparing agent, particularly in patients with prominent dermatologic manifestations. In general, hydroxychloroquine is considered a safe, well-tolerated medication. Side effects may include gastrointestinal intolerance, headache, lightheadedness, and skin hyperpigmentation. Rarely, retinal toxicity may occur; therefore, all children should have routine ophthalmologic monitoring assessing for changes in visual acuity, visual fields, color vision, and retinal changes.


Second-line medications, including immunosuppressive agents, are typically considered as adjunctive therapy in cases of steroid resistance, steroid dependence or unacceptable steroid toxicity. Of all the immunosuppressive drugs, methotrexate (MTX) is widely used as the preferred agent for refractory JDM (0.35–2 mg/kg/week; max dose = 50 mg). More recently, MTX has also been recommended as a component of initial therapy to additionally improve clinical outcome. Experience from the use of low-dose MTX in other pediatric rheumatologic diseases has proven its safety and limited long-term toxicity. Several small, uncontrolled, retrospective studies have also shown efficacy of MTX in JDM, demonstrating decreased disease activity, decreased calcinosis, as well as a more rapid discontinuation of corticosteroids and therefore decreased steroid toxicity. Initially, MTX is often administered orally, with a change to subcutaneous administration should gastrointestinal side effects evolve. In cases of suspected gastrointestinal vasculopathy with potentially impaired absorption, some authors may propose an earlier change to parenteral administration due to greater bioavailability. Overall, MTX is generally well tolerated, with typical side effects including gastrointestinal intolerance, risk of infection and hepatotoxicity. Although potentially a concern, these effects are often transient and resolve with discontinuation of the drug. In cases of persistent gastrointestinal intolerance, leucovorin (5 mg given 24 hours following the weekly dose of MTX) may be given to reduce potential toxicity.

Cytotoxic Agents

In addition to MTX, other immunosuppressive agents used in refractory JDM include azathioprine (AZA), cyclophosphamide (CYC), cyclosporine, and mycophenolate mofetil (MMF). Of these agents, the greatest amount of published evidence available for the use of these agents in JDM is for cyclosporine therapy (3–5 mg/kg/day); however these data are primarily based on case reports and retrospective reviews. These reports generally reveal favorable outcomes; however, the benefits must be weighed against the risks of side effects, particularly renal impairment, hypertension, and hepatotoxicity. Although few studies exist, some authors suggest AZA (1–3 mg/kg/day) may be as efficacious and a potentially safe steroid-sparing agent should MTX fail. Similarly, CYC (1 mg/kg/day oral or 0.5–1 g/ m /month IV) is seen as a potentially effective medication with minimal evidence of serious toxicity in short-term use, however mixed results have been seen in adult dermatomyositis. Potential side effects of CYC include alopecia, cytopenias, bladder toxicity, gastrointestinal intolerance, and infertility. In addition, there have been some recent reports suggesting the benefits of MMF with generally few side effects.

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIG) has been shown to be a safe and effective treatment in adults with dermatomyositis. Potential mechanisms of action of IVIG in autoimmune and inflammatory disorders are not fully understood, but data suggest that they involve modulation of expression and/or function of Fc receptors, increased activity of complement or proinflammatory cytokines, idiotype/anti-idiotype interactions, and effects of T, B, and dendritic cells. In a small, double-blinded, placebo-controlled trial, IVIG was shown to result in significant improvement in muscle strength, neuromuscular symptoms and histologic findings on muscle biopsy. In children, however, there are no controlled clinical trials, evidence is therefore based on retrospective reviews and anecdotal reports. These reports concluded that IVIG (1–2 g/kg/month) is beneficial in reducing clinical manifestations and sparing corticosteroid toxicity in cases of severe, refractory JDM. It appears that repeated treatments may be necessary for long-term benefits due to a tendency for relapse after the cessation of IVIG. Administration of IVIG to immunoglobulin A (IgA)–deficient patients may result in anaphylaxis; therefore, IgA levels should be routinely measured before administration, or as soon as possible if immediate use is indicated. In addition, reports suggest that children, particularly those with autoimmune disorders, may have increased incidence of side effects including fever, nausea, and vomiting. This may be related to concentrations of IgA more than 15 µg/mL; therefore, preparations with lower concentrations of IgA are preferred (Gammagard, Baxter, Deerfield, IL; 2.2 µg/mL). Other potential side effects include headache and aseptic meningitis.

Biologic Agents

Tumor necrosis factor-α (TNF-α) has been identified in high levels in patients with JDM, particularly in those with a prolonged disease course or complicated by calcinosis. The use of TNF-α inhibitors, particularly infliximab (6–10 mg/kg via infusions every 4–8 weeks) and etanercept (0.8 mg/kg; max 50 mg/week), appear to show promising results in severe, refractory JDM. Few small clinical trials have been published suggesting clinical benefits, including improved muscle weakness, joint range of motion, and regression of calcinosis. Similarly, rituximab, a monoclonal antibody to B cells, may have clinical benefits; however, clinical trials are still underway. In very severe cases of JDM that are recalcitrant to other therapies, plasmapheresis may also be considered.

Supportive Measures

In addition to the therapies listed earlier, supportive measures including skin care for ulcerations, nutritional assessments for risk of aspiration and malnutrition, psychological support and education, and physical therapy are essential in the management of patients with JDM. Despite active inflammation, physical therapy should be initiated at the time of diagnosis with passive range-of-motion exercises to prevent decreased range of motion. Once acute inflammation has subsided; active, muscle-strengthening exercises should be gradually introduced to minimize muscle atrophy and contractures.

One of the major aims of treatment in JDM is to avoid long-term complications, including calcinosis and lipodystrophy ( Fig. 19-6 ). Once these complications develop, there are no treatments that have proven to be consistently effective. Case reports and anecdotal evidence suggest that therapies including colchicine, warfarin, bisphosphonates, probenecid, diltiazem, and aluminum hydroxide may offer variable responses in the management of calcinosis. The authors have had some success with treatment with colchicine, especially when superficial calcinosis lesions cause ulceration and crystal-induced cellulitis. It should also be noted that calcinosis is often complicated by concurrent infection, and appropriate antibiotic administration can be critical. In addition, there is generalized consensus that early aggressive control of active disease inflammation; using corticosteroids, MTX, IVIG, and cytotoxic agents have a preventative role in the formation and progression of calcinosis. In some cases, calcinosis may spontaneously regress; however, depending on location, in rare cases surgical excision may be required ( Fig. 19-7 ). In addition, careful monitoring must be performed in the prevention of serious infections potentially associated with calcinosis and ulceration.

Figure 19-6

A, Six-year-old boy who was ultimately diagnosed with juvenile dermatomyositis. B, Same patient, 2 years later (age 8) showing significant facial lipodystrophy. Note absence of subcutaneous fat in the malar areas. Similar loss of fat was present in the extremities.

Figure 19-7

Skin grafting after excision of large tumoral calcinosis lesions in the axillae and antecubital fossae of an adolescent boy with juvenile dermatomyositis.


SLE is a chronic, autoimmune disease often characterized by the presence of widespread inflammation, multiorgan system involvement and an episodic course of disease flare and remission. For the most part, clinical features of pediatric SLE are similar to those in adult-onset SLE; therefore, for the purposes of this chapter, we focus on features unique to childhood disease and highlight differences in presentation, treatment, and prognosis between the two groups. Of all patients diagnosed with SLE, it is estimated that approximately 15% to 20% have disease onset in childhood, with the highest proportion in adolescence, female gender, positive family history and those of Native American, black, and Hispanic descent. Constitutional symptoms including unexplained fever, malaise, weight loss, rash and arthritis/arthralgias are the most common manifestations of SLE in children and adolescents ( Figs. 19-8 and 19-9 ). In addition, many children may have evidence of hematologic, neurologic, or cardiopulmonary involvement on presentation; renal disease, however, remains a major cause of morbidity and mortality, with more than 75% of children having some form of clinically evident nephritis.

Figure 19-8

Malar rash in a 9-year-old girl with juvenile systemic lupus erythematosus.

Figure 19-9

Classic palatal ulceration in an adolescent female with juvenile systemic lupus erythematosus.

Children with SLE are often reported to have a more aggressive clinical course with more significant internal organ involvement than adult-onset disease. Despite this, with medical advances in treatment and monitoring, the overall long-term prognosis has greatly improved over the years. Satisfactory outcome in children currently depends on an estimated 50- to 60-year survival time, resulting in a prolonged duration of potential disease burden and treatment-related morbidity. Assessments of disease activity and nonreversible damage that were developed for adults have been validated in children and include the SLE Disease Activity Index (SLEDAI), the Systemic Lupus Activity Measure (SLAM), the British Isles Lupus Assessment Group Activity Index (BILAG), and the Systemic Lupus International Clinics Damage Index (SLICC). Specific limitations, however, exist with regard to use in children including the variation in the definition of and significance given to the presence of renal involvement, the lack of clearly defined cognitive impairment (including behavioral changes and school failure), and the significance of prolonged corticosteroid therapy both on overall prognosis and long-term morbidity (including musculoskeletal and neurocognitive growth and development).

A 16-year-old girl, with no significant past medical history, presents with a history of prolonged fever of unknown etiology, fatigue, malaise, and a 10-pound weight loss over the last three weeks. She notes mild pain in her fingers bilaterally, and has noticed progressive difficulty writing in her morning classes at school. In addition, she has experienced a decline in school performance, which she attributes to her fatigue, recurrent school absences, and “not being able to focus and remember things as I used to.” Review of systems reveals recent hair loss and daily headaches. Physical exam reveals a thin female with prominent frontal alopecia. Head, eye, ear, nose, and throat (HEENT) examination reveals mild malar erythema, normal fundoscopic exam and enlarged cervical lymphadenopathy bilaterally. Musculoskeletal examination reveals tenderness, swelling, and erythema of the PIP joints bilaterally, as well as bilateral knee effusions. Laboratory evaluation reveals anemia, mild lymphopenia, highly elevated erythrocyte sedimentation rate (ESR) and a normal CRP. Urinalysis reveals proteinuria with a urine protein/urine creatinine elevated to 1.2. Further evaluation reveals an antinuclear antibody level of 1:320 speckled, increased anti-dsDNA, increased anti-SSa (Ro), and reduced levels of C3 and C4.


Differential Diagnosis

The differential diagnosis of SLE is extensive and highly variable based on clinical presentation. Among the vast differential diagnosis, the presence of nonspecific, constitutional symptoms including fever, malaise, and weight loss, often compel physicians to exclude other chronic and potentially life-threatening diagnoses including malignancy (particularly leukemia and lymphoma), infectious disease (such as human immunodeficiency virus [HIV], tuberculosis, Epstein-Barr virus [EBV], cytomegalovirus [CMV]), primary immunodeficiency, endocrinopathies (such as hypo/hyperthyroidism) and other rheumatologic disorders.


Owing to the potential for more severe disease, major organ involvement, longer disease burden, and morbidity of chronic corticosteroid use in pediatric SLE many physicians would support a more aggressive approach at the onset of disease and an earlier introduction of steroid toxicity–sparing agents. Challenges of management specific to adolescents with SLE include issues of defiance, noncompliance with therapy, fear of corticosteroid impact on body image, and impact of disease manifestations and frequent hospital visits on school performance.

General supportive treatment measures include establishing a multidisciplinary approach to care, providing psychosocial support, avoidance of unnecessary limitations on activity, and optimizing each individual’s childhood experience. Dietary counseling as well as supplementation with vitamins including calcium, vitamin D, and folic acid are important adjuvants to therapy, aiding in reduction of complications such as excessive weight gain, osteoporosis and atherosclerosis. In addition, all patients with SLE are advised to use sunscreen (SPF 30 or greater) with ultraviolet A and ultraviolet B protection year round, both indoors and outdoors, to prevent disease exacerbation. Finally, pneumococcal and meningococcal vaccination is highly recommended secondary to an increased incidence of functional asplenia among children with lupus.

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are primarily used in pediatric SLE for fever and mild musculoskeletal manifestations, including arthritis, myalgias, and arthralgias. Aspirin (ASA), another potential therapeutic option in these scenarios, is less commonly used in children due to the potential for hepatotoxicity and Reye’s syndrome. Toxicity from NSAIDs is limited; however, risks most often include gastritis, decreased glomerular filtration rate, and rarely aseptic meningitis. Pseudoporphyria has also been described in children using naproxen.


Hydroxychloroquine (6 mg/kg/day, max 400 mg/day) is routinely used at the onset of disease in children and adolescents with SLE to reduce symptoms of fatigue, mucocutaneous manifestations, and alopecia, as well as a steroid toxicity–sparing agent. Efficacy of antimalarials in SLE has been demonstrated in clinically stable adults, with removal of the drug, resulting in increased incidence of disease activity. Although typically well tolerated, the primary concern in the use of hydroxychloroquine is the rare incidence of retinal toxicity; therefore, yearly ophthalmologic monitoring is indicated.


The introduction of corticosteroids as the mainstay of treatment has greatly improved the prognosis in children with SLE, allowing for a more rapid control of acute manifestations and increased overall life expectancy. Depending on initial presentation, high-dose oral corticosteroids (prednisone 1–2 mg/kg/day, divided into two doses to maximize anti-inflammatory effects) are often initiated, particularly in cases of major organ involvement including renal, central nervous system (CNS), pulmonary and hematologic manifestations. In cases of severe CNS or renal involvement, IV methylprednisolone (30 mg/kg/day for 3 consecutive days) may be indicated to achieve a more rapid resolution of symptoms. In addition, intermittent monthly doses of intravenous methylprednisolone may aid in the long-term management of these patients while decreasing overall corticosteroid use and associated toxicity.

Although many children will respond to treatment with corticosteroids, complications often arise with prolonged use, including adrenal suppression, hypertension, hyperglycemia, cataracts, avascular necrosis, myopathy, CNS disturbances, immunosuppression, and dislipoproteinemia. Among the most concerning toxicities in children is the risk of significant osteopenia, osteoporosis, and growth retardation. In addition, alterations in emotional liability and physical appearance due to cushingoid facies, obesity, hirsuitism, and acne, may have significant impact on adolescent psychosocial well-being. Therefore, early introduction of a slow, gradual taper of corticosteroids while maintaining adequate disease control is critical. Steroid toxicity–sparing strategies may also include consolidation to a single morning dose initially and eventual reduction to alternate-day therapy.

Immunosuppressive Agents

The addition of an immunosuppressive or cytotoxic agent is often indicated in cases of proliferative glomerulonephritis, CNS involvement ( Fig. 19-10 ), and pulmonary hemorrhage; as well as with evidence of steroid dependence or unacceptable steroid toxicity. Common immunosuppressive agents currently used in pediatric SLE are CYC, AZA, cyclosporine, MMF, and MTX.

Figure 19-10

A, Magnetic resonance imaging scan with increased signal abnormality in the left cerebellar white matter in a 14-year-old patient with systemic lupus erythematosus and focal dysmetria. B, Evidence of bilateral signal abnormality in the basal ganglia of the same patient.

CYC has been considered the adjunctive therapy of choice for the most severe manifestations of SLE, particularly severe proliferative lupus nephritis and CNS disease, often resulting in reduced disease activity, preservation of renal and neurological function and overall reduction in corticosteroid dose. Although there have been no randomized, controlled trials in children, several case series and comparative studies have similarly reported efficacy and superiority over AZA or prednisone alone. Significant toxicity limits use in less severe cases, and caution must be taken in monitoring for bone marrow suppression, infection, alopecia, nausea, vomiting, and hemorrhagic cystitis. The incidence of alopecia, a potentially distressing complication in adolescents, may be reduced with the use of scalp-cooling techniques including cryogel packs, cold air circulation, and specialized caps with liquid coolant circulation. Long-term risks including secondary malignancy may be higher than that in adults; whereas permanent gonadal damage has been reported to be lower in the pediatric population. Although data are limited in children, semen cryopreservation and gonadotropin-releaseing hormone (GnRH)–analogs may provide additional protection in adolescents receiving CYC. Typically IV CYC (0.5–1 g/m 2 /month), given in an induction phase of seven monthly doses, followed by a maintenance phase of one dose every 3 months for 2 years, is preferred over oral CYC to reduce overall cumulative toxicity.

In cases of mild to moderate organ involvement other, less toxic, immunosuppressive agents may be necessary to obtain better disease control and reduced corticosteroid dosing. AZA (1–2 mg/kg/day, max 150 mg/day), has been used most frequently in pediatric SLE as an effective steroid-sparing agent with limited toxicity, including potential hematologic and gastrointestinal side effects. Controversy exists regarding efficacy in proliferative SLE nephritis; however, some reports suggest sustained disease remission with decreased long-term toxicity when used as maintenance therapy following CYC induction. Similarly, cyclosporine (3–5 mg/kg/day) may be an effective therapy in steroid-resistant or steroid-dependent children with SLE; however, its role in severe lupus nephritis is still undetermined. Potential for hypertension and nephrotoxicity with cyclosporine may further limit use in these cases. Recent experience with MMF (1–3 g/day) in pediatric SLE has shown promising results, particularly in cases of class V membranous glomerulonephritis and as maintenance therapy following CYC induction in cases of proliferative glomerulonephritis. Further reports suggest that MMF may be as effective as CYC with significantly less toxicity in adults with proliferative lupus nephritis; however, long-term data regarding risks and benefits, and use in pediatric SLE are still to be determined. Finally, the use of MTX has been suggested in the management of persistent arthritis and skin disease; however, sole use may be insufficient to control disease flare in cases of major organ system involvement.

Biologic Agents

Many biologic agents are currently being evaluated in adults with refractory SLE; however, data in pediatrics remain limited. Rituximab, an anti-CD20 monoclonal antibody (375–500 mg/m 2 /dose IV for two doses given 2 weeks apart) may be effective in treatment of severe autoimmune cytopenia and potentially as an adjunct to therapy in refractory nephritis. Interpretation of this data is difficult owing to the use of other immunosuppressive agents simultaneously with rituximab. Other agents, such as IVIG, B-cell modulators (LJP 394), anti-interleukin 10 monoclonal antibodies, and therapies targeted against CD-40/CD-40 ligand and CTLA4-Ig are currently being investigated.

Other Considerations

Children with SLE often show signs of dyslipoproteinemia, with evidence of elevated triglycerides and decreased high-density lipoproteins (HDLs), which may predispose them to early atherosclerosis and early cardiovascular sequelae. Therefore, routine screening is indicated, with early intervention with diet and exercise if levels are abnormal. In some cases. pharmacologic intervention with statins and bile acid sequestrants may be necessary. In addition, hydroxychloroquine may have some beneficial lipid-lowering effects.


Antiphospholipid antibody syndrome (APLS) is characterized by the presence of antiphospholipid antibodies in association with clinical signs of hypercoagulability, including arterial/venous thrombosis, pulmonary embolism, and stroke. Children with APLS are more likely to exhibit clinical manifestations including migraine, chorea, epilepsy, thrombocytopenia and hemolytic anemia. In addition, there is evidence that maternal antiphospholipid antibodies can cross the placenta and may have a partial role in the pathogenesis of neonatal thrombosis and long-term neurocognitive development; therefore, infants born to mothers with APLS should be closely monitored with routine neurodevelopmental monitoring.

There are limited data on management of pediatric APLS; therefore, recommendations are made primarily based on adult-based literature and algorithms. In general, therapeutic options of anticoagulation are chosen largely based on the presence of prior arterial or venous thrombosis. Children with serologic evidence of antiphospholipid antibodies who are asymptomatic typically do not require treatment. Antibodies must be confirmed on at least two occasions due to the incidence of transient, inconsequential elevations in antiphospholipid antibodies with many bacterial and viral infections in childhood, such as mycoplasma, parvovirus, cytomegalovirus, varicella zoster, HIV, staphylococcus, and streptococcus. Prophylactic treatment with low-dose ASA is typically not indicated in asymptomatic children, and caution must be taken owing to the risk of Reye’s syndrome. Similar to adults with APLS, the presence of arterial or venous thrombosis is an indication for anticoagulation with either low-molecular-weight heparin (LMWH) (starting at 1 mg/kg/dose every 12 hours) or coumadin (starting at 0.1–0.2 mg/kg/day; therapeutic International Normalized Ratio [INR] of 2–3). In cases of major organ thrombosis, arterial thrombosis, recurrent thrombosis, or recurrent fetal loss, long-term anticoagulation with a higher therapeutic target (INR 3–4) may be indicated. In addition, data are limited on the safety of anticoagulation in children; however, several reports have demonstrated that LMWH appears to be safe and efficacious in both the treatment and prophylaxis of thromboembolism in children.


Neonatal lupus erythematosus (NLE) is a rare syndrome caused by the transplacental passage of autoantibodies directed against Ro and La proteins, most commonly resulting in cardiac, dermatologic, hematologic, and hepatic manifestations. Although mothers with positive autoantibodies are at risk, only 1% to 3% of infants will actually develop the syndrome. The most severe complication associated with NLE is the development of complete congenital heart block, which occurs in 15% to 30% of infants with NLE. Cardiac manifestations are thought to be secondary to direct attack on fetal cardiocytes with prolonged inflammation and eventual fibrosis ( Fig. 19-11 ). Once scarring has developed, cardiac effects are essentially irreversible and mortality may occur in up to 30% of infants. Early detection with serial echocardiograms is critical, and intervention with fluorinated steroids (oral dexamethasone 4 mg/day) with or without IVIG may be beneficial in reducing early inflammation. In addition, persistent fetal bradycardia in utero may require the use of sympathomimetics or inotropic agents. Infants born with symptomatic congenital heart block require permanent pacemaker insertion shortly after delivery, whereas those who are asymptomatic may be cautiously monitored. Owing to the high incidence of morbidity and mortality in these patients, pacemaker placement is often required before the end of childhood. Other manifestations of NLE including discoid skin lesions, occurring primarily on the face, scalp, and neck ( Fig. 19-12 ); cytopenias and hepatic inflammation are reversible and typically resolve spontaneously. Occasionally, topical corticosteroids may be used to hasten the resolution of the dermatologic manifestations.

Figure 19-11

Proposed pathogenesis for the development of congenital heart block in an infant born to a mother with anti-Ro and anti-La antibodies.

(Redrawn from Clancy RM, Buyon JP. Autoimmune-associated congenital heart block: dissecting the cascade from immunologic insult to relentless fibrosis. Anat Rec A Discov Mol Cell Evol Biol 2004;280:1027–35.)

Figure 19-12

A, Classic discoid skin lesions in a 2-week-old infant with neonatal lupus erythematosus, noted predominantly on the face and scalp. B, Evidence of the rash on the trunk of the same infant.


Kawasaki Disease

KD, one of the most common vasculitides of childhood, is a febrile systemic vasculitis, characterized by inflammation in small and medium sized vessels. Typically, KD occurs in children younger than 5 years old, with an increased incidence in persons of Asian descent. Diagnostic criteria require fever for more than 5 days’ duration, plus four of the following: bilateral conjunctival injection, oral mucous membrane changes (injection, fissured lips and/or strawberry tongue), peripheral extremity changes (erythema, swelling or desquamation), polymorphous rash, and cervical lymphadenopathy greater than 1.5 cm ( Figs. 19-13 and 19-14 ). Although typically a self-limited illness, one of the most significant complications is the development of coronary aneurysms in 25% of untreated patients, making KD one of the most common causes of acquired heart disease in children in the developed world. Demonstration of coronary artery aneurysms in children whose febrile illness did not fulfill diagnostic criteria has led to the concept of incomplete or atypical KD. Proper diagnosis of these patients is critical, because treatment has been shown to prevent development of coronary aneurysms and subsequent life-threatening complications ( Table 19-1 ).

A 2-year-old boy presents with a fever for 6 days. According to the mother, the patient has been very cranky. She notes mild rhinorhea at the onset of symptoms, followed by the development of conjunctival erythema, cracked lips and an erythematous diaper rash. On physical examination, the patient is irritable, but nontoxic in appearance. Skin examination reveals an erythematous, macular rash in the perineal region with early signs of desquamation. HEENT exam reveals bilateral, nonexudative conjunctivitis with limbic sparing, dry lips and a strawberry tongue. The remainder of the physical examination is benign. Laboratory evaluation reveals significantly elevated ESR and CRP levels. In addition, the patient has normochromic, normocytic anemia, elevated liver transaminases and sterile pyuria on urinalysis. Based on the algorithm set forth by the American Heart Association (see Fig. 19-15 ), the patient met criteria for atypical KD. He was subsequently treated and underwent echocardiogram for further evaluation.


Figure 19-13

Erythematous, fissured lips (cheilosis) and polymorphous exanthem in a child with Kawasaki’s disease.

Figure 19-14

Desquamation and vasculitic infarcts in the foot of a patient with Kawasaki’s disease.

(Courtesy of Dr. Robert Sundel.)

Table 19-1

Clinical Features of Kawasaki’s Disease

  • Fever persisting for 5 days or more

  • Presence of at least four principal clinical features

    • Bilateral conjunctival injection without exudate

    • Polymorphous exanthem

    • Cervical lymphadenopathy (at least one node greater than 1.5 cm)

    • Oropharyngeal changes including erythema, dry/fissured lips, strawberry tongue, injected pharyngeal mucosa

    • Changes in extremities including erythema and/or edema of the hands and feet (acute) and periungal peeling of fingers (subacute)

  • Exclusion of other disease processes

Differential Diagnosis

The differential diagnosis of KD, at the onset of disease, includes a wide spectrum of illnesses commonly associated with fever and mucocutaneous manifestations. The differential diagnosis includes, but is not limited to, viral infections, toxin-mediated illnesses, immune reactions and other rheumatologic diseases. Viral illnesses, including measles, EBV, and adenovirus may have similar mucocutaneous manifestations; however, these illnesses generally lack extremity and cardiac involvement. In contrast, toxin-mediated illnesses, particularly group A streptococcal infections such as scarlet fever and toxic shock syndrome, may have significant signs of inflammation and major organ involvement. These illnesses, however, often lack the ocular and articular involvement seen in KD. Other infections, such as Rocky Mountain spotted fever, differ due to a predominance of headaches and gastrointestinal complaints. Finally, immune reactions such as Stevens-Johnson syndrome, serum sickness, and rheumatologic diseases including systemic-onset juvenile idiopathic arthritis, can mimic KD; however, subtle differences are seen in ocular and mucosal manifestations.


KD is an acute, self-limited illness, which often resolves spontaneously in less than 2 weeks without therapy. However, persistent vascular inflammation may result in the development of coronary artery aneurysms with the potential to cause severe complications and significant long-term morbidity and mortality. In general, goals of therapy include control of acute inflammation, resolution of symptoms and prevention of long-term sequelae. The American Academy of Pediatrics and the American Heart Association currently recommend that first-line therapy of KD should include high-dose ASA and IVIG given within the first 10 days of illness. In cases of suspected incomplete KD, algorithms developed by consensus, have been proposed to aid in clinical management ( Fig. 19-15 ).

Figure 19-15

Proposed algorithm for diagnosis and management of incomplete Kawasaki’s disease. (1) This algorithm represents the informed opinion of the expert committee. (2) Infants 6 months old on day 7 of fever without other explanation should undergo laboratory testing +/– echocardiogram. (3) Characteristics suggesting disease other than KD include exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy. (4) Supplemental laboratory criteria: albumin 3.0 g/dL, anemia for age, elevation of alanine amino-transferase, platelets after 7 days 450,000/ mm 3 , white blood cell count 15,000/ mm 3 , and urine 10 white blood cells/high-power field. (5) Can treat before echocardiogram. (6) Echocardiogram is considered positive for purposes of this algorithm if any of 3 conditions are met: z score of LAD or RCA 2.5, coronary arteries meet Japanese Ministry of Health criteria for aneurysms, or 3 other suggestive features exist, including perivascular brightness, lack of tapering, decreased LV function, mitral regurgitation, pericardial effusion, or z scores in LAD or RCA of 2–2.5. (7) If the echocardiogram is positive, treatment should be given to children within 10 days of fever onset and those beyond day 10 with clinical and laboratory signs (CRP, ESR) of ongoing inflammation. (8) Typical peeling begins under nail bed of fingers and then toes.

Only gold members can continue reading. Log In or Register to continue

May 19, 2019 | Posted by in RHEUMATOLOGY | Comments Off on Management of the Connective Tissue Diseases of Childhood

Full access? Get Clinical Tree

Get Clinical Tree app for offline access